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EFFECT OF ACUPUNCTURE ON HEART RATE
VARIABILITY AND OTHER NON-INVASIVE
HEMODYNAMIC PARAMETERS IN PATIENTS WITH
HEART FAILURE
A CLINICAL RESEARCH PROTOCOL
Nuno Cândido Maia Correia
Dissertação de Mestrado em Medicina Tradicional Chinesa
2010
I
Nuno Cândido Maia Correia
EFFECT OF ACUPUNCTURE ON HEART RATE VARIABILITY AND
OTHER NON-INVASIVE HEMODYNAMIC PARAMETERS IN HEART
FAILURE A CLINICAL RESEARCH PROTOCOL
Dissertação de Candidatura ao grau de Mestre
em Medicina Tradicional Chinesa submetida ao
Instituto de Ciências Biomédicas de Abel
Salazar da Universidade do Porto.
Orientador
– Prof. Doutor Henry Johannes Greten
Categoria – Professor Associado
Afiliação – Instituto de Ciências Biomédicas
Abel Salazar da Universidade do Porto.
Co-orientador
– Prof. Doutor Paulo Bettencourt
Categoria – Professor Associado
Afiliação – Faculdade de Medicina da
Universidade do Porto.
II
III
DEDICATION
To my beautiful Wife Vânia for all her love and support.
To the miracle of my life, my Son Leonardo.
IV
V
Scientific Chinese medicine, since its inception approximately 2100 years ago,
is based upon the consistent application solely of inductive synthesis. (..) all its
statements refer to the direct perception of dynamic and present effects.
Prof. Manfred B. Porkert [1]
Acupunctural neuroreflexotherapy is useful and is clearly therapeutic, it works out of
necessity through the channels of positive biology, without the interference of energetic
conceptions that are foreign to experimental deductive thought.
Francisco Abad-Alegría and Carlos Pomarón [2]
Traditional Chinese Medicine is a system of sensations and findings
designed to establish a functional vegetative state.
Prof. Henry Johannes Greten [3]
VI
VII
ACNKOWLEDGMENTS
I would like to thank my closest family for all their background support that has enabled
me to develop my own education.
To Maria das Dores Pombinho, a personal reference to me in life and Medicine, and
the “yin-yang” we have shared.
To my dear Professors Jorge Machado, Manuel Laranjeira, and Johannes Greten, for
their friendship, collegiality, and contagious braveness in the gracious quest of helping
patients.
To Professor Andrew Remmpis for his accurate guidance and scientific expertise.
To Professor Gerhard Litscher for sharing his experience and knowledge.
To Petra for her support in general management.
To my Biology teacher and dear friend Carlos Alberto, for his wisdom, excellence and
friendship.
To Professor Paulo Bettencourt for his open mind and scientific culture that enables an
internal medicine junior doctor to explore other “non-conventional” fields of health science
and knowledge, while training in this magnificent and holistic medical specialty.
To my research colleague and friend Eduardo Capitão, an outstanding Nurse
professional.
To some Humanity references whose historical legacy stands has an inspiration to me:
the unrepeatable Leonardo da Vinci; Siddharta Gautama; Abel Salazar, William Osler,
Mother Theresa of Calcutta; Albert Einstein; Nuno Grande, and Maria de Sousa.
To my few Friends for all their trust and tolerance.
Finally, to Medicine the mission I have struggled for as a way of helping my fellow
human beings and making some useful sense out of this ridiculous life-time.
VIII
IX
RESUMO
Introdução: a insuficiência cardíaca (IC) é um problema de saúde à escala mundial com
um prognóstico sombrio. Resulta principalmente de mecanismos complexos de activação
neuro-humoral que conduzem a uma desregulação autonómica. Investigação animal
parece suportar o conceito de que a acupunctura poderá desencadear reflexos
vegetativos que produzem substâncias endógenas inibitórias do efluxo simpático. Até ao
presente, a escassa investigação em pacientes com IC sugere que a acupunctura poderá
prolongar a distância de marcha bem como promover a variabilidade de frequência
cardíaca (VFC).
Objectivo: estudar o efeito da acupunctura em pacientes com IC através da avaliação da
VFC e de outros parâmetros hemodinâmicos não invasivos (PHNIs).
Métodos: apresenta-se um protocolo clínico de um estudo clínico preliminar, prospectivo,
aleatorizado, controlado, duplamente cego, e com um desenho do tipo cruzado. Uma
amostra de 20 doentes, do sexo masculino (idades entre 40 e 90 anos), com IC classe II
(classificação da New York Heart Association) e fracção de ejecção do ventrículo
esquerdo ≤40%, é seleccionada da consulta de IC de um hospital central. Cada paciente
é submetido a uma avaliação basal da distância de marcha, aferida pelo teste de marcha
gradual vaivém (TMGV), seguida de medição do grau de dispneia e fadiga através da
escala de Borg. Durante a fase de intervenção os doentes são expostos, numa sequência
aleatorizada, a uma sessão de electro-acupuntura “verdadeira” (EAv) e uma sessão de
eletro-acupuntura “falsa” (EAf), separadas por uma semana de washout. A EAv consiste
na estimulação bilateral de acupontos segundo o modelo de Heidelberg da Medicina
Tradicional Chinesa; a EAf é definida como EA bilateral em acupontos considerados
inactivos. Em ambas as intervenções, os parâmetros da VFC e PHNI são avaliados
enquanto a EA de baixa frequência (2Hz), seguida de um teste tilt, é aplicada durante 15
minutos. O TMGV e a escala de Borg são reavaliados após cada intervenção de EA,.
Outcomes principais: VFC, ratio baixa frequência/alta frequência (BF/AF; índice de
equilíbrio simpático) e alta frequência (AF; índice de modulação vagal), e vários PHNIs.
Parâmetros secundários: a distância de marcha e grau de dispneia e fadiga. Os dados
serão analisados utilizando o software PASW® e um p <0,05 será aceite como
estatisticamente significativo. O protocolo de investigação clínica foi aprovado pela
Comissão de Ética de uma instituição hospitalar.
X
Resultados: a revisão da literatura indica que a acupunctura exerce efeitos
simpaticolíticos, pro-vagotónicos, e anti-inflamatórios. Foi descoberta uma via neurológica
específica que participa na inibição, provocada pela EA, de reflexos cardiovasculares
excitatórios ao nível centro cárdio-regulador no núcleo ventro-lateral rostral bulbar. Igual
número de acupontos, verdadeiros e falsos, será submetido a estimulação com a mesma
frequência de EA. Espera-se que o estudo possa revelar um aumento significativo da
VFC, do ratio BF/AF e do poder de AF associado à intervenção com EAv versus EAf.
Uma correlação entre os outcomes principais e secundários poderá ser encontrada com
diferenças significativas entre EAv versus EAf.
Discussão: os resultados deste estudo preliminar poderão sugerir efeitos específicos dos
acupontos na fisiopatologia da IC associados a um possível benefício terapêutico. Os
dados obtidos podem vir a suportar um ensaio clínico de maior escala e com parâmetros
adicionais. No futuro, se a sua eficácia clínica for comprovada, a acupunctura poderá
constituir uma estratégia adjuvante no tratamento convencional da IC.
Palavras-chave: Insuficiência cardíaca; variabilidade da frequência cardíaca; teste de
marcha; sistema nervoso autónomo; acupunctura; electro-acupunctura; medicina Chinesa
tradicional.
XI
ABSTRACT
Introduction: Heart failure (HF) is a worldwide health problem with a dismal prognosis
mainly resulting from complex mechanisms of neurohumoral activation leading to system
wide autonomic deregulation. Animal research data support the concept that acupuncture
may elicit vegetative reflexes that release of endogenous substances which in turn inhibit
sympathetic outflow. To the present date, only two preliminary clinical trials have recently
suggested that acupuncture may prolong the 6-min walk distance and may increase heart
rate variability (HRV) in HF patients.
Objective: To study the effect of acupuncture in HF patients as measured by HRV and
other non-invasive hemodynamic parameters (NIHP).
Methods: It is presented the clinical protocol of a preliminary, prospective, randomized,
controlled, double-blinded, clinical trial in a cross-over design. Twenty male patients (ages
between 40 and 90 years old), with HF class II (New York Heart Association‟s
classification) and left ventricular ejection fraction ≤ 40%, are sampled from the Outpatient
HF Clinic of a central hospital. Each patient is submitted to a baseline assessment of
walking distance, using the incremental shuttle walk test (ISWT), followed by evaluation of
the degree of dyspnea and fatigue as measured by the Borg scale. During the intervention
patients are exposed, in a randomly sequence, to one session of “verum-
electroacupuncture” (vEA) and one session of “sham-electroacupuncture” (sEA),
separated by a one-week washout period. Verum-EA consists of bilateral stimulation of
acupoints following the Heidelberg Model of Traditional Chinese Medicine; sEA is defined
as bilateral EA in acupoints considered inactive for this disease. In both interventions low-
frequency EA (2Hz) is applied during 15 minutes, followed by a tilt test, while HRV and
NIHP parameters are measured. ISWT and the Borg scores are reassessed after each EA
intervention. Main parameters: HRV, low-frequency/high-frequency power ratio (LF/HF, an
index of sympathovagal balance) and high-frequency power (HF, an index of vagal
modulation), and several NIHP. Secondary parameters: walking distance and degree of
dyspnea and fatigue. Data will be analyzed using PASW® software and a p<0.05 will be
accepted as statistically significant. The research protocol was approved by the Ethics
Committee of the respective hospital.
XII
Results: review of the recent literature indicates that acupuncture exerts sympatholytic,
pro-vagotonic, and anti-inflammatory effects. It was discovered a specific neurological
pathway participating in EA inhibition of excitatory cardiovascular reflexes at the rostral
ventrolateral medulla cardiovascular center. Since both verum and sham acupoints are
stimulated by equal EA frequency, the study may reveal a significant increase in HRV, in
LF/HF power ratio and HF power in the vEA intervention versus sEA intervention. A
correlation between main and secondary outcomes may be observed with significant
differences between both interventions.
Discussion. Results from the proposed preliminary trial may demonstrate specific effects
of acupoints in the pathophysiology of HF which may be associated with a therapeutic
benefit. Collected data may support a full-scale clinical trial with additional parameters. In
the future, if its clinical efficacy is proved, acupuncture may become an adjuvant strategy
alongside the conventional treatment of HF.
Key-words: Heart failure; heart rate variability; walk test ; autonomic nervous system;
acupuncture; electroacupucture; traditional Chinese medicine.
XIII
Contents
INTRODUCTION ................................................................................................................................ 21
CHAPTER ONE ................................................................................................................................... 25
Theoretical framework ..................................................................................................................... 25
1.1. Heart failure a worldwide burgeoning problem ........................................................... 27
1.2. Etiopathophysiology of heart failure – modern understanding and ground for studies in
acupuncture ................................................................................................................................. 28
1.3. Conventional therapeutic approach to heart failure ....................................................... 39
1.4. Acupuncture an historical and scientific overview ....................................................... 45
1.6. Heart rate variability a tool for acupuncture studies in heart failure ........................... 81
1.7. Assessment of heart failure patients’ functional capacity in acupuncture trials ............. 85
CHAPTER TWO .................................................................................................................................. 86
Clinical research protocol ................................................................................................................. 86
CHAPTER THREE ............................................................................................................................. 100
Results ............................................................................................................................................ 100
CHAPTER FOUR ............................................................................................................................... 102
Discussion ....................................................................................................................................... 102
CHAPTER FIVE ................................................................................................................................. 108
Future perspectives ........................................................................................................................ 108
References ...................................................................................................................................... 112
XIV
XV
INDEX OF FIGURES
Figure 1. Evolution of the pathogenesis of heart failure with depressed efection fraction. 33
Figure 2. The neurohormonal system in heart failure .......................................................35
Figure 3. Stages in the evolution of HF and recommended therapy .................................41
Figure 4. The Heidelberg Model of TCM ..........................................................................52
Figure 5. Regulation as a technical process. ....................................................................52
Figure 6. The Fou Qi emblem: symbol for the regulatory meaning of yin, yang, and the
phases. ............................................................................................................................53
Figure 7. Phases of Chinese Medicine and physiological analogies .................................54
Figure 8. Schematic representation of the TCM methodology of diagnosis. .....................55
Figure 9. Chronic heart failure as a splendor yang syndrome in Algor Laedens theory. ...58
Figure 10. Acupuncture may be indicated in four areas of cardiovascular Disease. .........65
Figure 11. Proposed mechanism for acupuncture‟s modulation of sympathetic neural
activity in heart failure ......................................................................................................65
Figure 12. Experimental evaluation of peripheral and central neural mechanisms of action
of acupuncture on the cardiovascular system of anesthetized cats.. ................................70
Figure 13. Neural pathway of EA effect on cardiovascular neurons in rVLM. ..................71
Figure 14. Central modulation of heart rate variability. .....................................................81
Figure 15. Study cross-over design.. ................................................................................90
Figure 16. Experiment flow-chart.. ...................................................................................94
XVI
INDEX OF TABLES
Table 1. Etiologies of Heart Failure ..................................................................................30
Table 2. Frequency-dependent release of CNS opioid peptides by peripheral electrical
stimulation. ......................................................................................................................67
Table 3. Summary of research on heart rate variability (HRV) and acupupuncture. LF, low
frequency band; HF, high frequency band. EA, electroacupuncture. ................................84
Table 4. Eligibility criteria .................................................................................................92
Table 5. Schedule of the project ......................................................................................99
XVII
LIST OF ABBREVIATIONS
5-HT: 5-hydroxytriptamine
6-MWT: six-minute walk test
ACC/AHA: American College of
Cardiology/American Heart Association
ACE inhibitors: Angiotensin-converting enzyme
Ach: acetylcholine
AD: anno domini
ADH: antidiuretic hormone
AF: alta-frequência
AICD: automatic implantable cardioverter-
defibrillator
ANP: atrial natriuretic peptide
ANS: autonomous nervous system
ARB: angiotensin receptor blockers
ATPase: adenosine triphosphatase
AVP: arginine vasopressin
BaCl2: Barium chloride
BB: -blocker
BC: before Christ
BF: baixa-frequência
BNP: brain natriuretic peptide
BP: blood pressure
CAD: Coronary artery disease
CAM: complementary and alternative medicine
CCM: Cardiac contractility modulation
CR: Cardiac resynchronization therapy.
DP: deep peroneal nerve
EA: electroacupuncture
EAf: electro-acupunctura falsa
EAv: electro-acupunctura verdadeira
ECG: electrocardiogram
EF: Ejection fraction
eNOS: endothelial nitric oxide synthase
EP: evolutionary/evolutive phase
fMRI: functional magnetic resonance imaging
GABA: gamma-aminobutyric acid
GC: guiding-criteria
HF: (chronic) heart failure
HF: High-frequency
HRV: heart rate variability
IML: intermedio lateral
ISWT: incremental shuttle walking test
K: kidney meridian
LI: large intestine meridian
LF/HF: low-frequency/High-frequency ratio
LF: low-frequency
LV: left ventricular
LVEF: left ventricular ejection fraction
LU: lung meridian
MA: manual acupuncture
MI: myocardial infarction
MIBG: iodine-131-meta-iodobenzylguanidine.
MLWHFQ: Minnesota Living with HF
Questionnaire
MMPs: metalloproteinases.
MN: median nerve
MRE: magnetic resonance elastography
MTPs: myofascial trigger points
MTrPs: myofascial trigger points
NIHP: non-invasive hemodynamic parameters
NO: oxide
NRO: nucleus raphe obscurus
NTS: nucleus tractus solitari
NYHA: New York Heart Association
OC: optic chiasm
PA: placebo acupuncture
PAG: periaqueductal gray substance
PENS: percutaneous electrical nerve
stimulation
PC: pericardium meridian
PG: prostaglandins
XVIII
LIST OF ABBREVIATIONS (cont.)
PHNI: parâmetros hemodinâmicos não
invasivos
RAAS: renin-angiotensin-aldosterone system
rVLM: rostral ventrolateral medulla
S: stomach meridian
SDNN: standard deviation of all normal to
normal R-R intervals
sEA: sham-acupunture
SERCA2A: sarcoplasmic reticulum Ca2+
adenosine triphosphatase
SHRs: spontaneous hypertension rats
SNS: sympathetic nervous system
SPN: superficial peroneal nerve
SPN: superficial radial nerve
SR: sarcoplasmic reticulum
TCM: Traditional Chinese Medicine
TENS: transcutaneous electrical nerve
stimulation
TMGV: teste de marcha gradual vaivém
TNF: tumour necrosis factor alfa
US: United States
VA: verum acupuncture'
VAD: ventricular assist device
vEA: verum-acupuncture
VFC: variabilidade da frequência cardíaca
vlPAG: ventrolateral periaqueductal gray
vPAG: ventral periaqueductal gray
VS: vagal stimulation
WKY: Wistar–Kyoto rats
21
INTRODUCTION
22
23
Introduction
Chronic heart failure (HF) is a major health issue affecting millions of people and
carrying important economic health costs. Despite optimized standard therapeutics, the
prognosis remains dismal.
The majority of patients with HF are limited in daily life by dyspnea and fatigue and
reduced exercise capacity. The current state-of-the art medical treatment includes mainly
-blocker and angiotensin converting enzyme inhibitor in order to oppose the sympathetic
nervous system over activation and its consequences. Additionally, novel approaches
have been addressing the clinical benefit of selective electric vagal nerve stimulation to
normalize autonomic balance.
Acupuncture has shown to induce anti-sympathotonic, pro-vagotonic, anti-inflammatory
and immunomodulatory effects. Therefore, from a theoretical standpoint, acupuncture
might be an attractive, beneficial, low-cost and low-risk treatment strategy in addition to
standard HF medication.
The major aim of this thesis is to propose a clinical research protocol to test the effects
of acupuncture in heart failure patients.
To fulfill this goal the author firstly presents the most recent theoretical and laboratorial
background data based on an extensive literature research with the intention to support
the following proposed clinical research protocol.
The theoretical fundamentals are presented in the first part of the thesis (theoretical
framework, chapter one). A review of heart failure‟s epidemiology, etiopathophysiology
and state-of-the-art treatment is presented followed by an historical and scientific overview
of acupuncture. Thereafter a profound review of current data from acupuncture research
in provided with special emphasis in cardiovascular disease.
The theoretical framework is expected to provide the needed support for the following
detailed description of the proposed clinical research protocol (chapter two), the core of
this master thesis. Noteworthy, by the time of this thesis submission, the respective
research protocol has been approved by the Ethics Committee of the Hospital where the
study will be undertaken.
Since the laboratorial work is yet to be undertaken, the third and forth chapters,
respectively, of the thesis debate the expected results while the discussion is supported
by literature findings. Finally, the thesis is enclosed with the author‟s future perspectives in
regard to acupuncture research in the field of heart failure (chapter five).
24
25
CHAPTER ONE
Theoretical framework
26
27
1. Theoretical framework
1.1. Heart failure a worldwide burgeoning problem
Heart failure is a clinical syndrome that occurs in patients who, due to an inherited or
acquired abnormality of cardiac structure and/or function, develop a constellation of
clinical symptoms (dyspnea and fatigue) and signs (edema and crepitations) that lead to
frequent hospitalizations, a poor quality of life, and a shortened life expectancy [4].
Worldwide more than 20 million people are affected. The overall prevalence of HF in
the adult population in developed countries is 2%. HF prevalence follows an exponential
pattern, rising with age, and affects 6–10% of people over the age of 65. Although the
relative incidence of HF is lower in women than in men, women represent at least half of
the cases of HF because of their longer life expectancy. In North America and Europe, the
lifetime risk of developing HF is approximately one in five for a 40-year-old. The overall
prevalence of HF is thought to be increasing in part because current therapies of cardiac
disorders, such as myocardial infarction (MI), valvular heart disease, and arrhythmias, are
allowing patients to survive longer [5-8].
Diseases of the circulatory system or cardiovascular diseases are the main cause of
death in the European Union. They account for 42% of all deaths in the total population.
Diseases of the circulatory system are more common at advanced ages: 81% of male
deaths and 94% of female deaths are older than 65 years1. In Portugal, like in Europe,
cardiovascular disease is the major cause of death, accounting for 40% of the total
mortality2.
A 2006 Portuguese population-based study, with a representative sample of 739 non-
institutionalized adults with age equal or superior to 45 years old from the city of Porto,
found that the prevalence of heart failure in stage C (i.e., symptomatic heart failure
according to the classification of the American College of Cardiology/American Heart
Association), was 7,2%. The prevalence of HF in stage B (structural or functional heart
disease but asymptomatic) was of 21.4%. On the basis of risk factors assessment, 48%
were at high risk of heart failure despite the absence of structural or functional changes as
evaluated by heart ultrasound studies [9].
1 http://epp.eurostat.ec.europa.eu/cache/ITY_OFFPUB/KS-30-08-357/EN/KS-30-08-357-EN.PDF
2 http://www.min-
saude.pt/portal/conteudos/enciclopedia+da+saude/doencas/doencas+do+aparelho+circulatorio/doencascardiovasculares.htm
28
Despite many recent advances in the evaluation and management of HF, the
development of symptomatic HF still carries a poor prognosis.
Community based studies indicate that 30–40% of patients die within 1 year of
diagnosis and 60–70% die within 5 years, mainly from worsening HF or as a sudden event
(probably because of a ventricular arrhythmia).
Although it is difficult to predict prognosis in an individual, patients with symptoms at
rest have a 30–70% annual mortality rate, whereas patients with symptoms with moderate
activity have an annual mortality rate of 5–10%. These figures show that functional status
is an important predictor of patient outcome [10].
Although western science has developed a number of effective treatment strategies for
this disease, treatment is not perfect and often is associated with side effects.
It has long been a dream to cure diseases by non-invasive measures that activate self-
healing mechanisms, without using drugs or surgical operations.
In this context, there has been increasing interest from western countries in exploring
so-called “complementary” or “alternative” therapies such as the role of acupuncture in
cardiovascular disease.
1.2. Etiopathophysiology of heart failure – modern understanding and
ground for studies in acupuncture
In general, HF implies structural disease of the heart with functional consequences to
the circulation, and it can theoretically occur from any form of heart disease.
The pathophysiology of heart failure (HF) is to some extent dependent on the etiology
(table 1, page 30). There are many common features regardless of the underlying cause
and there are always some underlying structural abnormalities. The clinical symptoms, as
already mentioned, include dyspnea, fatigue, either at rest or during exertion, and in
advanced cases there is usually evidence of salt and water retention.
Until recently, HF was considered to arise primarily in the setting of a depressed left
ventricular ejection fraction (LVEF). However, epidemiological studies have shown that
approximately one-half of patients who develop HF have a normal or preserved ejection
fraction (EF) between 40–50%. Accordingly, heart failure is now broadly categorized into
one of two groups: (1) HF with a depressed EF (commonly referred to as systolic failure)
or (2) HF with a preserved EF (commonly referred to as diastolic failure) [10].
There is considerable overlap between the etiologies of these two conditions.
Hypertension, coronary artery disease (CAD), valvular heart disease, and cardiomyopathy
are leading causes of heart failure. Coronary artery disease is responsible for 60–75% of
29
cases of HF. Hypertension contribute to the development of HF in 75% of patients,
including most patients with CAD. Both CAD and hypertension interact to augment the risk
of HF, as does diabetes mellitus [10].
In 20–30% of the cases of HF with a depressed EF, the exact etiologic basis is not
known. These patients are referred to as having nonischemic, dilated, or “idiopathic”
cardiomyopathy. Prior viral infection or toxin exposure (e.g., alcoholic or
chemotherapeutic) may also lead to a dilated cardiomyopathy. Moreover, a large number
of the cases of dilated cardiomyopathy may be secondary to specific genetic defects,
most notably those in the cytoskeleton. Most of the forms of familial dilated
cardiomyopathy are inherited in an autosomal dominant fashion. Mutations of genes
encoding cytoskeletal proteins (desmin, cardiac myosin, vinculin) and nuclear membrane
proteins (lamin) have been identified thus far. Dilated cardiomyopathy is also associated
with Duchene‟s, Becker's, and limb girdle muscular dystrophies. Conditions that lead to a
high cardiac output (e.g., arteriovenous fistula, anemia) are seldom responsible for the
development of HF in a normal heart. However, in the presence of underlying structural
heart disease, these conditions can lead to overt HF.
Rheumatic heart disease remains a major cause of HF in Africa and Asia, especially in
the young. Hypertension is an important cause of HF in the African and African-American
populations. Chagas' disease is still a major cause of HF in South America. Not
surprisingly, anemia is a frequent concomitant factor in HF in many developing nations. As
developing nations undergo socioeconomic development, the epidemiology of HF is
becoming similar to that of Western Europe and North America, with CAD emerging as
the single most common cause of HF. Although the contribution of diabetes mellitus to HF
is not well understood, diabetes accelerates atherosclerosis and is often associated with
hypertension [10].
30
Table 1. Etiologies of Heart Failure
Depressed Ejection Fraction (<40%)
Coronary artery disease Nonischemic dilated cardiomyopathy
Myocardial infarction Familial/genetic disorders
Myocardial ischemia Infiltrative disordersa
Chronic pressure overload Toxic/drug-induced damage
Hypertensiona Metabolic disordera
Obstructive valvular diseasea
Viral
Chronic volume overload Chagas' disease
Regurgitant valvular disease Disorders of rate and rhythm
Intracardiac (left-to-right) shunting Chronic bradyarrhythmias
Extracardiac shunting
Chronic tachyarrhythmias
Preserved Ejection Fraction (>40–50%)
Pathological hypertrophy Restrictive cardiomyopathy
Primary (hypertrophic cardiomyopathies)
Infiltrative disorders (amyloidosis, sarcoidosis)
Secondary (hypertension) Storage diseases (hemochromatosis)
Aging Fibrosis
Endomyocardial disorders
Pulmonary Heart Disease
Cor pulmonale
Pulmonary vascular disorders
High-Output States
Metabolic disorders Excessive blood-flow requirements
Thyrotoxicosis Systemic arteriovenous shunting
Nutritional disorders (beriberi) Chronic anemia
31
1.2.1. Adaptive responses of the myocardium in heart failure
The heart is capable of short-term adaptations to off-set a perceived reduction in
myocardial performance or excessive hemodynamic load.
The Frank-Starling mechanism, which states that the energy of contraction is a function
of the muscle fiber length, allows increased preload or enhanced end-diastolic volume to
sustain cardiac performance, both under normal conditions and during heart failure. The
sympathetic nervous system (SNS) is activated, thus increasing the force of contraction of
the heart and of the heart rate. It also facilitates the activation of the renin-angiotensin-
aldosterone system (RAAS), which operates to restore circulating volume and protect
blood pressure, maintaining perfusion of vital organs, via physiologic effects of
angiotensin II.
The heart under chronic “siege” can also increase its own mass, with or without
chamber dilatation, to augment the number of contractile filaments. The increase in
myocardial mass and remodeling of the heart occurs over a prolonged period of time,
while activation of the Frank-Starling mechanism, the sympathetic nervous system, and
the RAAS occur nearly instantaneously. Together, the mechanisms converge to allow the
heart to physiologically adapt to impaired function and perverse loading conditions.
Circulatory homeostasis and cardiac output can be maintained despite a reduced ejection
fraction. The adaptative myocardial responses allow blood pressure to be protected and
allow the development of clinical overt heart failure to be forestalled. Additionally, release
of counter-regulatory peptides from the heart (e.g. natriuretic peptides) promotes
peripheral vasodilatation, natriuresis and diuresis, and off-sets the activation of the SNS
and the RAAS.
These adaptive responses are evolutionary remnants that have provided a survival
advantage long before heart failure was ever a threat.
1.2.2. Heart failure pathogenesis - how does heart failure begin?
HF may be viewed as a progressive disorder that is initiated after an index event (figure
1). This event may be clinically obvious, such as the sudden loss of large amounts of
contractile tissue (e.g. acute myocardial infarction), or it might be insidious, such as the
development of hypertension, aortic stenosis or insufficiency, or mitral insufficiency. The
index event might go undiagnosed, such as the onset of lymphocytic infiltrative
myocarditis or amyloid heart disease. It may also behave clinically silent, such as the
expression of mutant gene or genes that eventually lead to hypertrophic or dilated
cardiomyopathy.
32
The recognition of this primordial event and the position of the patient in the natural
history of the syndrome are important in order to define an appropriate medical approach
and treatment. However, in the “real world” many patients with heart failure do not have
an obvious underlying cause identified, despite extensive evaluation.
The pace at which the natural history of HF unfolds is highly variable and depends on
many extrinsic factors (diet, response to medications, compliance of drug therapy, etc.) as
well as intrinsic factors (gene expression, age, severity of index event, etc) that often lie
beyond the physician control.
Regardless of the nature of the inciting event, the feature that is common to each of
these index events is that they all, in some manner, produce a decline in the pumping
capacity of the heart. In most instances patients remain asymptomatic or minimally
symptomatic following the initial decline in pumping capacity of the heart, or develop
symptoms only after the dysfunction has been present for some time. Thus, when viewed
within this conceptual framework, LV dysfunction is necessary, but not sufficient, for the
development of the syndrome of HF.
1.2.3. The “muscle hypothesis” for chronic heart failure
During exercise the majority of patients with CHF are limited by dyspnea and fatigue
with delayed recovery [11]. In parallel with the severity of circulatory failure, peak oxygen
consumption is decreased, the ventilatory threshold appears earlier and the slope of the
increase in oxygen consumption versus time is reduced [11]. Remarkably, this exercise
limitation is independent of the impairment of left ventricular ejection fraction (LVEF).
Therefore, the „muscle hypothesis‟ was proposed: raised levels of inflammatory cytokines
are causing skeletal muscle fatigue and activation of muscle ergoreceptors, subsequently
leading to an increase in ventilation, sensation of breathlessness, perception of fatigue
and finally, autonomic dysbalance [12-14].
1.2.4. How adaptations in heart failure go wrong
Most of the adaptations that occur in patients with heart failure evolved for short-term
benefit, such as to allow “fight or fright” (the SNS), to ward off hemodynamic compromise
from blood loss (SNS and RAAS) or severe dehydration (RAAS). As rudimentary life-
forms gradually moved from the salty oceans to land, those who developed mechanisms
to conserve salt and water ensured themselves a survival advantage. These are very old
evolutionary steps (approximately 600 million years old) and although they may still be
33
adaptive in the early stages of heart failure, ultimately become counterproductive,
contributing to the pathophysiology of HF. The exact reasons why patients with left
ventricular (LV) dysfunction may remain asymptomatic isn‟t yet clearly understood. One
potential explanation is that a number of compensatory mechanisms become activated in
the presence of cardiac injury and/or LV dysfunction, and they appear to be able to
sustain and modulate LV function for a period of months to years (figure 1).
Compensatory mechanisms that have been described thus far include (figure 2):
(1) Activation of the renin-angiotensin-aldosterone and adrenergic nervous systems,
which are responsible for maintaining cardiac output through increased retention of salt
and water
(2) Increased myocardial contractility.
(3) Activation of countervailing vasodilatory molecules that offset the excessive
peripheral vascular vasoconstriction, such as the atrial and brain natriuretic peptides (ANP
and BNP), prostaglandins (PGE2 and PGI2), and nitric oxide (NO).
(4) Genetic background, gender, age, or environment may influence these
compensatory mechanisms, which are able to modulate LV function within a
physiologic/homeostatic range, such that the functional capacity of the patient is
preserved or is depressed only minimally.
Figure 1. Pathogenesis of heart failure with depressed ejection fraction. The transition
from adaptive to maladaptive activation of the SNS and RAAS, and from early structural
changes in the heart and vasculature to progressive organ dysfunction, characterizes the
pathophysiology of HF. The exact mechanisms that are responsible for this transition from
asymptomatic to symptomatic are not known. Ultimately, there is the increased activation
of potentially detrimental neurohormonal, adrenergic, and cytokines systems, more
perverse loading condition, change in the size and shape of the heart, ineffective
circulatory homeostasis, and multi-organ failure [10].
34
Neurohumoral activation characterizes a state in which the neural and hormonal
systems designed to maintain adequate organ perfusion are turned on to excessively high
levels. This activation may include the sympathetic nervous system (SNS), renin-
angiotensin-aldosterone-system, vasopressin, and atrial natriuretic peptide. [15]. Although
initially this is an adaptive response to cardiac injury, prolonged activation of these support
systems inevitably leads to progressive heart failure symptoms and ultimately cardiac
death.
In an animal model of early left ventricular dysfunction without overt heart failure,
plasma norepinephrine levels are elevated, indicative of early SNS activation [16].
Power spectral analysis of heart rate variability suggests that there is sympathetic
activation early in the course of left ventricular dysfunction in a canine model of heart
failure [17].
In humans, it was demonstrated that sympathetic activation with ventricular dysfunction
occurs even in the absence of heart failure, after the finding of high plasmatic levels of
norepinephrine in this situation [18]. Using the technique of microneurography to record
muscle sympathetic nerve activity directly from a peroneal nerve in humans, it was found
that even in patients with mild heart failure, sympathetic nerve activity to the muscle
circulation is increased. Interestingly, patients with heart failure secondary to diastolic
dysfunction do not have elevated plasma norepinephrine [19]. These findings indicate that
the neurohormonal excitation reflects systolic ventricular dysfunction and not simply
clinical heart failure.
The heart is the first organ to be targeted by the increase in SNS activation [20].
Measurements of cardiac adrenergic activity using MIBG (iodine-131-meta-
iodobenzylguanidine) scintigraphy indicate that cardiac sympathetic nerve activity is
increased in patients with heart failure at a time when volume and pressure overload are
not present [21, 22]. In patients with mild heart failure, cardiac sympathetic nerve activity,
as reflected by norepinephrine levels, is increased threefold above control before
increased sympathetic nerve activity to the kidney or muscle circulations.[20]
Sympathetic nerve activation decreases ventricular fibrillation threshold, predisposing
to sudden death [23]. Heart failure patients with the greatest activation of the sympathetic
nervous system are associated with poorest prognosis, progression of the disease, and
higher mortality [24-30].
Possible mechanisms implicated in the sympathetic activation in heart failure include 1)
attenuation of tonically inhibitory input to the central nervous system; 2) activation of
excitatory input to the central nervous system; and/or 3) changes in humoral or local brain
factors affecting central neural sympathetic regulation (figure 2). Attenuation of the normal
inhibitory baroreflex restraint on SNS would lead to SNS activation [15].
35
Sympathetic stimulation of the kidney leads to the release of renin, with a resultant
increase in the circulating levels of angiotensin II and aldosterone. The activation of the
renin-angiotensin-aldosterone system promotes salt and water retention and leads to
vasoconstriction of the peripheral vasculature, myocyte hypertrophy, myocyte cell death,
and myocardial fibrosis.
Figure 2. Activation of the
neurohormonal system in heart
failure [10].
Patients with heart failure have a blunted Starling relationship at rest and during
exercise. For any degree of stretching of the myocardium due to elevated end-diastolic
volume, there is less incremental change in the contractile state of the myocardium.
Ventricular function curves cannot be elevated to normal ranges by the adrenergic
overdrive, in part because the failing heart is relatively depleted of tissue norepinephrine
and 1-receptor density. The ability of patients to respond to increased end-diastolic
volume is clearly diminished, i.e., they manifest less “cardiac reserve” when called upon to
increase myocardial contractility.
Heart failure is accompanied by an increased vascular tone in attempt to maintain
perfusion pressure in the face of falling blood pressure. This mechanism is parallel to the
setting of volume depletion, which has had millions of years to allow for favorable mutation
to counteract the problem, so that species could adjust to the paucity of salt and water
36
and enhance perfusion to vital organs. This net outcome results from the activity of the
SNS and RAAS, and they are activated in very early asymptomatic HF.
Distribution of blood flow is altered in HF, directing it towards vital organs (brain, heart,
splanchnic beds), in spite of the reduction in cardiac output. Skeletal muscle flow in
augmented at rest in HF, while renal blood flow is diminished. Structural changes in
vessel walls also take place, reducing vascular compliance. Sodium content of the
vascular wall is increased, contributing to arterial stiffening.
Baroreceptors are sensory receptors that sense changes in mechanical stretch and
their activity may also be influenced by local ionic or humoral mechanisms. Arterial
baroreceptors tonically inhibit central sympathetic neural outflow. In heart failure,
baroreflex control of sympathetic nerve activity is abnormal [31, 32], leading to heightened
sympathetic activity. It has been demonstrated that SNS activity is only elevated to those
organs and tissues subject to baroreflex restraint in heart failure and not to all organs and
tissues [33, 34]. SNS activation to muscle circulation, which is under baroreflex control, is
elevated [19, 33, 35]. In contrast, sympathetic nerve activity directed to the skin, a tissue
free from baroreflex control, is not elevated, even in patients with advanced heart failure
[33]. Sympathetic neural responses to baroreceptor modulation are abnormal in heart
failure patients, even in those with mild heart failure [36]. This blunted baroreflex restraint
would lead to elevated sympathetic traffic.
Response to hyperemia is also blunted and exercise-induced vasodilatation is
attenuated. This is at least in part the consequence of peripheral vascular endothelial
dysfunction. Vasodilator response can be restored by administration of L-arginine, a
precursor of endothelium-derived nitric oxide (NO). The NO‟s role is discordant in the
peripheral vasculature and heart muscle: the expression of NO synthase in peripheral
vasculature is impaired, whereas inducible NO synthase may be increased in
myocardium, NO may mediate the effects of inflammatory cytokines (tumor necrosis
factor-) on -adrenergic receptor function, leading to diminished myocardial
responsiveness to catecholamines [37].
Redistribution of blood flow to more vital organs likely offers and additional survival
advantage. Over time such adaptive responses may worsen renal function, impair
exercise tolerance, favor tissue and circulatory congestion. The activation of the SNS in
HF is still not clearly understood.
Changes in size, shape, geometry of the heart are likely the result of excessive SNS
and RAAS activity, which act as growth factors to promote myocyte hypertrophy [38].
37
1.2.5. Ventricular remodeling
When the heart is under volume or pressure overload, the excessive loading condition
leads to myocyte hipertrophy. Pressure overload causes concentric hypertrophy and
volume overload tends to eccentric hypertrophy. Cellular division of cardiac myocytes is a
possibility, but very unusual. The change in size and shape of the heart has been called
myocardial remodeling. It seems that different gene patterns are implicated for each of the
above mentioned hypertrophy phenotypes, and usually there is a hybrid of the two[39]. As
the LV chamber dilates, systolic wall stress increases, impairing LV systolic function.
Elongation of myocytes is associated with chamber dilation, including cell dropout
(apoptosis and necrosis) and “slippage” of myocytes away from proper alignment [40].
The large, less economical, dilated heart is more prone to dysrhytmias, and dyssynchrony
(electrical and mechanical). Cardiomyopathy is the byproduct of long-standing adverse
loading conditions, unrelenting neurohormonal stimulation, increased production of matrix
metalloproteinases (MMPs) and cell dropout (apoptosis or necrosis). Alterations in
calcium excitation-contraction coupling, -adrenergic receptor coupling to downstream
proteins, myosin adenosine triphosphatase (ATPase) activity, regulatory proteins, occur in
HF. Their quantitative contribution has been elusive.
The decreased cardiac output in HF patients results in an "unloading" of high-pressure
baroceptors in the left ventricle, carotid sinus, and aortic arch. This unloading leads to the
generation of afferent signals to the central nervous system (CNS) that stimulate
cardioregulatory centers in the brain which stimulate the release of arginine vasopressin
(AVP) from the posterior pituitary. AVP [or antidiuretic hormone (ADH)] is a powerful
vasoconstrictor that increases the permeability of the renal collecting ducts, leading to the
reabsorption of free water. These afferent signals to the CNS also activate efferent
sympathetic nervous system pathways that innervate the heart, kidney, peripheral
vasculature, and skeletal muscles [10].
The increase in wall thinning along with the increase in afterload created by LV dilation
leads to a functional afterload mismatch that may contribute further to a decrease in
stroke volume. Moreover, the high end-diastolic wall stress might be expected to lead to:
(1) hypoperfusion of the subendocardium, with resultant worsening of LV function; (2)
increased oxidative stress, with the resultant activation of families of genes that are
sensitive to free radical generation (e.g., TNF and interleukin 1); and (3) sustained
expression of stretch-activated genes (angiotensin II, endothelin, and TNF) and/or stretch
activation of hypertrophic signaling pathways [10].
38
Simultaneously to the increasing in myocyte size, there is augmented collagen
deposition within the heart (reactive or replacement collagen). In HF, fibroblasts produce
more collagen, and its deposition alters the function of the heart, since it makes the
chamber stiff. Synthesis of collagen may be related to activation of fibroblasts by
angiotensin II, aldosterone, and altered stress /strain forces on the heart. It has been
assumed that MMP are active in HF contributing the collagen deposition. The action of
tissue MMP inhibitors (TIMPs) may be decreased in myocardium, thus facilitating the
degradation of collagen.
Despite the reduction or dissolution of collagen normally present to align myocytes, the
increased interstitial collagen may contribute for diastolic dysfunction [41]. Muscle and
chamber stiffness is overall increased which has important consequences for LV filling
pressure and its relation to left ventricular end-diastolic volume.
There is a reduction in the density of -receptor, due to excessive local concentration
of norepinephrine, and there appears to be an unhinging of the membrane bound -
receptors from the Gs proteins and a tighter coupling to the Gi proteins, thus attenuating
the response to excessive norepinephrine on the heart. This is presumably an
evolutionary conserved protective effect, preventing lethal overstimulation of the heart by
catecholamines. However, the net result is a likely reduction in myocardial reserve.
Coronary blood flow at rest is often normal in patients with heart failure, but has been
found to be reduced in some patients with dilated cardiomyopathy and in some with
ischemic cardiomyopathy. Capillary density may be reduced has LV mass increases.
Patients with LVH demonstrate a reduced coronary reserve, consistent with diminished
hyperemic response common to many vascular beds in the setting of heart failure.
Coronary blood flow may also diminish to match reduced contractile state, a condition
referred to as “hibernating myocardium”, which is viable muscle tissue, thus may improve
with revascularization [42].
1.2.6. Systolic Dysfunction
In order to understand how the changes that occur in the failing cardiac myocyte
contribute to depressed LV systolic function in HF, it is important to understand the
biology of the cardiac muscle cell. Sustained neurohormonal activation results in
transcriptional and posttranscriptional changes in the genes and proteins that regulate
excitation-contraction coupling and cross-bridge interaction. Collectively, these changes
impair the ability of the myocyte to contract and, therefore, contribute to the depressed LV
systolic function observed in patients with HF [10].
39
1.2.7. Diastolic Dysfunction
Myocardial relaxation is an ATP-dependent process that is regulated by uptake of
cytoplasmic calcium into the sarcoplasmic reticulum (SR) by sarcoplasmic reticulum Ca2+
adenosine triphosphatase (SERCA2A) and extrusion of calcium by sarcolemmal pumps.
Accordingly, reductions in ATP concentration, as occurs in ischemia, may interfere with
these processes and lead to slowed myocardial relaxation. Alternatively, if LV filling is
delayed because LV compliance is reduced (e.g., from hypertrophy or fibrosis), LV filling
pressures will similarly remain elevated at end diastole. An increase in heart rate
disproportionately shortens the time for diastolic filling, which may lead to elevated LV
filling pressures, particularly in noncompliant ventricles. Elevated LV end-diastolic filling
pressures result in increases in pulmonary capillary pressures, which can contribute to the
dyspnea experienced by patients with diastolic dysfunction. Importantly, diastolic
dysfunction can occur alone or in combination with systolic dysfunction in patients with
HF.
Controversy still remains regarding the definition of “diastolic heart failure” and what the
core lesion might be. Importantly, the two conditions (i.e., systolic and diastolic heart
failure) often coexist and are indistinguishable at the bedside [10, 43].
1.3. Conventional therapeutic approach to heart failure
In the past treatment of heart failure was focused on drugs to improve ventricular
function directly with positive inotropic drugs. Nowadays, therapeutic modulation of
neurohumoral activation is a key to successful treatment of heart failure.
Although the failing heart may include both systolic and diastolic dysfunctions, to the
present body of knowledge, the initial step is to differentiate the predominant dysfunction
(systolic from diastolic heart failure).
Noteworthy, the overwhelming number of studies in HF population has been performed
in patients with the syndrome of systolic dysfunction.
Although there is a growing recognition that as many as 30-50% of all hospitalized
patients with HF have preserved ejection fraction (EF>40-50%) there remains a paucity of
evidence-based recommendations for this group of diastolic HF. Most reviews underline
the importance of excluding significant coronary ischemia and that control of hypertension
is critical. Control of heart rate is useful in those patients presenting with atrial arrhythmias
(e.g. atrial fibrillation). A search for exacerbating drugs may be fruitful since these patients
frequently have comorbid conditions (obesity, diabetes, arthritis, renal failure). It is also
appropriate to screen sleep apnea [44, 45].
40
Dyspnea may be treated by reducing total blood volume (dietary sodium restriction and
diuretics), decreasing central blood volume (nitrates), or blunting neurohormal activation
with angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers
(ARB), and/or beta-blockers. Treatment with diuretics and nitrates should be initiated at
low doses to avoid hypotension and fatigue.
In patients with systolic dysfunction (EF<40%) it is mandatory to search for reversible
or correctable causes of the low systolic function. In the United States (US) the most
common cause of dilated cardiomyopathy is chronic ischemia related to coronary artery
obstruction [46-52]. Other correctable etiologies include illicit drug use or alcohol use,
thyroid disorders, uncontrolled hypertension.
It is important to exclude the role of coronary artery disease (CAD) as the cause of left
ventricular dysfunction, since it has been estimated that CAD is the cause of HF in two-
thirds of patients with left ventricular dysfunction [53].
In patients with HF and angina coronary revascularization was shown to improve
symptoms and survival, although patients with markedly impaired ventricular function
were not included in these studies.
As many as one-third of patients with nonischemic cardiomyopathy may complain of
chest pain suggestive of angina and in these patients noninvasive imaging may
demonstrate perfusion defects and segmental wall motion abnormalities. It is therefore
reasonable to proceed directly to coronary angiography in young patients with HF, angina
and left ventricular dysfunction. However, it is still a matter of debate whether or not
routine coronary angiography is warranted in all patients who present with HF and left
ventricular dysfunction in the absence of chest pain, because coronary revascularization
has not been clearly demonstrated to improve survival in patients without angina [53].
Nonetheless, there are data to suggest that revascularization might improve ventricular
function. Therefore, it is a reasonable strategy to exclude coronary artery disease in all
patients with newly diagnosed HF and left ventricular systolic dysfunction even in the
absence of chest pain.
The ACC/AHA guidelines for the evaluation and management of chronic heart failure in
the adult has been instrumental in more clearly articulating the early stages of HF, or the
preclinical phase of the disease, and the patterns of disease associated with subsequent
progression to clinical symptoms. A new approach to the classification of HF was
established in order to appropriately characterize HF evolution in 4 stages (figure 3) [54].
41
Figure 3. Stages in
the evolution of HF
and recommended
therapy by stage
proposed by the
ACC/AHA guideline
s for the evaluation
and management of
chronic HF in adults
[54].
HF should be viewed as a continuum that is comprised of four interrelated stages.
Stage A includes patients who are at high risk for developing HF but without structural
heart disease or symptoms of HF (e.g., patients with diabetes mellitus or hypertension).
Stage B includes patients who have structural heart disease but without symptoms of HF
(e.g., patients with a previous myocardial infarction (MI) and asymptomatic LV
dysfunction). Stage C includes patients who have structural heart disease and have
developed symptoms of HF (e.g., patients with a previous MI with dyspnea and fatigue).
Stage D includes patients with refractory HF requiring special interventions (e.g., patients
with refractory HF who are awaiting cardiac transplantation).
In this continuum, every effort should be made to prevent HF, not only by treating the
preventable causes of HF (e.g., hypertension) but by treating the patient in Stages B and
C with drugs that prevent disease progression (e.g., ACE inhibitors [ACEi] and beta
blockers [BB]) and by symptomatic management of patients in stage D. Once patients
have developed structural heart disease, their therapy depends on their NYHA functional
classification. Although this classification system is notoriously subjective and has large
interobserver variability, it has withstood the test of time and continues to be widely
applied to patients with HF. For patients who have developed LV systolic dysfunction but
remain asymptomatic, the goal should be to slow disease progression by blocking
neurohormonal systems that lead to cardiac remodeling. For patients who have developed
symptoms the primary goal should be to alleviate fluid retention, lessen disability, and
reduce the risk of further disease progression and death. These goals generally require a
strategy that combines diuretics (to control salt and water retention) with neurohormonal
interventions (to minimize cardiac remodeling).
42
1.3.1. Treating elevated cardiac filling pressures
When volume overload is identified the strategy is focused on relieving congestion.
Diuretics produce symptomatic benefits more rapidly than any other drug used for HF.
Although some patients with dilated cardiomyopathy who have been stabilized on a
standard regimen of neurohormonal antagonists may be effectively managed without
diuretics, the large majority of patients will need a regular dose of diuretics.
1.3.2. Neurohormonal antagonists
All patients with low EF, in the absence of aortic outflow obstruction, are treated with
both ACE inhibitor and a -blocker. For historical reasons, clinicians commonly start an
ACE inhibitor first and add a -blocker as a second agent but recent data suggest that
starting a B-blocker as initial therapy has some advantages. The ultimate task is to
maintain patients on both drugs and at the highest tolerated dosages. Some patients not
tolerate ACE inhibitor due to dry cough, exacerbation of renal failure, and angioedema.
Such patients may be treated with direct ARBs, which bind to angiontensin II receptors,
and are also a proven effective treatment in HF.
Additional pharmacological agents in HF symptomatic patients despite treatment with
adequate doses of -blocker and ACE inhibitor are digoxin and aldosterone antagonists.
The use of digoxin is a Class I indication in conjunction with diuretics, ACEi, and BB
(3). It has been demonstrated that digoxin use conveys a significant decrease in risk of
dead or hospitalizations due to worsening HF and that it is well-tolerated and associated
with few adverse side effects.
Aldosterone antagonists are recommended in patients with symptoms of HF despite
the use of digoxin, diuretics, ACEi, and BB. The aldosterone antagonists, spironolactone,
conferred a significant reduction in the risk of death as well as a reduction in the risk of
hospitalization from cardiovascular causes.
1.3.3. Conventional non-pharmacological therapies
Chronic heart failure generates many debilitating symptoms for the sufferer.
Nonpharmacologic treatment modalities play an important role, alongside effective
modern pharmaceutical, surgical, and device therapies. These treatments include those
lifestyle measures that reduce the risk of underlying diseases (coronary artery disease,
diabetes, hypertension, hyperlipidemia, and those lifestyle interventions that benefit either
the symptoms or prognosis of established heart failure.
43
HF patients should be advised to stop smoking and to limit alcohol consumption to two
standard drinks per day in men or one per day in women. Patients suspected of having an
alcohol induced cardiomyopathy should be urged to abstain from alcohol consumption
indefinitely. Extremes of temperature and heavy physical exertion should be avoided.
Certain drugs are known to make HF worse and should also be avoided. For example,
nonsteroidal anti inflammatory drugs, including cyclooxygenase 2 inhibitors, are not
recommended in patients with chronic HF because the risk of renal failure and fluid
retention is markedly increased in the presence of reduced renal function or ACE inhibitor
therapy. Patients should receive immunization with influenza and pneumococcal vaccines
to prevent respiratory infections. It is equally important to educate the patient and family
about HF, the importance of proper diet, as well the importance of compliance with the
medical regimen.
Although heavy physical labor is not recommended in HF, routine modest exercise has
been shown to be beneficial in patients with NYHA class I–III HF. For euvolemic patients,
regular isotonic exercise such as walking or riding a stationary bicycle ergometer, as
tolerated, should be encouraged. Some trials of exercise training have led to encouraging
results with reduced symptoms, increased exercise capacity, and improved quality and
duration of life. One study evaluated the effects of combined endurance/resistance
training on NT-proBNP levels in patients with HF. Results suggested that combined
endurance/resistance training significantly reduced circulating levels of NT-proBNP in
patients with HF arguing against any increase in adverse remodeling. Regarding cardiac
rehabilitation, some supervised in-hospital training is necessary, and home-based training
can also be recommended in well-evaluated patients.
The benefits of weight loss by restriction of caloric intake have not been clearly
established. Dietary restriction of sodium (2–3 g daily) is recommended in all patients with
HF and preserved or depressed EF. Further restriction (<2 g daily) may be considered in
moderate to severe HF. Fluid restriction is generally unnecessary unless the patient
develops hyponatremia (<130 mEq/L), which may develop because of activation of the
renin-angiotensin system, excessive secretion of antidiuretic hormone, or loss of salt in
excess of water from diuretic use. Fluid restriction (<2 L/day) should be considered in
hyponatremic patients or for those whose fluid retention is difficult to control despite high
doses of diuretics and sodium restriction. Caloric supplementation is recommended for
patients with advanced HF and unintentional weight loss or muscle wasting (cardiac
cachexia); however, anabolic steroids are not recommended for these patients because of
the potential problems with volume retention. The use of dietary supplements
("nutraceuticals") should be avoided in the management of symptomatic HF because of
the lack of proven benefit and the potential for significant (adverse) interactions with
44
proven HF therapies. Some authors have demonstrated an important role for the dietician
in a multidisciplinary HF program, by showing significant improvements in quality of life
scores after the dietician intervention, suggesting improved nutrition and avoidance of
worsening HF due to excessive sodium intake [55].
The management of patients with systolic HF includes the evaluation for additional
nonpharmacologic therapies that have been demonstrated to improve survival.
Cardiac resynchronization therapy (CRT) may reduce symptoms, improve functional
capacity, and possible improve mortality in select patients with systolic HF [56, 57].
Currently patients who may benefit from CRT are those presenting with a prolonged QRS
interval (>140ms). However, the surface electrocardiogram lacks sensitivity in identifying
patients who have contraction dyssynchrony [58]. It is appropriate to consider CRT in
patients with refractory symptoms of HF and evidence of either interventricular or
intraventricular dyssynchrony.
1.3.4. Refractory heart failure
Cardiac transplantation is an option for only very select few of this group. In patients
who are not candidates for cardiac transplantation, permanent ventricular assist devices
(VAD) may improve survival and quality of life [59-62]. These devices may become
technologically improved in the future and may become a wider available solution.
In this group of patients, repeat discussion about end-of-life decisions and wishes must
be undertaken. Home inotropic therapy may increase mortality but it may improve quality
of life. Recent studies demonstrated that in many patients with stage D, quality of life is
more desired than length of life. Hospice is an appropriate alternative for many patients,
as compared to an endless cycle of increasingly longer hospital admissions [63].
Implantable cardiac defibrillators (ICDs) in systolic HF are indicated in patients with
cardiac arrest due to ventricular tachycardia or ventricular fibrillation or hemodynamically
significant sustained VT. It is class IIa indication in patients with ischemic cardiomyopathy
with an EF less than 30% who are at least 1 month post myocardial infarction or 3 months
post coronary artery revascularization [10, 64-68].
45
1.4. Acupuncture an historical and scientific overview
The word "acupuncture" is derived from the Latin words "acus"
(needle) and "punctura" (penetration). Acupuncture originated in
China approximately 2500 years ago (one of the oldest medical
procedures in the world) and is a treatment based on the ancient
Chinese Medicine.
Over its long history and dissemination, acupuncture has
diversified and encompasses a large array of styles and
techniques. Common styles include Traditional Chinese,
Japanese, Korean, Vietnamese, and French acupuncture, as well
as specialized forms such as hand, auricular, and scalp
acupuncture.
Acupuncture also refers to a family of procedures used to stimulate anatomical points.
Aside from needles, acupuncturists can incorporate manual pressure, electrical
stimulation, magnets, low-power lasers [69-71], heat, and ultrasound.
Despite this diversity, the techniques most frequently used and studied are manual
manipulation and/or electrical stimulation of thin, solid, metallic needles inserted into skin.
The precise origin of acupuncture is a source of debate. There is no single
archaeological finding that points to a momentary emergence of acupuncture. Rather
evidence exists for a variety of potential antecedent practices like bloodletting, tattoos for
religious purposes, and use of bones to extract abscess [72]. Older recompilations and
analyses of the system and new archaeological findings suggest that Chinese Medicine
did not start with the Yellow Emperor‟s Classic on Internal Medicine 2300 years ago. It
seems that Chinese Medicine may be three times older than that, leading to the fact that
the origin and the bibliographic sources are within the dark of history [73].
According to other authors, texts on acupuncture date back to 206 BC, although the
Yellow Emperor, Huang Di, the originator of traditional Chinese medicine lived in 2697
BC. Others mention that the first written document to record the use of acupuncture is the
Nei Jing (Inner Classic of the Yellow Emperor) dated approximately 100 BC. It is a
collection of 81 treatises divided into two parts [74]. By the time of its compilation,
acupuncture was already a signature therapy of Chinese medicine.
The importance of acupuncture as medical therapy emerged around the same time that
Confucianism and Taoism gained prominence in China. These philosophies are imprinted
in the fundamental principles of acupuncture theory, and their influence is patently evident
throughout the ancient texts [72, 75]. Acupuncture underwent significant development and
expansion within the ensuing 1500 years and arguably climaxed in the Ming era (1368-
46
1644) when The Great Compendium of Acupuncture and Moxibustion was published in
1601 [76]. Afterwards, it experienced waxing and waning popularity due to political and
social pressures arising from Western influences, but it gained a modern resurgence after
Mao ZeDong encouraged its use among "barefoot doctors" [72].
Historically there are around 10,000 treatises on acupuncture from the centuries
preceding the modern era [77]. Past acupuncture scholars freely edited prior texts and
added personal interpretations, commentaries, and clinical experiences[75]. As a result,
present copies of ancient texts often represent the work of multiple acupuncture scholars
and demonstrate a medley of teachings, each susceptible to variable interpretations. This
has contributed to the marked heterogeneity seen in acupuncture practice.
Acupuncture was disseminated to Korea and Japan in the sixth century, to Southeast
Asia around the ninth century through commercial trade routes from China, and to Europe
as early as the sixteenth century when Asian texts and translations were brought back by
traders and missionaries [78]. Acupuncture became relatively established in some parts of
Europe, such as France, around the eighteenth century and persisted due to perpetual
colonial influences (e.g., Indochine) [75].
In the United States, traces of acupuncture appeared as early as 18th century and
appeared in the early editions of William Osler's Principle and Practice of Medicine [79].
However, acupuncture did not enter the mainstream until 1971, when a New York Times
journalist, James Reston, visited China and reported his experiences with acupuncture for
postoperative pain relief [80]. Acupuncture has gained increasing acceptance by the lay
public, partly as a result of increasing communication between the US and China since
the early 1970s [78, 81].
A survey from 2002 estimated that 8.2 million US adults had ever used acupuncture,
and an estimated 2.1 million had used acupuncture in the previous year [82]. The five
most commonly treated conditions were back pain, neck pain, joint pain, headache, and
"head/chest cold". Other commonly treated conditions include fatigue, anxiety, insomnia,
and depression. Several surveys suggest that acupuncture is the complementary and
alternative medicine (CAM) therapy most likely to be recommended by conventional
medical professionals [83].
1.4.1. Basic theory of acupuncture
Acupuncture's early development coincided with the rise and prominence of two major
Chinese philosophies, Confucianism and Taoism. As a result acupuncture theory is
largely grounded in these philosophies [72].
One notable, early influence of these philosophies was the recognition that one's
observation and experience were sufficient to explain the human condition [84]. This was
47
a significant departure from primordial Chinese healing arts which usually ascribed illness
to some superstitious force or moral punishment [84].
The two philosophies, particularly Taoism, emphasized the importance of
understanding the laws of nature and for humans to integrate and abide by these laws
rather than to resist them. The human body was regarded as a microcosmic reflection of
the macrocosm of the universe. For this reason, concepts used to explain nature, such as
yin/yang and Five Elements (described below), became central to acupuncture theory
[75]. The goal of the clinician was to maintain the body harmonious balance both internally
and in relation to the external environment.
Eastern medicine values the clinician's initial assessment and encourages the
practitioner to value his/her own intuition to extract additional information. Eastern thought
perceives the world as dynamic and interconnected [85]. To the acupuncturist, it makes
little sense to isolate a symptom such as back pain. Symptoms necessarily arise from a
particular context. Acupuncture treatments are therefore usually individualized, and two
patients with the same symptoms often do not get the same treatment. The same patient
also may not receive the same treatment on subsequent visits.
Three important concepts in acupuncture are qi, yin/yang, and Five Elements.
Qi (pronounced "chee") is frequently translated as "vital energy" [86]. It is felt to
permeate all things, may assume different forms, and travel through meridians located
on the body. It can be described as stagnant, depleted, collapsed, or rebellious.
Whether qi is a quantitative force or a metaphoric way of depicting and experiencing
interconnections is not clear. It likely provides a rationale for explaining change and
linking phenomena [84].
Yin and yang are felt to be complementary opposites and are used to describe all
things in nature. Yin is used to represent more material, dense states of matter while
yang represents more immaterial, rarefied states of matter [87]. The interplay between
the two opposites is dynamic and cyclical. To the acupuncturist, health is a constant
state of dynamic balance and one must employ a series of qualitative assessments to
establish a patient's present disposition. The evaluation is more complex than merely
designating a patient as "more yin" or "more yang". An intricate set of qualitative
measures, examination tools, and symptom evaluations are used [87].
Five Elements along with yin/yang theory form the basis of Chinese medical
theory. The Five Elements are wood, water, fire, earth, and metal. These elements are
not basic constituents of nature, but represent different basic processes, qualities, or
phases of a cycle [87]. Each element can generate or counteract another element. Most
vital organs, acupuncture meridians, emotions, and other health-related variable are
48
assigned an element, thus providing a global description of the balancing dynamics
seen in each person.
The Eastern Medical practitioner relies on these principles for diagnosis and treatment
selection. Once the nature of imbalance is determined, the practitioner aims to shift the
constitution towards balance with the use of various interventions. Acupuncture is one
important option.
1.4.2. Research in acupuncture
Acupuncture therapy has nearly 5000 year history in China, but research on
acupuncture therapy in modern scientific ways has just started and its evaluation remains
yet uncertain in many different diseases. Since acupuncture therapy has been developed
from empirical trials for 2000 years, scientific studies for endorsing its clinical
effectiveness and benefit are mandatory.
In 1997, a consensus conference sponsored by the National Institute of Health (USA)
concluded that more research must be performed in order to clarify the totality of
biological effects and clinical efficacy of acupuncture [88, 89].
Traditional Chinese medicine (TCM) practitioners believe these meridians conduct
energy throughout the body. However, recent evidence indicates that the needles
stimulate sensory nerves underlying meridians to alter neurotransmitter release in regions
of the central nervous system concerned with regulation of the autonomic nervous.
Eastern scientists have translated these TCM concepts into a neurophysiologic
paradigm in which acupuncture, by evoking the release of inhibitory neurotransmitters
(endorphins, enkephalins, and possibly endomorphins) in the hypothalamus, midbrain,
and medulla, in turn, reduces activity of premotor neurons concerned with sympathetic
outflow to the heart and vascular system [81, 90-92].
1.4.3. Translating Traditional Chinese Medicine into Western Medicine knowledge
The trigger points theory
The term "trigger point" was coined in 1942 by Dr. Janet Travell to describe a clinical
finding with the following characteristics [93]:
Pain related to a discrete, irritable point in skeletal muscle or fascia, not caused by
acute local trauma, inflammation, degeneration, neoplasm or infection.
The painful point can be felt as a tumor or band in the muscle and a twitch
response can be elicited on stimulation of the trigger point.
49
Palpation of the trigger point reproduces the patient's complaint of pain, and the
pain radiates in a distribution typical of the specific muscle harboring the trigger
point.
The pain cannot be explained by findings on neurological examination.
The main innovation of Travell's work was the introduction of the myofascial pain
syndrome concept, described as a focal hyperirritability in muscle that can strongly
modulate central nervous system functions. Travell el al. distinguishes this from
fibromyalgia, which is characterized by widespread pain and tenderness and is described
as a central augmentation of nociception giving rise to deep tissue tenderness that
includes muscles. Studies estimate that in 75–95% of cases, myofascial pain is a primary
cause of regional pain. Myofascial pain is associated with muscle tenderness that arises
from trigger points, focal points of tenderness, a few millimeters in diameter, found at
multiple sites in a muscle and the fascia of muscle tissue. Biopsy tests found that trigger
points were hyperirritable and electrically active muscle spindles in general muscle tissue
[94-99].
A 2008 review in Archives of Physical Medicine and Rehabilitation of two recent studies
concludes they present groundbreaking findings that can reduce some of the controversy
surrounding the cause and identification of myofascial trigger points (MTPs). The study by
Chen on the use of magnetic resonance elastography (MRE) imaging of the taut band of
an MTP in an upper trapezius muscle may present a convincing demonstration of the
cause of MTP symptoms. MRE is a modification of existing magnetic resonance imaging
equipment to image stress produced by adjacent tissues with different degrees of tension.
This report presents an MRE image of the taut band that shows the chevron-shaped
signature of the increased tension compared with surrounding tissues [100]. Results were
all consistent with the concept that taut bands are detectable and quantifiable with MRE
imaging. The findings in the subjects suggest that the stiffness of the taut bands in
patients with myofascial pain may be 50% greater than that of the surrounding muscle
tissue. The findings suggest that MRE can quantify asymmetries in muscle tone that could
previously only be identified subjectively by examination [101].
In the study by Shah et al. it was shown the feasibility of continuous, in vivo recovery of
small molecules from soft tissue without harmful effects. With this technique, they have
been able to investigate the biochemical milieu of muscle in subjects with active, latent, or
absent myofascial trigger points (MTrPs) and to contrast this with that of the noninvolved
muscle [102].
Therefore, trigger points can be defined as hyperirritable spots in skeletal muscle that
are associated with palpable nodules in taut bands of muscle fibers [103].
50
In 1977, Melzack et al. found that a remarkably high degree (71%) of correspondence
was found between trigger points and acupoints [104].
Later, Dorsher et al. confirmed a strong correlation between the locations of trigger
points and classical acupuncture points, finding that 92% of the 255 trigger points
correspond to acupuncture points, including 79.5% with similar pain indications [105, 106].
This close correlation suggests that trigger points and acupuncture points for pain,
though discovered independently and labeled differently, represent the same
phenomenon and can be explained in terms of the same underlying neural mechanisms
[107].
The Heidelberg Model of TCM or “TCM as novel vegetative medicine”[3]
Kroenke and Mangelsdorff [108, 109], in a study to determine the incidence, diagnostic
findings, and outcome of 14 common symptoms, reviewed the records of 1,000 patients.
Although diagnostic testing was performed in more than two thirds of the cases an organic
etiology was demonstrated in only 16%. In another words, 84% of the complaints patients
present in an outpatient medical setting can‟t be correlated with measurable laboratorial
findings. This has enormous costs related to the process of medical investigation in
searching for a possible organic cause and may even cause adverse side effects related
to diagnostic tools.
It has been suggested that this large number on unexplainable complaints could be
psychologically induced psychosomatic disorders or reflect autonomic nervous system
dysfunctions [3].
The integration of Chinese Medicine in Western Healthcare systems requires three
preconditions [3]:
1) Chinese Medicine should be rationally accessible.
2) Scientific evidence of the underlying mechanisms, clinical efficacy and
general safety has to be raised.
3) Quality control measures have to be put up on the basis of the developing
knowledge of this medical system.
Besides acupuncture, Chinese medicine includes other therapeutic modalities: Chinese
herbal therapy, dietetics, tuina (Chinese manual therapy), Taiji-Qiong (biofeedback
neurovegetative exercises), psychotherapy of TCM.
51
The apparent irrationality of the shortened versions of TCM exported after the 1950s
from China can give rise to misunderstanding which is against a comprehensible
theoretical basis for this medical system [3].
On the basis of the pioneering works of the medical-sinologist Prof. Manfred Porkert
[110-115], the Heidelberg Model was developed by Prof. Greten [3] as a scientific model
to allow a rational access to Chinese medicine. It stresses the value of the internal logic of
the Chinese Medicine. Since Prof. Porkert devised a systematic account of the Chinese
Medicine theories, based on primary Chinese sources, he used a precise terminology in
Latin, which better define the original Chinese concepts at a philological level (e.g. the
latin terms calor or algor, meaning “heat/cold”). Accordingly, the Heidelberg Model makes
use of this terminology.
Based on Leibniz‟ analysis of the I Ging (“The Book of Changes”), the oldest book of
mankind, Prof. Greten developed a novel recompilation of the central ideas of Chinese
Medicine, thereby explaining it as a logical model of system biology based on a
mathematical language [3].
The yin and yang signs of this book can be considered as a mathematical expression
of numbers. Leibniz developed the binary numbering system out the I Ging, which enables
to describe circular processes. There is evidence that in Classical China, even before the
Yellow Emperor‟s Classic, these regulatory fluctuations were described by circulatory
functions in a simplistic manner resembling a sinus wave. This wave is part of the so-
called monad (Leibniz) or Taiji sign (figure 6).
The biological network of regulation in humans is polygenic and therefore not linear. In
TCM four main descriptive models have evolved to organize the complex relationships of
body regulation. In essence these models describe the guiding criteria in the regulation of
the human body at four different physiological levels, which together constitute a complex
regulatory network model.
These central ideas of the underlying categorization of Chinese Medicine are
condensed in the theory of the so-called guiding criteria (bagang). These four levels of
control are the neurovegetative level, humorovegetative level, the neuroimmunologic
level, and the cellular level (figure 4). Current understanding of these criteria is that they
consist of an extension of the vegetative regulatory curve on processes such as
microcirculation (“heat/cold”), defense mechanisms (theory of six stages of the Shan Han
Lun) and the relation of the amount of the cell population and the respective regulatory
processes (the yin, “substance”) [116].
52
Figure 4. The Heidelberg Model of TCM establishes a parallelism between TCM concepts
of disease and physiological processes at four levels of regulation: neurovegetative,
humorovegetative, neuroimmunological, and cellular level.
The laws of regulation indicate that most of the regulatory processes are based on
periodic fluctuations of the actual value around a target value of regulation. Applying this
model of regulation to the vegetative system results in the categorization of symptoms
leading to the so-called orbs, or organs patterns, of Chinese Medicine. This reveals that
these “organs patterns” can be rather understood as physiological patterns of vegetative
origin than as organs, thus allowing to translate ancient Chinese physiology in terms of
western vegetative physiological knowledge [116].
The technical and regulatory dimension of Yin/Yang and the evolutionary phases (EP),
i.e., Wood, Fire, Earth, Metal, Water, can be seen in an analogous example of the
regulation of temperature in a water basin by a thermostat system. Due to the inherent
fluctuations, the actual temperature value moves around the set point approximately in a
sinus wave. (figure 5).
Figure 5. Regulation as a technical process. The
temperature profile of the pool is not constant
(straight line), but rather sinusoidal. Temperature is
on the y-axis and time plotted on the x-axis, which
corresponds to the desired temperature.
53
It is in such a sinusoidal course that almost all biological systems are regulated. For
this reason, this regulatory curve must be considered in the evaluation of many biological
phenomena. TCM has developed its own language to describe such changes around the
set point, which could be applied to the regulation of autonomic nervous system in the
human body: Yang-states are above the set point; Yin-states are below the set point. The
phases (EPs) designate the sections (quadrants) of this sinusoid curve
A sine curve can also be seen as a circular function. Graphically, if a circle is drawn
around the whole picture, in which the sine curve is included, the result is the Fou qi
character. This character comes from the Song dynasty (960-1279 AD). The signs in the
Fou qi character have thus the basic mathematical meaning of the description of a circular
motion (figure 6). Yang is therefore includes the wood and fire evolutionary phases; yin
includes metal and water phases. This model can also be applied to explain the “flavors”
as vegetative effective directions, the concept of Yin-deficiency and the six-stage theory of
the “Shang Han Lun” [3].
Figure 6. A sinusoid wave is a circular function
around a shall-be value in biological systems.
Graphically, the Fou qi emblem is drawn. This well
known sign of Yin/Yang may enclose a mathematical
meaning. Yin and yang are terms of regulation that
can be further differentiated in evolutive phases (e.g.
“wood”).
The Heidelberg Model hypothesizes a relation between this sinusoidal-pattern
“evolutive phases” and the differential activity of the autonomic nervous system and its
major molecular effectors (e.g. hormones, neurotransmitters, etc) (figure 7).
54
Figure 7. Postulated
assignment of phases of
Chinese medicine into the
autonomic nervous system with
respective analogies between
the phases and the
neurohormonal mechanisms.
W – Wood phase. F – Fire
phase. M – Metal phase.
Scientific proof of efficacy based on this model has been reached by a novel double
and even triple blinded assay of evaluation in acupuncture research. Greten et al. [3] have
shown that in double or triple blinded study design, acupuncture based on this
reconstruction of classical theory is almost double as effective as current “western”
acupuncture . Analogue data has been shown for polyneuropathy [117], in congestive
heart failure[118, 119], pain following sternotomy in heart surgery, respiration after heart
surgery, pain after tonsillectomy [120], walking distance and peripheral arterial occlusive
disease [116]. Nevertheless more studies are needed to support this model.
55
Diagnosis according to the Heidelberg Model of TCM
Along the lines of this model, the Chinese medicine functional diagnosis is composed
of three steps: (1) the constitution; (2) the agent (pathogenic factor); (3) the “orb”, and (4)
the guiding criteria.
Figure 8. Schematic representation of the TCM methodology of diagnosis.
The constitution refers to the individual functional properties and the inner nature of
the patient based in his/her phenotype.
The agent is regarded as a functional power (vector) that changes the individual
functional properties (caused by the constitution), produces clinical signs of its own and
induces groups of diagnostically relevant signs called “orb” (vegetative patterns). Agents
may be divided in exterior [wind (ventus), cold (algor), dryness (ariditas), summer heat
(aestus), glow (ardor)], interior [(Ira (“anger”); Voluptas (“lust”); Maeror (“grief”), Timor
(“anxiety”); Pavor (“shock”); Solicitude (“worriedness”); Cogitation (“thinking”)] and neutral
agents.
The guiding-criteria (GC) are regulatory models of physiology, as previously stated,
that allow the interpretation of the actual symptoms on the background of overall body
regulation.
The first GC is repletion/depletion (“excess/emptiness”). It evaluates clinical signs
that in Chinese Medicine are believed to originate from qi and orbs and phases. In
western terms, these signs are of primary neurovegetative origin. In general, signs of
repletion indicate too much qi in the organism as the origin of symptoms. Sing of depletion
indicate lack of qi. In a simplified approach, repletion is analogous to relative over-
56
excitation of neurovegetative activating mechanisms. Depletion is a lack of respective
activation or excess de-activation.
The second GC is “calor/algor” (heat/cold). It evaluates signs which in Chinese
medicine are believed to originate from the effects of xue (“blood”) which is the second
power (“energy”) of Chinese medicine. From a western medical view, refers to clinical
signs predominantly originated from the humorovegetative system. These signs include:
(1) the effect of microcirculation within the disease on a systemic and regional level (local
interdependent mechanisms of the plasma, blood cells, endothelium, and functional
tissue); (2) the activation of body fluids, evoking vegetative and systemic responses in the
context of fluid distribution, fluid supply and circulation (e.g. Changes in thirst, urine
output, heart rate). Signs of over-activation of xue are called “calor”; signs of a lack of
functional microcirculation are called “algor”.
The third GC is “extima/intima” (“exterior/interior”). It evaluates signs that in Chinese
medicine are believed to originate from the effects of a pathogenic factor (agent) invading
the body from the exterior. The most common pathophysiological model behind is the
model of the six stages (Shang Han Lun), the process of the agent “algor damaging the
body” or “algor laedens theory” (ALT), according to Prof. Porkert. From the western
perspective, it refers to clinical signs induced by neuroimmunological mechanisms. In
case of “algor” affecting the system, a regional lack of microcirculation may be caused by
defense reflexes to cold, by viruses (adhesion molecules, complement system,
coagulation); the counter-reaction consists of a general increase in microcirculation,
inflammation, fever and sepsis. This counter-reaction is called “reactive calor” and is a
regulated process in itself.
The fourth GC is yin/yang. It evaluates signs which, according to TCM, distinguish
between primary deregulation (yang) and secondary deregulation due to structural
deficiency (yin). If a functional tissue is deficient, it will be excessively up-regulated to
achieve appropriate function. As this augmentation of tissue function cannot be kept up,
functional deficiency follows. From the western perspective: a deficient cell population can
be vegetatively overstimulated causing vegetative clinical signs named under repletion.
Thereafter, a phase of almost functional break-down may arise with signs similar to
depletion. As such, in diseases described by yin, symptoms are due to deficiency of the
functional tissue (“body substance”, yin). Other types of yin deficiency may be due to lack
of due (lack of microcirculation within the tissue), lack of body fluids (lack of milieu-
factors), lack of jing (functional deficits like in impaired functions of the cell nucleus, or in
genetic deficits).In yang-diseases symptoms are due primarily to deregulation described
by the first three guiding-criteria.
57
Four kinds of mechanisms may cause disease according to TCM on a dogmatic level:
(1) excess of an agent; (2) transitional problems from one “evolutive phase” to the next;
(3) imbalance of antagonist phases; (4) yin deficiency.
In summary, Chinese Medicine developed as a doctrine based on clinical signs which
allow the definition of the regulatory status of the individual. Chinese Medicine can be
considered a vegetative medicine, largely based on reflexology and a rational theory of
vegetative (autonomic) nervous system activation patterns.
Acupuncture treatment of heart diseases according to the Heidelberg Model of TCM
From the Chinese Medicine perspective the agents “humor” and “algor” may be the
predominant pathogenic factors in heart failure. The vegetative patterns (orbs) more
frequently deregulated may be the cardial, pulmonary and renal. Regarding the guiding-
criteria, depletion of Qi occurs. The signs of humorovegetative origin, with disturbances of
circulation, are secondary to algor which in turn affects the intima. The algor agent
induces lack of microcirculation which leads to xue stasis as a consequence of reactive
calor. Yin deficiency predominates in this disease.
Following Prof. Porkert research in Chinese Medicine, three mechanisms may be
present in the heart failure syndrome [1] according to an individualized functional TCM
diagnosis:
a) Blockade of the circulation in the conduits of the cardial and pericardial
orbs. This causes symptoms such as palpitations, diaphoresis, irregular sleep, and
heat flushes.
b) Depletion of the renal orb leads to disorders of the pulmonary orb. In this
case, oppressed breathing, orthopnea, fatigue occurs by the slightest effort.
c) Depletion of the pulmonal orb. The ensuing insufficiency in the
“refrigeration” action of the pulmonal orb, produces symptoms of heat (calor):
constipation, low urinary output. Indirectly, depletion of the renal orb may be
induced, causing symptoms such as: edemas, ascites, bloating, palpitations,
stabbing precordial pain, shallow breathing and periodically rises in the
temperature.
According to Professor Greten‟s Heidelberg Model of TCM, the heart failure syndrome
may also be interpreted within the theory of the “harmful cold disease” disease (described
in the Shang Han Lun, 2nd AC) or algor laedens theory (ALT) as a splendor yang
syndrome (ALT stage II; figure 9) [3]. A lack of microcirculation induced by the agent algor
provokes an augmentation of the phase Wood (sympathetic overtone), as reactive calor,
58
diminishing the vagal function. As a consequence, a dysbalance of the phase Fire leads to
an ardor (inflammation) chronic state. Humour excess causes edema, dyspnea, and
fatigue, and during this process pituita (“phlegm”) is generated (atherosclerosis, metabolic
syndrome). A down-regulation counter-reaction of the Stomach function is produced
causing nausea, vertigo, blurred vision or even collapse. These crossroad abnormalities
of wood, fire, and stomach orbs leads to a dysfunction in the body island “heart” [3].
Heart Failure as a splendor yang syndrome in TCM
Figure 9. Chronic heart failure as a splendor yang syndrome in Algor Laedens theory
(ALT). Algor causes upregulation of the wood phase (sympathetic overflow as reactive
calor) inducing a dysbalance in fire phase (generating ardor) and a stomach orb counter-
regulation, which result in heart body island pathology [3].
One of the most used acupoint in the experimental studies previously reported is the
point PC6 (pericardium 6). This point is designated as clusa interna or “Neiguan”, the
“inner pass gate”. It is a principal acupoint to be stimulated for the regulation of the Qi, for
the soothing of pain and stabilization of the cardial orb. It is establishes a “communication”
between the pericardial conduit and the yin retaining sinartery (yin weimo) [121-133].
59
Several studies also tested the action of S36 (stomach 36) in heart disease. This
acupoint is also known as Zusanli or vicus tertius pedis, “third hamlet of the foot”, or the
“soldier‟s point”.[121-133].
1.4.4. General proposed mechanisms of action of acupuncture
Multiple physiologic models have been proposed to explain the effects of acupuncture.
Various models have implicated cytokines, hormones (e.g., cortisol and oxitocin),
biomechanical effects, electromagnetic effects, the immune system, and the autonomic
and somatic nervous systems.
For many proposed models, the data have been either too inconsistent or inadequate
to draw significant conclusions.
Endorphins: The most thoroughly studied application of acupuncture is for pain
relief. Studies performed in the 1970s and 1980s have contributed tremendously to
our present understanding of acupuncture's analgesic effects [134-155]. According
to this theory, acupuncture stimulation is associated with neurotransmitter effects
such as endorphin release at both the spinal and supraspinal levels [156, 157]. In
support of this theory, there is evidence that opioid antagonists block the analgesic
effects of acupuncture [158]. In contrast to this theory, however, the endorphin
effects appear to be short-term, only lasting 10 to 20 minutes and possibly up to
several days [159], while many acupuncture clinical trials have documented longer
effects [159-161]. Additionally, endorphin release can be induced by strongly
stimulating any free nerve ending or muscle afferents. The specificity of
acupuncture point location and the rationale for needling certain points in various
conditions remain unexplained. For these and other reasons, researchers have
acknowledged the limitations of the endorphin-related mechanism [162]
Functional MRI: Functional MRI (magnetic resonance imaging) studies have
demonstrated physiologic effects with acupuncture. In one study, needling Bladder
Points located on the foot (purported to treat visual disorders) was associated with
changes in MRI signals at the visual cortex [163]. Multiple other acupuncture-MRI
studies have also shown effects [164-168].
60
Connective tissue and mast-cell degranulation: Another theory is that
acupuncture points are associated with anatomic locations of loose connective
tissue. A study that looked at points and meridians in the arm concluded that such
an association was present. It is possible that such an association might relate to
the concept of "grasp" noted by practitioners. It has been proposed that
acupuncture needling elicits mast-cell degranulation [169-180].
1.4.5. Acupuncture clinical application
There have been hundreds of controlled trials of acupuncture for various conditions.
Conditions for which acupuncture has been studied and appears to have possible efficacy
(whether or not it has greater efficacy than sham acupuncture) include: chronic pain [181-
184], postoperative nausea and vomiting [185], chemotherapy induced nausea [186-188],
acute pain including dental pain [189-200], headache [201-207], hypertension [208].
Acupuncture has been studied for many other conditions including stroke [209-213],
depression [214], fibromyalgia [215, 216], and tobacco use [217, 218], but the evidence is
insufficient to recommend the use of acupuncture for these conditions.
1.4.6. Acupuncture-related adverse events
Acupuncture is generally safe, but can lead to the complications seen with any type of
needle use. These include transmission of diseases, needle fragments left in the body,
nerve damage, pneumothorax, pneumoperitoneum, organ puncture, cardiac tamponade,
and osteomyelitis [219, 220]. Local complications include bleeding, contact dermatitis,
infection, pain, and paresthesias [221].
Despite the variety of listed complications and the occasional case reports in major
journals [222-225], major adverse events are exceedingly rare and are usually associated
with poorly trained unlicensed acupuncturists [226].
A prospective study in Japan of 65,482 acupuncture treatments reported no major
adverse events [227-230].
A prospective investigation in Germany of 97,733 patients constituting 760,000
treatment sessions reported that the two most frequently reported adverse events were
needling pain (3.3%) and hematoma (3.2%) [231]. Potentially serious adverse events
included two cases of pneumothorax. An asthma attack, a vasovagal reaction, an acute
hypertensive crisis, and an exacerbation of depression were considered to be possibly
related to treatment.
Another two surveys performed in the United Kingdom totaling 66,000 treatments
reported no serious adverse events [231, 232].
61
In general, local contraindications to acupuncture include active infection at insertion
sites as well as malignancy at such sites, since there is a theoretical risk of causing
metastatic dispersal of tumor cells [233].
Electroacupuncture should generally be avoided in patients with an automatic
implantable cardioverter-defibrillator (AICD) or pacemaker [234]. Any disruption of the skin
should be avoided in patients with severe neutropenia as seen after myelosuppressive
chemotherapy [235].
Pregnancy is not an absolute contraindication, since acupuncture has been used and
studied for gestational conditions such as breech presentation and pregnancy-associated
nausea. According to acupuncture theory, however, some points can induce labor, and
the acupuncturist should be informed of the pregnancy [236-245].
Bleeding disorders and use of anticoagulants are also not absolute contraindications
[246]. Acupuncture needles are nearly always thinner than the intravenous catheters or
phlebotomy needles routinely administered in hospitals. The acupuncturist should be
notified of any bleeding risks.
In summary: acupuncture is considered very safe if rates of adverse effects are
compared to those seen in many pharmacologic treatments. Practitioners should use
sterile needles to prevent transmission of disease. In the US, acupuncture practitioners
are required to use disposable sterile needles.
1.4.7. Challenges in acupuncture research: the issue of good control, placebo
effect, and point specificity.
A consensus conference sponsored by the National Institutes of Health in 1997
suggest that more research needs to be conducted to fully understand the biological
actions and the clinical efficacy of acupuncture [89]. This conclusion was reinforced in the
executive summary of a special report stemming from a workshop in 2001 examining the
state of complementary and alternative medicine in cardiovascular, lung and blood
research [247].
There have been more than 500 randomized controlled clinical trials in acupuncture
over the last 30 years [248]. A randomized controlled trial should be hypothesis driven,
prospective, blinded (preferably double blinded), adequately powered with sufficient
numbers of subjects, well controlled and analyzed using appropriate statistical
methodology. Additionally, description of the randomization process and dropouts should
be provided. Many of these issues have not been adequately addressed in previous
clinical acupuncture research [249].
Some of the problems encountered with acupuncture randomized trials are shared by
trials in many domains: inadequate sample size, lack of follow up, imprecise outcomes,
62
improper statistical analysis, and others. Some problems, however, are particular to
acupuncture research. Issues include:
Identifying an acupuncture treatment for a biomedical defined disease can be difficult.
One disease in biomedicine can be many "patterns" within the Eastern medicine
classification schema[84]. As an example, diabetes can have Eastern medical diagnoses
of "stomach fire", "kidney fire", or "lung fire" [75].
Individualized treatments seen in acupuncture run counter to the standardized
treatments used in randomized trials. Researchers have tried to deal with this by
performing pragmatic trials (where acupuncturists are given full freedom) or trials using
semi standardized treatment (where acupuncturists are assigned mandatory points but
given additional individualized options). Whether this latter approach approximates real
acupuncture treatments is uncertain, as few studies have reported on the acupuncturists'
perceptions of whether their treatments were constrained.
Acupuncture entails many different styles and techniques. In the United States alone,
at least eight different styles of acupuncture are taught in the various accredited schools.
Differences exist on what points are to be needled, how the needle should be
manipulated, how long the needle should be kept in, and what is the appropriate response
elicited from the patient. Thus it is difficult to know whether the results of a trial of single
type of acupuncture can be generalized to other types. [250-255]
Due to the heterogeneity of acupuncture, an optimal control for one style may not be
ideal for another.
It is difficult to perform a double-blind acupuncture study. Acupuncturists are typically
able to distinguish real treatment from sham treatment.
Delivering acupuncture is not as simple as administering pills, and much like
psychotherapy and surgery, experience may play a critical role in determining outcome.
Although acupuncture may provoke beneficial effects in the cardiovascular system,
several aspects need to be addressed regarding clinical trials with acupuncture [256, 257].
First, it is difficult to blind subjects and almost impossible to blind the therapist. If patients
have any previous experience with acupuncture, they will already expect a sensation of de
qi. It has been shown that acupuncture is likely to be most beneficial in patients who have
high expectations of benefit [258]. Additionally, it is not possible to avoid the interaction
between the therapist and the patient, and this is the basis of many placebo responses
(the Rosenthal Effect) [259]. One possible solution is to select subjects that are
acupuncture-naive, and to confirm that there is a feeling associated with the needling (de
qi), Also, individuals performing data analysis should be blinded to the intervention.
63
Criticism of prior acupuncture studies include a lack of objective endpoints and
inadequate or absent controls [260]. In studies addressing acupuncture in human
subjects, different types of experimental controls have been described in the literature:
False acupuncture (sham) in which the needle guide-tube is applied without the needle,
simulating the touch of the needle on the skin [261]; inserting a guide-tube with a toothpick
inside; using a needle that recoils without touching the skin (placebo needle of
Streitberger) [262, 263].
Needling points on the skin not considered to be acupuncture points, also called “non-
acupoints” or “dummy points” [261, 264, 265]. However, non-acupoint acupuncture has
been shown to have analgesic effects in up to 50% of study patients ([266]
Superficial needling [267].
Needling of non-acupuncture points with minimal stimulation, an “invasive sham”
acupuncture procedure ([268]. However, both minimal acupuncture and the placebo
acupuncture with the sham acupuncture needle touching the skin evoke activity in
cutaneous afferent nerves. This afferent nerve activity has pronounced effects on the
functional connectivity in the brain resulting in a 'limbic touch response'. Clinical studies
showed that both acupuncture and minimal acupuncture procedures induced significant
alleviation of migraine and that both procedures were equally effective. In other conditions
such as low back pain and knee osteoarthritis, acupuncture was found to be more potent
than minimal acupuncture and conventional non-acupuncture treatment. It is probable that
the responses to 'true' acupuncture and minimal acupuncture are dependent on the
etiology of the pain. Furthermore, patients and healthy individuals may have different
responses. As such, some authors argue that minimal acupuncture is not valid as an inert
placebo-control despite its conceptual brilliance[269].
Needling in the same “meridian” of the experimental acupoint or in other acupoints on
the same meridian of the experimental point which is considered to be “inactive” to the
aimed effect. [270].
Laser acupuncture, in which the control refers to turning off the laser. [271, 272].
Control without any treatment or placebo tablet [265].
Needling without manual or electrical stimulation [132].
Recently, experimental studies have shown that insertion of a needle without
manipulation or electrical stimulation does not activate afferent pathways and hence does
not provide information to the central nervous system [132]. In the absence of any
information transmitted to the CNS, any response would have to a placebo effect.
64
Mayer (2000) reviewed a number of acupuncture studies in treatment of pain and
nausea and vomiting and made a convincing argument that the strongest control is to
perform acupuncture along a meridian at an inactive acupoint or in the same segment
outside a meridian, but that simply tapping the skin with a needle to stimulate acupuncture
constitutes a weak control [273]. However this consideration brings up the concept of
point specificity. which states that separate physiological and clinical responses result
from stimulation of different acupoints, with some acupoints causing a profound response
and others causing a small or no response at all [274].
Clearly, acupuncture‟s success derives, in part, from a practitioner‟s ability to stimulate
the best single or best combination of acupoints for a particular condition. For example, it
has been shown that there is a hierarchy of acupoints that influence cardiovascular
function [275]. Thus, it seems very possible that the most active and inactive acupoints for
a specific clinical conditions, such as heart failure, can be identified for intervention and
control stimulation.
It is questionable the adequacy of stimulation outside a meridian as control since a
large bundle of afferent fibers would not be stimulated sufficiently to cause the sensation
of de qi, thus allowing the patient and certainly the acupuncturist to discern differences
between active and control stimulation. Using a tablet placebo and comparing
acupuncture to usual therapy without any surrogate form of acupuncture stimulation are
still weaker and really are unacceptable controls. It is important to control for placebo
responses since acupuncture, like most medical therapies, can be associated with clinical
responses simply by virtue of a nonspecific interaction between the therapist and the
patient [124, 273].
Studies of point specificity indicate that inactive acupoints along meridians can be
readily identified as control points in studies of acupuncture‟s influence on the
cardiovascular system [121, 132, 274, 276].This type of control has a particular advantage
in humans because major neural pathways are stimulated to induce a feeling of de qi,
which makes it difficult for patients and potentially even the acupuncturist to distinguish
between active acupuncture stimulation and the control acupoint. Hence there is a
possibility of double blinding, if the patient and the acupuncturist are not informed about
the clinical endpoint. In a recent study of the effects of manual acupuncture and
electroacupuncture[277], it was observed that insertion of a needle in active acupoints
(Jianshi-Neiguan, P5-6), without any subsequent mechanical or electrical stimulation,
caused only brief afferent fiber excitation and, as such, did not stimulate median nerve
afferent fibers for a sufficiently long period to inhibit the cardiovascular excitatory response
to gastric distension. Thus, simple insertion of a needle at an active acupuncture point
may be one of the best controls to use in acupuncture studies. This in turn brings into
65
question the practice of some acupuncturists of needle insertion without stimulation, as a
presumed active intervention that causes an acupuncture response beyond placebo. Data
suggest that stimulation of an inactive acupoint along a known meridian or needle
insertion without any form of mechanical or electrical stimulation constitute the best
controls to compare with active acupuncture stimulation.
1.4.8. Acupuncture and the autonomous nervous system – current evidence and
rationale for acupuncture research in heart failure
The mechanism by which acupuncture is believed to benefit the subject with heart
failure is through its ability to modulate neural activity in several regions of the brain and
thus reduce sympathetic outflow to the heart and vascular system [124, 278].
A consensus document on Complementary and Integrative Medicine published by the
Foundation of the American College of Cardiology concluded that acupuncture may be
indicated in four areas of cardiovascular disease: ischemic cardiovascular disease,
hypertension, heart failure, and arrhythmias (figure 10) [279].
According to the World Health Organization, acupuncture is effective in more than 40
medical conditions including cardiac pain and hypertensio [89].
Figure 10. Acupuncture may be indicated
in four areas of cardiovascular Disease
according to the American College of
Cardiology.
The rationale for using acupuncture to treat myocardial ischemia, hypertension, and
arrhythmias and heart failure stems from its ability to inhibit sympathetic outflow (figure
11) [280].
Figure 11.
Proposed mechanism for
acupuncture‟s modulation of
sympathetic neural activity in
heart failure [281].
66
Brain functions are regulated by chemical messengers that include neurotransmitters
and neuropeptides (e.g. opioid peptides in pain control and neuropeptide in appetite
modulation, among others).
Severe painful stimulus induces the release of opioid peptides to ease pain and
sucking of the nipples promotes milk secretion. Oxytocinergic neurons fire at a very low
rate (0.1 – 2.6 Hz) in basal condition, but prolonged sucking by ten or more pups can
bring the firing rate up to 16-50 Hz, followed by strong milk ejection within 10-12 seconds
[3]. This findings suggests that neuropeptide release could be modulated by external
stimulation. In addition, intracranial or intra-spinal electrical stimulation has been used to
provide relief of chronic pain with success rates of 50-80% after one year of treatment.
This pain-relief effect could involve the release of neuropeptides raising the attractive
possibility that non-invasive methods might be used to modulate neuropeptide release for
therapeutic intervention.
Peripheral stimulation can be provided via electrodes placed on the skin
(transcutaneous electrical nerve stimulation, TENS) or via a probe inserted through skin
into tissue (percutaneous electrical nerve stimulation, PENS). If the point of stimulation is
selected according to traditional acupuncture therapy, the process is then called
electroacupuncture (EA). One study compared the analgesic potency and the underlying
neurobiological mechanisms of EA and TENS, with the acupuncture needles or the skin
electrodes placed at the same “acupoints”, and conclude that they operate through very
similar, if not identical, mechanisms.
To facilitate the release of opioid peptides in the CNS, either manual acupuncture or
EA [17] stimulation can be used, although EA may have more potent effects.
One fundamental experiment has shown that analgesia induced by low-frequency (4
Hz) stimulation, but not that induced by high-frequency (200 Hz) stimulation, can be
reversed by low doses of the opioid antagonist naloxone. This suggests that low-
frequency stimulation can increase the release of opioid peptides in the CNS. Further
experiments manipulating naloxone dosage or using opioid receptor subtype-specific
antagonists verified that either low or high-frequency stimulation are both mediated by
opioid peptides. It was shown that the former was mediate by and /or opioid receptors,
whereas the latter was mediated by opioid receptor. These results indicate that different
kinds of opioid peptides are released under these different conditions.
Several studies in vitro and in humans using antibody against different neuropeptides
supported the proposition that either high or low-frequency stimulation activates specific
neuropeptide release for either experimental or therapeutic purposes [282-286] (table 2).
67
Table 2. Frequency-dependent release of CNS opioid peptides by peripheral electrical
stimulation.
Frequency of electrical
stimulation Opioid receptors Opioid peptides
Low-frequency (4 Hz) , Endomorphin,
Enkephalins,
-Endorphin
High-frequency (200Hz) Dynorphin
Numerous experimental studies have shown that acupuncture, particularly low
frequency (2 to 4 Hz) electroacupuncture, causes the release of opioids in a number of
regions in the hypothalamus, midbrain, and medulla that are concerned with processing
information that ultimately influences sympathetic neural activity [282-286]. Thus, by
releasing endorphins, endomorphins, or enkephalins, which act as neuromodulators that
likely reduce function of excitatory neurotransmitters, acupuncture appears to be able to
inhibit sympathetic outflow and clinical events associated with heightened sympathetic
activity [122, 143]. Other neurotransmitters that might be associated with the influence of
acupuncture on sympathetic neural activity important in cardiovascular regulation include
gamma-aminobutyric acid (GABA), serotonin or 5-hydroxydopamine (5-HT), acetylcholine,
and nociceptin (also known as orphanin FQ) [143, 287].
High-frequency electroacupuncture (100 Hz) may influence the cardiovascular system
through another opioid neurotransmitter/neuromodulator called dynorphin, which has been
proved to have a potent analgesic effect [143, 288].
Afferent impulses induced by acupuncture have been characterized to be mainly
transmitted by A and A fibers. Wang and colleagues have conducted a series of
experiments to analyze the possible neural pathways responsible for the frequency-
specific release of different opioids peptides in rat CNS. Lesion of the arcuate nuclei of the
hypothalamus abolished analgesia induced by low-frequency EA but not that induced by
high-frequency EA, whereas selective lesion of the parabrachial nuclei of the brainstem
attenuated the effects of high-frequency EA but not those of low-frequency EA. The
periaqueductal grey matter is a common element for both the descending pain inhibitory
systems. These findings have been partially supported by subsequent morphological
68
studies using fos gene expression as marker of brain activation in the rat, and functional
magnetic resonance imaging (fMRI) study in human volunteers.
Experimental studies have shown that low current, low-frequency electroacupuncture
(EA) employed over deep nerves, such as the acupoints PC5–6 (“pericardial meridian”)
overlying the median nerve, effectively inhibits cardiovascular sympathoexcitatory reflexes
and the rostral ventrolateral medulla (rVLM) presympathetic neuronal responses.
Conversely, electrical stimulation of acupoints in regions that do not overlie major somatic
pathway or simple insertion of a needle without manual or electrical stimulation evokes
little or no acupuncture- cardiovascular response [132].
Since the 1980s Li et al. demonstrated that cardiovascular neurons in the rostral
ventrolateral medulla (rVLM), an important cardiovascular center, receive inputs from
hypothalamic and midbrain defense areas, the splachnic nerves, and Neiguan and Zusanli
acupoints. It was shown that EA applied to these acupoints for 20-30min inhibits the
excitatory effects of the former three inputs to the rVLM. Inhibition of these neurons was
shown to last 1-2h, and is related to activation of opioid receptors. It was found that low-
frequency and low-current (1-3mA, 2-5Hz) at Zusanli and Neiguan acupoints activates the
nucleus arcuatus in the hypothalamus, which send excitatory projection to the ventral
periaqueductal gray (vPAG) and, in turn, to the nucleus raphe obscurus (NRO). Excitation
of NRO neurons inhibits cardiovascular neurons in the rVLM by activating opioid, GABA,
and 5-HT receptors to reduce sympathetic outflow, which ultimately exerts a therapeutic
effect on hypertension, arrhythmias, cardiac ischemia, and in the heart failure syndrome.
Conversely, EA with high current stimulation activates the cholinergic system and excites
rVLM neurons, leading to an increase in blood pressure, to alleviate shock and
bradycardia [289].
Others have confirmed that somatic afferent stimulation during EA activates neurons in
the ARC and ventrolateral periaqueductal gray (vlPAG) and inhibits activity in the rVLM.
Longhurst and colleagues, using a feline model of gallbladder stimulation with bradykinin
(table 3), evaluated the cardiovascular response during low-frequency (2-4 Hz), low-
intensity (4 mA, 0.5 ms) stimulation of acupoints located at Neiguan-Jianshi (P5 – P6)
along the pericardial meridian over the median nerve, Shousanli-Quchi (LI 10-LI11) on the
large intestine meridian over the deep radial nerve, Hegu-Lique (LI 4 – L7) on the large
intestine and ling meridians over branches of the median and superficial radial nerves,
Zusanli-Shangjiuxu (ST 36- ST 37) along the stomach meridian over the deep peroneal
nerve, Pianli-Wenlui (LI 6 – LI 7) on the large intestine meridian over the superficial radial
nerve, and Yougquan-Zhiyin (K 1- Bl 67) along the kidney and bladder meridians over
terminal branches of the tibial nerve [127]. The influence of stimulating each individual set
of acupoints on the reflex cardiovascular response was evaluated as also the responses
69
from a group of rVLM cardiovascular neurons was measured using micropipettes for
extracellular recordings during stimulation of each set of points. It was found that
stimulation at Neiguan-Jianshi or Shousanli-Quchi each caused similar large reductions in
the reflex blood pressure responses, averaging 40% that lasted for 70 and 60 minutes,
respectively. Hegu-Lique and Zusanli-Shangjiuxu led to more modest decreases,
averaging 20-30%, and lasting for ~30 minutes. Pianli-Wenlui and Yougquand-Zhiyin did
not influence the gallbladder-blood pressure reflex. Concordant changes in the rVLM
neuronal evoked response were observed during short-term stimulation of each of these
sets of acupoints. Prolonged stimulation for 30 minutes during EA reduced activity of
these rVLM neurons in a graded fashion that paralleled the point-specificity effects of EA
on the blood pressure responses. Administration of the nonspecific opioid antagonist
naloxone near the rostra ventral lateral medulla (rVLM) reversed the acupuncture
response immediately after termination of the 30-minute period of stimulation, indicating
that the acupuncture-cardiovascular response is mediated through the opioid system and
that the rVLM serves as one important site for central integration of the acupuncture-
cardiovascular response [290-292].
Thus, point specificity exists in EA with some acupoints exerting a strong
cardiovascular influence, others a more moderate effect, and still others causing no
response. The rVLM, a source of bulbospinal sympathetic premotor fibers, an important
area that receives input from many cardiovascular afferent systems, including
baroreceptors and chemoreceptors, and that regulates sympathetic outflow, was identified
as a brain stem nucleus that processes input from somatic sensory nerves activated
during acupuncture. During short-term stimulation of acupoints, neuronal activity in the
rVLM increases but following prolonged somatic afferent stimulation, as occurs during the
clinical application of acupuncture, neuronal activity in the rVLM is suppressed, most likely
through a mechanism that relies, in part, on the production of opioid neurotransmitter
modulators [127].
Table 3. Effect of gallbladder bradykinin-induced blood pressure reflex response [127].
Acupoints Meridian Innervation Results
Pc 5-Pc 6
LI 10- LI 11i
Pericardiac
Large Intestine
Median n.
Deep radial n.
40% reduction
60-70 minutes
LI 4-L 7
S36-S37
Large intestine
Lung
Stomach
Median n.
Superficial radial n.
Deep peroneal n
20-30% reduction
30 minutes
LI6-LI7
K1-Bl 67
Large intestine
Kidney and bladder
Superficial radial n.
Tibial n.
No influence
70
Figure 12. Experimental evaluation of peripheral and central neural mechanisms of action of
acupuncture on the cardiovascular system of anesthetized cats. Low-frequency (2-4 Hz) electro-
acupuncture of Neiguan (P5) and Zusanli (S35) during 30 minutes lowered blood pressure
bradykinin-induced reflex by 40-50% beginning 10-15 minutes after initial application for a period
that exceeded 1 hour after termination of acupuncture stimulation. Acupuncture sensory signals are
transmitted in the median (MN) and deep peroneal (DP) nerves. Inputs are centrally processed in
the rostral ventral lateral medulla (rVLM), hypothalamic arcuate nucleus (ARC) near the optic
chiasm (OC) and mammilary bodies (MM) and the midbrain ventral lateral periaqueductal gray
(vlPAG). The brain stem rVLM is an important site for signal processing and acupuncture influence,
since it provides premotor bulbospinal projection to the intermedio lateral (IML) spinal cord , where
preganglionic sympathetic neurons exit to innervate the heart and blood vessels. During
acupuncture, modulatory neurotransmitters, including opioid peptides like endorphins and
enkephalins and non-opioid peptides likes nociceptin, released through a long-loop pathway that
involves the ARC and the vlPAG inhibit activity in premotor sympathetic neurons in the rVLM to
ultimately reduce sympathetic outflow and elevated blood pressure [293].
Tjen-A-Looi and colleagues have shown data from a feline model in favor of acupoint
specificity. EA at LI6-7 and K1-B67 acupoints as well as direct stimulation of the
superficial radial nerve did not cause any cardiovascular or rVLM neuronal effects.
Cardiovascular neurons in the rVLM (a subset of which are classified as premotor
sympathetic cells), responded to stimulation of the splanchnic nerve as well as the
acupoints PC5-PC6, LI 10-11, L14-7,S36-37, K1-B6 [276].
71
In another study, using a feline model, Li et al., found that low-frequency
electroacupuncture (5Hz) stimulated type III and IV sensorial fibers, and myocardial
ischemia induced by reflex activation of the cardiovascular system was improved after 30
min of EA. It was also shown that the administration of naloxone intravenously or directly
into the rVLM inhibit the anti-ischemic effect of EA [123].
The rVLM may thus mediate the sympatholytic effects of acupuncture in heart failure
[294, 295].
In summary, this data indicates that there are clear point specific cardiovascular
responses during and after EA stimulation. Current data also strongly suggest the
existence of an ARC-vIPAG-rVLM neuronal pathway that serves as part of a long-loop
pathway participating in EA inhibition of excitatory cardiovascular reflexes (figure 13) [123,
130].
Figure 13. Neural pathway of EA
effect on cardiovascular neurons
in rVLM.
dPAG: dorsal periaqueductal gray
substance; vPAG: ventral
periaqueductal gray substance;
rVLM: rostral ventrolateral medulla;
ARC: nucleus arcuatus;
NRO: nucleus raphe obscurus;
DPN: deep peroneal nerve;
MN: median nerve;
SPN: superficial radial nerve; IML:
intermedio lateral. Ach:
acetylcholine [123, 130].
1.4.9. Acupuncture’s stimulation modality: manual versus electroacupuncture.
Acupuncture can be stimulated either manually by simply inserting a needle in an
acupuncture point, then either leaving it in place or twisting and thrusting the needle, until
a sensation of dullness, warmth, fullness, tingling or aching in the tissue is achieved (the
de qi feeling). The acupuncturist may sense the needle being grasped or tugged (“like a
fish biting the hook”) [1].
72
Electroacupuncture consists of stimulating the needles with a small amount of electrical
current at low frequency (2 to 4 Hz) or high frequencies (100-200Hz) [296, 297].
Acupuncture points can also be stimulated by heat, pressure, laser light [298] and
shockwaves [299]. While manual acupuncture (MA) has been practiced for almost 3000
years, electroacupuncture (EA) has been introduced more recently and it appears to be
the strongest form of acupuncture [158], inducing a long clinical response in rats lasting
from 1 to 12 h [280] according to animal experiments. These responses have led to
treatment regimens of 30 to 45 min of acupuncture administered two to three times per
week for 2 to 4 weeks. In experimental protocols, EA has the advantage over manual
acupuncture since it is measurable and reproducible, and it allows a continuous and
stable stimulation for any period of time [158, 300].
Many practitioners use manual acupuncture at several acupoints including acupoints
within the same spinal segment, called “segmental acupuncture,” or a combination of
segmental and distant acupoints (i.e., auricular acupuncture). In the treatment of pain,
there are numerous variations of these techniques, including inserting needles at
myofascial trigger points and at the specific site of pain [301]. Few data exists on the
efficacy of different techniques of acupuncture with respect to cardiovascular treatment.
Longhurst and colleagues conducted a study comparing MA and EA. Manual and
electroacupuncture were matched using low-frequency stimulation (~2 Hz) applied for 120
seconds every 10 minutes over a 30-minute period and it was found virtually identical
effects on the cardiovascular reflex response to gastric distension in rats. The only
difference in response was a slightly more prolonged effect of EA as compared to MA,
lasting for 30 and 20 minutes, respectively, after termination of stimulation. Both forms of
stimulation caused nearly identical responses of afferent single units recorded in the
median nerve. It is not surprising, therefore, that the inhibitory influence of MA and EA on
the gastric distension blood pressure reflex was nearly identical [132].
Scientific reports have suggested that both low- (2-6 Hz) and high- (100 Hz) frequency
EA or transcutaneous electrical stimulation can modulate sympathetic vasomotor changes
and pain [302, 303]. A recent study found that low-frequency EA (2 Hz) caused large
reduction in the reflex cardiovascular response to gastric distension, while higher
frequency (50 and 100 Hz) did not alter the gastric reflex [132]. In concert with a previous
experiment using a feline-model[293], the effectiveness of low-frequency EA was
demonstrated to rely on sensory neural responses, since it was observed only a modest
response at 10 Hz and no afferent response at 20Hz. Thus, high frequencies of
acupuncture appear to block the ability of somatic afferents to conduct information to the
CNS. This was confirmed in a very recent study[133] in which sympathoexcitatory
sympathetic premotor neurons in the rVLM were found to respond similarly to MA and EA,
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specifically low-frequency and not high-frequency EA. This study raised considerable
question about the ability of high-frequency EA to provide afferent input to the CNS to
regulate sympathetic outflow. Differences between this study and previous studies of pain
from other laboratories may be that high frequency EA may provide sufficient input to the
spinal cord to allow sufficient segmental influence of afferent neural transmission to
influence spinal centers involved in pain modulation. Alternatively, high-frequency
acupuncture may modulate cellular activity in higher neural centers more concerned with
processing pain as compared to the cardiovascular centers (rVLM). A final difference may
be related to the species involved in these studies. Perhaps afferent systems in rats, in
contrast to cats, respond differently to higher levels of stimulation. However, afferent
nerves in mammalian species respond similarly to electrical stimulation suggesting that a
species difference is unlikely. The absence of significant response of the somatic nerves
to frequencies of 20 Hz suggests that the clinical or physiological responses to high-
frequency stimulation (>20 Hz) could be a placebo effect. The response to high-frequency
TENS cannot be directly compared with acupuncture, since the neural response to
external stimulation may be quite different than the response to a needle placed in or
immediately adjacent to a neural pathway. TENS uses much higher currents and likely
involves stimulation of much larger areas than that occurring during EA, which involves
stimulation of a single major somatic neural pathway. As such, it is quite possible that
afferent information during TENS may be very different from needle acupuncture. In
summary, in contrast to low-frequency acupuncture, high-frequency EA is not an effective
inhibitory cardiovascular stimulus. Although the literature suggests that high-frequency EA
or TENS may regulate pain, it is uncertain if there is sufficient input to the CNS to evoke
responses over and above placebo. It is also difficult to extrapolate from studies utilizing
TENS since this form of stimulation likely is quite different than EA:
1.5.11. Acupuncture and stable angina
Studies from several groups, including Ballegaard [304] and Richter [305], have
examined the role of acupuncture in treatment of patients with stable angina. Ballegaard,
in an initial study, was unable to document a decrease in angina in humans as measured
by a decrease in the rate of anginal attacks, consumption of nitroglycerin or exercise
tolerance, comparing true acupuncture to sham acupuncture [304, 306]. The group
concluded that true acupuncture cannot be distinguished from sham acupuncture in which
needles were placed outside traditional meridians. Two other studies by the same group
showed an acupuncture-related improvement in exercise capacity and rate-pressure
product [307], particularly when acupuncture reduces sympathetic neural outflow [306].
74
Separately, Richter [305] observed that acupuncture exerted a beneficial effect in
patients with severe stable angina who had been aggressively treated with medical
therapy. Manual acupuncture reduced the number of anginal attacks per week, the
severity of chest pain, electrocardiographic evidence of myocardial ischemia, and
increased the workload required to provoke angina in patients with CAD and stable angina
[305]. The latter study used a tablet placebo control. These studies involved small
numbers of patients, were unblinded, and did not use the most appropriate sham controls.
1.5.12. Acupuncture and peripheral blood flow
Prolonged peripheral vasodilatation, measured by peripheral thermography, occurs
following electroacupuncture [305]. Acupuncture or its non-invasive surrogate,
transcutaneous electrical nerve stimulation (TENS), appears to influence peripheral blood
flow in patients with Raynaud‟s syndrome [308], skin flap survival in experimental
preparations ([309, 310], and skin temperature in patients with polyneuropathy [311]. The
primary form of Raynaud‟s cold-induced vasoconstriction, assessed by Doppler flowmetry
and clinical symptoms, is reduced by acupuncture compared to sham treatment [308].
Secondary forms of Raynaud‟s appear to be less influenced by acupuncture. Survival of
ischemic musculocutaneous skin flaps is increased in experimental preparations treated
with either manual or electroacupuncture [309]. Similarly, patients undergoing
reconstructive surgery who are treated with TENS experience improved microvascular
flow and reduced edema and capillary stasis relative to placebo TENS [312]. Low-
frequency TENS leads to a prolonged increase in skin temperature in patients with
diabetic polyneuropathy [311]. Most studies on the peripheral circulatory effects of
acupuncture are small and were not blinded; confirmation of their observations is needed.
1.5.13. Acupuncture and hypertension
A review of the literature reveals multiple published reports of the effectiveness of
acupuncture on blood pressure and other hemodynamic parameters in humans [280, 313-
329]. Several small trials suggest that hypertension may be improved by acupuncture
[316, 328-331]. The magnitude of the effect of acupuncture on blood pressure in patients
with hypertension is small but significant; reductions of 5 to 10 mm Hg have been noted.
There is a suggestion that one to four courses of 10 days‟ treatment with acupuncture
lowers blood pressure (5 to 25 mm Hg) in some (e.g., borderline and essential
hypertension) but not in all types of hypertension [293, 296, 328, 330].
75
Kim et al. tested the hypothesis that acupuncture on acupoint stomach 36 point (S36)
reduces hypertension by activating nitric oxide synthase signaling mechanisms. Using a
two-kidney, one-clip renal hypertension (2K1C) hamster model, submitted to thirty-minute
daily electroacupuncture treatment for 5 days, it was observed a reduction in mean arterial
pressure from 160.0 ± 7.6 to 128.0 ± 4.3 mmHg (mean ± SEM), compared to 115.0 ± 7.2
mmHg in sham-operated hamsters. Activation of eNOS (endothelial nitric oxide synthase)
and nNOS (neuronal nitric oxide synthase) is one of the mechanisms through which ST-
36 electroacupuncture reduces blood pressure.
Electroacupuncture in acupoint Neiguan (PC6) in anesthetized open-chest dogs
provided a stable cardiovascular function under normotension and an anti-shock effect on
hemorrhage-induced hypotension [332].
Experiments were also performed on conscious dogs. EA applied to Zusanli (S36)
acupoint with a current of 2–4 V, 1–100 Hz had no significant effect in normotensive dogs
(132F13 mm Hg). However, noradrenaline infused intravenously (iv) at a constant rate
raised systolic blood pressure to 178/20 mm Hg within a few minutes, a level that could be
maintained for more than 1 h. EA applied to Zusanli or Neiguan acupoints for 20–30 min
decreased blood pressure (BP) by 20–30 mm Hg, a statistically significant effect
compared to the basal BP before EA or control group (P < 0.01). BP was maintained at
low level during EA and returned slowly to the pre-EA high level 30–40 min after EA was
terminated. This inhibitory effect of EA was not found in anesthetized dogs. Further
analysis showed that the depressor effect of EA is mainly caused by vasodilatation of
mesenteric vessels and due to inhibition of sympathetic vasoconstrictor tone. Experiments
also showed that the depressor effect of EA in this kind of hypertension was due to the
inhibition of arterial chemoreceptor pressor reflexes, but not to the activation of the
baroreceptor reflexes. The central inhibition of EA was related to the activation of opiate
receptors in the periaqueduct gray (PAG), hypothalamic supramammillary area and the
dorsal hippocampus.
Yao et al. [280] used awake adult spontaneous hypertension rats (SHRs) and their
normotensive controls, Wistar–Kyoto rats (WKY), to study the influence of acupuncture on
BP. Baseline BP and heart rate (HR) of the SHRs averaged 160 mm Hg and 400
beats/min, respectively. After stimulation of the sciatic nerve with low frequency and low
current for 30 min to mimic EA, BP was decreased 20 mm Hg below the pre-stimulation
level, and did not fully recover to its high pre-stimulation level until 12 h after the
termination of sciatic nerve stimulation. The HR and splanchnic sympathetic discharge
outflow decreased in parallel with BP. WKY rats revealed no significant response of BP
and HR following sciatic nerve stimulation. The long-lasting post-stimulation depressor
response was unchanged by sino-aortic nerve transection. They reported the use of a
76
current for the stimulation of the sciatic nerve to elicit a depressor effect that was above
the threshold for activating group III fibers. Further study showed that endorphins and
serotonin were involved in the post-stimulation depressor response.
In stress-induced hypertension in rats, stimulation of the deep peroneal nerve (DPN)
underneath the Zusanli acupoint with a low current and low frequency for 10 min reduced
BP markedly with a nadir occurring 1 h later. Microinjection of naloxone into the rostral
ventrolateral medulla (rVLM) blocked this depressor effect, suggesting that this depressor
effect is related to the activation of opiate receptors in this region of the medulla.[333]
In a well-designed double-blinded, randomized, controlled trial a significant long-term
antihypertensive effect of acupuncture was reported. Yin et al report BP declines of
14.8/6.9 mmHg in their active acupuncture group (n=15) versus 4.0/1.1 mm Hg in the
sham group (n=15; p=0.05) after 8 weeks of twice-weekly treatments[334].
The SHARP3 pilot study, although not designed to detect small effect, is the most
recent and largest study on acupuncture for hypertension [335]. The authors concluded
that categorizing participants by age, race, gender, baseline BP, history of
antihypertensive use, obesity, or primary traditional Chinese medicine diagnosis did not
reveal any subgroups for which the benefits of active acupuncture differed significantly
from sham acupuncture. Furthermore, active acupuncture provided no greater benefit
.than invasive sham acupuncture in reducing systolic or diastolic BP.
Possible mechanisms by which acupuncture reduces blood pressure in hypertensive
patients include decreases in the plasma renin, aldosterone and angiotensin II activity
([314-316, 318, 336], increased excretion of sodium [337], and changes in plasma
norepinephrine, serotonin and endorphin levels ([317, 338]). Enkephalins and -endorphin
mediate acupuncture‟s effects to attenuate bradykinin-induced experimental hypertension
in laboratory cats [122, 286]. Some of these mechanisms are the same as ones targeted
by pharmacological antihypertensive agents (e.g. ACEi). Chiu et al found lower
angiotensin I levels in hypertensive patients who received acupuncture, compared with a
control group of hypertensive patients who did not receive acupuncture [316].
3 Stop Hypertension with Acupuncture Research Program
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1.5.14. Acupuncture and myocardial ischemia
Experimental studies indicate that acupuncture reduces demand-induced myocardial
ischemia in felines ([293]), catecholamine- or stress-induced hypertension [296, 297, 333,
339], or genetically associated hypertension ([280]). These studies also demonstrate that
acupuncture limits myocardial ischemia by reducing myocardial oxygen demand rather
than by increasing coronary blood flow in a feline model ([293]).
The solitary tract nucleus integrates all the visceral sensorial information and
modulates the sympathetic outflow. Laboratorial studies have demonstrated convergence
of the STN activation during stimulation of the Neiguan acupoint during myocardial
ischemia. This data have shown that stimulation of this acupoint modulates a
cardiovascular reflex protecting the heart from ischemia and thus may be studied in other
disturbances, such as heart failure [340-344].
1.5.15. Acupuncture and arrhythmias
Acupuncture also can inhibit ventricular extra systoles induced by stimulating the
hypothalamus ([345]), paraventricular nucleus ([345]) or following administration of BaCl2
([297].
In urethane–chloralose anaesthetized rabbits, ventricular extra systoles were induced
by stimulation of the hypothalamus (in the vicinity of the fornix, dorsomedial or
ventromedial nucleus). The number of extra systoles was constant over a period of more
than 1 h, if stimulation to this region was applied for 5 s every 5 min. EA applied to Zusanli
or Neiguan acupoint inhibited these extra systoles. Direct low current and low frequency
stimulation of the DPN or median nerve (MN) underneath Zusanli and Neiguan acupoints,
respectively, resulted in a similar response, while stimulation of the superficial peroneal
nerve (SPN) or superficial radial nerve (SRN) exerted excitatory responses [297, 346].
Transection of the vagus and buffer nerves bilaterally did not block the inhibitory effect of
somatic nerve stimulation. Further experiments showed that the inhibitory effect of DPN or
MN stimulation is mediated by inhibition of the cardiac sympathetic center, the rVLM. The
rVLM is an essential link in the efferent sympathetic pathway with respect to the inhibitory
effect of DPN stimulation on extra systoles, through activation of opiate, GABA and 5-HT
receptors in this region. Conversely, the excitatory effect of SPN stimulation appears to be
related to the activation of cholinergic receptors in the rVLM [297, 346].
In urethane–chloralose anesthetised rabbits, vagally evoked bradycardia was induced
by stimulation of the aortic nerve or nucleus tractus solitari (NTS). Electrical stimulation
with low current and low frequency (0.1–0.3 mA, 5 Hz) of the SPN or SRN for 10–15 min
to mimic EA produced partial blockage of the evoked bradycardia, which lasted up to 35
78
min after the termination of somatic nerve stimulation. Stimulation of the DPN or MN with
high current (0.6–0.8 mA), but not with low current, also inhibited the evoked bradycardia.
It was hypothesized that this blocking effect was related to the activation of group IV
fibers. Experiments also demonstrated that activation of endogenous cholinergic receptors
in the rVLM contributes to the inhibitory effect of somatic afferent stimulation on the vagal
evoked bradycardia. Activation of rVLM neurons, in turn, suppresses postsynaptically both
baroreceptor sensitive neurons within the dorsal vagal nucleus and nucleus ambigus.
GABAergic and opiate mechanisms in the NTS, dorsal vagal nucleus and nucleus
ambigus were shown to play important roles in the mediation of baroreflex inhibition. [297,
347, 348].
To evaluate the effect of acupuncture in the ANS various research tools have been
applied, such as: skin temperature [349], thermography, [302, 350]; pletismography [351];
peripheral nerves micrography [261, 281, 339, 352, 353], sympathetic electric response
[354], blood pressure [349] or heart rate variability [264, 265].
1.5.16. Acupuncture in heart failure – overview of current research
Heart failure is characterized by neurohumoral activation, as previously mentioned,
including activation of the sympathetic nervous system. Patients with the greatest
sympathetic activation have the poorest survival [355].
In humans with heart failure, an increase in resting muscle sympathetic nerve activity is
the rule. Sympathetic nerve activation present at rest may render heart failure patients
more susceptible to the sympathomodulatory effect of acupuncture.
Interestingly, novel approaches evaluate the clinical benefit of selective electric vagal
nerve stimulation to normalize autonomic balance [356].
Experimentally, it was demonstrated that vagal stimulation (VS) is protective in chronic
heart failure (HF) [356, 357]. In man, VS has been used in refractory epilepsy but only
recently experiments were performed in cardiovascular diseases. This study used
CardioFit (BioControl Medical), a VS implantable system delivering pulses synchronous
with heart beats through a multiple contact bipolar cuff electrode, in 8 patients (mean age
54 years). There was a significant improvement in NYHA class, Minnesota quality of life
(from 52+/-14 to 31+/-18, p < 0.001), left ventricular end-systolic volume (from 208+/-71 to
190+/-83 ml, p = 0.03), and a favorable trend toward reduction in end-diastolic volume.
Cardiac contractility modulation (CCM) by means of nonexcitatory electrical currents
delivered during the action potential plateau has been shown to acutely enhance systolic
function in humans with HF [358-365].
79
Pappone et al. [366] conducted a multicenter study to assess the chronic safety and
preliminary efficacy of an implantable device delivering this novel form of electrical
therapy. Thirteen patients with drug-resistant HF (New York Heart Association [NYHA]
class III) were consecutively implanted with a device (OPTIMIZER II) delivering CCM
biphasic square-wave pulses (20 ms, 5.8-7.7 V, 30 ms after detection of local activation)
through two right ventricular leads screwed into the right aspect of the interventricular
septum. CCM signals were delivered 3 hours daily over 8 weeks (3-hour phase) and 7
hours daily over the next 24 weeks (7-hour phase). Preliminary clinical efficacy, as
expressed by changes in ejection fraction (EF), NYHA class, 6-minute walking test (6-
MWT), peak O2 uptake (peak VO2), and Minnesota Living with HF Questionnaire
(MLWHFQ), was assessed at baseline and at the end of each phase. At the end of follow-
up (8.8 +/- 0.2 months), all patients were alive, without heart transplantation or need for
left ventricular assist device. Serial 24-hour Holter analysis revealed no proarrhythmic
effect. No devices malfunctioned or failed for any reason other than end-of-battery life.
Throughout the two study phases, EF improved from 22.7±7% to 28.7±7% and 37±13%
(p=0.004), 6-MWT from 418±99m to 477±96 m and 510±107m (p = 0.002), MLWHFQ
from 36±21 to 18±12 and 7±6 (P = 0.002), peak VO2) from 13.7 ± 1.1 to 14.9±1.9 to 16.2 ±
2.4 (p=0.037), and NYHA class from 3 to 1.8± 0.4 to 1.5±0.7 (p < 0.001). The authors
concluded that CCM gradually and significantly improves systolic performance,
symptoms, and functional status, and that the technique appears to be attractive as an
additive treatment for severe HF.
Data obtained from a randomized, double blind, crossover study of cardiac contractility
modulation in patients with HF and left ventricular dysfunction suggested that CCM
signals were safe; exercise tolerance and quality of life (MLWHFQ) were significantly
better while patients were receiving active treatment with CCM for a 3-month period [363].
CCM by non-excitatory electrical currents has been considered the new frontier for
electrical therapy of heart failure, although more controlled randomized studies are
needed to validate this novel concept [367].
As above discussed in detail, acupuncture has been shown to exert antisympathotonic,
pro-vagotonic [368] and anti-inflammatory effects [369]. Therefore, it might be attractive
and beneficial in addition to standard heart failure medication, as the experiments with
vagal stimulation and cardiac contractility modulation also suggest.
A randomized blinded clinical pilot study by Middlekauff et al. with fifteen advanced
heart failure patients that underwent acute mental stress testing before and during a
single session of real acupuncture, non-acupoint acupuncture and no-needle
acupuncture, demonstrated that the resting level of sympathetic nerve activity directed to
muscle was unchanged, but surges in sympathetic activation during mental stress (a
80
potent stimulus to the ANS) were eliminated by acupuncture. Since the patients were
submitted to only one session of acupuncture, this findings cannot be extrapolated to the
normal average 10 sessions acupuncture performed in clinical practice. The authors
concluded that acute acupuncture attenuates sympathoexcitaion during mental stress in
advanced heart failure patients [261].
Kristen et al. conducted a randomized prospective study to test the therapeutic
potential of acupuncture for life-threatening diseases such as CHF. Seventeen stable
patients with CHF (New York Heart Association class II/ III, EF <40%, receiving optimized
heart failure medication were randomized into a verum acupuncture (VA) and placebo
acupuncture (PA) group. Cardiopulmonary function, heart rate variability and quality of life
were also explored. Needling (VA or PA) was performed during 10 sessions. No
improvements of the cardiac ejection fraction or peak oxygen uptake were observed, but
the ambulated 6 min walk distance was remarkably increased in the VA group (+32±7 m)
but not the PA group (-1±11 m; p<0.01). Accordingly, post-exercise recovery after
maximal exercise and the VE/VCO2 slope, a marker of ventilatory efficiency, were
improved after VA but not PA. Furthermore, heart rate variability increased after VA, but
decreased after PA. The „general health‟ score and „body pain‟ score of the quality-of-life
questionnaire SF-36 tended to be improved after VA.
Regarding the potential anti-inflammatory effects of acupuncture, the authors observed
in five patients treated with VA and three with PA; an excessive reduction of TNF in all
patients undergoing VA (median TNF before VA 4.6 (3.3-9.4) pg/ml, after VA 1.3 (0.6-
2.2) pg/ml but not of the patients undergoing PA [median TNF before PA 4.3 (2.7-6.8)
pg/ml, after PA 4.6 (4.2-6.1) pg/ml].
The collected data suggested that the beneficial effects of VA were mediated by an
improved oxygen metabolism and skeletal muscle function rather than an improvement of
the cardiac output. The authors concluded that acupuncture may become an additional
therapeutic strategy to improve the exercise tolerance of patients with CHF, potentially by
improving skeletal muscle function [370].
Reduction of LVEF causes skeletal muscle sympathy that in turn results in ergoreflex
activation and subsequently sympathoexcitation and increased ventilation that further
worsen CHF. This vicious cycle links the symptoms of breathlessness and fatigue [12-14,
371].
Thus, therapeutic strategies focusing on a decrease of sympathetic activity and an
increase of parasympathetic activity, such as acupuncture, may further reduce the
morbidity and mortality of patients with HF. This concept is currently also under
investigation using electrical vagal nerve stimulation [356]. This therapeutic benefit of
vagal nerve stimulation has been demonstrated in an experimental model of HF and was
81
associated with pronounced anti-inflammatory effects and is based on neuroinflammatory
reflexes [372].
These reflexes consist of an afferent arc of homoeostatic autonomic reflexes activated
by oxygen, glucose and other metabolites, finally resulting in activation of the efferent
motor neural arc that transmits the signal to modulate immune responses. Direct
stimulation of the vagus nerve inhibits cytokine production by innate immune cells in
different organs for example, spleen, liver, gastrointestinal tract and the heart [373]. A
feature of CHF is immune activation, with proinflammatory cytokines overexpressed both
in the systemic circulation and locally in the failing myocardium [374]. TNF has several
properties that lead to metaboreceptor activation [375-378] and are particularly
detrimental in CHF, such as negatively inotropic effects, the promotion of left ventricular
remodeling and the induction of dilated cardiomyopathy. Furthermore, TNF can cause
skeletal muscle wasting and apoptosis, and, therefore, may be important in the
development of cardiac cachexia and exercise limitation [379].
1.6. Heart rate variability a tool for acupuncture studies in heart failure
Analysis of heart rate variability (HRV) is non-invasive method that evaluates the
autonomic modulation over the heart rate [380-387].
HRV is measured as the percentage change in sequential chamber complexes (RR-
intervals) in the electrocardiogram (ECG) which is controlled by the blood-pressure
control-system, influence by the hypothalamus, and, in particular, controlled by the vagal
cardiovascular center in the lower brainstem (figure 14).
Figure 14. Central modulation of heart rate variability.
82
Heart rate variability can be quantified over time using the percentage of changes in
RR-intervals as well as changes in the frequency range by analysis of ECG power
spectra.
In 1987, Gerhard Litscher group showed rigidity in variability as a sign for interrupted
central nervous control mechanism of heartbeat in deep-comatose patients or in subjects
with brain death [388]. HRV not only provides important data in the fields of
anesthesiology and intensive medicine but also yields objective data for investigating the
vegetative effects of acupuncture.
Spectral analysis allows the classification of variability in single spectral ranges which
represent biological rhythms that seem to be distinguishable among the following [388]:
1. Respiratory sinus arrhythmia (0.15-0.5 Hz). Central nervous respiratory impulses
and interaction with pulmonary afferents (band IIIa; band IIIb)
2. The so-called “10-s rhythm” (0.05-0.15 Hz). A natural rhythm of cardiovascular
active neurons in the lower brainstem (circulatory center and its modulation by
feedback with natural vasomotoric rhythms via baroreceptor feedback (band II).
3. Longer wave HRV-rhythms (<0.05 Hz). Effects from the renin-angiotensin system
or temperature regulation as well as metabolic processes (band I)
Frequent-domain spectral analysis allows the discrimination of the components of the
autonomic neural heart control with a strong correlation with the vagal tonus [389].
An increment of the vagal tonus to the sino-auricular nodule is shown by a reduction of
the low-frequency/high-frequency ratio [389]. Several studies indicate that the low-
frequency band (LF band, 0.04-0.15 Hz) is mediated by the sympathetic nervous system,
while the high-frequency band (HF band, 0.15-0.4 Hz) reflects the activity of the
parasympathetic counterpart [380, 390, 391].
Recently, many signal processing algorithms applied to heart rate allowed to establish
a relationship of HRV with autonomic function and explore its changes in different
pathological situations [392].
In the clinical sphere, it has been proved that HRV has a prognostic value in heart
failure. [267, 393], and is a predictor of survival after myocardial infarction and of survival
in Intensive Care Units [394]. Barreto et al. shown that increased muscle sympathetic
nerve activity predicts mortality in heart failure patients [395].
HRV may therefore be applied to investigate the presumably autonomic modulation
associated with acupuncture.
In fact, already different research groups have published data that demonstrates
acupuncture effects in the autonomic nervous system activity as measured by the
changes in HRV associated with the puncture stimuli [267, 380, 396].
83
In a study with patients with minor depression and anxiety disorders, the acupuncture
group when compared to a control, revealed a reduction in the LF component and an
increase in the HF band [397].
Another study demonstrated an increase of both the parasympathetic and sympathetic
inputs after stimulating the Hoku point (LI4) and an increase only in the parasympathetic
component associated with the stimulation of Lung 1 (LU 1) in the cavum concha of ear
[267].
Wang et al. demonstrated that manual acupuncture in the Sishencong (Ex-HN) points
enhanced cardiac vagal and suppressed sympathetic activities in humans [264].
In another study, stimulation of PC6 increased the activity of high-frequency band and
diminished the ratio LF/HF [265].
EA applied to the acupoint BL15 induced a significant increase in the HF component of
HRV as well as a significant decrease in the LF power; moreover, both heart rate and
pulse rate were reduced in the analysis of the time domain, suggesting that EA in this
point can cause relaxation and slow down heart rate [380].
Controlled studies performed to evaluate the effects of acupuncture central and
vegetative nervous system activity as measured by electroencephalography and HRV
point to a specific modulation of cerebral function by vegetative effects during acupuncture
[398-400].
A summary of current scientific literature on the topic of acupuncture and heart rate
variability is listed in table 4 [396]
84
Table 4. Summary of research on heart rate variability (HRV) and acupuncture. LF, low frequency band; HF, high frequency band. EA, electroacupuncture.
Author Year Parameters n Research topic Results Acupuncture
Agelink [397] 2003 HRV LF/HF 36 Patients with anxiety or depression
Changes in LF/HF ratio
Manual
Chang [401] 2005 HRV LF/HF 15 Volunteers No influence on atropine-induced HRV-alterations
EA
Fuchs [388] 1997 HRV LF/HF 11 Volunteers
Changes in HF-band between vagotone and sympathotone
Manual
Goidenko [402] 2003 HRV 163 Children with neurotic diseases
Changes in HR spectrum
Manual plus acupressure
Haker [267] 2000 HRV LF/HF 12 Volunteers Increase in parasympathetic activity
Manual (ear acupuncture)
Hsu [380] 2006 HRV LF/HF 10 Volunteers Changes in HRV-spectrum by BL-15
EA
Hsu [400] 2007 HRV LF/HF 10 Volunteers
LW-waves increased after acupuncture at Ex6 and Shenmen
Manual; ear acupuncture
Huang [265] 2005 HRV LF/HF 111 Volunteers Alterations of HRV-spectrum by PC6
Manual
Hübscher [403] 2007 HRV 45 Non-.smoking male volunteers
No HRV effects on PC6
Laseracupuncture
Li [404] 2001 HRV LF/HF 20 Rats Increase of HRV, mainly LF band, at Zusanli
EA
Li [405, 406] 2003 HRV LF/HF 40 Male volunteers Changes in LF and HF bands
Needle
Li [407] 2005 HRV LF/HF 29 Volunteers Increase of HRV and LF at Hegu and Neiguan
Needle
Napadow [408] 2005 HRF LF/HF 5 Volunteers
Correlation of fMRI activity in hypothalamus, the dorsal raphe nucleus, the periaqueductal gray, rostroventral medulla with LF/HF ratio
EA
Neri [242] 2002 HRV(fetal) 12 Pregnant
No fetal changes in long and short term variability in BL67
Needle; moxibustion
Shi[409] 1995 HRV LF/HF 20 Coronary heart disease
Changes in LF-band
Needle; EA
85
1.7. Assessment of heart failure patients’ functional capacity in
acupuncture trials
Dyspnea and fatigue are common symptoms in HF patients causing functional
impairment in daily life activities [410, 411]. In HF the most important aspect determining
survival is exercise physiology [410].
Preliminary studies from two independent groups, Greten et al.), in 2008 [118, 119] and
Kristen et al. in 2010 [370], in Heidelberg, Germany, suggest that acupuncture may
improve walking distances as measured by the 6-min walk test.
Greten‟s group studied the effect of acute acupuncture in HF patients. It was performed
a prospective, single-blinded clinical trial (n=21) in a cross-over design comparing one
session of acupuncture following an individual Chinese diagnosis according to the
Heidelberg Model of Chinese Medicine (i-ACU)versus a standardized treatment on points
with no relation to a TCM diagnosis (u-ACU). It was found that i-ACU was associated with
a mean improvement in 6-min walk test of 36 meters in comparison to u-ACU.
Kristen‟s group evaluated the impact of a “chronic acupuncture intervention”. A
prospective, single-blinded, parallel, placebo-controlled pilot study was conducted in
which 17 stable HF patients were randomized into a verum-acupuncture group and
placebo group (using a blunted, telescopic placebo needle) during 10 sessions over 5
weeks. No improvements of the cardiac ejection fraction or peak oxygen uptake were
observed, but the ambulated 6 min walk distance was remarkably increased in the VA
group (+32±7 m) but not the PA group (-1±11m; p<0.01). Accordingly, post-exercise
recovery after maximal exercise and the minute ventilation/carbon dioxide production
slope, a marker of ventilatory efficiency, were improved after VA but not PA. Furthermore,
heart rate variability increased after VA, but decreased after PA. The „general health‟
score and „body pain‟ score of the quality-of-life questionnaire SF-36 tended to be
improved after VA.
The incremental shuttle walking test (ISWT) was initially developed to evaluate
functional capacity in patients with chronic respiratory disease. It has been validated in
individuals with chronic heart failure [412, 413]. This test has shown to be an independent
predictor of the peak oxygen consumption, as opposite to 6-min walk test. It was also
shown that it is a better predictor of event-free survival at one-year than the 6-min walk
test [414-416]. Others have shown that ISWT was as reliable as a treadmill test in
claudication evaluation and that patients preferred ISWT to treadmill testing [417]. For
these reasons the authors and allied research team have chosen this walking test as a
measurement tool in the proposed clinical trial (see under).
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CHAPTER TWO
Clinical research protocol
87
2. Clinical research protocol
Title: Effects of sensorial stimulation (acupuncture) in patients with chronic heart failure –
a prospective, randomized, controlled, double-blinded, pilot study
1. Academic and medical background
The development of this research project occurs as part of the Master Program in
Traditional Chinese Medicine and research activities of the Department of Internal
Medicine of Hospital de São João in which the author is currently training for Specialist in
Internal Medicine.
The research topic (acupuncture in heart failure) and clinical research protocol is
shared with another student of the Master Program in TCM (Eduardo Capitão). Together,
the authors established a research team and partnership. However both authors‟ research
interests rely on different issues. The main interest of the author of this thesis lies on the
physiological changes and mechanisms of acupuncture on the heart failure syndrome.
Differently, effects of acupuncture in exercise tolerance and functional capacity of heart
failure patients is the main interest of the co-author Eduardo Capitão.
2. Background
Heart failure (HF) is a worldwide health problem with a dismal prognosis despite
optimized medication. This clinical syndrome results from complex mechanisms of
neurohumoral activation leading to system wide autonomic dysbalance.
Traditional Chinese Medicine (TCM) has become widely spread in western
societies and acupuncture is being increasingly integrated into health-care
institutions.
Evidence from animal studies supports the concept that acupuncture may elicit
vegetative reflexes with release of endogenous substances which in turn inhibit
sympathetic outflow. Therefore acupuncture may have a therapeutic potential in
HF.
Few studies evaluating the biological mechanisms and therapeutic potential of
acupuncture have been accomplished in patients with heart failure.
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3. Research team
3.1. Main investigators
3.1.1. Nuno Correia
Physician attending the specialist training in Internal Medicine at the
Department of Internal Medicine at Hospital de São João.
Master student of Traditional Chinese Medicine at Abel Salazar
Institute for Biomedical Sciences
3.1.2. Eduardo Capitão
Nurse working in the Intensive Care Unit at Hospital de São João.
Master student of Traditional Chinese Medicine at Abel Salazar
Institute for Biomedical Sciences
3.2. Research supervisors
3.2.1. Main supervisor: Prof. Doutor Henry Johannes Greten. Head of the
Heidelberg School of Traditional Chinese Medicine; President of the German
Society of Traditional Chinese Medicine (DGTCM), Heidelberg, Germany.
3.2.2. Co-supervisor: Prof. Doutor Paulo Bettencourt. Head of Department of
Internal Medicine at Hospital de São João, Porto, Portugal.
3.3. Research co-worker: Dr. João Freitas. Head of the Center for studies in
Autonomic Function. Department of Cardiology at Hospital de São João.
3.4. Research advisor: Prof. Doutor Andrew Remppis. Deputy Chief, Department of
Internal Medicine III, Head of Heart Failure Department, Head of Catheterization
Laboratory, Head of HELUMA Registry, Member of the Board of the German
Society of Traditional Chinese Medicine (DGTCM), Heidelberg, Germany.
3.5. Statistical analyses: statistical analyses will be conducted in cooperation with
Faculty of Medicine of Hospital São João.
4. Objectives
4.1. General objective: To evaluate the effects of acupuncture in patients with heart
failure.
4.2. Specific objectives: We aim to answer the following questions:
4.2.1. Are the effects of acupuncture in heart failure explained by
neurophysiologic parameters related with the autonomic nervous system
activity?
We hypothesize that acupuncture will show a sympatholytic and vagotonic
effects.
89
4.2.2. Does acupuncture improve the symptoms of dyspnea and fatigue in
patients with heart failure?
We hypothesize that acupuncture is more effective in improving dyspnea
and fatigue compared to sham acupuncture.
4.2.3. Does acupuncture improve walking distances in heart failure patients?
We hypothesize that acupuncture is more effective in improving functional
capacity compared to sham acupuncture.
4.2.4. Is there a correlation between the effects of acupuncture in the autonomic
nervous system and the clinical outcomes (dyspnea, fatigue, walking
distance)?
We hypothesize that the degree of clinical benefits is correlated with
sympathetic outflow inhibition on the cardiovascular system.
5. Methods
5.1. Setting
This study will be performed in the Department of Internal Medicine in
cooperation with the Center for Studies in Autonomic Function in Hospital de São
João at the city of Porto, Portugal.
5.2. Study population
This study will focus on male patients between 40 and 90 years-old with chronic
systolic heart failure followed in the Heart Failure Outpatient Clinic of the Internal
Medicine Department of Hospital São João.
5.3. Study design:
The study will be an experimental, prospective, pilot clinical trial, with a
randomized, controlled, and double-blinded cross-over design (figure 15).
A crossover design was chosen in order to eliminate inter-individual variability
when comparing control point versus the experimental point, also representing a
methodological improvement in comparison to previous studies in the literature.
Each subject will be enrolled in two sessions of electroacupuncture (EA)
separated by a wash-out period: one session of verum-EA (vEA) and one
session of sham-EA (sEA).
Based on previous studies and theoretical considerations regarding the short-
term and long-term physiological and clinical effects of acupuncture, and the
traditional practice, we have established a wash-out period of 1 week in order to
prevent any carry-over effects. (figure 15) [280].
90
Figure 15. Study cross-over design. A sample of 20 male patients with systolic heart
failure, class II of the New York Heart Association, will be enrolled in a cross-over type of
study. Each patient is submitted to acupuncture in active acupoints (vEA) and inactive
acupoints (sEA).
5.3.1. Randomization to intervention groups
To control for possible carryover effects due to the sequence of applied
acupuncture treatment, the selected 20 patients will be randomly assignment to
the experimental (vEA) or control group (sEA) by the method of the coin flip.
5.3.2. Primary outcomes
5.3.2.1. Heart rate variability parameters: HRV, SDNN (standard deviation
of all normal to normal R-R intervals), low-frequency/high-frequency
power ratio (LF/HF, an index of sympathovagal balance) and high-
frequency power (HF, an index of vagal modulation).
5.3.2.2. Non-invasive hemodynamic parameters: baroreflex sensitivity;
total peripheral resistance; total arterial compliance; cardiac output;
stroke volume; left ventricular ejection time; rate pressure product;
mean, systolic and diastolic blood pressures; rate pressure product,
heart rate, respiratory frequency, saturation of peripheral oxygen.
91
This data will be measured by the device Finometer Pro ®4, a validated
instrument that collects various hemodynamic data; data will be processed by
the software Beatscope® and Nevrokard®5.
5.3.3. Secondary outcomes
5.3.3.1. Degree of dyspnea and fatigue evaluated by the modified Borg
scale (see attachment 2)
5.3.3.2. Walking distances evaluated by the incremental shuttle walk test
(“ISWT”, see attachment 3)
5.4. Eligibility criteria
Entry inclusion and exclusion criteria (table 4) were developed with the goal of
maximizing enrollment at local clinical setting; establishing a homogenous group
regarding the type of heart failure dysfunction, and avoid or minimizing possible
confounding factors interfering with the hypothesized interaction between
acupuncture and the autonomic nervous system.
4 http://www.finapres.com
5 http://www.nevrokard.eu/
92
Table 5. Eligibility criteria
Inclusion criteria
Male sex
Age ≥ 40 and ≤ 90 years old.
Written informed consent.
Diagnostic of heart failure more than three months ago and based on clinical, analytical and
medical imaging criteria.
New York Heart Association class II.
Heart rate between 50 and 100 bpm.
Sinus rhythm
Left ventricular systolic dysfunction with ejection fraction ≤ 40%.
Arterial systolic pressure between ≥90 mmHg and ≤ 180 mmHg and diastolic blood pressure ≤
100mmHg.
Respiratory rate between ≥ 10 e ≤ 30 cpm.
Hemoglobin level ≥ 10 g/dl.
Stable medication according to the guidelines for the past 3 months.
Exclusion criteria
Previous experience with acupuncture.
Needle phobia
Medical contraindications to perform walk tests.
Moderate to severe pulmonary hypertension
Chronic renal failure with an estimated glomerular filtration rate, calculated by the MDRD
equation, equal or less than 30 ml/min/1,73m2
Past history of syncope or dizziness
Thyroid disease
Skin lesion in the local of the acupoints used in the experimental protocol
Consumption of tobacco during the day of the intervention
Intake of psychopharmaceuticals
Intake of dietetic stimulating supplements
Acute or chronic pain
Intake of analgesic drugs
Neurological disease
Psychiatric disease
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5.5. Sampling and recruitment procedures
Based on the review of clinical files and database of patients from the Heart
Failure Outpatient Clinic, male patients with ages between 45 and 90 years old
with systolic heart failure will be selected and listed according to eligibility criteria.
The main researchers will contact the potential participants, explaining the study,
asking questions regarding eligibility requirements and inviting them to
participate, according to standardized document in a computer program.
From those eligible, a sample will be obtained using a simple random sampling
method through a computer-generated list of random numbers. Individuals will be
then be contacted by phone in order to gather 20 subjects and to schedule their
participation in the experimental protocol. In the first day, subjects will sign the
written informed consent.
5.6. Experimental protocol
5.6.1. Day 0: “Baseline”, pre-intervention phase
All patients will be enrolled into a pre-intervention phase. In this phase, the
study staff will guide the patient through the consent process in which
patients will be informed about the study design, including the use of
penetrating needles, and the possible risks of acupuncture treatment
(hematoma, infection and fainting). Once written consent is obtained, an
appointment is made to collect biographic and medical data and measure
the scores of baseline ISWT and Borg scale.
5.6.2. Day 1 and day 2: “intervention and post-intervention phase”
Subjects are randomly assigned to the vEA or sEA and after the washout
period they cross to the other branch of the study. During the intervention,
patients will be submitted to EA during 15 minutes. After each intervention
(vEA or sEA) ISTW and Borg scale will be again measured.
94
Figure 16. Experiment flow-chart. After a baseline evaluation participants will be randomly
assigned to verum-EA or sham-EA (day 1 or 2), which are separated by a 1 week wash-
out interval.
5.6.3. Intervention acupuncture treatments
Verum-electroacupuncture is based on a concept of acupuncture
following a functional individualized diagnosis according to the
Heidelberg Model of Traditional Chinese Medicine and includes
acupoints that have proved to influence autonomic function:
H 7: heart 7, Porta Shen / Shenmen
PC 6: pericardium 6, Clusa Interna / Neiguan
S 34: Monticulus Septi / Liangqiu
S 36: Vicus Tertius Pedis / Zusanli (vagotonic)
Sham-electroacupuncture is an invasive control regimen using
acupoints with (1) no indication in heart failure treatment according to
TCM and (2) without known autonomic effects.
LI 8: large intestine 8, Angustiae Inferae Manus / Xialian.
T 9: triple burner 9, Incilis Quarti / Sidu.
GB 32: gall bladder 32, Incile Medium / Zhongdu.
Liv 9: liver 9, Foramen Uteri / Yinbao.
Both treatments will be carried out using equal number of needles and
same electroacupuncture parameters, applied bilaterally, in a quiet,
temperature stable and with moderate light laboratorial setting.
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Electroacupuncture will be done using a device that produces continuous
electrical waves that can be set to alternating low-high frequencies
according electrostimulation predefined programs.
Stainless steel needles will be used with Ø=0,25mm and length of 25mm.
The acupuncturist will be a trained health professional with certified
education in Acupuncture or Traditional Chinese Medicine as recognized by
national standards.
6. Blinding procedures
The same number of needles will be used bilaterally either in the vEA or sEA branches
using the same technique. Subjects will not be informed about the type of EA they are in
each of the two sessions. Since the subjects are naïve to acupuncture, they are not
expected to differentiate between vEA and sEA. Nevertheless, to assess blinding and
subjects‟ expectations questions will be posed to each patient as explained under.
The acupuncturist is an invited participant in this study, unaware of study details, and
whose exclusive task is to needle vEA or sEA points according to the randomization
assignments for each subject. The acupuncturist is a health professional with certified
education in acupuncture or Traditional Chinese Medicine according to national
standards.
All experimental data during the intervention day will be collected by staff that will not
be aware of the actual assignment of the patient into the vEA or sEA branches.
Only the principal investigators will know the randomization profile.
6.1. Acupuncture expectations
Patient‟s beliefs or expectations regarding the efficacy of a medical intervention can
influence their response [418-421].
It will be employed a self-administered instrument based on the “treatment credibility
scale” of Borkovec and Nau [422] to assess beliefs and expectations regarding the
efficacy of acupuncture for the treatment of heart failure. Various versions of this
instrument have been employed in acupuncture studies. Vincent found one version to
have good internal consistency and test-retest reliability. In this regard, four questions will
be employed:
(1) How confident do you feel that electroacupuncture will alleviate your dyspnea and
fatigue and improve your walking distance?
(2) How confident would you be in recommending acupuncture treatments to a friend
with heart failure?
(3) Does treating heart failure with electroacupunture make sense to you?
96
(4) How successful do you think this treatment would be in alleviating other
complaints?
Responses will be assessed using a five-point Likert scale. This instrument will be
administered at the baseline day (pre-intervention phase) and at the end of each
intervention (control and experimental).
6.2. Acupuncture masking
The success of patient masking will be assessed with a self-administered instrument.
Patients are asked to indicate which treatment group they thought they are randomized to
by circling one of 3 choices: the real acupuncture, the false acupuncture and “don‟t know”.
If they indicate one of the two treatment groups, a second question will ask how confident
they are in their answer on a 5-point Likert scale. A list of 5 questions addresses which
factors their assessment their assessment was based on, including: improvement (or lack
of it) in walking distance; improvement (or lack of) in dyspnea or fatigue; overall well
being; sensation of numbness during the acupuncture needling; location of acupuncture
points; “just guessing”.
7. Statistical plan
Results from this preliminary trial will allow an accurate estimation of power
calculations and sample size for a subsequent clinical trial since statistical data from
previous studies is scarce [118, 370].
It is established a sample size of 20 patients to be enrolled in this two-treatment
crossover pilot trial on an ad hoc basis. Estimation of this sample size and power
calculations are based on the results obtained from the change of walking distances from
prior similar studies [118, 370]. Based on these studies it is estimated a probability of 99
percent that the study will detect a treatment difference at a two-sided 0.05 significance
level, if the true difference between treatments is 30.0 units (meters). This is based on the
assumption that the within-patient standard deviation of the response variable is 15
meters. This calculation was made using PASS® 2008.
Results of the experimental protocol will be analyzed using PASW® v18 software with
support from a professional statistician.
Since the sample size is less that 30, and based on above mentioned studies, it is
anticipated that results will not be normally distributed. Therefore non-parametric tests will
be used and all results will be expressed as median and range. Continuous variables of
the two groups at baseline will be compared using Mann-Whitney test and categorical
variables by Fisher‟s exact test. Intra-session and inter-session group comparisons will be
97
evaluated with the Wilcoxon signed-rank test. Other tests may be used to study
correlations between primary and secondary outcomes. A level of p<0.05 will be accepted
as statistically significant.
8. Ethical considerations, protection of human subjects and assessment of safety
This study protocol was approved by the Ethics Committee (EC) of Hospital de São
João (see appendix 1). Any amendments will be submitted to the EC.
The study is to be conducted according to the 1964 Helsinki Declaration and
international standards of Good Clinical Practice requirements [423, 424].
All subjects for this study will be provided a consent form describing this study and
providing sufficient information for subjects to make an informed decision about their
participation in this study. Subjects are informed about the goals, methods, expected
benefits, and potential risks or discomforts, and have the right to decide to withdraw or
continue at any moment during his/her participation; subject is also aware that no
prejudice will result if him/her refuses to participate or withdraws from the study.
This informed consent is obtained from all participants before randomization and is
considered an inclusion criteria. This consent form has been approved by the EC and
must be signed by the subject or legally acceptable surrogate and the investigator-
designated research professional obtaining the consent.
There will be no interference or any change in patient‟s usual care and medication.
The incidence of adverse effects of acupuncture in multiple studies is low [231, 425-
430].
Subjects will be asked about adverse experiences at each visit, defined as any
unfavorable and unintended sign, symptom or disease temporally associated with the use
of the acupuncture treatments.
Any adverse event that is life-threatening or results in death, hospitalization, a
persistent or significant disability/incapacity, or cancer, will be promptly recorded and
reported to the Ethical Committee of Hospital de São João.
The trial will be stopped if the investigators believe there is an unacceptable risk of
serious adverse events in one of the treatment arms.
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9. Study finances
9.1. Funding source: In order to obtain grant support for the expected project budget
an application form will be submitted to a high prestige institution (e.g.: Science
and Technology Foundation of the Portuguese Ministry of Science, Technology
and Higher Education).
9.2. Conflict of interest: nothing to declare.
10. Publication plan
The main investigators will submit the clinical research protocol for publication in the
open-access journal “BMC Complementary and Alternative Medicine” (impact factor of
.1.94).
After conclusion of the clinical trial, the authors will submit manuscripts for publication
in indexed scientific journals.
Neither the complete nor any part of the results of the study carried out under this
protocol, nor any of the information provided by the sponsor for the purposes of
performing the study, will be published or passed on to any third party without the consent
of the study sponsor. Any investigator involved with this study is obligated to provide the
sponsor with complete results and all data derived from the study.
99
11. Schedule of the project: Table 6
Project phases Dates Tasks
Phase 1:
Preparation
October 2008
– October
2009
Bibliographic research
Contact with researchers with indexed
publication in the field of acupuncture, Chinese
Medicine, and heart failure.
Establish research team; inviting co-workers
and project advisors.
November
2009 – July
2010
Writing down the research project
Submission of project to Ethics Committee of
Hospital de São João.
Search for grant support.
Search for material support from specialized
companies.
August –
September
2010
Preparation of research laboratory setting. Trial
with volunteers to optimize procedures.
Selection of participants. Contact with
participants. Informed consent.
Submission of application for grant support.
Submission of clinical research protocol for
publication in indexed scientific journal.
Phase 2:
Development
October –
December
2010
Experimental protocol with participants.
Data collecting.
Phase 3:
Results
evaluation
January –
February 2011
Statistical analyses. Results evaluation and
interpretation. Writing of scientific articles.
Phase 4:
communicatio
n of results.
After February
2011
Submission of articles to journals. Presentation
in scientific events.
12. Project references
A list of references is presented at the end of this thesis.
100
CHAPTER THREE
Results
101
3. Results
The proposed clinical trial protocol has been approved by the Ethics Committee of a
central school Hospital in Portugal (appendix 1) and plans towards its completion are
being accomplished.
The trial will hopefully provide additional valid data regarding vEA specific modulation
of neurocardiovascular parameters in patients with heart failure.
Since no data is yet available at the time of this thesis submission, the author may only
comment on foreseen outcomes based on the study hypothesis.
It is expected to find a significant increase in HRV, in low-frequency/high-frequency
ratio (an index of sympathovagal balance) and high-frequency power (an index of vagal
modulation) in association with verum-electroacupuncture in comparison with sham-EA.
It is anticipated that an improvement in the autonomic balance will show a positive
correlation with an increase in the walking distance (as measured by the ISWT) and a
negative correlation with the modified Borg scale (meaning less degree of dyspnea and
fatigue).
In clinical terms, vEA should be more efficacious than sEA by means of a stronger
attenuation over the sympathetic activity. Patients with a worse HF syndrome will probably
show more heart rate variability changes as described already in the literature.
As such, it will be interesting to evaluate the magnitude of EA effects in these patients
and subgroups analyses may be possible to perform.
102
CHAPTER FOUR
Discussion
103
4. Discussion
The fact that TCM and acupuncture have existed for several thousand years means
that, not only has this intervention stood the test of time, but that there is a lot of truth in its
ability to treat a number of condition including pain, nausea and vomiting, and possibly
certain cardiovascular abnormalities.
Acupuncture appears to be potentially useful as a therapeutic option that is effective in
treating symptoms, including the pathophysiology causing the symptoms, rather than
treating the underlying disease process itself. However, a number of well-constructed
experimental studies indicate that acupuncture works through neurohumoral mechanisms
that have the capability of improving disease, such as, reducing blood pressure,
decreasing myocardial ischemia, improving peripheral blood flow and perhaps improving
exercise tolerance in heart failure patients.
Available evidence, as demonstrated by the above literature research, clearly indicates
that acupuncture exerts sympatholytic, pro-vagotonic, and anti-inflammatory effects.
Animal data supports the hypothesis that acupuncture in specific sites may attenuate
sympathetic nerve activation. Furthermore it strongly suggests the existence of a “nucleus
arcuatus-periaqueduct gray substance-rostral ventrolateral medulla” pathway participating
in EA inhibition of excitatory cardiovascular reflexes, mediated by the activation of
neuropeptides receptors. In animals, electrical acupuncture at Zusanli (S36) acupoint, for
example, resets the neural arc of arterial baroreflex ant is able to attenuate sympathetic
nerve activity [123].Cardiovascular neurons in the rostral ventrolateral medulla (rVLM)
receive inputs from hypothalamic and midbrain defense areas, the splanchnic nerves, and
certain proven acupoints. Analysis of neural pathways has shown that EA activates the
nucleus arcuatus (ARC) in the hypothalamus, which sends excitatory projections to the
ventral periaqueduct gray (vPAG) and, in turn, to the nucleus raphe obscures (NRO).
Excitation of NRO neurons inhibits cardiovascular neurons in the rVLM by activating
opioid, GABA, and 5-HT receptors to reduce sympathetic outflow, which ultimately exerts
a therapeutic effect in heart failure.
To the best of the author‟s knowledge, only three clinical studies have evaluated the
impact of acupuncture in heart failure patients. The study by Middlekauff (2002) [261]
provided first evidence that inhibits sympathetic activation during mental stress in
advanced heart failure patients. The pioneer study by Greten (2008) [118] showed that
acupuncture prolonged 6 min walk distance of about 36 meters after one session of
acupuncture. This result was similar to the study conducted by Kristen (2010) [370], in
104
which after 10 sessions of acupuncture, patients in the true acupuncture group shown a
significant increase in the 6 min walk distance (+32±7 meters). Additionally, this study
found no improvements of the ejection fraction or peak oxygen uptake, but post-exercise
recovery and ventilatory efficiency were improved after true acupuncture, as also the
general health and body pain score of the SF36 questionnaire.
It is interesting to note that the above mentioned increase in walking distance of
approximately 30 meters is comparable to observations with the use of ACE inhibitors,
interval training, and cost-intensive cardiac resynchronization therapy in HF patients [431-
433].
Studies with heart rate variability in acupuncture have also shown that acupuncture is
able to diminish the sympathetic components and promote the parasympathetic indexes,
thus providing a physiological framework for acupuncture studies in heart failure.
In the last 10 years, news perspectives have been gained on the peripheral and central
neural mechanisms that underlie acupuncture‟s influence on the cardiovascular system.
Acupuncture has shown to be capable of limiting increases in blood pressure and
myocardial ischemia that result from increased demand for oxygen. Acupuncture needles
stimulate major neural pathways beneath points located along meridians, which serve as
road maps directing practitioners where they should stimulate. Stimulation during either
manual or EA activates both finely myelinated and unmyelinated somatosensory
pathways that provide information to several locations in the brain, including the arcuate
nucleus in the ventral hypothalamus, the ventrolateral periaqueductal gray in the midbrain,
and most importantly the rVLM, which regulates sympathetic outflow from the thoracic
spinal cord. It is know that low-frequency, low-intensity EA is more effective that high-
frequency EA but is very similar to manual acupuncture when two forms of stimulation are
matched for frequency and duration. With respect to its action on the cardiovascular
system, acupuncture is very effective at certain acupoints on the arm and leg that overlie
deep neural pathways and is less effective at acupoints located over very superficial
somatic nerves.
However, there are several aspects of acupuncture that are not fully understood.
The first is why it has such a long mechanism of action. One part of the answer is the
apparent long-loop pathway through the hypothalamus and midbrain that it activates. It
seems clear that the long-term effect is related to chronic alterations in the brain, perhaps
with neurotransmitter synthesis or altered baseline discharge activity of the medullary
neurons that regulate sympathetic outflow.
Second, it is not fully understood all of the interactions between the various regions of
the brain and the neurotransmitter systems involved. Opioids and opioid-like
105
neurotransmitters are involved, but what about other inhibitory neurotransmitters like
GABA?
Also what is the importance of EA-mediated activation in some regions (arcuate
nucleus and rVLM) during short-term stimulation and inhibition in other regions (vlPAG-
rVLM) during long-term stimulation as normally occurs during acupuncture. And, are the
neurotransmitters-neuromodulators acting pre- or postsynaptically to influence neuronal
responsiveness and activity?
Third, are other regions of the brain involved and does acupuncture influence
cardiovascular system through other mechanisms, for example, the parasympathetic
nervous system or the humoral system, such as the renin-angiotensin system?
Methodological concerns in acupuncture trials are still a challenge. It is important to
attenuate sources of bias and to study the specificity effects of acupuncture needling (as
opposed to needling any point in skin and to evaluate specific effects among different
acupoints).
Problematic issues are: the study design, the blinding methods, selection of an
adequate control, short term vs. long term acupuncture, ethical issues over the use of
true-acupuncture vs. false-acupuncture, testing electroacupuncture vs. manual
acupuncture, evaluating acupuncture according to a TCM diagnosis or schematic
acupuncture based on predefined points.
In our project a crossover design was implemented to eliminate inter-individual
variability when comparing control point versus the experimental point, also representing a
methodological improvement in comparison to previous studies.
As control points we have chosen true acupoints that are considered to be inactive in
HF according to Chinese Medicine principles. This was a strategy in order to permit the
blinding of the invited acupuncturist who in not informed of the study details or purposes. If
we used non-acupoints, the acupuncturist would recognize them and his blinding would
be impossible.
The experimental acupoints were selected on the basis of published previous literature
which demonstrated attenuation of sympathetic activity (PC6, S36) which are located in
the areas of innervations of the meridian nerve and deep peroneal nerve, respectively.
The other experimental points were selected on the basis of the Heidelberg Model of
Chinese Medicine.
To the author‟s knowledge the presenting clinical research trial is the first of its kind
Portugal, addressing Portuguese patients with heart failure. Importantly it has been
accepted by the Ethics Committee of a major hospital in Portugal.
While much research has been done, much more is still needed to allow a complete
understanding of how acupuncture can influence cardiovascular function.
106
Since the most effective pharmacological therapies in heart failure are known to work
through interaction with the autonomic nervous system, further studies of acupuncture
efficacy and its mechanisms in HF are mandated.
A better understanding, particularly a mechanistic comprehension, in addition to
rigorous randomized, well-controlled clinical trials will aid substantially in increasing
acceptance of this promising integrative medicine modality be the western and scientific
communities.
107
108
CHAPTER FIVE
Future perspectives
109
5. Future perspectives
Acupuncture has been widely study in particular in the field of pain and its efficacy is
more or less established according to different pain etiopathologies. Although acupuncture
has been historically traditionally applied in the treatment of other disorders beside pain,
research is scarce regarding the treatment of heart conditions, namely heart failure in
humans.
The long history of clinical practice has proven that acupuncture may have therapeutic
effects in heart disease but its physiological basis needs more scientific study.
Promising results from two clinical trials have already provided some insight on the
clinical benefits and mechanisms of acupuncture suggesting that acupuncture may offer
an additional clinical value.
Future research is needed to address several pending issues:
Fully understanding of acupuncture mechanisms in heart failure patients.
Direct sympathetic nerve recordings and blood measurements of inflammatory and
other biomarkers in patients with heart failure will lend further support to the
sympatholytic and anti-inflammatory potential of acupuncture.
The ideal duration of each acupuncture session and the ideal number of
acupuncture sessions.
The short-term and long-term therapeutic effects of acupuncture in heart
failure. On the one hand it is necessary to understand duration of neurophysiologic
changes. On the other hand, duration of clinical effects also needs to be
evaluated.
Comparing the effects of acupuncture according to TCM diagnosis in
comparison with the so-called contemporary, neurofunctional, or standardized
acupuncture.
Evaluating the magnitude of possible placebo effects associated with
acupuncture treatment.
Evaluate specific functions of different acupoints in the autonomous
nervous system, its pathways, mechanisms, and impact in heart failure patients.
Evaluate the effects of acupuncture in heart failure with diastolic
dysfunction
Study the effect of acupuncture in different etiologies and stages of HF and
gender differences.
Evaluating acupuncture cost-effectiveness in health-care systems.
110
With the presented research project, the author expects to gather data to justify a full-
scale trial and to support further research about the neurophysiologic mechanisms of
acupuncture and its clinical therapeutic potential in heart disease. It may also open a new
space for education of other health professionals and researchers in this field of
Acupuncture/TCM, in which knowledge is still infinite and more research contributions are
warranted.
The theoretical framework of this research team focuses on the concept of traditional
Chinese Medicine as a system that describes the functional state of a patient and thus it
would be of great interest to investigate the impact of Chinese medical interventions on
electrophysiological and molecular levels. The present line of research addresses the
hypothesis that acupuncture elicits neurohumoral changes that may balance the
autonomic nervous system activity, reduce inflammation and have immunomodulatory
effects, leading to a beneficial net effect in the treatment of heart failure patients.
Additionally, in the field of TCM, other modalities with therapeutic potential for heart failure
may be a target of research including: Tai-Chi/Qi-Gong and Chinese phytotherapy.
As the Heidelberg School of TCM has developed a new cybernetic model of vegetative
pathophysiology that has been accepted as the leading working hypothesis by the
Chinese State Department of Chinese medicine, this group is interested in investigating
the interface of western medicine and the eastern vegetative system.
Since the beginning of this project, contacts have been established in order to create
research partnerships with the Heidelberg School of Chinese Medicine and the heart
failure group of Heidelberg University in Germany in cooperation with Prof. Doutor Henry
Greten6 and Prof. Doutor Andrew Remppis7, respectively.
6 http://www.dgtcm.de/ ; http://www.hscm.asia/
7 http://www.klinikum.uni-heidelberg.de/Remppis.3780.0.html
111
112
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143
Appendix 1. Approval statement of the Ethics Committee of
Hospital de São João, EPE.
144
145
146
147
Appendix 2. Informed consent.
DECLARAÇÃO DE CONSENTIMENTO
Considerando a “Declaração de Helsínquia” da Associação Médica Mundial (Helsínquia 1964; Tóquio 1975; Veneza 1983; Hong Kong 1989; Somerset West 1996 e Edimburgo 2000)
Designação do Estudo (em português):
Efeito da estimulação sensorial (acupunctura) na insuficiência cardíaca crónica –
um estudo preliminar
Eu, abaixo-assinado, (nome completo do participante) -----------------------------------------
-------------, compreendi a explicação que me foi fornecida, por escrito e verbalmente, da
investigação que se tenciona realizar, para qual é pedida a minha participação. Foi-me
dada oportunidade de fazer as perguntas que julguei necessárias, e para todas obtive
resposta satisfatória.
Tomei conhecimento de que, de acordo com as recomendações da Declaração de
Helsínquia, a informação que me foi prestada versou os objectivos, os métodos, os
benefícios previstos, os riscos potenciais e o eventual desconforto. Além disso, foi-me
afirmado que tenho o direito de decidir livremente aceitar ou recusar a todo o tempo a
minha participação no estudo. Sei que se recusar não haverá qualquer prejuízo na
assistência que me é prestada.
Foi-me dado todo o tempo de que necessitei para reflectir sobre esta proposta de
participação.
Nestas circunstâncias, decido livremente aceitar participar neste projecto de investigação,
tal como me foi apresentado pelo investigador.
Data: ____ / _________________ / 20____
148
Assinatura do(a) participante:
__________________________________________________________________
O Investigador responsável:
Nome:
_______________________________________________________________________
Assinatura:
_____________________________________________________________________________
149
INFORMAÇÃO AO PARTICIPANTE
Caro Participante,
o presente estudo no qual participará designa-se “Efeito da estimulação sensorial
(acupunctura) em doentes com insuficiência cardíaca crónica – um estudo
preliminar”.
O objectivo do estudo é perceber se a aplicação da acupunctura nos doentes com
insuficiência cardíaca crónica leva a uma melhoria dos sintomas associados a esta
doença e quais as alterações fisiológicas provocadas pela acupunctura.
Para estudar o efeito da acupunctura será sujeito a um teste de marcha para avaliação
da sua capacidade de mobilidade funciona e terá de preencher questionários de
avaliação sobre os sintomas. Durante estes procedimentos estará acompanhado por
médico e/ou enfermeiro.
Será solicitada a sua participação de forma voluntária numa primeira sessão para
preenchimento de questionários e realização de um teste de marcha inicial.
Posteriormente, será sujeito a duas sessões de electro-acupunctura de baixa frequência
separadas por uma semana de intervalo. Será aleatoriamente alocado a uma sessão de
electro-acupunctura verdadeira e depois a uma sessão de electro-acupunctura falsa. Não
terá conhecimento do tipo de electro-acupunctura (verdadeira ou falsa) a que será
submetido. Cada sessão de electro-acupunctura durará cerca 15 minutos. Antes e depois
destas sessões iremos proceder aos referidos testes de avaliação de forma a avaliar o
efeito da acupunctura. Será ainda submetido a um teste de provocação autonómica (teste
TILD) após cada sessão de acupunctura. No total, esta experiência poderá ter uma
duração total de uma a duas horas e implicará a sua deslocação ao hospital durante 3
dias da semana a combinar consigo.
O tratamento com electro-acupunctura será efectuado por um profissional de saúde com
formação em Acupunctura ou Medicina Chinesa Tradicional certificada pela Universidade
pública portuguesa.
Com o tratamento de acupunctura esperamos contribuir para melhoria da sua
doença, nomeadamente, para alívio da sua falta de ar ou cansaço e para promover a sua
capacidade de marcha.
150
Note que a acupunctura não substituirá o tratamento médico convencional será
apenas um tratamento complementar ao seu tratamento habitual. Para além disso, não
se espera que a acupunctura prejudique o tratamento convencional a que será sujeito
nem haverá qualquer interferência no seu plano de tratamento habitual.
Todas as agulhas de acupunctura são esterilizadas e descartáveis (ou seja, de uso
único). Antes da inserção das agulhas, a pele será desinfectada com uma solução anti-
séptica alcoólica.
Os riscos associados a acupunctura são mínimos. Poderá sentir algum grau de dor
ou desconforto e formigueiros no local das picadas com as agulhas de acupunctura. Para
além disto, poderá sentir algumas tonturas, ansiedade ou náuseas. É possível que após a
picada com a agulha possa aparecer um ligeiro hematoma que resolverá
espontaneamente e/ou ligeiro sangramento local, em particular se estiver a tomar a tomar
medicamentos anti-agregantes (ex.: Aspirina, ácido acetilsalicílico) ou hipocoagulantes
(ex.: Varfine ® (varfarina); Sintrom ®, acenocumarol). Caso esteja a tomar esta
medicação deverá informar a equipa de investigação deste estudo.
O teste de Tilt (teste da mesa inclinada) é um meio auxiliar de diagnóstico relativamente
seguro utilizado para reproduzir perda de conhecimento ou desmaio relacionada com o
funcionamento do coração e vasos sanguíneos. Para realizar este teste, será deitado
num cama basculante que será levantada a 70 graus durante 30-45 minutos, o que
poderá desencadear tonturas ou perda dos sentidos (síncope), sendo o teste
imediatamente interrompido, com colocação da cama a 0 graus e elevação das suas
pernas. Este teste servirá como ferramenta para estudo dos efeitos da electro-
acupunctura.
Note que durante estes procedimentos estará sempre acompanhado por Médico e
Enfermeiro com treino em suporte avançado de vida e que o Hospital de São João está
dotado de uma Equipa de Ressuscitação Interna durante 24 horas e de actuação rápida
caso seja necessário que é activada por telefone interno.
Sendo a sua participação voluntária terá o que tempo que necessitar para ponderar
sobre a sua participação neste estudo. É livre de consultar a opinião dos seus familiares
ou amigos. Caso decida aceitar, poderá posteriormente a qualquer momento
recusar continuar no estudo.
Se recusar continuar neste estudo, o tratamento médico convencional não será
afectado e toda a assistência habitual é-lhe garantida pelos profissionais de saúde.
151
Ao entrar neste estudo será garantida a sua privacidade, através de confidencialidade
dos dados e regras do sigilo médico. Todos os resultados obtidos serão devidamente
codificados. Caso pretenda, poderá ter acesso aos resultados, mas não os poderá
divulgar ou usar para fins científicos. Os dados serão apenas do conhecimento dos
investigadores principais e dos orientadores do estudo e do eventual patrocinador do
estudo e poderão ser posteriormente publicados em revistas científicas ou apresentados
em eventos científicos. Será sempre mantido o seu anonimato.
Note ainda que este estudo foi aprovado pela Comissão de Ética do Hospital de São
João.
Para seu conhecimento, os investigadores principais deste estudo são o Dr. Nuno
Correia e o Enfermeiro Eduardo Capitão.
Para qualquer esclarecimento poderá entrar em contacto com o Dr. Nuno Correia
para o telemóvel 91 3741405 ou Enfermeiro Eduardo Capitão para o telemóvel
919070990.
A equipa de investigação agradece a sua participação e está ao seu dispor para qualquer
esclarecimento.
Hospital São João, Data:___/___/___
Com os melhores cumprimentos,
__________________________
Dr. Nuno Correia
__________________________
Enfermeiro Eduardo Capitão.
152
153
Appendix 3. Treatment credibility scale
(1) How confident do you feel that electroacupuncture will alleviate your dyspnea and
fatigue and improve your walking distance?
1 2 3 4 5
Strongly
disagree Disagree
Neither agree
nor disagree Agree Strongly agree
(2) How confident would you be in recommending acupuncture treatments to a friend
with heart failure?
1 2 3 4 5
Strongly
disagree Disagree
Neither agree
nor disagree Agree Strongly agree
(3) Does treating heart failure with electroacupunture make sense to you?
1 2 3 4 5
Strongly
disagree Disagree
Neither agree
nor disagree Agree Strongly agree
(4) How successful do you think this treatment would be in alleviating other
complaints?
1 2 3 4 5
Strongly
disagree Disagree
Neither agree
nor disagree Agree Strongly agree
154
155
Appendix 4. Assessment of masking
Assessment of masking questionnaire
1) Please indicate which treatment group you think you were submitted to
True acupuncture False acupuncture I don‟t know
2) How confident are you in the previous answer?
1 2 3 4 5
Strongly
disagree Disagree
Neither agree
nor disagree Agree Strongly agree
3) From the following list indicate factors that influenced your previous
answers
Improvement (or lack of it) in walking distance.
Improvement (or lack of) in dyspnea or fatigue.
Overall well being.
A particular sensation during the acupuncture needling.
Location of acupuncture points.
Just guessing.