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Coronary microvascular dysfunction
in arterial hypertension
Paolo G Camici, MD, FESC, FACC, FAHA, FRCPVita-Salute University and San Raffaele Hospital Milan
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9070503010-10
0
1
2
3
4
5
6
7
Co
ron
ary
Va
so
dila
tor
Re
se
rve
Y = 6.73 - 0.13x + 7.8x̂ 2 r = 0.77 (N = 35)
Percent diameter stenosis
= patients with CAD
= normal subjects
Percent diameter stenosis
Co
ron
ary
flo
w r
ese
rve
In vivo anatomy
ATS: Coronary stenosis
Coronary ATS and Myocardial Ischemia
Camici et al. New Engl J Med 1994; 330: 1782-1788
Stress MPI
Rest MPI
Regional perfusion abnormality
CFR reduction with stenosis severity
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26
3428
60
0
10
20
30
40
50
60
70
NHLBI,n=1755
COURAGE,n=2287
SYNTAX,n=1800
BARI-2D,n=1434
Angina is frequent after PCI% of patients with angina at baseline versus 1 year post-PCI
CAD + diabetes
1
2 3 4
1- Holubkov R et al. Am Heart J. 2002;144:826-833. 2- Boden WE et al. N Engl J Med. 2007;356:1503-1516.
3- Cohen DJ et al. N Engl J Med. 2011;364:1016-1026. 4- Dagenais GR et al. Circulation. 2011;123:1492-1500.
(%)
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Case report
• Female, DoB 25/06/1964
• Family history for hypertension
• Never smoked
• Menopause since 7 years
• Hypertension diagnosed during pregnancy
• Since 4-5 years she complains of retrosternal pain with radiation to the left armthat occur both during exercise and at rest. During the episode sometimes shealso experiences dyspnea.
• Recently she was admitted to hospital (ECG shows ST depression) for a prolonged episode of chest (no troponin). Coronary angiography shows normalsmooth epicardial coronary arteries.
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Baseline ECG
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ECG during chest pain
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The emerging concept of coronary “microvascular disease”
Courtesy of M Gibson MD
The tip of the iceberg - Resolution >500mm Resolution <500mm
Camici PG, Crea F. N Engl J Med. 2007;356-830-40.
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Crea F, Camici PG, Bairey Merz CN Eur Heart J. 2014 May;35(17):1101-11
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Data adjusted for the modified Duke clinical risk score and rest LVEF
Microvascular dysfunction and MACE at follow up
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Patients with microvascular angina aremore likely to develop HFpEF
Taqueti et al. Eur Heart J. 2017;39:840-9.
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Signs and/or symptoms of angina
Objective evidence of myocardial ischemia
Absence of obstructive CAD (or coronary stenoses not responsible for ischemia)
Coronary microvascular dysfunction (i.e. CFR <2.5 or microvascular spasm)
Abbreviations: CAD, coronary artery disease; CFR, coronary flow reserve
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In normal subjects myocardial
blood flow (MBF) increases 3- to 5-fold
during near-maximal pharmacologically
induced vasodilatation (i.v. adenosine)
In the absence of coronary stenosis,
maximum MBF reflects microvascular function
There is no in vivo technique for imaging the coronary microcirculation; Maximum myocardial blood flow is an index of microvascular function
MBF
Flow deficit
Patients with impaired
microvascular function
Normal subjects
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Camici PG, Rimoldi OE. J Nucl Med. 2009; 50:1076–1087.
PET with H215O or 13NH3 allows accurate, reproducible and non-invasive
measurement of absolute (ml/min/g) myocardial blood flow in man
PET: the gold standard for the non-invasivemeasurement of myocardial blood flow
Reproducibility of PET MBFmeasurement
Accuracy of PET MBFmeasurement
1
2
3
4
5
6
PET
MB
F (m
L. g-1
. min
-1)
0 1 2 3 4 5 6
Microspheres MBF (mL.g-1.min-1)
y=0.15+0.97x, r=0.87, r2=0.76
0
1
2
3
4
5
6
MB
F (m
l/m
in/g
)
0
Baseline Adenosine
Baseline 1 Baseline 2 Ado 1 Ado 2
Microspheres MBF (mL.g-1.min-1)
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In the absence of obstructive CAD a reduced CFR suggests microvascular dysfunction
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Symptoms associated with Coronary Microvascular Dysfunction
Symptoms of myocardial ischemia
a. Predominantly effort angina (±rest) b. Angina equivalents (i.e. shortness of breath)c. Predominantly rest angina
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Typically diffuse reduction of CFR
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Microvascular Angina in Hypertension
• Angina and/or ischemic signs on ECG are common in patients with primary or secondary LVH
• Maximum myocardial blood flow and CFR are reduced despite angiographically normal coronary arteries
Rimoldi O & Camici PG. J Hypert 2014
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Structural changes
Mechanisms of Coronary Microvascular Dysfunction“Vascular”
Camici PG, d'Amati G, Rimoldi O Nat Rev Cardiol. 2015 Jan;12(1):48-62
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Remodelling of coronary arterioles
Normal heart
• Peri-myocitic fibrosis• Thickening of the wall
of intramural arterioles• Increased wall/lumen ratio
Camici & Crea N Engl J Med. 2007;356:830-40
Hypertension
Normal EpicardialCoronary Arteries
Microcirculation
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Coronary arteriolar remodellingprecedes onset of hypertensionIn the SHR model
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Lazzeroni D, Rimoldi O and Camici PG Circulation J 2016
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Fibrosis in primary and secondary LVH
In HCM the late enhancement was predominantly antero-septaland infero-septal whilst in AH no specific pattern of fibrosis could be identified
Rudolph et al. J Am Coll Cardiol 2009;53:284-91
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Microvascular ischemia
The pathway from hypertension to HF “Role of microvascular ischemia”
Adapted from Drazner et al, Circulation, 2011
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Can we treat microvascular remodelling in LVH?
Thickened small intramural vessel with luminal narrowing (Bar indicates 20 μm)
Kanzaki Y et al. Circulation 2012;125:738-739
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Pro- and anti-growth stimuli
The homogeneity of cardiac tissue is achieved through a balanced equilibrium between stimulator and inhibitor signals of cell growth
Stimulatorsangiotensin II aldosteronedeoxycorticost.endothelincatecholamine
Inhibitorsnitric oxidebradykinin prostaglandinANPglucocort.
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Neglia D, et al. J Hypertens. 2011;29:364-372.
*P<0.01n=20 Baseline After 6 months’ treatment
0
25
50
75
100
(g/m
2)
Left ventricular mass
(MRI)
Blood pressure
0
25
50
75
100
125
150
175
200
(mm
Hg)
Systolic blood
pressure
Diastolic blood
pressure
Effects of perindopril/indapamide on blood pressure and LVH
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Myocardial blood flow in patients after 6 months treatment with perindopril/indapamide
Hyperaemic (dipyridamole)
Baseline
0
0.25
0.50
0.75
1.00
1.25
1.50
M0 M60
0.5
1.0
1.5
2.0
2.5
3.0
3.5
M0 M6
Baseline
0
50
100
150
200
250
M0 M60
25
50
75
100
125
M0 M6
Neglia D, et al. J Hypertens. 2011;29:364-372.
Minimal(dipyridamole)
Coronary
resistance (mmHg/ml/min/g)
Myocardial
Blood Flow (ml/min/g)
*P < 0.05, **P < 0.01 M0 vs M6
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Coronary flow in SHR
Placebo Per + Ind0
2
4
6
8
Placebo Per + Ind0
5
10
15
20
25
Placebo Per + Ind0
10
20
30
Placebo Per + Ind0
2
4
6
8
10
Baseline Minimal (hyperaemic)
Neglia D, et al. J Hypertens. 2011;29:364-372.
Baseline Hyperaemia
Coronary
flow (ml/min/g)
Coronary
resistance (mmHg/ml/min/g)
**P < 0.01 placebo vs perindopril/indapamide
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Correlation between microvascularremodelling and coronary flow
Placebo Per/ind0
1
2
3
4
5
Placebo Per/ind
0
5000
10000
15000
Placebo
10µm
Perindopril/indapamide
10µm
Neglia D, et al. J Hypertens. 2011;29:364-372.
Medial area (µm2)
Peak/baseline coronary flow
**P < 0.001
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H. Yazawa, et al. J Cardiac Fail. 2011;17:1041-1050.
Perindopril promotes Bradykinin and NO production
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Symptoms associated with Coronary Microvascular Dysfunction
Symptoms of myocardial ischemia
a. Effort and rest anginab. Angina equivalents (i.e. shortness of breath)c. Predominantly rest angina
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Functional changes
Mechanisms of Coronary Microvascular Dysfunction“Vascular”
Camici PG, d'Amati G, Rimoldi O Nat Rev Cardiol. 2015 Jan;12(1):48-62
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Baseline
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ACH – 20µg
No symptoms
No ECG changes
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ACH – 100µg
Typical chest pain
Flat T waves
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ACH – 200µg
Microvascular SpasmTypical chest pain
ST depression
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3731745-09
Anginal symptoms and documented myocardial ischemia*
Coronary stenosis**
FFR
Absent Severe >70%
Acetylcholine test
<0.80≥0.80
• No or <90% diameter reduction
• No angina• No ischemic ECG changes
• No or <90% diameter reduction
• + angina• + ischemic ECG changes
• ≥90% diameter reduction• + angina• + ischemic ECG changes
Adenosine testMicrovascular spasm Epicardial coronary
artery spasm Ischemia likely due to severe atherosclerotic
coronary artery disease
Investigate abnormal nociception
Microvascular anginaEndothelium independent
dysfunction
Likely false positive tests for ischemia
*As assessed by ECG, SPECT, ECHO, Cardiac MRI
Moderate 50-70%
Mild<50%
CFR≥2.5IMR<25
CFR<2.5IMR ≥ 25
Assess CFR non-invasively (PET, ECHO, CMRI)
CFR≥2.5
Microvascular angina
Previous coronary angiogram showing
normal coronary arteries or non-
obstructive coronary artery disease
Coronary Angiography
** Coronary diameter reduction
CFR<2.5
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ConclusionsMyocardial ischemia can be due to a number of
different mechanisms that act alone or in combination
• Each mechanism can be investigated using a combination of invasive and non invasive tests
• Understanding the underlying mechanism is the pre-requisite for the choiceof the most appropriate therapeutic strategy
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