left atrial remodeling and function in advanced heart...

Left Atrial Remodeling and Function in Advanced Heart Failure With

Preserved or Reduced Ejection Fraction

Melenovsky et al: LA Dysfunction in HF

Vojtech Melenovsky, MD, PhD1,2; Seok-Jae Hwang, MD, PhD1;

Margaret M. Redfield1, MD; Rosita Zakeri, MBChB1; Grace Lin, MD1;

Barry A. Borlaug, MD1

1Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN

2 Department of Cardiology, Institute of Clinical and Experimental Medicine - IKEM, Prague,

Czech Republic

Correspondence to Vojtech Melenovsky, MD, PhD Department of Cardiology, IKEM Videnska 1958/9, Prague 4, 140 28, Czech Republic E-mail:[email protected] Fax: 420-261-362-486 Phone: 420-732-816-242

DOI: 10.1161/CIRCHEARTFAILURE.114.001667

Journal Subject codes: Heart failure:[110] Congestive, Hypertension:[18] Pulmonary circulation and disease, Heart failure:[11] Other heart failure

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Abstract

Background—Left atrial (LA) structure and function are altered in most heart failure (HF)

patients, but there may be fundamental differences in LA properties between HF with preserved

(HFpEF) and reduced ejection fraction (HFrEF).

Methods and Results—198 HF patients (51% HFpEF, NYHA 3.1±0.7) and 40 HF-free controls

underwent catheterization, echocardiography and follow-up. Compared to controls, HF patients

had larger and more dysfunctional left atria. At identical mean LA pressure (20 vs 20 mmHg,

p=0.9), HFrEF patients had larger LA volumes (LAVI 50 vs 41 ml.m-2 p<0.001), while HFpEF

patients had higher LA peak pressures, lower LA minimal pressures, higher LA stiffness (0.79 vs

0.48 mmHg.ml-1, p<0.001), greater LA pulsatility (19 vs 13 mmHg, p<0.001) and higher wall

stress variations. Despite smaller LA volumes, better function and less mitral regurgitation,

HFpEF patients had more atrial fibrillation (AF: 42 vs 26%, p=0.02). LA dysfunction was

associated with increased pulmonary vascular resistance and right ventricular dysfunction in both

HF phenotypes. After a median follow-up of 350 days, 31 HFpEF and 28 HFrEF patients died.

LA function (total LA EF) was associated with lower mortality in HFpEF (HR 0.43, 95% CI 0.2-

0.9, p<0.05), but not in HFrEF.

Conclusions—HFrEF is characterized by greater eccentric LA remodeling, while HFpEF by

increased LA stiffness, which might contribute to greater AF burden. LA function is associated

with pulmonary vascular disease and right heart failure in both HF phenotypes, but is associated

with outcome more closely in HFpEF, supporting efforts to improve LA function in this cohort.

Key Words: heart failure; heart failure with preserved EF; left atrial function; atrial fibrillation;

pulmonary hypertension; right ventricle

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The left atrium modulates left ventricular (LV) filling by acting as an elastic reservoir, passive

conduit and active booster.1 Left atrial (LA) dysfunction and remodeling are commonly observed

in patients with heart failure (HF). Growing evidence suggests that LA dysfunction is an active

contributor to symptoms2-5 and to disease progression.3, 6, 7 HF-related LA remodeling is poorly

understood and it is not known if there are fundamental differences between HF patients with

preserved (HFpEF) or reduced LV ejection fraction (HFrEF), though prior studies suggest

greater adverse effects from loss of LA function in HFpEF compared to HFrEF.8

The LA also serves as a watershed between the LV and the pulmonary circulation,

buffering pressure and flow oscillations due to the cyclic nature of cardiac work. Impaired LA

function can thus impose greater hemodynamic stress on the pulmonary vasculature, promoting

remodeling and worsening pulmonary hypertension (PH), as observed in patients with mitral

stenosis.9,10 Increased pulmonary vascular resistance and stiffness may elevate right ventricular

(RV) afterload,11 driving further the progression to RV failure.12-15

We hypothesized that LA function is abnormal in patients with HF, that LA remodeling

differs between patients with HFrEF and similarly advanced HFpEF and that LA dysfunction is

associated with abnormal pulmonary vascular properties and RV dysfunction. To test this

hypothesis, we examined HFrEF and HFpEF patients undergoing invasive and noninvasive

hemodynamic assessment and compared them to HF-free controls to address the differences in

LA structure, function and to assess the impact of LA dysfunction on pulmonary vasculature,

right heart and clinical outcomes.

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Methods

Study subjects

Consecutive patients referred to Mayo Clinic (Rochester, MN) undergoing right heart

catheterization and echocardiography within a 48-hour window with sufficient raw data available

for detailed assessment (pressure waveforms and echocardiographic images) were identified. HF

was defined by cardiologist-adjudicated HF diagnosis (Framingham criteria) of >6 month

duration and elevated pulmonary artery wedge pressure (PAWP 15 mmHg at rest or 25 mmHg

at exercise). HFpEF and HFrEF were defined by LV EF 50% and <50%, respectively. Patients

with congenital heart disease, endocarditis, carcinoid, amyloid, constrictive, restrictive or

hypertrophic cardiomyopathy, intracardiac shunt (other than patent foramen ovale), high output

HF, non-Group II PH, mitral valve replacement, organic valvular disease, acute coronary

syndrome or hemodynamic instability were excluded.

Subjects with no cardiovascular disease other than Stage 1 arterial hypertension were

identified from patients undergoing preoperative evaluation, percutaneous closure of patent

foramen ovale, or evaluation for dyspnea with no identifiable cardiovascular cause. Past medical

history, medication use and contemporaneous laboratory data (±1 week) were abstracted from

the medical records. Significant CAD was defined as one or more 70% epicardial artery

stenosis or previous revascularization (angiography available in 28% controls, 82% of HFpEF

and 100% of HFrEF). For time-to-event analysis, patient vital status was determined using

outpatient records and the Social Security Death Index. Patients who underwent heart

transplantation or ventricular assist device insertion were censored as alive at the day of surgery.

The study was approved by Mayo Clinic institutional review board.

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Assessment of Hemodynamics and Cardiac function

Right heart catheterization was performed in the supine position via the jugular or femoral vein

using a balloon-tipped catheter as previously described.16 Right atrial (RA), RV, pulmonary

artery (PA) pressures and PA wedge pressure (PAWP) were determined at end-expiration. All

atrial waveforms were visually inspected by an experienced cardiologist blinded to clinical data

and group allocation to determine minimal, maximal, v wave and a wave pressures within one

cardiac cycle (Figure 1). Transpulmonary gradient (TPG) was calculated as PA mean-PAWP

pressure, pulmonary vascular resistance (PVR) was calculated as TPG/cardiac output and PA

compliance was calculated as stroke volume/PA pulse pressure.

Two-dimensional and Doppler echocardiography was performed according to ASE

guidelines17 by experienced sonographers and cardiologists. Cardiac output was derived from

heart rate, LV outflow tract diameter and pulsed Doppler time-velocity integral. LV mass was

calculated using the Devereux formula5. Diastolic function was assessed by measurements of

transmitral flow velocities (E and A), E-wave deceleration, mitral annulus tissue velocities in

early and late diastole (E´ and A´, average of septal and lateral) using pulsed Doppler

echocardiography. Diastolic dysfunction was graded as described previously18. Valve

regurgitations were quantified according established guidelines19. LV EF was determined by the

modified Quinones formula that corrects for endocardial echo dropouts and image

foreshortening.20

Apical 4-chamber views were reviewed off-line to measure maximal LA volume (frame

prior to mitral valve opening), diastasis LA volume (frame prior to LA contraction) and minimal

LA volume using area-length method. Global and reservoir LA function was characterized by

total LA EF7, LA conduit function was characterized by passive LA EF and contractile function

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was characterized by active LA EF (Figure 1).21 Atrial function was also assessed by LA

function index (LAFI), which normalizes function to stroke volume and is rhythm-independent.3

Operant LA diastolic stiffness was approximated as the slope of linear regression of minimal and

maximal LA pressure-volume coordinates (Figure 1).22, 23 Meridional LA wall stress was

calculated from maximal to minimal LA volume and pressure using established formulas24,

assuming atrial wall thickness of 0.2 cm.25 RV function was assessed as previously26 by tracing

the RV endocardium in the apical 4-chamber view in systole and diastole to obtain fractional

area change (RV FAC %). The right atrial endocardium was tracked in the frame prior to

tricuspid valve opening in order to obtain maximal RA volume using the area-length method.27

Statistical Methods

Data were analyzed using JMP10 (SAS Institute Inc., Cary, NC). Distributions of continuous

variables were visually assessed for normality and summary data in the tables are reported as

mean (standard deviation) or median (25th-75th interquartile range). Between-group differences

were compared by ANOVA with Tukey post-hoc test, 2x2 ANOVA or 2 tests as appropriate.

Univariate and multivariate Cox proportional hazard model were used to examine the impact of

LA function on outcome. To allow comparisons, parameters describing LA function were z-

standardized in individual subgroups. Graphs represent mean±SE.

Results

Clinical characteristics of controls (n=40) and both HF groups (HFpEF: n=101, HFrEF: n=97)

are summarized in Table 1. Both HF groups were highly symptomatic (74% NYHA III-IV) with

80% of chronic diuretic use. Similar to prior studies28, HFpEF patients were slightly older,

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more likely to be women, more obese and more often in atrial fibrillation (AF). Prevalence of

CAD, diabetes and renal dysfunction was similar. HFpEF patients had higher systemic blood

pressure, cardiac output, LV EF and transmitral flow velocities, but smaller LV size, LV mass

and mitral regurgitation grade compared to HFrEF (Table 2).

LA structure and function in HFpEF vs HFrEF

Compared to controls, patients with HFrEF and HFpEF displayed LA dilatation, coupled with

reduced LA active contractile, reservoir and conduit functions (Table 2 and Figure 2). Patients

with HFpEF displayed greater LA stiffness while HFrEF patients displayed more eccentric LA

remodeling (Figure 2). At similar mean LA pressure (Table 2), patients with HFrEF had larger

LA volumes and more depressed LA systolic function than HFpEF. In contrast, patients with

HFpEF were characterized by higher maximal LA pressure (v-wave), lower minimal LA

pressures and increased LA stiffness (Table 2), with a steeper, leftward-shifted LA diastolic

pressure-volume relationship (Figure 2). Differences in LA volume and stiffness between HFpEF

and HFrEF persisted after adjustments to gender, age, body size and mass, AF or mitral

regurgitation grade (adjusted p-values <0.02).

Left atrial pulsatility (LA max-min pressure) and wall stress variation was higher in

HFpEF compared to HFrEF (Table 2). LA function curves (preload-stroke volume plots) were

shallower in both HFpEF and HFrEF compared to controls, indicating LA contractile

dysfunction regardless of LA geometry (Figure 3). LA functional index (LAFI) and A’ mitral

annular velocities were also more reduced in HFrEF than in HFpEF or controls (Table 2).

The presence of AF was associated with more severe LA dilatation, lower total LA EF

and higher LA stiffness, particularly in HFpEF group (Supplemental Figure). Both atrial rhythm

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and HF phenotype impacted LA structure and function as shown by factorial analysis. LA

volume and stiffness increased, while total LA EF decreased with worsening NYHA class

(Figure 4). Mitral regurgitation had greater effects in HFpEF than HFrEF, with higher peak LA

pressure (LA v-wave) and greater LA wall stress variation with increasing mitral regurgitation in

HFpEF compared to HFrEF (Figure 3).

The Left Atrium and Pulmonary Artery-Right Heart Function

Pulmonary hypertension was common in HF patients (82% HFpEF, 79% HFpEF), due to

combination of elevated PAWP and increased transpulmonary gradient (Table 3). Mean PA

pressure, transpulmonary gradient, pulmonary vascular resistance (PVR) and pulmonary arterial

compliance (PAC) were similarly increased in both HF groups (Table 3), while PA pulse

pressure was higher in HFpEF. Global left atrial function (total LA EF) correlated inversely with

PVR and positively with PAC in both HF groups, but not in controls, and the slope the

relationship was similar between HFpEF and HFrEF (Figure 5). Similarly, LA stiffness

correlated with PAC in HFpEF and HFrEF (r=-0.35 and r=-0.41, both p<0.001), but only weakly

with PVR in HFpEF (r=0.23, p=0.03) and was unrelated to PVR in HFrEF (r=0.12, p=0.3). LA

volume was unrelated to PVR or PAC in both HF phenotypes.

Both HFpEF and HFrEF patients displayed RV dilation, but RV systolic function was

somewhat lower in HFrEF. Global LA function (total LA EF) positively correlated with RV

function in HFpEF and HFrEF with similar slope (Figure 5).

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Impact of LA dysfunction on prognosis

Over a median follow-up duration of 350 days (IQR: 82-870) there were 59 deaths (HFpEF=28,

HFrEF=31). Outcome was ascertained in 100% of HF subjects. In univariate Cox analysis,

reduced global and active LA function (total LA EF and active LA EF), increased LA volume

and AF were all associated with an increased risk of death in HFpEF, but not in HFrEF (Figure

6). In multivariate Cox model that included age and gender, known predictors of mortality in

HFpEF29, either total LA EF or active LA EF remained a significant predictor of death in HFpEF

(p=0.03 and p=0.05), while LAVI was no longer predictive (p=0.16). NT-pro-BNP levels were

not predictive of mortality in either HF group.

Discussion

This study examined LA structure and function in HF by combining invasive pressure and

noninvasive volume data while contrasting LA parameters in the two HF phenotypes. Compared

to controls, both HF types displayed abnormal LA size and function. The HFrEF group was

characterized by greater eccentric LA remodeling, while the HFpEF group was characterized by

increased LA stiffening and greater LA pressure pulsatility, indicating that higher wall stress

variations may contribute to greater burden of AF observed in HFpEF. In both groups, LA

function was associated with pulmonary vascular disease and right heart failure. While global

LA function was less impaired in HFpEF than HFrEF, LA dysfunction was more strongly

associated with mortality in this cohort, suggesting greater vulnerability to loss of LA function in

HFpEF. These data highlight the importance of atrial dysfunction in HF and suggest that

strategies to optimize LA function and/or to prevent its deterioration may mitigate progression of

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pulmonary vascular and right heart dysfunction while improving outcomes in HF patients and

particularly in HFpEF.

Few studies have compared LA structure/function in HFpEF and HFrEF, and none of

have reported associations between LA function and outcome.6, 30 31 In an echocardiographic

study, Triposkiadis et al compared LA remodeling in HFpEF and HFrEF and found more

eccentric LA remodeling in HFrEF group, similarly to the current data.31 In a smaller sample,

Kurt et al reported that HFpEF patients had LA enlargement, reduced LA function and increased

LA stiffness compared to controls, but in contrast to the current study, LA stiffness was not as

high in HFpEF as in HFrEF.30 However, the Kurt study measured only mean PAWP rather than

peak and minimal LA pressures, and the authors estimated LA stiffness simply as the ratio of

mean PAWP to LA systolic strain, in contrast to the more robust methods used in the current

study incorporating maximal and minimal LA pressure-volume coordinates. The current

observation of smaller and stiffer left atrium in HFpEF as compared to HFrEF is congruent with

known structure-function differences noted at the left ventricular level, supporting the notions

that HFpEF and HFrEF represent two distinct pathophysiological entities32 and that the systemic

processes favoring stiffening in all cardiac chambers, such as microvascular inflammation or

impaired nitric oxide availability, may contribute to the pathophysiology of HFpEF.33

Two overarching mechanisms are thought to drive the development of atrial dysfunction

in HF - chronic changes in loading (increased atrial preload and afterload) and the loss of normal

atrial electrical activity.10, 34 Experimental and limited human studies22, 35 have illustrated that

with increased preload, LA contractility initially rises22, 35, 36 but later declines, coinciding with

adverse changes in remodeling, apoptosis, myosin isoform expression, collagen matrix turnover

and reduced intrinsic contractility.36-38 As shown in the current data at the macro level, this

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translates to an increase in atrial wall stiffness reflected by the steeper and upward-shifted

pressure-volume relationship, predominantly in HFpEF and by a shift to the larger LA volumes,

predominantly in HFrEF. Despite the difference in LA volumes, we noted that LA function

curves (preload-stroke volume relations) were similarly flattened in HFrEF and HFpEF,

indicating presence of intrinsic LA dysfunction. In HFpEF, the increase of LA stroke volume by

preload recruitment (Frank-Starling mechanism) can be blunted by increased LA stiffness, as

recently suggested.39

As shown in the current study, loss of normal atrial electrical activity in HF patients with

AF is associated with more pronounced LA dilatation, systolic dysfunction and passive stiffening

(Supplemental Figure). However, HF patients in sinus rhythm also demonstrated LA systolic

impairment (active LA EF reduced by 37% in HFpEF and 54% in HFrEF), confirming that atrial

mechanical dysfunction in HF is not restricted to patients with AF.40-42 At similar mean LA

pressures, HFpEF patients demonstrated larger LA pressure pulsatility43 and greater LA wall

stress variation. We speculate that this may contribute to the higher prevalence of AF noted in

HFpEF compared to HFrEF, despite smaller LA volumes, similar LA pressures, and similar HF

severity and mortality risk.44

The differences in LA structure-function also appear to influence how the LA copes with

mitral regurgitation. With increasing regurgitation, LA pressure and wall stress increases much

more steeply in HFpEF than in HFrEF, which may promote stretch-mediated atrial ectopy that

plays a role in initiation of AF.34 While LA function was less impaired in HFpEF than HFrEF, its

association with outcome was more pronounced, congruent with previous reports regarding the

differential impact of AF on outcomes in HFpEF or HFrEF.8 The current data provide insight

into the mechanisms by which this HF phenotype-specific difference may originate.

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Previous studies have suggested a potential association between atrial dysfunction and

pulmonary hemodynamics, but these non-invasive studies were not able to discriminate between

the impact of intrinsic LA properties from passive LA pressure elevation due to volume

overload.9, 30, 45 We observed that impaired LA global systolic function (quantified by total LA

EF)7 correlated with increased PVR and reduced PAC measured directly by cardiac

catheterization. Impaired diastolic LA function (LA stiffness) was associated with reduced PAC,

a measure of oscillatory PA load. The relations between LA functional properties and pulmonary

vasculature were similar between HFpEF and HFrEF. The current data strongly implicate that

LA dysfunction belongs among the mediators of pulmonary vascular disease in HF.11 By having

impact in PA hemodynamics, LA dysfunction can also indirectly influence RV function and

contribute to progression towards biventricular failure with poor prognosis.26, 46

These data suggest that maintenance or restoration of normal LA function may help to

“protect” the pulmonary vasculature, and in doing so, to prevent deterioration of the right heart.

Further studies are required to assess whether this approach is beneficial. Conversely, these data

also indicate that LA interventions that might increase stiffness or impair systolic function might

have unintended adverse consequences on the pulmonary vasculature. Left atrial wall scarring

and volume reductions after repeated radiofrequency AF ablations have recently been associated

with development of pulmonary hypertension,47 and removal of LA appendage, the most

contractile and compliant part of the left atrium, increases atrial stiffness and reduces atrial

performance.37 As LA interventions such as device closure and ablation become more widely

utilized in HF patients, the potential for deleterious effects on pulmonary vascular-right heart

function should be considered and evaluated in future trials.

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13

Limitations

This study is retrospective, observational and is influenced by referral bias. All subjects

underwent cardiac catheterization, so this sample is generally limited to patients with more

advanced HF and may not be applicable to the entire HF population. The use of PAWP for

inclusion into HF group assured that the patients studied truly had HF, but because patients with

less advanced HF may have normal PAWP at rest, these results may not apply to HF patients

with earlier stage disease. The primary cause of ventricular dysfunction in HF patients could not

be assessed in this retrospective study. The control group was drawn from consecutive patients

referred for invasive assessment, so by virtue of being referred for cardiac catheterization, this is

not representative of completely healthy comparator group. However, this invasive study would

not be feasible in healthy volunteers. Hemodynamic and echocardiographic data were not

acquired simultaneously, but both occurred within a 48 hour time frame. The relations between

HF phenotype and atrial characteristics were studied cross-sectionally so all inferences about

causality are hypothesis-generating. Despite age-adjusted comparisons, differences in age

between groups may confound the conclusions. Data on quality of life were not systematically

recorded and all measures were performed at rest and in the supine position, so we were unable

to address the relation of our findings to exertional symptoms or quality of life.

LA pressures were not measured directly, but assessed by PAWP, which is dampened

compared to directly measures LA pressures, leading to systematic underestimation of diastolic

LA stiffness and pulsatility, though this underestimation was uniform between HF groups and

controls. The number of enrolled subjects and deaths was moderate, which both prevented

multivariable analysis. Thus, further work is needed to confirm the univariate relationships we

observed between LA size / function and outcomes, which could be potentially cofounded by

for cardiac cathththhthhhee

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14

other intermediary factors. However, follow-up was complete in 100% of patients, enhancing

confidence in our results.

In conclusion, the current data provide insight into pathophysiology of LA dysfunction

and pulmonary hypertension in HF. The LA remodeling in HFpEF and HFrEF differs, with more

dilation and systolic dysfunction in HFrEF and with increased stiffness, pulsatility and

predilection for AF in HFpEF. Restoration of LA mechanical function may have favorable

effects on pulmonary vasculature and right heart, while processes and interventions that reduce

atrial contractility or adversely affect LA compliance may promote and exacerbate pulmonary

hypertension, leading to right heart dysfunction and increased risk of adverse outcomes,

especially in patients with HFpEF.

Sources of Funding

VM is supported by the Czech Ministry of Health (DRO institutional support IKEM 00023001;

IGA NT14050-3/2013 and NT14250-3/2013), by the Grant Agency of Czech Republic (15-

14200S), by the Czech Ministry of Education (MSMT-LK12052-KONTAKT II), by EU-funded

project CEVKOON (CZ.2.16/3.1.00/22126) and by the Fulbright Foundation.

Disclosures

None.

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the severity ofofoooooeeeeechchchchchchchocococococococararararararardididididididiogogogogogogogrrrrararr phphphphphphph

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Table 1. Clinical and laboratory characteristics

Controls

n = 40

HFpEF

n=101

HFrEF

n=97

p

Age, years 63 ± 7 71 ± 10 * 61 ± 13 † < 0.0001

Female gender 53 % 58% 20% *† < 0.0001

BMI, kg.m-2 29 ± 5.8 34 ± 8.6 * 31 ± 6.9 † 0.006

BSA, m2 2.0 ± 0.3 2.0 ± 0.3 2.1 ± 0.3 * 0.02

NYHA grade 1.0 ± 0.2 3.0 ± 0.6 * 3.2 ± 0.7 *† < 0.0001

HF hospitalization, ever 0 43 % 91 % < 0.0001

HF diagnosis duration, years 0 1.0 (1.5 – 2.0) 3.0 (1.0-7.5) < 0.0001

Coronary artery disease 0 % 44 % * 46 % * < 0.0001

Hypertension 57 % 93 % * 56 % † < 0.0001

Pacemaker or ICD 0 % 12 % * 66 % *† < 0.0001

Atrial fibrillation 0 % 42 % * 26 % *† < 0.0001

Diabetes mellitus 0 % 47 % * 41 % * < 0.0001

Diuretics 23 % 83 % * 87 % * < 0.0001

Loop diuretics daily dose, mg 0 45 ± 46 * 75 ± 97 *† < 0.0001

BB/ACEi or ARB / AldoRA, % 13 / 42 / 5 67* / 59 / 16 95*† / 82*† / 38*† all < 0.0001

NT-pro-BNP, pg.ml-1 19 (14-65) 1142 (408–2914) * 2481 (1174-4757)*† < 0.0001

GFR §, ml.min.1.73 m-2 71 ± 32 47 ± 21 * 46 ± 21 * 0.01

.7 †††

%

†

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44 %%%% * 46 % *

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20

Values a means±SD or medians (IQR). ANOVA and Tukey post-hoc test or Chi-square test. * p<0.05 vs controls, † p<0.05 vs HFpEF. NTproBNP tested after log-transformation. § GFR: glomerular filtration rate, estimated with MDRD formula. BMI: body mass index, BSA: body surface area, BB: beta-blockers, ACEi: angiotensin-converting enzyme inhibitors, ARB: angiotensin receptor blockers, AldoRA: aldosterone receptor antagonists.



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Table 2. Left atrial and left ventricular function Controls

n = 40

HFpEF

n = 101

HFrEF

n = 97

p

Left atrial function

LA pressure mean, mmHg 8.1 ± 2.8 20 ± 6.1 * 20 ± 8.1 * < 0.0001

minimum, mmHg 5.5 ± 3.7 16 ± 6.1* 18 ± 7.3*† < 0.0001

A§ and V wave, mmHg 12±4 / 12±5 23±8 * / 34±13 * 24±9 */ 30±12 * < 0.0001 / < 0.0001

min-max difference, mmHg 7.9 ± 2.8 19 ± 10 * 13 ± 7.8 *† < 0.0001

LA volume max, ml 45 ± 12 85 ± 28 * 104 ± 38 *† < 0.0001

pre-A§, ml 30 ± 10 55 ± 17 * 77 ± 29 *† < 0.0001

min, ml 16 ± 6.3 54 ± 27 * 71 ± 35 *† < 0.0001

LA volume max/BSA, ml.m-2 23 ± 5 41 ± 12 * 50 ±17 *† < 0.0001

LA EF - total, % 65 ± 8.9 39 ± 17 * 35 ± 15 *† < 0.0001

- active §, % 48 ± 11 30 ± 14 * 22 ± 13 *† < 0.0001

- passive§, % 33 ± 11 26 ± 9.3 * 21 ± 10 *† < 0.0001

LA stiffness, mmHg.ml-1 0.30 ± 0.20 0.79 ± 0.75 * 0.48 ± 0.44 † < 0.0001

LA function index (LAFI) 220 ± 118 60 ± 65 * 30 ± 37 *† < 0.0001

LA wall stress max, kdynes.cm-2 80 ± 31 294 ± 120 * 281 ± 123 * < 0.0001

min, kdynes.cm-2 38 ± 25 137 ± 59 * 167 ± 74 *† < 0.0001

change, kdynes.cm-2 41 ± 18 158 ± 92 * 113 ± 74 *† < 0.0001

††

†

41 ± 12 * 50 ±17 *†

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54 ± 22227 7 77 * 717171717 ± 35 *†

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Values a means±SD. ANOVA and Tukey post-hoc test or Chi-square test. * p<0.05 vs controls, † p<0.05 vs HFpEF. LA: left atrial, EF: ejection fraction, BSA: body surface area, LV: left ventricular. § parameters available only in HF patients with sinus rhythm (n=130).

Left ventricular function

Heart rate, min-1 68 ± 13 69 ± 13 72 ± 14 0.14

Cardiac index, l.min-1.m-2 3.0 ± 0.5 3.0 ± 0.5 2.4 ± 0.6 *† < 0.0001

Systemic pressure mean, mmHg 123 ± 13 128 ± 19 107 ± 18 *† < 0.0001

pulse, mmHg 49 ± 13 60 ± 18 * 42 ± 13 *† < 0.0001

LV end-diastolic diameter, mm 48 ± 41 49 ± 5.8 67 ± 11 *† < 0.0001

LV ejection fraction, % 62 ± 4.3 62 ± 5.9 24 ± 9.7 *† < 0.0001

LV mass index, g.m-2 85 ± 18 102 ± 31 * 149 ± 46 *† < 0.0001

Mitral regurgitation grade, (0-3) 0.8 ± 0.8 1.8 ± 0.8 * 2.5 ± 0.9 *† < 0.0001

Transmitral E vel., cm.s-1 68 ± 18 106 ± 31 * 89 ± 27 *† < 0.0001

A vel.§, cm.s-1 67 ± 21 74 ± 31 52 ± 27 † < 0.0001

E deceleration time, ms 210 ± 27 189 ± 54 155 ± 46 *† < 0.0001

Mitral annulus E‘ vel., cm.s-1 8.0 ± 1.2 7.7 ± 2.2 6.2 ± 2.1 *† < 0.0001

A‘ vel,§ cm.s-1 11 ± 2.3 8.5 ± 3.5 5.7 ± 2.9 *† < 0.0001

Diastolic dysfunction grade, %

indeterminate/0/1/2/3 8/50/25/17/0 34/9/15/23/19 27/0/5/16/52 < 0.0001

†††††††

1.8 ± 0.8 * 2.5 ± 0.9 *†11111.8 ± 0.8 * 2.5 ± 0.9 *****†††††

101066 ±±± 3131313131 * 888889 9999 ±±± 27727 *† †

74 ±±± 3333311111 525252 ±±±±± 22227777 7 †††††



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23

Table 3. Right heart and pulmonary vascular function

Controls

n = 40

HFpEF

n = 101

HFrEF

n = 97

p

ANOVA

RA mean pressure, mmHg 5.3 ± 3.0 13 ± 5.6 * 12 ± 6.6 * < 0.0001

PA pressure systolic, mmHg 28 ± 6.2 56 ± 19 * 51 ± 15 * < 0.0001

diastolic, mmHg 9.0 ± 3.8 21 ± 7.3 * 22 ± 8.1 *† < 0.0001

mean, mmHg 17 ± 4.4 35 ± 11 * 35 ± 10 * < 0.0001

pulse, mmHg 19 ± 4.0 35 ± 14 * 28 ± 10 *† < 0.0001

Transpulmonary gradient, mmHg 8.7 ± 3.1 15 ± 8.0 * 14 ± 6.6 * < 0.0001

Pulm. arterial compliance (PAC), ml.mmHg-1 4.5 ± 1.5 3.1 ± 1.4 * 3.0 ± 1.4 * 0.0004

Pulm. vascular resistance (PVR), w.u. 1.5 ± 0.6 2.6 ± 1.7 * 3.0 ± 1.7 * 0.005

RV end-diastolic area, cm2 15 ± 3.7 21 ± 6 * 22 ± 7 * < 0.0001

RV fractional area change (RV FAC) % 50 ± 7.3 40 ± 10 * 36 ± 13 *† < 0.0001

RA max volume, ml 37 ± 12 72 ± 37 * 83 ± 44 * < 0.0001

Tricuspid regurgitation grade, (0-3) 0.7 ± 0.8 2.2 ± 1.1 * 2.3 ± 1.0 * < 0.0001

Values a means±SD. ANOVA and Tukey post-hoc test. * p<0.05 vs controls, † p<0.05 vs HFpEF. RA: right atrial, RV: right ventricular, w.u.: Wood´s units.

±±±±±±± 11111110 0 0 0 0 0 0 *******

8

4

19 99 99 ±± ±±± 4.4444 0 0000 35 ± 14 * 222228 ± ±±±± 10 *†

8.77.7.7.7 ± 3.1.1.1.1.1 1515151515 ±±±±± 88888 0000.0 * 11114 444 ± ±± 6.6.6.6.6 6 666 ****

4.5 ± 1.5 33333.11111 ±±±±± 1111.44444 * 3333.00000 ± 1.4 *



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Figure Legends

Figure 1. Characteristics of left atrial (LA) function. A) Representative ECG, LA pressure

and LA volume waveforms. B) Schematic example of LA pressure-volume loop with smaller a-

loop and larger v-loop. LA stiffness is represented by slope of dashed line ( ) that connects

maximal and minimal pressure-volume points. C) Equations used for LA functional

characterization.

Figure 2. Left atrial (LA) remodeling and dysfunction in controls vs HFpEF and HFrEF.

A) increased maximal, diastasis and minimal LA volumes and B) reduced total, active and

passive LA ejection fraction in patients with HFpEF and HFrEF compared to controls. C) Slope

of P-V relationships in controls and in patients with HFpEF or HFrEF. *p< 0.05 vs controls, #p<

0.05 vs HFrEF. Thus, HFrEF patients display greater LA chamber dilation and lower

contractility, while HFpEF patients display stiffer LA chambers.

Figure 3. LA performance in HF and controls and the influence of mitral regurgitation on

the left atrium. A) Relations between LA volume prior the onset of LA contraction (LA pre-A

volume) and LA active stroke volume in controls and HF patients with sinus rhythm (n=130). B)

The impact of mitral regurgitation grade on peak LA pressure (LA v-wave, left) and min-max

LA wall stress change (right) in controls, HFrEF and HFpEF. Lines represent results of linear

regression with 95% confidence intervals and correlation coefficients. Thus, LA performance is

reduced due to impairment of the Frank-Starling mechanism in both HF groups, while the

presence of mitral regurgitation is associated with higher wall stress variations and greater v-

wave height in HFpEF.

nd B) reduceeeeed d ddddd

F compmpmpmpmpmpmparararararararededededededed tttttttooooooo coc

5

T a

H

iiiiinn nnn controrororoolslslslsls aaaaandndndndnd iiin n nn n papapapapatitititit enenenene tsssss wwithhh HFHFHFFHFpEpEpEpEpEFFFFF orororo HHHHHFrFrEFEFEFEFEF.. ... *ppppp<<<<< 0.0.0.0.0.05000r

Thuhuhuhuuss,ss,s, HHHHHFrFrFrFrFrEFEFEFEFEF pppppattieieieieientntntntntsss dididididispspspspsplalalall y yyyy grgrgrgrgreaeaeaeaeateteteteter rr LALALALALA cccchahahahahambmmbmm ererererer dddddilililii a

HHFpFpEFEF pppppatatatieientntntsss didispspsppplalay y y y stststififfeferrr LALA ccchahambmbererersss.



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25

Figure 4. The impact of HF severity on the left atrium. The impact of HF severity (NYHA

functional class) on LA characteristics assessed by ANOVA and Tukey post-hoc test, *p<0.05 vs

controls, §p< 0.05 vs NYHA II, #p<0.05 vs NYHA III. LAVI max: body surface area-indexed

maximal LA volume. Thus, LA dysfunction is related to HF severity.

Figure 5. The left atrium and pulmonary vascular properties/right heart function. A)

Relation of global LA function (total LA EF, %) to pulmonary vascular resistance (PVR) and

pulmonary artery compliance (PAC) and right ventricular systolic function (RV fractional area

change, RV FAC %) in HFrEF (red), HFpEF (blue) controls (black). Lines represent results of

linear regression with 95% confidence intervals, r: Pearson´s correlation coefficient. Thus, LA

dysfunction is associated with greater pulmonary vascular disease and RV dysfunction in HF.

Figure 6. The impact of LA characteristics and atrial fibrillation on survival in HFpEF and

HFrEF. Univariate Cox model was used to determine the hazard ratio for death associated with

being in a group above median of a parameter (or yes/no for AF). Continuous parameters were z-

standardized within HF subgroups.*p<0.05. Thus, LA dysfunction is associated with mortality in

HFpEF but not HFrEF.

orororororororrererererererelalalalalalalatitititititiiononononononon cccccccoeoeoeoeoeoeoeffffffffffffff

iated with greater pulmonary vascular disease and RV dysfu

a a

h

iateteteteted dd d d wiwiwiwiwithtttt gggggreater pulmonary vvvvvasaaasascular diseassssseeeee and RV dysfu

acttttt ooooof fff LALALALALA ccccchahahahaharararararactctcterereree isisisisstttitt cscscscscs aaaaandndndndnd atatatatatriririririalalalalal fffffibibibibibriririririllllllllllatatatatatioioioioi n nnnn ononononon sususuurvrvrvrvr ivivivvivaaa

CCoxoxox mmmododelel wwwasasas uuusesesedd tototo ddetetetererermiminenene ththeee hahazazazardrd rrratatatioio ffororor ddeaeaeathth



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LA volume

LA pressure

A

a wavev wave

x

LA stiffness =

Active LA EF =Vdiastasis – Vmin

Vdiastasis

Figure 1

Total LA EF =Vmax – Vmin

Vmax

Passive LA EF =Vmax – Vdiastasis

Vmax

C

Vdiastasis

Vmin

Vmax

LA pressure

LA volume

Vmin Vdiastasis Vmax

Pmax

Pmin

B

a loop

v loop

ECG

a a a a l

P

VmiminnVV

PPPPPmimimimiinnnnnP



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Figure 2

C B A



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A B

Figure 3



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Figure 4



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Figure 5



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Figure 6

Total mortality, hazard ratio



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BorlaugVojtech Melenovsky, Seok-Jae Hwang, Margaret M. Redfield, Rosita Zakeri, Grace Lin and Barry A.

Ejection FractionLeft Atrial Remodeling and Function in Advanced Heart Failure With Preserved or Reduced

Print ISSN: 1941-3289. Online ISSN: 1941-3297 Copyright © 2015 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation: Heart Failure published online January 15, 2015;Circ Heart Fail.

http://circheartfailure.ahajournals.org/content/early/2015/01/15/CIRCHEARTFAILURE.114.001667World Wide Web at:

The online version of this article, along with updated information and services, is located on the

http://circheartfailure.ahajournals.org/content/suppl/2015/03/12/CIRCHEARTFAILURE.114.001667.DC2 http://circheartfailure.ahajournals.org/content/suppl/2015/01/15/CIRCHEARTFAILURE.114.001667.DC1

Data Supplement (unedited) at:

http://circheartfailure.ahajournals.org//subscriptions/

is online at: Circulation: Heart Failure Information about subscribing to Subscriptions:

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click Request Permissions in the middle column of the Web page under Services. Further information about thisEditorial Office. Once the online version of the published article for which permission is being requested is located,

can be obtained via RightsLink, a service of the Copyright Clearance Center, not theCirculation: Heart Failure Requests for permissions to reproduce figures, tables, or portions of articles originally published inPermissions:



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Supplemental MaterialSupplemental Figure. The impact of HF type or atrial rhythm (SR: sinus rhythm, AF: atrial fibrillation) on LA characteristics

assessed by 2‐way ANOVA in HF subjects. Thus, LA dysfunction is not simply ascribable to AF, but there is atrial

dysfunction even in SR.

Original Articles

10 Circulation: Heart Failure

구혈률저하 심부전의 좌심방은 크기가 증가하고

기능이 저하되나, 구혈률보존 심부전에서는

좌심방 경직도가 증가하여 심방세동이 증가한다

최 진 오 교수 · 삼성서울병원 순환기내과

초록

배경

대부분의 심부전 환자에서 좌심방의 구조와 기능은 변화한다.

구혈률보존 심부전(heart failure with preserved ejection

fraction)과 구혈률저하 심부전(heart failure with reduced

ejection fraction) 간에 좌심방의 변화 양상에는 근본적인

차이가 있을 수 있다.

방법 및 결과

총 198명의 심부전 환자(구혈률보존 심부전 환자 51%,

뉴욕심장학회 기능 분류 3.1±0.7)와 40명의 심부전이

없는(heart failure-free) 대조군 환자에게 심도자 및

심초음파 검사를 시행하고, 그 경과를 추적하였다. 대조군에

비하여 심부전 환자들은 좌심방이 크고, 기능이 저하되어

있었다. 심부전 환자군 간의 비교를 보면, 평균 좌심방압

(20 vs. 20mmHg; P=0.9)은 차이가 없었으나, 구혈률저하

심부전군의 좌심방은 크기가 더 증가되어 있었다(좌심방

용적지수 50 vs. 41mL/m2; P<0.001). 반면, 구혈률보존

심부전군은 좌심방 최대 압력이 더 높고 최소 압력은 더 낮아,

더 높은 좌심방 경직도를 보였고(0.79 vs. 0.48mmHg/mL;

P<0.001), 좌심방 박동성(19 vs. 13mmHg; P<0.001)과

벽장력의 변동성(wall stress variations)이 더 증가되어

있었다. 구혈률보존 심부전군은 좌심방 용적이 더 작고,

기능 은 더 좋았으며, 승모판 역류도 덜 심하였지만,

심방세동은 더 많았다(42 vs. 26%; P=0.02). 양 군 모두

좌심방의 기능부전은 폐혈관 저항의 증가 및 우심실기능

저하와 연관되어 있었다. 추적 관찰 기간(중앙값 350일)

중에 구혈률보존 심부전 환자 31명과 구혈률저하 심부전

환자 28명이 사망하였다. 좌심방기능(총 좌심방 구혈률)은

구혈 률보존 심부 전에 서는 낮은 사 망률과 연관되어

있었으나(HR 0.43; 95% CI, 0.2-0.9; P<0.05), 구혈률저하

심부전에서는 연관이 없었다.

결론

구혈률저하 심부전에서의 좌심방 리모델링은 편심성

(eccentric) 확장이 주된 양상인 반면, 구혈률보존 심부전에서

는 좌심방 경직도가 증가하는 것이 특징으로, 이는 심방세동

의 발생에 영향을 줄 수 있다. 좌심방기능은 양 군 모두에서 폐

혈관질환 및 우심부전과 관련되었으나, 구혈률보존 심부전이

보다 더 밀접하게 연관되어 있었으며, 이는 구혈률보존 심부전

환자들에서 좌심방기능을 호전시키기 위한 노력에 대한 의학

적 근거가 될 것이다.

left atrial remodeling and function in advanced heart...

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