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, PhD 1,2 ; Seok-Jae Hwang, MD, PhD 1 ; Margaret M. Redfield 1 , MD; Rosita Zakeri, MBChB 1 ; Grace Lin, MD 1 ; Barry A. Borlaug, MD 1 1 Division 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 al al al al al al al M M M M M M Med ed ed ed ed ed edic ic ic ic ic ic icin in in in in in ine e e e e e e - - IK IK K K K K K y i 4 140 28 C hR bli y, MD, PhD io iol logy, IK IK IK IK IKEM EM EM EM EM 4 4 4 1 1 140 40 40 2 2 28 8 8 C C C h h h R R R b b bli li li by guest on January 16, 2015 http://circheartfailure.ahajournals.org/ Downloaded from by guest on January 16, 2015 http://circheartfailure.ahajournals.org/ Downloaded from by guest on January 16, 2015 http://circheartfailure.ahajournals.org/ Downloaded from
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Left Atrial Remodeling and Function in Advanced Heart Failure With Preserved … · 2015-09-08 · 3 The left atrium modulates left ventricular (LV) filling by acting as an elastic
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Left Atrial Remodeling and Function in Advanced Heart Failure With
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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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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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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
e i
e data while contrasting LA parameters in the two HF pheno
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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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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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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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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).
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.
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