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J Am Coll Cardiol, 2007; 49:198-207, doi:10.1016/j.jacc.2006.08.050 (Published online 28 December 2006).
© 2007 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: HEART FAILURE

Cardiovascular Features of Heart Failure With Preserved Ejection Fraction Versus Nonfailing Hypertensive Left Ventricular Hypertrophy in the Urban Baltimore Community

The Role of Atrial Remodeling/Dysfunction

Vojtech Melenovsky, MD*,{dagger},§,1, Barry A. Borlaug, MD*, Boaz Rosen, MD*, Ilan Hay, MD*, Luigi Ferruci, MD, PhD{ddagger}, Christopher H. Morell, PhD§, Edward G. Lakatta, MD{dagger}, Samer S. Najjar, MD{dagger} and David A. Kass, MD*,*

* Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland
{dagger} Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
{ddagger} Clinical Research Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
§ Department of Mathematical Sciences, Loyola College in Maryland, Baltimore, Maryland.

Manuscript received January 18, 2006; revised manuscript received August 8, 2006, accepted August 14, 2006.

* Reprint requests and correspondence: Dr. David A. Kass, Ross 835, Division of Medicine, Johns Hopkins Medical Institutions, 720 Rutland Avenue, Baltimore, Maryland 21205. (Email: dkass{at}jhmi.edu).


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 Appendix
 References
 
OBJECTIVES: The purpose of this study was to identify cardiovascular features of patients with heart failure with preserved ejection fraction (HFpEF) that differ from those in individuals with hypertensive left ventricular hypertrophy (HLVH) of similar age, gender, and racial background but without failure.

BACKGROUND: Heart failure with preserved ejection fraction often develops in HLVH patients and involves multiple abnormalities. Clarification of changes most specific to HFpEF may help elucidate underlying pathophysiology.

METHODS: A cross-sectional study comparing HFpEF patients (n = 37), HLVH subjects without HF (n = 40), and normotensive control subjects without LVH (n = 56). All subjects had an EF of >50%, sinus rhythm, and insignificant valvular or active ischemic disease, and groups were matched for age, gender, and ethnicity. Comprehensive echo-Doppler and pressure analysis was performed.

RESULTS: The HFpEF patients were predominantly African-American women with hypertension, LVH, and obesity. They had vascular and systolic-ventricular stiffening and abnormal diastolic function compared with the control subjects. However, most of these parameters either individually or combined were similarly abnormal in the HLVH group and poorly distinguished between these groups. The HFpEF group had quantitatively greater concentric LVH and estimated mean pulmonary artery wedge pressure (20 mm Hg vs. 16 mm Hg) and shorter isovolumic relaxation time than the HLVH group. They also had left atrial dilation/dysfunction unlike in HLVH and greater total epicardial volume. The product of LV mass index and maximal left atrial (LA) volume best identified HFpEF patients (84% sensitivity, 82% specificity).

CONCLUSIONS: In an urban, principally African American, cohort, HFpEF patients share many abnormalities of systolic, diastolic, and vascular function with nonfailing HLVH subjects but display accentuated LVH and LA dilation/failure. These latter factors may help clarify pathophysiology and define an important HFpEF population for clinical trials.

Abbreviations and Acronyms
  Ea = arterial elastance
  Ees = end-systolic elastance
  HF = heart failure
  HFpEF = heart failure with preserved ejection fraction
  HLVH = hypertensive left ventricular hypertrophy
  LA = left atrial
  LV = left ventricular
  LVH = left ventricular hypertrophy
  PAWP = pulmonary artery wedge pressure

Nearly one-half of patients with heart failure have an ejection fraction (EF) at or above 50% (1). Despite the high prevalence, morbidity, and economic burden (2–4) of heart failure with preserved ejection fraction (HFpEF), its pathophysiology remains somewhat controversial and evidence-based guidelines for management are lacking. A majority of HFpEF patients are elderly women with a history of systolic hypertension, many with cardiac hypertrophy and obesity (1,5–9). These are common features in the general population, and frequent among African-American women, who have the highest prevalence of hypertension worldwide (10). Most are without heart failure (HF) symptoms, and although they may have preclinical disease (11) only a subgroup develops clinical HFpEF.

Cardiovascular features that might best distinguish patients with HF symptoms from those with similar clinical features such as hypertensive left ventricular hypertrophy (HLVH) but without HF remain unknown, because most studies have contrasted HFpEF patients to healthy normotensive (non-LVH) control subjects. Abnormal diastolic function (2,12–16), vascular stiffening (17–19), and increased ventricular end-systolic stiffness (elastance [18]) have all been implicated, but it is unclear which descriptors are most specific and independent. Accordingly, the goal of the present study was to comprehensively assess resting ventricular and vascular physiologic properties in an inner-city cohort of HFpEF patients, and compare the findings with those obtained in 2 control groups with similar mean age, race, and gender with or without chronic HLVH. We hypothesized that many ventricular and arterial abnormalities thought to underlie HFpEF would be shared by asymptomatic HLVH subjects, but that other changes would be observed more selectively in HFpEF that might highlight critical maladaptations and/or novel pathophysiology.


   Methods
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 Abstract
 Methods
Results
 Discussion
 Appendix
 References
 
Study subjects.   The HFpEF patients were prospectively identified from admission records at Johns Hopkins Hospitals between January 2002 and June 2005. Heart failure was rigorously defined by Framingham criteria (see the ) (20–22) and independently adjudicated by 2 cardiologists. All HFpEF subjects had been hospitalized for pulmonary congestion diagnosed by chest radiogram and clinical examination, had EF >50% within 24 to 72 h of index admission, and were required to be in sinus rhythm. There were no other a priori inclusion criteria. Patients with active ischemic heart disease (i.e., angina, positive stress test, acute coronary syndrome), segmental wall motion abnormalities, atrial flutter/fibrillation, valvular disease (more than trace regurgitation or stenosis), primary hypertrophic or other cardiomyopathy (e.g., amyloid), pericardial disease, anemia (hemoglobin <10 g/dl), hyperthyroidism, renal failure (creatinine >3 mg/dl or requiring dialysis), advanced pulmonary disease or pulmonary hypertension (estimated pulmonary artery systolic >60 mm Hg), or cognitive impairment precluding participation were excluded.

Two control groups were studied. The HLVH subjects were identified from outpatient echocardiogram records and screened using hospital records, interview, and formal history and physical to confirm lack of diagnosis, treatment, or symptoms for clinical HF. The other group was made up of normotensive subjects without LVH, recruited from participants in the Baltimore Longitudinal Study of Aging (8). The latter were asymptomatic and had no prior diagnosis, history, or hospitalization for HF or cardiovascular disease (except for mild and well controlled hypertension in some). Both control groups were selected from a larger screening pool so that the predominant ethnicity (African American), gender (female), and age (>50 years) matched the mean values for the HFpEF group. Identical exclusion criteria used for HFpEF patients applied to the control groups. The study was designed as prospective. Owing to application of selection criteria, studied subjects were nonconsecutive. The protocol was approved by the Johns Hopkins Medical Institutions and National Institute on Aging Institutional Review Board, and written informed consent was obtained.

Study procedures.   Clinical symptoms were assessed in the HFpEF and HLVH groups by the Minnesota Living with Heart Failure Questionnaire (MLHFQ). All subjects were studied in a stable compensated state (>1 month after discharge from an HF hospitalization for HFpEF). Measurements were made after >15 min rest in a supine position and involved comprehensive echo-Doppler (Sonos 5500, Philips, Andover, Massachusetts), pulse tonometry (VP2000, Omron Healthcare Inc., Bannockburn, Illinois), and arm-cuff (Dinamap, Tampa, Florida) pressure measurements. Reserve function to acute afterload increase (sustained isometric handgrip, 30% of maximal) was tested in the HFpEF and HLVH groups, recording blood pressure and cardiac echo-Doppler images.

Cardiac function analysis.   Echo-Doppler images were analyzed off line by a single investigator blinded to subject group. Stroke volume (SV) was determined as LV outflow-tract area x flow velocity time integral by pulsed Doppler (23). Ejection fraction was calculated from parasternal long-axis views using the Teichholz formula. The LV end-diastolic volume (EDV) was equal to SV/EF (24). The LV mass (25) was indexed to body height (LVMI = g/m2.7), and LVH was defined using gender-specific thresholds (26). Geometry was indexed by relative wall thickness (LV septum + posterior wall thickness)/LV internal diameter) and LVM/EDV. Total epicardial volume was calculated from 2 hemiellipsoids containing both atria or ventricles using an apical 4-chamber view.

Systolic function included EF, endocardial and midwall fractional shortening (mFS) (27), ratio of observed (o) to predicted (p) mFS (o/pmFS, a contractility index [12]; pmFS = 29.08 – 0.0006 x circumferential wall stress [28]), and peak systolic chamber elastance (Ees) (29). Diastolic function was assessed by peak early (E) and late (A) mitral Doppler flow velocity, deceleration time, isovolumic relaxation time, pulmonary venous systolic/diastolic velocity ratio (pvS/D), longitudinal early (E') and late (A') tissue velocity (pulsed Doppler) at both mitral annular insertions, and averaged data. Mean pulmonary artery wedge pressure (PAWP) was estimated by E/E' (30–32). Diastolic dysfunction was graded according to mitral, pulmonary vein flow and myocardial tissue Doppler profiles using a modified scale (see the ) (33). Left atrial (LA) volumes were calculated by area-length method from apical 4-chamber views (34) to measure maximal, minimal, and diastasis LA volumes (LAVmax, LAVmin, and LAVdiastasis) and active and passive emptying function. In a subset of patients (HFpEF, n = 21; HLVH, n = 25), tissue-Doppler images were obtained in color-code mode from the apical 4-chamber view (Vivid7, GE Healthcare, Chalfont St. Giles, United Kingdom) at rest and at peak of a 6-min sustained handgrip exercise to assess atrial and cardiac reserve.

Arterial function.   Arterial function was assessed by carotid artery applanation tonometry (35) and oscillometric brachial pressure. Carotid systolic pressure augmentation (augmentation index) was calculated from digitalized (1.2 kHz) waveforms by standard algorithm, and waveforms were calibrated to match brachial mean and diastolic blood pressure (35). Total arterial compliance was estimated by SV/carotid pulse pressure ratio (36), and effective arterial elastance (Ea), a measure of total LV afterload, was estimated by the LV end-systolic pressure/SV ratio (37).

Statistical analysis.   Data are reported as mean ± SD, and p values are 2-sided with p < 0.05 considered to be significant. Between-group differences were assessed by 1-way analysis of variance with a post hoc Bonferroni test for 3 comparisons, and categorical variables were assessed by chi-square test (version 12.0, SPSS Inc., Chicago, Illinois). Correlations were tested by the Pearson coefficient. Between-group differences were further evaluated by analysis of covariance to adjust for effects of specific covariates.

To identify variables that best identified HFpEF from HLVH groups, linear discriminant analysis with backward elimination was used to generate a linear predictor function that provided the best between-group discrimination (version 9.1.2, SAS Institute, Cary, North Carolina). Remaining variables were entered into a classification/regression tree analysis (CART) yielding binary splits at optimal values according to the largest improvement of goodness of the fit (S-PLUS 7.0, Insightful, Seattle, Washington).


   Results
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 Abstract
 Methods
 Results
Discussion
 Appendix
 References
 
Demographics and comorbidities.   The HFpEF patients were predominantly older African-American (76%) women (84%). While not required for inclusion, all HFpEF patients had hypertension and ventricular hypertrophy, and most were obese (body mass index [BMI] >30 kg/m2 in 86%) (Table 1). The HFpEF patients had a higher prevalence of noninsulin-dependent diabetes (61%), coronary artery disease (CAD) history (42%), anemia, and mild renal dysfunction, consistent with earlier reports (5). The HFpEF patients were symptomatic, with a mean quality of life (QOL) score similar to that of severe systolic failure. The HLVH subjects were less obese (BMI >30 kg/m2 in 50%), less treated with diuretics, beta-blockers, and angiotensin-converting enzyme inhibitors (ACEI), and had a QOL score in the low to normal range. The control subjects had a prevalence of well controlled HTN typical for their age.


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  		Table 1. Clinical Characteristics
 
Hemodynamics and vascular properties.   Heart rate and stroke volume were nearly identical among groups (Table 2). The latter remained so after indexing to either body height or body surface area (BSA) (p = 0.5 and 0.3). Brachial and carotid pressures, total arterial resistance (raw and BSA indexed), and Ea were greater in HFpEF than in control subjects, and total arterial compliance was reduced—all consistent with arterial stiffening and systolic hypertension. Cardiac output was similar, although cardiac index was slightly lower in HFpEF than in control subjects (see the ). Nearly identical changes were observed in HLVH, suggesting they were due to coexisting clinical features and not specific to HFpEF.


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  		Table 2. Central and Peripheral Hemodynamic Parameters
 
Left ventricular structure and systolic function.   Ventricular hypertrophy was quantitatively greater in HFpEF than in HLVH whether expressed as absolute mass or indexed to body height, BSA (see the ), or height2.7 (Table 3). LV end-diastolic volume was similar among groups (Table 3) and remained so after normalizing to body height, height2.7, or BSA (see the ). The LV mass/volume or wall thickness/dimension concentricity indexes were highest in HFpEF (Table 3, see the ). The EF was near-identical, whereas the mitral-annular systolic velocity was slightly lower in HFpEF and HLVH, consistent with LVH. Peak ventricular systolic stiffness (Ees) was higher in HFpEF than in control subjects, as previously reported (18), but similarly elevated in HLVH subjects. This change remained after adjusting for medication use.


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  		Table 3. Left Ventricular Structure and Systolic Function
 
Diastolic ventricular function.   The HFpEF patients had several diastolic abnormalities compared with control subjects (Table 4); however, once again, many were similarly altered in non-HF HLVH subjects. Only 2 parameters differed between HFpEF and HLVH. The E/E' ratio, an estimate of PAWP, was somewhat higher in HFpEF, with more patients exceeding 18 mm Hg in HFpEF (57.1%) than in HLVH (31.6%) (p = 0.03). This disparity persisted after adjusting for LVMI or BSA (p = 0.024 and p = 0.001, respectively). Isovolumic relaxation time (IVRT) was shorter in HFpEF than in HLVH, which could relate to a higher PAWP, although the variables were not significantly correlated (p = 0.27).


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  		Table 4. Left Ventricular Diastolic Function and Left Atrial Morphology and Function
 
Figure 1 shows diastolic dysfunction grades, revealing substantial overlap in HFpEF and HLVH subjects. Although 59.4% of HFpEF patients had mild to moderate dysfunction (grades I and II), this also applied to 67.5% of HLVH subjects (p > 0.4). Advanced dysfunction (grade III) was rare in both groups (p = 0.26), and no dysfunction occurred in 16.2% of HFpEF versus 30% of HLVH (p = 0.15). Even 35.7% of the control subjects displayed some dysfunction (p < 0.001). Remaining subjects were not classifiable by this scheme.


Figure 1
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  		Figure 1 The Prevalence of DD Grades in Each Subject Group

Patients unclassifiable by the scheme are noted as indeterminate. There was substantial overlap in the prevalence of diastolic dysfunction (DD) in symptomatic heart failure with preserved ejection fraction (HFpEF) and asymptomatic hypertensive left ventricular hypertrophy (HLVH) subjects.

 
Atrial volumes and function.   Left atrial size and function were similar in the HLVH and control subjects but abnormal in the HFpEF subjects (Table 4). The LAVmax was 68% higher in HFpEF than in control subjects and 40% greater than in HLVH (both p < 0.0001). These disparities were preserved after indexing to BSA or by multivariate adjustment to BSA, LV mass, and estimated PAWP (p < 0.007) (Fig. 2). Therefore, differences in LA volume were not related to resting high filling pressures, altered ventricular geometry, or differences in anthropometry, although they could still have related to differential elevation of LA pressures during exercise. The LA volume before and after atrial contraction showed similar disparities. Atrial total, passive, and active emptying fraction was reduced in HFpEF versus control or HLVH subjects. The LAVmax was best predicted by the combination of LVMI, BSA, E/E', and age (z-standardized ß coefficients 0.34, 0.26, 0.24, and 0.15, respectively, by multiple regression with backward elimination; final r2 = 0.41).


Figure 2
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  		Figure 2 Comparison of LA Volumes and Emptying Fractions Adjusted for LV Mass Body Surface Area and Estimated Pulmonary Artery Wedge Pressure for Each Subject Group

Plots show the adjusted mean and 95% confidence interval. HFpEF subjects had significantly greater atrial size and reduced function. *p < 0.05 HFpEF versus LVH. LA = left atrial; LV = left ventricular; other abbreviations as in Figure 1.

 
The combination of biatrial and right ventricular enlargement, ventricular hypertrophy, and normal LV cavity size led to greater total heart (epicardial) volumes (Fig. 3, see the ). This is potentially important, because this volume relates to pericardial constraint and right-left heart interaction and could contribute to higher LV diastolic pressures.


Figure 3
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  		Figure 3 Total Epicardial Versus Left Ventricular End-Diastolic Chamber Volumes

Increase in total (epicardial) heart volume with similar end-diastolic volume (EDV) in HFpEF versus HLVH, and both versus control subjects. *p < 0.01 versus HLVH; {dagger}p < 0.001 versus control subjects. Abbreviations as in Figure 1.

 
Atrial reserve was assessed during sustained isometric handgrip in HFpEF and HLVH groups. The increases (percentage change from baseline) of heart rate (8% vs. 11% for HFpEF and HLVH, respectively; p = 0.2), cardiac output (12% vs. 15%; p = 0.8), and total arterial resistance (12% vs. 15%, p = 0.9) were similar. However, arterial pressure response was diminished in HFpEF (systolic: 18% vs. 25%, p = 0.02; diastolic: 22% vs. 33%, p = 0.02). Handgrip exercise did not alter LV EF, end-diastolic volume, Ees, or systolic and early-diastolic tissue velocities. However, late-diastolic annular tissue velocity (A') rose in HLVH subjects but was unchanged in HFpEF ({Delta} 34.9% vs. {Delta} 5.1%; p = 0.004) (Fig. 4), supporting reduced active atrial contractile reserve in the HF group.


Figure 4
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  		Figure 4 Reduced Atrial Systolic Reserve in HFpEF Patients

The effect of isometric handgrip exercise on late diastolic (A') annular tissue velocity in patients with HFpEF (n = 21) and asymptomatic HLVH subjects (n = 25). Unlike HLVH subjects, HFpEF patients had minimal increases in A' with handgrip-exercise. Data shown are mean ± SEM. *Between group ANOVA. Abbreviations as in Figure 1.

 
What parameters best differentiate HFpEF from HLVH subjects?.   Discriminate function analysis was performed to determine which parameter set best separated HFpEF from HLVH subjects. Thirty-nine variables (indicated by {ddagger} in tables, all reflecting parameters with significant differences between groups but avoiding colinearity) were entered, and 8 remained (misclassification error rate 0.145). These were (in order of influence): LVMI, history of CAD, LAVmax, relative wall thickness, diastolic blood pressure, history of CAD, total LA emptying fraction , Ees, and ACEI therapy. Interestingly, no resting vascular or conventional LV diastolic or systolic parameter (including diastolic dysfunction grade and tissue Doppler-derived indices) remained. Analysis of the remaining variables by CART-derived binary classification yielded LVMI (>71 g/m2.7) as the major predictor for HFpEF. A smaller mass but history of CAD and LAVmax >83 ml also predicted HFpEF, with a misclassification rate of 0.148.

The discriminatory capacity of individual parameters was further examined by histograms and receiver-operating curves (ROC). Distributions for E/E' ratio and diastolic dysfunction grade (Fig. 5A) revealed substantial overlap (particularly for HFpEF and HLVH), whereas those for LVMI and LAVmax (Fig. 5B) had greater separation. The LVMI and LAVmax were only weakly correlated (Fig 5C); therefore, their product (LVMI x LA-Volmax)—a marker of combined LV and LA morphologic change—provided the best discrimination (Figs. 5D and 5E) with an area under the ROC of 0.85. An optimal cut-off value of 4,418 ml·g/m2.7 separated both groups, with a sensitivity of 83.8% and a specificity of 82.5%.


Figure 5
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  		Figure 5 LV Mass and Atrial Volumes Better Distinguish HFpEF From HLVH Subjects Than Indexes of Diastolic Dysfunction

Histograms for group distributions of E/E' ratio and diastolic dysfunction (DD) grade (A) versus LVMI and LAVmax (B). The latter show better separation between HFpEF and HLVH subjects. (C) LA enlargement was weakly correlated to LVMI, particularly in the HFpEF subjects. (D) Product of LVMI and LAVmax provides the best separation among study groups. (E) Receiver-operating curves for discriminating between HFpEF and HLVH. The most optimal characteristic was found for LVMI x LAVmax (AUC = 0.85), followed by LVMI (AUC = 0.79) and LAVmax (AUC = 0.77). E/E' ratio (AUC = 0.69) and DD grade (AUC = 0.68) were poorer discriminators. The optimal cut-off value (4,418 ml x g/m2.7) of LVMI x LAVmax (arrow) separated the groups with a sensitivity 0.838 and specificity 0.825. AUC = area under the curve; E = early diastolic tissue velocity; E' = longitudinal early tissue velocity; LAV = left atrial volume; LVMI = left ventricular mass index; other abbreviations as in Figures 1 and 2.

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
Appendix
 References
 
The present study provides the first comprehensive comparison between cardiovascular function in HFpEF subjects and individuals with hypertension and LVH without symptoms, diagnosis, or treatment history of HF. We further matched age, gender, and ethnicity and included a third group without HLVH. Multiple ventricular systolic, diastolic, and vascular abnormalities were observed in HFpEF patients compared with normotensive non-LVH control subjects, as previously reported (14,15,17,18). However, most of these changes were similarly observed in HLVH subjects, suggesting they were primarily related to coexisting clinical features. Between the 2 groups, LVH magnitude and atrial dilation/failure differed most, providing the best separation based on regression modeling and ROC analysis. The results suggest that atrial function may be a key compensatory mechanism countering evolution of HFpEF, and they highlight the diagnostic utility of atrial failure as a marker of the disease.

The term "heart failure with a preserved ejection fraction" is descriptive of a syndrome involving multiple cardiovascular abnormalities that may each contribute to symptoms. Vascular and ventricular stiffening exacerbate blood pressure fluctuations, promote ventricular hypertrophic response, increase cardiac systolic load particularly during stress, and compromise systolic reserve (18,38). Diastolic abnormalities lead to higher filling pressures to achieve adequate filling, contributing to the redistribution of blood to the central thorax. Increased heart volume and exaggerated epicardial constraint may also contribute (18). Finally, atrial dilation and dysfunction likely represent loss of an important compensation which becomes increasingly important given the other abnormalities. By comparing HFpEF with HLVH, we were better able to resolve what may be the "last straw" that finally separates preclinical hypertensive heart disease from HFpEF. Our data do not refute results of earlier work designed to elucidate the pathophysiology of HFpEF (i.e., contribution of individual factors). Rather, they show that when comparing preclinical HLVH with HFpEF, the amount of concentric LV hypertrophy, LA remodeling, and epicardial volume enlargement are particularly abnormal.

The present results are in concert with earlier studies that compared HFpEF subjects with normotensive and/or nonhypertrophied control subjects (1,9,13–18,20,39). However, the fact that many similar abnormalities were observed in subjects with HLVH without HF makes it more difficult to assign primary causality to any one change. Advanced age, race, hypertension, gender, LVH, and obesity each significantly influences vascular and ventricular function (8,38,40,41), yet their presence does not guarantee HF symptoms. The present HFpEF patients were predominantly African American, reflecting our inner-city referral population, but this is an important group that often has been overlooked. African Americans have a high prevalence of hypertension and a higher propensity to develop LVH (7), display an earlier presentation of HFpEF (5), and may have a worse prognosis with this disease (42).

Ventricular function in HFpEF.   Rest contractility appeared normal in HFpEF, consistent with recent data (12), although some systolic parameters were altered. Systolic tissue velocity was lower, as previously reported (43), but was similarly reduced in HLVH, likely reflecting concentric LVH. Also as previously reported, HFpEF subjects had greater end-systolic stiffening (Ees) than non-LVH control subjects (18), yet this too was similarly observed in HLVH. It remains unclear if contractility reserve is more limited in HFpEF, as some studies have suggested (44).

Both E/E' and IVRT differed between HFpEF and HLVH. As with the higher E/E', a shorter IVRT could reflect elevated diastolic pressures in HFpEF, although the lack of correlation between variables may suggest another mechanism. Higher diastolic pressures can also be due to increased LV filling (39), although this was not observed in the present study, or to reduced chamber compliance (14), although E-wave deceleration time, which estimates diastolic compliance (45), was similar between HFpEF and HLVH groups. Another cause is exaggerated ventricular interdependence from pericardial constraint, which can elevate diastolic pressures even without diastolic ventricular stiffening. This would be expected if total epicardial heart volume increased (owing to atrial dilation and increased LV mass), which we observed. In this setting, pericardial contributions to intracavitary LV pressure become more apparent, a finding supported by invasive analysis of the end-diastolic pressure-volume relations in HFpEF (18). Approximately 35% of resting LV diastolic pressure in humans is attributable to external forces from right heart and pericardial loads (46). This does not imply pericardial constriction but rather a greater pericardial contribution to measured LV diastolic pressures.

Concentric LVH, atrial enlargement, and dysfunction.   Increased LA volumes are increasingly viewed as a marker for diastolic dysfunction (33) and are an independent predictor of coronary heart failure and worsened mortality in previously asymptomatic elderly subjects with preserved EF (47). Atrial dilation occurs with age and can contribute to alterations in LA pressure and therefore reduced early diastolic filling (48). In the present study, age was similar across groups, yet further LA enlargement was observed in HFpEF. Although this could be explained by the greater LVH or higher diastolic pressures in this cohort, disparate LA size and function persisted after adjusting for these parameters (Fig. 2). There may be disproportionate elevation of diastolic pressures during exercise in HFpEF compared with HLVH subjects, which could underly chronic atrial dilation/dysfunction and/or the blunted A' response during handgrip. However, this remains speculative. Furthermore, ventricles exposed to chronic pressure overload do not uniformly dilate or develop depressed function, and one cannot presume that all atria do either. The HFpEF subjects also had a greater prevalence of CAD, diabetes (49), impaired renal function, and obesity (50), and these factors can favor volume retention and potentially contribute to muscle damage in an overloaded atria.

The unique feature of atrial size (and function) was that it was significantly altered only in HFpEF and, along with LVMI, provided the most sensitive and specific parameters to differentiate HFpEF from HLVH subjects. The product of the 2 does not convey a single physical property but serves as a simple way to combine both findings in a diagnostic index. This could also be done by a regression model. The lack of specific easily employed diagnostic entry criteria has been a barrier for clinical trials in HFpEF, and this index may be useful in this regard and further help identify preclinical patients at higher risk to develop incident HF.

Study limitations.   Although we observed highly significant differences for many parameters in HLVH and HFpEF versus control subjects, lack of differences between the former 2 groups could relate to sample size (type II error). However, the fact that we observed marked differences in LV mass, atrial size, and function underscores the robustness of the comparison. Furthermore, the sample size was similar or greater than in most other detailed cardiovascular studies (12,14,15,18).

We used noninvasive measures of cardiovascular function, and although these have limitations and can yield values that depend on the specific methods used (e.g., pulsed versus color-mode Doppler), differences between HFpEF and control subjects were compatible with earlier invasive data (12,14,18). We estimated PAWP by E/E', which may be less accurate in subjects without LV dysfunction (32) but has been found to be reliable in HFpEF (31). The HFpEF group was 76% African American, reflecting our urban inner-city referral population. This may limit its applicability to the broader population of HFpEF, because the degree of ventricular remodeling is affected by race (7). Nevertheless, many of the HFpEF results are similar to those reported in a cohort that was 30% African American (5). Coronary artery disease was not directly assessed in most subjects, and its role in HFpEF potentially was overestimated, because HLVH subjects were less often tested for CAD, and the incidence of oligosymptomatic CAD was probably higher than their records or history conveyed (51). Finally, given the modest sample size, there is potential instability in the pooled statistical analysis, and some other features might prove more discriminatory in a larger data set.

Conclusions.   Although multiple indexes of LV systolic, diastolic, and vascular function are abnormal in HFpEF, HLVH subjects of similar age, gender, ethnicity without HF share many of these abnormalities. Quantitative differences in diastolic function exist between the groups, but with substantial overlap they appear difficult to use as a robust distinguishing feature. The presence of more marked concentric hypertrophic remodeling of LV and left atrial dysfunction/remodeling may provide more specific positive diagnostic identifiers for HFpEF subjects and help assess prognosis. The fact that these differences were present when comparing HFpEF and HLVH suggests that excessive LVH, atrial dysfunction, and epicardial volume enlargement may represent important decompensations in the pathogenesis of HFpEF. It would be intriguing if reversal of these changes converted symptomatic HFpEF patients back to more compensated HLVH subjects, but this remains to be determined.


   Appendix
Top
 Abstract
 Methods
 Results
 Discussion
 Appendix
References
 
For supplemental Tables A, B, and C, please see the online version of this article.


   Acknowledgments
 
The authors greatly thank Tricia Marhin, RN, Patricia Fizgerald, RN, Laura Shively, RN, Beverly Gorman, Ela Chamera, and Kristy Kessler, RN, for their excellent work on the project.


   Footnotes
 
Supported by a grant from the National Institute on Aging (NIA) (AG:18324) and Intramural Research Program of the National Institutes of Health, NIA.

1 Dr. Melenovsky’s current address is the Institute of Clinical and Experimental Medicine (IKEM), Prague, Czech Republic. Back


   References
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 Methods
 Results
 Discussion
 Appendix
 References
 

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