Although concentric remodeling (CR) and concentric hypertrophy (CH) are common forms of left ventricular (LV) remodeling in heart failure with preserved ejection fraction (HFpEF), eccentric hypertrophy (EH) can also occur in these patients. However, clinical characteristics and outcomes of EH have not been well described in HFpEF. We prospectively studied 402 patients with HFpEF, divided into 4 groups based on LV structure: normal geometry (no LV hypertrophy [LVH] and relative wall thickness [RWT] ≤0.42); CR (no LVH and RWT >0.42); CH (LVH and RWT >0.42); and EH (LVH and RWT ≤0.42). We compared clinical, laboratory, echocardiographic, invasive hemodynamic, and outcome data among groups. Of 402 patients, 48 (12%) had EH. Compared with CH, patients with EH had lower systolic blood pressure and less renal impairment despite similar rates of hypertension. After adjustment for covariates, EH was associated with reduced LV contractility compared with CH: lower LVEF (β coefficient = −3.2; 95% confidence interval [CI] −5.4 to −1.1%) and ratio of systolic blood pressure to end-systolic volume (β coefficient = −1.0; 95% CI −1.5 to −0.5 mm Hg/ml). EH was also associated with increased LV compliance compared with CH (LV end-diastolic volume at an idealized LV end-diastolic pressure of 20 mm Hg β coefficient = 14.2; 95% CI 9.4 to 19.1 ml). Despite these differences, EH and CH had similarly elevated cardiac filling pressures and equivalent adverse outcomes. In conclusion, the presence of EH denotes a distinct subset of HFpEF that is pathophysiologically similar to HF with reduced EF (HFrEF) and may benefit from HFrEF therapy.
Left ventricular (LV) structure in heart failure with preserved ejection fraction (HFpEF) has been classically defined as a small, thick ventricle. Contemporary studies show that most patients with HFpEF have a normal sized LV. Indeed, concentric remodeling (CR) and concentric hypertrophy (CH) have been demonstrated to be the most common LV structural abnormalities observed in HFpEF. A smaller subset of HFpEF patients demonstrate eccentric hypertrophy (EH) ; however, EH has not been well described in the setting of HFpEF. We sought to define HFpEF based on LV geometry, with a focus on the subset of patients with EH. We hypothesized that this group, while less prevalent, represents a unique pathophysiologic subset of HFpEF patients who may benefit from tailored therapy, which may include medications typically used to treat patients with heart failure and reduced ejection fraction (HFrEF).
Methods
Between March 2008 and May 2011, consecutive patients were prospectively enrolled from the outpatient clinic of the Northwestern University HFpEF Program as part of a systematic observational study of HFpEF ( ClinicalTrials.gov identifier # NCT01030991 ), as described previously. All patients were recruited after hospitalization for HF. Patients were initially identified by an automated daily query of the inpatient electronic medical record at Northwestern Memorial Hospital. The list of patients generated was screened daily, and only those patients with an LV ejection fraction (EF) >50% and who met Framingham criteria for HF were offered post discharge follow-up in a specialized HFpEF outpatient program. The HF diagnosis was confirmed in the posthospitalization, outpatient HFpEF clinic. On the basis of previously published criteria, in addition to the presence of symptomatic HF and EF >50%, we required evidence of either significant diastolic dysfunction (grade 2 or 3) on echocardiography or evidence of elevated LV filling pressures on invasive hemodynamic testing. Patients with greater than moderate valvular disease, previous cardiac transplantation, previous LVEF <40%, LV end-diastolic volume (EDV) >97 ml/m 2 , or diagnosis of constrictive pericarditis were excluded. For the present analysis, patients with known sources of extracardiac volume overload or high output HF were also excluded. All study participants gave written, informed consent, and the institutional review board at Northwestern University approved the study.
We collected the following data in all study participants: demographics, race/ethnicity, New York Heart Association functional class, co-morbidities (as defined in Table 1 ), medications, vital signs, body mass index, and laboratory data, including serum sodium, blood urea nitrogen, creatinine, hemoglobin, and B-type natriuretic peptide.
| Clinical Characteristic | Normal Geometry (n = 49) | CR (n = 111) | CH (n = 194) | EH (n = 48) | p Value ∗ |
|---|---|---|---|---|---|
| Age (yrs) | 56 ± 13.2 | 67 ± 12.1 | 66 ± 12.3 | 62 ± 13.9 | <0.001 ‡ |
| Female gender | 29 (59%) | 55 (50%) | 132 (68%) | 35 (73%) | 0.005 ‡ |
| Race | |||||
| White | 34 (69%) | 60 (54%) | 87 (45%) | 28 (58%) | 0.01 |
| African-American | 10 (20%) | 41 (37%) | 85 (44%) | 18 (38%) | 0.03 ‡ |
| Other | 5 (10%) | 10 (9%) | 22 (11%) | 2 (4%) | 0.50 |
| New York Heart Association functional class | |||||
| I | 14 (29%) | 16 (14%) | 16 (8%) | 4 (8%) | 0.001 ‡ |
| II | 24 (49%) | 49 (44%) | 68 (35%) | 16 (33%) | 0.16 |
| III | 9 (18%) | 45 (41%) | 103 (53%) | 26 (54%) | <0.001 ‡ |
| IV | 2 (4%) | 1 (1%) | 6 (3%) | 1 (2%) | 0.57 |
| Coronary artery disease § | 21 (43%) | 60 (54%) | 92 (47%) | 21 (44%) | 0.47 |
| Hypertension ‖ | 25 (51%) | 84 (76%) | 163 (84%) | 37 (77%) | <0.001 ‡ |
| Hyperlipidemia ¶ | 18 (37%) | 63 (57%) | 108 (56%) | 28 (58%) | 0.08 |
| Diabetes mellitus | 6 (12%) | 30 (27%) | 73 (38%) | 19 (40%) | 0.003 ‡ |
| Chronic kidney disease # | 5 (10%) | 35 (32%) | 75 (39%) | 14 (29%) | 0.002 ‡ |
| Smoker | 18 (37%) | 48 (43%) | 78 (40%) | 19 (40%) | 0.88 |
| Atrial fibrillation | 14 (29%) | 27 (24%) | 55 (28%) | 14 (29%) | 0.87 |
| Obesity ∗∗ | 19 (39%) | 44 (40%) | 114 (59%) | 33 (69%) | <0.001 ‡ |
| Chronic obstructive pulmonary disease | 16 (33%) | 43 (39%) | 71 (37%) | 18 (38%) | 0.91 |
| Heart rate (beats/min) | 71 ± 14.7 | 71 ± 14 | 71 ± 13.6 | 68 ± 13.3 | 0.62 |
| Systolic blood pressure (mm Hg) | 118 ± 16 | 121 ± 17 | 129 ± 22 | 121 ± 19 † | <0.001 ‡ |
| Diastolic blood pressure (mm Hg) | 70 ± 10 | 70 ± 10 | 71 ± 13 | 67 ± 13 | 0.23 |
| Pulse pressure (mm Hg) | 49 ± 13 | 51 ± 15 | 59 ± 18 | 54 ± 19 | <0.001 ‡ |
| Body mass index (kg/m 2 ) | 28 ± 6.5 | 29 ± 6.7 | 34 ± 9.6 | 36 ± 11.1 | <0.001 ‡ |
| Serum sodium (mEq/L) | 139 ± 2.1 | 138 ± 3.1 | 138 ± 2.8 | 138 ± 3.2 | 0.75 |
| Blood urea nitrogen (mg/dl) | 17.7 ± 11.2 | 24.9 ± 18.1 | 26.6 ± 17 | 22 ± 11.5 | 0.006 |
| Serum creatinine (mg/dl) | 1.01 ± 0.4 | 1.41 ± 1.2 | 1.85 ± 1.8 | 1.29 ± 0.9 † | <0.001 |
| Estimated GFR (ml/min/1.73 m 2 ) | 76 ± 26.8 | 60 ± 26.3 | 52 ± 25.5 | 64 ± 29.2 † | <0.001 ‡ |
| Fasting glucose (mg/dl) | 99 ± 20 | 125 ± 66 | 121 ± 54 | 121 ± 52 | 0.05 |
| Hemoglobin (g/dl) | 12.0 ± 1.8 | 12.1 ± 1.9 | 11.8 ± 1.8 | 11.6 ± 2.1 | 0.46 |
| B-type natriuretic peptide (pg/ml) | 131 (54–245) | 230 (59–402) | 278 (101–664) | 261 (94–473) | <0.001 ‡ |
| Number of antihypertensive medications | 2.0 ± 1.1 | 2.3 ± 1.5 | 3.0 ± 1.4 | 2.7 ± 1.3 | <0.001 ‡ |
| Medications | |||||
| Angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker | 27 (55%) | 51 (46%) | 113 (58%) | 30 (63%) | 0.13 |
| β-blocker | 29 (59%) | 69 (62%) | 138 (71%) | 32 (67%) | 0.26 |
| Calcium antagonist | 6 (12%) | 27 (24%) | 77 (40%) | 15 (31%) | <0.001 ‡ |
| Nitrate | 0 (0%) | 13 (12%) | 39 (20%) | 6 (13%) | 0.003 ‡ |
| Loop diuretic | 29 (59%) | 54 (49%) | 124 (64%) | 27 (56%) | 0.08 |
| Thiazide diuretic | 6 (12%) | 26 (23%) | 50 (26%) | 12 (25%) | 0.25 |
| Statin | 17 (35%) | 54 (49%) | 98 (51%) | 28 (58%) | 0.12 |
| Aspirin | 17 (35%) | 57 (51%) | 91 (47%) | 21 (44%) | 0.27 |
∗ p value by analysis of variance among groups (or Kruskal-Wallis test for right-skewed variables).
† p value <0.05 and remains significant after correction using false discovery rate <5% for comparison of EH versus CH.
‡ p value <0.05 and remains significant after correction using false discovery rate <5% for comparison of LVH versus no LVH.
§ Presence of physician-documented history of coronary artery disease, known coronary stenosis >50%, history of myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting, or abnormal stress test results consistent with myocardial ischemia.
‖ Systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg, physician-documented history of hypertension, or current use of antihypertensive medications.
¶ Physician-documented history of hyperlipidemia or current use of lipid-lowering medications.
# Estimated GFR <60 ml/min/1.73 m 2 .
All study participants underwent comprehensive 2-dimensional echocardiography with Doppler and tissue Doppler imaging using commercially available ultrasound systems with harmonic imaging (Philips iE33 or 7500, Philips Medical Systems, Andover, Massachusetts; or Vivid 7, GE Healthcare, General Electric, Waukesha, Wisconsin). Cardiac structure and function were quantified as recommended by the American Society of Echocardiography. Relative wall thickness (RWT) was calculated as 2 * (posterior wall thickness) / LV end-diastolic dimension. LV hypertrophy (LVH) was defined as LV mass indexed to height 2.7 >44 g/m 2.7 in women and >48 g/m 2.7 in men. Normal geometry was classified as RWT ≤0.42 and no LVH; CR was defined as RWT >0.42 and no LVH; CH was defined as RWT >0.42 and LVH; and EH was defined as RWT ≤0.42 and LVH. All measurements were made by an experienced research sonographer (blinded to clinical data and outcomes) using ProSolv 4.0 software (ProSolv CardioVascular; Indianapolis, Indiana) and verified by a board-certified echocardiographer.
End-systolic elastance (E es ) was estimated by the single-beat method. The relationship between end-systolic pressure (P es ) and end-systolic volume (ESV) was related by the equation: [P es = E es (ESV − V 0 )]. Using 0.9 * (systolic blood pressure) as an estimate of P es , we estimated V 0 , the volume-axis intercept for each patient. We then used the average V 0 and E es to define the end-systolic pressure volume relationship (ESPVR) in the EH and CH groups. We also generated the estimated ESV at an idealized P es of 120 mm Hg (ESV 120 ) for each patient as a basis for comparison of ESPVR between groups. The effective arterial elastance (E a ) was estimated using the following equation: E a = 0.9 * SBP/stroke volume. The end-diastolic pressure-volume relationship (EDPVR) was also characterized by a single-beat method using the equation: LVEDP = α(LVEDV) β . The parameters α and β were calculated for each individual based on their LVEDV and LVEDP (as estimated by [11.96 + (lateral E/e′ ratio) * 0.596]). These parameters were then used to calculate the LVEDV at an idealized LVEDP of 20 mm Hg (EDV 20 ) for each patient as a basis for comparison of EDPVR among groups.
Right-sided heart catheterization was performed from either the right internal jugular or right femoral vein approach using standard Seldinger technique under fluoroscopic guidance. Participants underwent recording of invasive hemodynamics using a fluid-filled, 6Fr pulmonary artery catheter (Edwards Lifesciences, Irvine, California) and a properly zeroed pressure transducer. Pressure recordings were analyzed offline using a WITT Hemodynamic Workstation (Philips Medical Systems) at a 50 mm/s paper speed with adjustment of pressure (mm Hg) scale as needed. All hemodynamic pressure measurements were made at end-expiration and in duplicate using a standardized measurement protocol by a physician blinded to all clinical data.
After enrollment, study participants were evaluated in the Northwestern HFpEF Program as clinically indicated but at least every 6 months. At each visit, intercurrent hospitalizations were documented, reviewed, and categorized as due to cardiovascular or noncardiovascular causes. Every 6 months, participants (or their proxy) were contacted to determine vital status with verification of deaths through query of the Social Security Death Index. Enrollment date was defined as the first visit to the outpatient HFpEF clinic. Date of last follow-up was defined as date of death or last HFpEF clinic visit. Follow-up was complete in all patients. The combined outcome included any hospitalization for HF or any cardiovascular cause, or death.
Study participants were divided into 4 groups based on LV geometry (normal, CR, CH, and EH). Clinical characteristics, laboratory data, and echocardiographic parameters were compared between groups. Categorical variables were compared using chi-square tests, and continuous variables were compared using analysis of variance (or Kruskal-Wallis test, when appropriate). Pairwise group comparisons were made using t tests (or Wilcoxon rank-sum test, when appropriate). Variables from the univariate analysis that were significantly different between EH and CH groups were compared using multivariable-adjusted linear regression models. Covariates, chosen on the basis of known associations between the variable of interest and LV geometry, included age, gender, African-American race, hypertension, hyperlipidemia, diabetes mellitus, obesity, heart rate, log B-type natriuretic peptide, glomerular filtration rate (GFR), and wall motion abnormality on echocardiography.
Finally, we used Cox proportional-hazards analyses and the log-rank statistic to evaluate the relationship between LV geometry groups and outcomes. Covariates included in multivariate Cox regression models, chosen based on clinical relevance, included age, sex, African-American race, hypertension, diabetes mellitus, obesity, and estimated GFR. To correct for multiple testing, false discovery rate methods were applied using all calculated p values. False discovery rate Q values were calculated using the Benjamini-Hochberg method. False discovery rate <5% corresponded to p values <0.0172, which was therefore used as the threshold for statistical significance. All analyses were performed using Stata 12 (StataCorp, College Station, Texas).
Results
We prospectively enrolled 402 consecutive outpatients with HFpEF after hospitalization for HF. The majority of subjects had CH, followed by CR, and similar frequencies of normal geometry and EH ( Figure 1 ). Although less frequent than other forms of LV remodeling, EH was not rare, occurring in 12% of the study cohort. Table 1 displays the clinical and demographic characteristics by LV geometry. Those with normal geometry were significantly younger than those in any other group. Significant differences among the 4 groups, especially in co-morbidities, were largely driven by the differences between those with and without LVH.
However, there were significant differences in kidney function and blood pressure between the EH and CH groups. Those with EH had a mean systolic blood pressure (SBP) of 121 mm Hg (95% confidence interval [CI] 115 to 127 mm Hg), whereas those with CH had a mean SBP of 129 mm Hg (95% CI 127 to 132 mm Hg); p = 0.01. Mean diastolic blood pressure was also lower among those with EH compared with CH. Despite the differences in blood pressure, prevalence of hypertension, and number of antihypertensive medications were not significantly different between the EH and CH groups. Patients with EH also had lower serum creatinine and higher GFR compared with those with CH, reflecting better renal function in the EH subgroup.
Echocardiographic analysis ( Table 2 ) revealed that subjects with EH had larger LV volumes, lower relative wall thickness, and lower LV mass/volume ratio compared with those with CH. Contractile function was worse in EH compared with CH. Patients with EH had lower LVEF, lower SBP/ESV ratio, and higher ESV 120 , indicative of worse contractility on LV pressure-volume analysis ( Figure 2 ). Patients with EH also demonstrated less arterial stiffening, as E a and pulse pressure/stroke volume ratio were significantly lower in EH compared with CH. HFpEF patients with EH also had less LV diastolic stiffness (increased LV compliance) compared with patients with CH as shown in Table 2 and Figure 2 with a rightward- and downward-shifted EDPVR curve, as indicated by a larger EDV 20 . Diastolic relaxation (i.e., e′ velocity) was also less impaired in EH compared with CH. However, LV filling pressures (E/e′ ratio and PCWP) were similarly elevated in EH and CH ( Tables 2 and 3 ). Pulmonary artery systolic pressure was higher in LVH compared with no LVH but was similar in EH and CH groups ( Table 3 ). Rates (and severity) of mitral regurgitation did not vary between groups, and no patient had greater than mild aortic regurgitation.
| Echocardiographic parameter | Normal Geometry (n = 49) | Concentric Remodeling (n = 111) | Concentric Hypertrophy (n = 194) | Eccentric Hypertrophy (n = 48) | p Value ∗ |
|---|---|---|---|---|---|
| LV end-systolic volume index (ml/m 2 ) | 17 ± 5 | 15 ± 4 | 16 ± 6 | 21 ± 9 † | <0.001 ‡ |
| LV end-diastolic volume index (ml/m 2 ) | 42 ± 10 | 38 ± 8 | 40 ± 11 | 48 ± 15 † | <0.001 ‡ |
| Relative wall thickness | 0.38 ± 0.03 | 0.50 ± 0.07 | 0.59 ± 0.17 | 0.38 ± 0.03 † | <0.001 ‡ |
| LV mass index (g/m 2.7 ) | 36 ± 6 | 37 ± 6 | 64 ± 19 | 56 ± 10 † | <0.001 ‡ |
| LV mass/volume ratio (g/ml) | 1.9 ± 0.4 | 2.2 ± 0.5 | 3.2 ± 1.2 | 2.3 ± 0.5 † | <0.001 ‡ |
| LVEF (%) | 60 ± 5 | 62 ± 6 | 62 ± 7 | 58 ± 6 † | <0.001 |
| Stroke volume (ml) | 50 ± 16 | 46 ± 12 | 50 ± 15 | 56 ± 17 † | <0.001 ‡ |
| Cardiac index (L/min/m 2 ) | 1.7 ± 0.5 | 1.6 ± 0.5 | 1.7 ± 0.5 | 1.9 ± 0.7 | 0.12 |
| End-systolic volume 120 (ml) | 40 ± 13 | 34 ± 13 | 35 ± 16 | 52 ± 22 † | <0.001 ‡ |
| Systolic blood pressure/end systolic volume ratio | 3.5 ± 1.3 | 4.3 ± 1.6 | 4.2 ± 1.7 | 2.9 ± 1.4 † | <0.001 |
| Effective arterial elastance (mm Hg/ml) | 2.3 ± 0.8 | 2.6 ± 0.7 | 2.5 ± 0.8 | 2.1 ± 0.7 † | 0.004 |
| Pulse pressure/stroke volume ratio (mm Hg/ml) | 1.06 ± 0.41 | 1.18 ± 0.45 | 1.24 ± 0.48 | 1.06 ± 0.53 | 0.02 |
| End-diastolic volume 20 (ml) | 86 ± 28 | 75 ± 20 | 82 ± 25 | 101 ± 32 † | <0.001 ‡ |
| Left atrial volume index (ml/m 2 ) | 33 ± 12 | 32 ± 17 | 35 ± 14 | 35 ± 11 | 0.30 |
| E/A ratio | 1.5 ± 0.6 | 1.3 ± 0.6 | 1.3 ± 0.8 | 1.5 ± 0.8 | 0.23 |
| E deceleration time (ms) | 220 ± 57 | 227 ± 56 | 236 ± 77 | 224 ± 53 | 0.38 |
| Isovolumic relaxation time (ms) | 84 ± 20 | 85 ± 20 | 91 ± 23 | 87 ± 26 | 0.07 |
| Septal e′ tissue velocity (cm/s) | 8.4 ± 3.5 | 7.6 ± 2.9 | 6.4 ± 2.2 | 7.1 ± 2.4 | <0.001 ‡ |
| Lateral e′ tissue velocity (cm/s) | 11.2 ± 4.8 | 10.0 ± 4.0 | 8.4 ± 3.2 | 9.7 ± 4.0 | <0.001 ‡ |
| Average E/e′ ratio | 12.6 ± 7.1 | 13.4 ± 7.3 | 16.9 ± 9.0 | 14.9 ± 6.7 | <0.001 ‡ |
| Tricuspid annular plane systolic excursion (cm) | 2.30 ± 0.71 | 1.89 ± 0.64 | 1.97 ± 0.61 | 2.06 ± 0.54 | 0.002 |
| Mitral regurgitation | |||||
| None | 26 (53%) | 70 (63%) | 109 (56%) | 23 (48%) | 0.31 |
| Mild | 13 (27%) | 29 (26%) | 55 (28%) | 16 (33%) | 0.82 |
| Moderate | 10 (20%) | 11 (10%) | 29 (15%) | 8 (17%) | 0.32 |
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