Exercise intolerance is the primary chronic symptom in heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure in older patients; however its pathophysiology is not well understood. Recent data suggest that peripheral factors such as skeletal muscle (SM) dysfunction may be important contributors. Therefore, 38 participants, 23 patients with HFpEF (69 ± 7 years) and 15 age-matched healthy controls (HCs), underwent magnetic resonance imaging and cardiopulmonary exercise testing to assess for SM, intermuscular fat (IMF), subcutaneous fat, total thigh, and thigh compartment (TC) areas and peak exercise oxygen consumption (peak VO 2 ). There were no significant intergroup differences in total thigh area, TC, subcutaneous fat, or SM. However, in the HFpEF versus HC group, IMF area (35.6 ± 11.5 vs 22.3 ± 7.6 cm 2 , p = 0.01), percent IMF/TC (26 ± 5 vs 20 ± 5%, p = 0.005), and the ratio of IMF/SM (0.38 ± 0.10 vs 0.28 ± 0.09, p = 0.007) were significantly increased, whereas percent SM/TC was significantly reduced (70 ± 5 vs 75 ± 5, p = 0.009). In multivariate analyses, IMF area (partial r = −0.51, p = 0.002) and IMF/SM ratio (partial r = −0.45, p = 0.006) were independent predictors of peak VO 2 whereas SM area was not (partial r = −0.14, p = 0.43). Thus, older patients with HFpEF have greater thigh IMF and IMF/SM ratio compared with HCs, and these are significantly related to their severely reduced peak VO 2 . These data suggest that abnormalities in SM composition may contribute to the severely reduced exercise capacity in older patients with HFpEF. This implicates potential targets for novel therapeutic strategies in this common debilitating disorder of older persons.
The primary chronic symptom in patients with heart failure (HF) with preserved ejection fraction (HFpEF) is severe exercise intolerance, measured objectively as decreased peak oxygen uptake (peak VO 2 ). The mechanisms for decreased peak VO 2 are not well understood; however, “peripheral” noncardiac factors may contribute to reduced exercise tolerance and may be the major contributors to its improvement after exercise training. Specifically, using dual energy x-ray absorptiometry, we recently reported that older patients with HFpEF had reduced percent total and leg lean body mass compared with age-matched healthy controls (HCs). Moreover, the slope of the relation of peak VO 2 with percent leg lean mass was markedly reduced in the HFpEF versus HC group. These data suggested that the “quality” of skeletal muscle (SM) may be abnormal and contribute to the reduced peak VO 2 found in older patients with HFpEF. Currently, there is no information regarding SM composition and its relation to exercise capacity in patients with HFpEF. The purpose of this study was to test the hypothesis that older patients with HFpEF have adverse SM composition and that this contributes to their severe exercise intolerance.
Methods
As previously described in studies reported from our laboratory, HFpEF was defined as symptoms and signs of HF according to the National Health and Nutrition Examination Survey HF clinical score of ≥3 and the criteria of Rich et al. Age-matched sedentary HCs were recruited and screened and excluded if they had any chronic medical illness, were on any long-term medication, had current complaints or an abnormal physical examination (including blood pressure ≥140/90 mm Hg), had abnormal results on the screening tests (electrocardiogram, cardiopulmonary exercise, and spirometry), or were regularly exercising.
Doppler echocardiograms were performed and left ventricular filling patterns were categorized as previously described.
Exercise testing was performed, as previously described, in the upright position on an electronically braked bicycle using a staged protocol starting at 12.5 W for 2 minutes, increasing to 25 W for 3 minutes, and with 25 W per 3-minute increments thereafter to exhaustion. Breath-by-breath gas exchange data were measured continuously (CPX-2000; MedGraphics, Minneapolis, Minnesota) during exercise and averaged every 15 seconds, and peak values were averaged from the last two 15-second intervals during peak exercise.
The left thigh of each subject was scanned with 1.5-T Horizon (General Electric Medical Systems, Milwaukee, Wisconsin) whole body magnetic resonance imaging system. A scout film of the inferior head of femur was obtained by single-phase multislice coronal acquisition. Slices were 10-mm thick with a 5-mm gap, had a 256 × 128 matrix, a 40-cm field of view, a 30° flip angle, an autorepetition time, and a minimum echo time. Straight axial scans superior to the inferior head of the femur were obtained by single-phase multislice acquisition. Slices were 8-mm thick with a 50-mm gap, had a 256 × 128 matrix, a 14- to 20-cm field of view, a 20° flip angle, an autorepetition time, and minimum echo time.
Images were transferred to an image analysis workstation and the slice corresponding to a constant location of the midthigh was selected in a manner as previously described. The cross-sectional areas of SM, subcutaneous fat (SCF), intermuscular fat (IMF), and bone were measured using a commercially available software (TomoVision, Montreal, Quebec). Total thigh area was calculated as the sum of all 4 components (SM, SCF, IMF, and bone) and thigh compartment (TC) area was calculated as the sum of SM, IMF, and bone. To determine the intraobserver reproducibility of SM, SCF, and IMF areas, duplicate measurements from 10 randomly chosen subjects were analyzed in a blinded fashion. The Pearson correlation coefficients for SM, SCF, and IMF were 0.99, 0.99, and 0.90, respectively. These values are similar to previously reported values that range from 0.94 to 0.99, representing excellent reproducibility.
Descriptive statistics are reported as means and SDs for continuous variables and as n (number in the category) and percentage for categorical variables. Intergroup comparisons were made by independent samples t tests for continuous variables, Fisher’s exact tests for binomial variables, and chi-square tests for categorical variables. Comparisons of peak exercise variables between groups were made by analysis of covariance, adjusting for age and gender. Likewise, comparisons of thigh composition variables between groups were made by analysis of covariance, adjusting for body surface area. The relations between SM, IMF, and IMF/SM and peak VO 2 were assessed by Pearson correlations. Finally, a multivariate regression model was used to assess predictors of peak VO 2 . Competing variables were selected a priori based on their known impact on peak VO 2 . A 2-tailed p value of <0.05 was required for significance.
Results
The patients were clinically stable (New York Heart Association class II and III) with typical characteristics of HFpEF, including advanced age, female preponderance, abnormal left ventricular diastolic filling, left ventricular hypertrophy, increased left atrial size, and severely reduced peak exercise VO 2 ( Table 1 ). HFpEF and HC groups were well matched for age and gender. Body weight, body mass index (BMI), and body surface area were higher for HFpEF than HCs ( Table 1 ); however, the mean HFpEF BMI was similar to that observed in multiple, large, population-based studies of older patients with HFpEF, including Cardiovascular Health Study, Framingham, and Olmsted County studies.
| Variable | HFpEF (n = 23) | HC (n = 15) | p Value |
|---|---|---|---|
| Age (yrs) | 69 ± 7 | 70 ± 8 | 0.78 |
| Women | 15 (65) | 11 (73) | 0.73 |
| White | 16 (70) | 13 (87) | 0.27 |
| Weight (kg) | 84 ± 19 | 67 ± 12 | 0.003 |
| BMI (kg/m 2 ) | 30.4 ± 5.7 | 24.6 ± 2.9 | <0.001 |
| Body surface area (m 2 ) | 1.9 ± 0.2 | 1.7 ± 0.2 | 0.01 |
| Systolic blood pressure (mm Hg) | 146 ± 22 | 129 ± 15 | 0.02 |
| Diastolic blood pressure (mm Hg) | 84 ± 13 | 77 ± 7 | 0.06 |
| Left ventricular mass (g) | 212 ± 72 | 167 ± 29 | 0.08 |
| Left ventricular mass/end-diastolic volume ratio | 3.21 ± 1.36 | 2.60 ± 0.64 | 0.27 |
| Left atrial diameter (cm) | 3.6 ± 0.7 | 3.0 ± 0.4 | 0.02 |
| Ejection fraction (%) | 63.5 ± 10.0 | 63.5 ± 10.5 | 0.99 |
| Diastolic filling | |||
| Normal | 1 (4) | 12 (80) | <0.001 |
| Impaired relaxation | 14 (61) | 3 (20) | |
| Pseudonormal | 6 (26) | 0 (0) | |
| Restrictive | 1 (4) | 0 (0) | |
| Indeterminate (atrial fibrillation) | 1 (4) | 0 (0) | |
| B-type natriuretic peptide (pg/ml) | 50 ± 44 | 23 ± 12 | 0.07 |
| History of hypertension | 21 (91) | — | — |
| Diabetes mellitus | 6 (26) | — | — |
| New York Heart Association class | |||
| II | 11 (48) | — | — |
| III | 12 (52) | — | — |
| Medications | |||
| Diuretics | 15 (65) | — | — |
| Angiotensin receptor blockers | 7 (30) | — | — |
| Angiotensin-converting enzyme inhibitors | 7 (30) | — | — |
| β Blockers | 7 (30) | — | — |
| Calcium channel blockers | 8 (35) | — | — |
| Nitrates | 2 (9) | — | — |
Peak exercise VO 2 , workload, exercise time, and 6-minute walk distance were severely reduced in the HFpEF versus HC group ( Table 2 ). Peak systolic and diastolic blood pressures were not significantly different between HFpEF and HC groups ( Table 2 ). Although respiratory exchange ratio was slightly lower in the HFpEF versus HC group, the mean was ≥1.15 in both groups, indicating exhaustive exercise effort. As described in previous reports from our group and others, peak heart rate was reduced in HFpEF versus controls.
| Variable | Raw Data | Adjusted Data ∗ | ||||
|---|---|---|---|---|---|---|
| HFpEF | HC | p Value | HFpEF | HC | p Value | |
| Oxygen uptake (ml/min) | 1,177 ± 256 | 1,348 ± 419 | 0.12 | 1,236 ± 57 | 1,451 ± 72 | 0.02 |
| Oxygen uptake (ml/kg/min) | 14.3 ± 3.1 | 20.1 ± 4.5 | <0.001 | 14.5 ± 0.8 | 20.6 ± 1.0 | <0.001 |
| Carbon dioxide production (ml/min) | 1,330 ± 292 | 1,630 ± 471 | 0.02 | 1,395 ± 65 | 1,743 ± 82 | 0.002 |
| Exercise time (minutes) | 8.5 ± 2.3 | 11.7 ± 3.4 | 0.001 | 8.9 ± 0.5 | 12.4 ± 0.7 | <0.001 |
| Workload (W) | 61 ± 20 | 86 ± 31 | 0.004 | 65 ± 5 | 93 ± 6 | <0.001 |
| Respiratory exchange ratio | 1.15 ± 0.09 | 1.22 ± 0.08 | 0.01 | 1.14 ± 0.02 | 1.21 ± 0.02 | 0.02 |
| Heart rate (beats/min) | 130 ± 25 | 153 ± 13 | 0.002 | 127 ± 4 | 149 ± 6 | 0.003 |
| Systolic blood pressure (mm Hg) | 193 ± 22 | 193 ± 19 | 0.92 | 192 ± 5 | 193 ± 6 | 0.92 |
| Diastolic blood pressure (mm Hg) | 92 ± 12 | 89 ± 11 | 0.50 | 92 ± 3 | 90 ± 3 | 0.56 |
| Ventilation/carbon dioxide slope | 31.3 ± 3.8 | 32.9 ± 3.0 | 0.18 | 31.7 ± 0.7 | 33.4 ± 0.9 | 0.12 |
| 6-Minute walk distance (m) | 428 ± 73 | 554 ± 54 | <0.001 | 430 ± 15 | 559 ± 18 | <0.001 |
∗ Adjusted for age and gender and presented as least square means ± standard error.
No significant difference in SCF, SM, bone, total thigh, or TC areas was found between groups ( Table 3 ). However, despite no difference in SCF, IMF area, IMF area as a proportion of TC area, and the ratio of IMF/SM were significantly increased in the HFpEF versus HC group ( Table 3 ). SM as a proportion of TC was significantly reduced in HFpEF ( Table 3 ). Adjusting for height, height 2.7 , femur length, or BMI instead of body surface area did not alter these results other than a modest reduction in the significance level (to p = 0.07) when IMF area was adjusted for BMI. Figure 1 shows examples of magnetic resonance imaging axial images of the midthigh from subjects from each group. Notably, IMF area was substantially increased in patients with HFpEF compared with the HC group despite similar SCF area.
| Variable | Raw Data | Adjusted Data ∗ | ||||
|---|---|---|---|---|---|---|
| HFpEF | HC | p Value | HFpEF | HC | p Value | |
| Total thigh area (cm 2 ) | 233 ± 54 | 221 ± 30 | 0.46 | 226 ± 9 | 233 ± 11 | 0.63 |
| SCF (cm 2 ) | 95 ± 49 | 110 ± 37 | 0.33 | 97 ± 10 | 107 ± 12 | 0.55 |
| TC area (cm 2 ) | 138 ± 34 | 112 ± 25 | 0.02 | 128 ± 4 | 126 ± 4 | 0.68 |
| Femur (cm 2 ) | 6.1 ± 0.9 | 5.9 ± 1.3 | 0.57 | 5.8 ± 0.2 | 6.2 ± 0.2 | 0.17 |
| SM (cm 2 ) | 96 ± 27 | 83 ± 22 | 0.14 | 89 ± 3 | 94 ± 4 | 0.40 |
| IMF (cm 2 ) | 35.6 ± 11.5 | 22.3 ± 7.6 | <0.001 | 33.4 ± 1.8 | 25.7 ± 2.2 | 0.01 |
| IMF/TC (%) | 26 ± 5 | 20 ± 5 | 0.002 | 26 ± 1 | 20 ± 1 | 0.005 |
| SM/TC (%) | 70 ± 5 | 75 ± 5 | 0.008 | 69 ± 1 | 75 ± 1 | 0.009 |
| IMF/SM | 0.38 ± 0.10 | 0.28 ± 0.09 | 0.003 | 0.38 ± 0.02 | 0.28 ± 0.03 | 0.007 |
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