Mechanisms of exercise intolerance in patients with hypertrophic cardiomyopathy
Article Outline
Aim
To determine the relation between echocardiogram findings and exercise capacity in hypertrophic cardiomyopathy (HCM).
Methods and Results
Sixty-three patients (48 ± 15 years) were referred for cardiopulmonary testing and exercise echocardiography. They were classified by morphology: proximal (n = 11), reverse curvature (n = 32), apical (n = 7), and concentric HCM (n = 13).
There were more women in proximal and reverse curvature groups. Proximal HCM patients were older. Maximal left ventricular thickness was highest in reverse curvature group. At peak exercise, concentric HCM achieved the lowest percent predicted maximal Vo2. Excluding apical group, no significant differences in gradient were noted between groups. Overall, no statistically significant correlation was found between peak Vo2, wall thickness, and gradient. Significant correlations were noted between peak Vo2 and indexed left atrial (LA) volume (r = −0.52), lateral E′ (r = 0.50), and lateral E/E′ ratio (r = −0.46). A multivariate model including age, lateral E′, indexed LA volume, and mitral A wave explained 46% of the variance in peak Vo2 (P = .01).
Conclusion
Lateral E′ and indexed LA volume are negatively correlated with functional capacity. Although patients with concentric morphology achieved the lowest peak Vo2, wall thickness and gradient did not predict exercise capacity.
Background
Hypertrophic cardiomyopathy (HCM), caused by mutations in sarcomeric contractile proteins, is characterized by left ventricular hypertrophy (LVH), myocardial fibrosis, and myocyte disarray. As a result, many experience functional limitations. Although abnormal peripheral vasodilatory responses, reduced stroke volume, diastolic dysfunction, microcirculatory dysfunction, LVH, and left ventricular outflow tract (LVOT) obstruction may all contribute to exercise intolerance,1 the exact mechanisms remain uncertain. Being phenotypically diverse,2 it can be also speculated that different morphologies of HCM might be associated with differential responses to exercise.
Although practical, the New York Heart Association (NYHA) classification used in many studies3 has been shown to underestimate the severity of exercise intolerance in various heart disease populations. Moreover, classification based on shortness of breath was initially developed to characterize the symptomatology of patients with systolic dysfunction and may not be appropriate for HCM populations, which more frequently present with diastolic dysfunction and atypical chest pain. Exercise capacity can therefore be better estimated using predicted metabolic equivalents (METs) from external work rate.4 However, this is frequently inaccurate, and use of inappropriate protocols with large incremental stages may result in an overestimation of exercise capacity.5 The use of symptom-limited cardiopulmonary testing with expired gas analysis (CPX) is therefore crucial in the accurate assessment of functional capacity in subjects with predominantly diastolic dysfunction.6
Because LVOT gradients are often identified only with exercise,3 exercise echocardiography is a particularly helpful tool for the assessment of functional capacity. The role of dynamic gradients is still debated. In previous studies, many patients with severe symptoms were excluded and conventional indices of diastolic dysfunction as well as more recent tissue Doppler imaging (TDI)-derived indexes were not evaluated. Others have demonstrated diastolic dysfunction to be the main limiting factor.7, 8 However, without the inclusion of imaging at peak exercise, the correlation between dynamic parameters, such as peak gradients, and maximal exercise capacity was not evaluated.
This study attempts to (1) elucidate the mechanisms of exercise limitation with the use of combined CPX and stress echocardiography and (2) evaluate exercise capacity and response by pattern.
Methods
Study population
Sixty-six consecutive patients underwent CPX with stress echocardiography between October 2006-July 2008 at Stanford Hospital and Clinics. Three were excluded due to poor effort. History data were gathered prior to testing. All subjects gave written informed consent. The study was approved by the Stanford University Institutional Review Board.
Cardiopulmonary exercise testing
Subjects underwent CPX using an individualized ramp protocol.5 Medications were not changed prior to testing. Individualized ramp protocols were followed such that maximum exertion was achieved in 8 to 12 minutes, based on a pretest questionnaire.9 Blood pressure (BP) was taken manually every two minutes during exercise, at peak exercise, and during recovery. Twelve-lead electrocardiograms were recorded continuously. Subjects were placed in the supine position immediately after exercise.
Abnormal BP response was defined as a systolic BP (SBP) that decreased or failed to increase ≥20 mm Hg from the resting value.4 Exercise capacity (in METs) was calculated from treadmill speed and grade.10 Heart rate was recorded from the electrocardiogram while standing at rest, at each 20-second interval during the test, and at peak exercise. Chronotropic incompetence was defined as an inability to reach 80% of predicted maximal heart rate (220 − age).11
Ventilatory expired gas analysis was performed using a metabolic cart (Viasys Inc., Yorba Linda, CA). Before each test, the system was calibrated in standard fashion using reference gases. Minute ventilation (VE, body temperature and pressure), oxygen uptake (Vo2, standard temperature and pressure, dry [STPD]), carbon dioxide production (Vco2, STPD), and other variables were acquired breath-by-breath and averaged over 30-second intervals. All patients were required to have an respiratory exchange ratio (RER) ≤0.85 before the test. Peak Vo2 (in mL/kg per min and as percent predicted maximal Vo2 corrected for age, sex, and body size12) and peak RER were defined as the highest measured 30-second interval value obtained during the test. Seventeen subjects did not reach a RER ≥1.09. VE and Vco2 responses throughout exercise were used to calculate the VE/Vco2 slope via least squares linear regression.13 The ventilatory threshold (VT) was determined by the analysis of ventilatory equivalents.14
Echocardiography
Patients underwent resting echocardiography <1 month or immediately before testing. Diagnosis of HCM was based on the presence of a hypertrophied, nondilated left ventricular (LV) (wall thickness>12 mm) in the absence of other primary causes of LVH.15 Patients were classified according to their predominant site of hypertrophy (Figure 1).2 Images were reviewed by the primary and senior author. Standard views for M-mode and cross-sectional studies were performed. Dimensions, fractional shortening, pressure gradients, valvular regurgitation, and transmitral LV filling velocities were evaluated in accordance with American Society of Echocardiography guidelines.16 Indexed left atrial (LA) volume was obtained by: LA volume/body surface area (mL/m2).16 Systolic anterior motion of the mitral valve was defined as any contact of the leaflet with the septum during systole.17 Peak instantaneous LVOT flow velocity was measured at rest and during the strain phase of the Valsalva maneuver using continuous-wave Doppler in apical views. The mitral regurgitation jet was interrogated with attention paid to the flow pattern to accurately distinguish it from the subaortic obstruction jet. Tissue Doppler imaging was performed in the apical view, with a small sample volume placed at the lateral margin of the mitral annulus. Early (E′) and late (A′) diastolic velocities were measured. Lateral E/E′ ratio was calculated. Patients in atrial fibrillation during testing and with a history of mitral valve replacement, myotomy-mectomy, or alcohol septal ablation were excluded from diastolic function and LA dimensions analyses.
Figure 1.
Morphology classification. A, proximal, B, reverse curvature, C, apical, D, concentric HCM.
After exercise, the patient was immediately placed in the left lateral decubitus position. Imaging was performed by an experienced technician. Peak gradient was measured first, and degrees of mitral regurgitation (MR) were then assessed.
Statistical analysis
Differences between groups were compared using the χ2, Mann-Whitney U, unpaired t test, or analysis of variance tests when appropriate. Post hoc testing was performed using the method of Fisher. Vo2 measurements met the assumptions of normal distribution. To evaluate the association between peak Vo2 and other variables, Pearson correlation was performed. Multivariate regression analysis was performed to assess predictors of peak Vo2. Only variables with significant association (P < .05) with peak Vo2 in univariate analyses were entered into the forward stepwise model. Statistical analyses were performed using NCSS (NCSS Inc, Kaysville, UT).
No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all analyses, the drafting and editing of the article, and its final contents.
Results
Baseline characteristics
The cohort consisted of 63 subjects (18 females) (Table I). Eleven had a proximal pattern of HCM; 32, a reverse curvature pattern; 7, an apical pattern and 13 a concentric pattern. Most were NYHA I (52.4%). One patient had mitral valve surgery, 4 had alcohol septal ablation, and 4 had undergone surgical myotomy-myectomy.
Table I. Baseline characteristics
| Entire population | HCM patterns | |||||
|---|---|---|---|---|---|---|
| (n = 63) | Proximal (n = 11) | Reverse curvature (n = 32) | Apical (n = 7) | Concentric (n = 13) | P | |
| Age (y) | 48 ± 15 | 61 ± 13* | 47 ± 14 | 44 ± 12 | 44 ± 17 | .02 |
| Women (no. [%]) | 18 (28.6) | 4 (36.4) | 13 (40.6) | 0 | 1 (7.7) | .04 |
| Family history (no [%]) | ||||||
 HCM | 22 (35.5) | 2 (18.2) | 13 (41.9) | 2 (28.6) | 5 (38.5) | .53 |
| Sudden cardiac death | 22 (35.5) | 2 (18.2) | 16 (51.6) | 2 (28.6) | 2 (15.4) | .06 |
| CAD | 10 (16.1) | 1 (9.1) | 8 (25.8) | 1 (14.3) | 0 | .17 |
| NYHA class | 027 | |||||
| I | 33 (52.4) | 7 (63.6) | 23 (37.5) | 6 (85.7) | 8 (61.5) | |
| II | 16 (25.4) | 2 (18.2) | 11 (34.4) | 1 (14.3) | 2 (15.4) | |
| III | 14 (22.2) | 2 (18.2) | 9 (28.1) | 0 | 3 (23.1) | |
| Myotomy-myectomy (no [%]) | 4 (6.4) | 0 | 3 (9.4) | 0 | 1 (7.7) | .63 |
| Mitral valve surgery (no [%]) | 1 (1.6) | 0 | 1 (1-6) | 0 | 0 | .80 |
| Alcohol septal ablation (no [%]) | 4 (6.4) | 0 | 4 (12.5) | 0 | 0 | .25 |
| History of atrial fibrillation (no [%]) | 18 (28.6) | 2 (18.2) | 9 (28.1) | 3 (42.9) | 4 (30.8) | .73 |
| Diabetes (no [%]) | 7 (11.1) | 1 (9.1) | 4 (12.5) | 0 | 2 (15.4) | .75 |
| Hypertension (no [%]) | 20 (32.3) | 3 (27.3) | 11 (35.5) | 2 (28.6) | 4 (30.8) | .95 |
| Dyslipidemia (no [%]) | 22 (36.7) | 7 (63.7) | 9 (31.0) | 0 | 6 (46.2) | .04 |
| CAD (no [%]) | 5 (8.0) | 1 (9.1) | 3 (9.4) | 0 | 1 (7.7) | .97 |
| Smoking (no [%]) | ||||||
| Ever | 11 (17.5) | 4 (36.4) | 3 (9.4) | 2 (28.6) | 2 (15.4) | .37 |
| Currently | 5 (7.9) | 0 | 4 (12.5) | 0 | 1 (7.7) | .48 |
| Pulmonary disease† (no [%]) | 2 (3.2) | 0 | 2 (6.3) | 0 | 0 | .57 |
| Medications (no [%]) | ||||||
| β-Blocker | 41 (65.1) | 9 (81.8) | 21 (65.6) | 3 (42.9) | 8 (61.5) | .40 |
| Calcium-channel blocker | 17 (27.0) | 2 (18.2) | 10 (31.3) | 0 | 5 (38.5) | .24 |
| Anti-arrhythmic‡ | 6 (9.5) | 1 (9.1) | 4 (12.5) | 0 | 1 (7.7) | .97 |
| ACE/ARB | 17 (27.0) | 1 (9.1) | 12 (37.5) | 1 (14.3) | 3 (23.1) | .24 |
| Device (no [%]) | ||||||
| Pacemaker | 4 (6.4) | 0 | 2 (6.3) | 0 | 2 (15.4) | .39 |
| ICD | 12 (19.1) | 1 (9.1) | 10 (31.3) | 1 (14.3) | 0 | .07 |
| Previous ICD therapy (no [%]) | 3 (4.8) | 0 | 3 (9.4) | 0 | 0 | .38 |
⁎P < .05 between proximal versus others. |
†Included asthma and chronic obstructive pulmonary diseases. |
‡Included amiodarone, propafenone, disopyramide and digitalis. |
Patients with proximal HCM were significantly older. The prevalence of women was highest in proximal and reverse curvature groups. Dyslipidemia was most prevalent in the proximal HCM group, possibly reflecting greater age.
Determinants of exercise capacity
Univariate and multivariate regression models are presented in Table II, Table III. No statistically significant correlations were found between peak Vo2, dimensions, and gradients (Figure 2). Similar results were obtained after exclusion of patients without rest gradient (not shown). While the mitral a wave demonstrated a correlation with exercise capacity (r = −0.39; P = .01) no relations were found with early mitral inflow velocity (E), E/atrial mitral inflow velocity (A), and deceleration time (DT). Indexed LA volume (r = −0.52; P = .0007), lateral E′ (r = 0.50; P = .001), and E/E′ ratio (r = −0.46; P = .005) showed the strongest correlations with peak Vo2. These variables were not correlated with VE/Vco2 slope.
Table II. Correlations with peak Vo2 by univariate regression analysis
| Variables | r | P |
|---|---|---|
| Age | −0.56 | <.001 |
| LVEDD | −0.07 | .58 |
| LVESD | −0.21 | .16 |
| Maximal LV thickness | −0.08 | .58 |
| Rest gradient | −0.1 | .46 |
| Peak gradient | 0.08 | .61 |
| Mitral E | −0.15 | .33 |
| Mitral a | −0.39 | .01 |
| DT | −0.15 | .37 |
| Lateral E′ | 0.50 | .001 |
| Indexed LA volume | −0.52 | <.001 |
| Lateral E/E′ | −0.46 | .005 |
Table III. Explanation of peak Vo2 by multiple regression analysis
| Variables | R | R2 | New variance explained (%)⁎ | P |
|---|---|---|---|---|
| Multivariate model | .01 | |||
| Lateral E′ | 0.55 | 0.3 | .06 | |
| Age | 0.59 | 0.35 | 5 | .13 |
| Indexed left atrial volume | 0.63 | 0.4 | 5 | .16 |
| A wave | 0.68 | 0.46 | 6 | .17 |
Figure 2.
Univariate correlations between peak Vo2 and A, Lateral E′, B, Indexed LA volume, C, Rest and, D, Exercise LVOT gradients.
Stepwise multiple regression analysis results are presented in Table III. The model only included variables with significant association with peak exercise in univariate analyses. The significant predictors were age, lateral E′, the indexed LA volume and a wave. The model explained 46% of the variance in peak Vo2 (P = .01).
Morphology and gradient
None of the subjects had a resting ejection fraction ≤55%. The median interventricular septum dimension was 16 mm (range, 8-33 mm) and maximal thickness was 19 mm (range, 12-33 mm) (Table IV). Rest systolic anterior motion (SAM) was present in 36 (55.6%) subjects, and only 1 had more than rest moderate MR. As for diastolic markers, for the entire group, E wave measured 81 cm/s (range, 45-178 cm/s), a wave 75 ± 36 cm/s, E/A ratio 1.16 (range, 0.59-2.38), DT 236 ± 79 milliseconds, lateral E′ 8.9 ± 3.1 cm/s, lateral E/E′ ratio 11.3 ± 5.4 and the indexed LA volume was 33 ± 15 mL/m2. At peak exercise, no patient with a degree of MR of <2 developed a degree of MR ≥3. The median rest LVOT gradient for the entire group was 9 (range, 0-111) mm Hg, which increased to 17 (range, 0-144) mm Hg with Valsalva maneuver and to 26 (range, 0-213) mm Hg with exercise. Thirty-two subjects did not have rest gradient (gradient<10 mm Hg): 6 developed a gradient of ≥10 mm Hg with Valsalva maneuver, and 16 developed a gradient>10 mm Hg with exertion.
Table IV. Echocardiography data
| Entire Population | Patterns | |||||
|---|---|---|---|---|---|---|
| n = 63 | Proximal (n = 11) | Reverse Curvature (n = 32) | Apical (n = 7) | Concentric (n = 13) | P | |
| LA | ||||||
| Major axis (mm) | 61 ± 9 | 61 ± 9 | 61 ± 8 | 62 ± 7 | 62 ± 15 | .99 |
| Minor axis (mm) | 44 ± 9 | 47 ± 10 | 47 ± 9 | 38 ± 7 | 40 ± 8 | .06 |
| Indexed volume (mL/m2) | 33 ± 15 | 38 ± 14 | 34 ± 15 | 32 ± 4 | 26 ± 17 | .44 |
| LVEDD (mm) | 44 ± 7 | 40 ± 9 | 44 ± 6 | 50 ± 7 | 46 ± 7 | .02 |
| LVESD (mm) | 26 ± 7 | 24 ± 8 | 24 ± 6 | 30 ± 5 | 28 ± 7 | .10 |
| Interventricular septum (mm) | 16 (8-33) | 15 ± 7 | 19 ± 5§ | 13 ± 3 | 16 ± 2 | .001 |
| Maximal LV thickness (mm) | 19 (12-33) | 17 ± 3 | 21 ± 5* | 17 ± 6 | 18 ± 4 | .02 |
| LV posterior wall (mm) | 12 (6-22) | 12 ± 1 | 12 ± 4 | 12 ± 2 | 15 ± 3‡ | .008 |
| Fractional shortening (%) | 43 ± 9 | 47 ± 9 | 44 ± 10 | 39 ± 6 | 40 ± 8 | .30 |
| LVOT dimension (mm) | 22 (17-29) | 23 ± 3 | 22 ± 3 | 25 ± 2 | 23 ± 2 | .08 |
| SAM (no [%]) | 35 (556) | 8 (72.7) | 23 (71.9) | 0 | 4 (30.8) | .03§ |
| Rest mitral regurgitation | .04 | |||||
| None trace | 17 (27.0) | 1 (9.1) | 6 (18.8) | 4 (57.2) | 6 (46.2) | |
| 1+ | 25 (40.0) | 7 (63.6) | 14 (18.8) | 2 (28.6) | 2 (15.4) | |
| 2+ | 20 (31.8) | 2 (18.2) | 12 (37.5) | 1 (14.3) | 5 (38.5) | |
| 3+ | 1 (1.6) | 1 (9.1) | 0 | 0 | 0 | |
| E (cm/s) | 81 (45-178) | 96 ± 39 | 88 ± 26 | 64 ± 9 | 80 ± 20 | .14 |
| A (cm/s) | 75 ± 26 | 87 ± 23 | 71 ± 29 | 63 ± 18 | 75 ± 28 | .32 |
| E/A | 1.16 (0.59-2.38) | 0.97 (0.71-2.34) | 1.26 (0.78-1.86) | 1.08 (0.59-1.58) | 1.04 (0.74-2.38) | .76 |
| DT (milliseconds) | 236 ± 79 | 239 ± 63 | 225 ± 86 | 232 ± 78 | 258 ± 86 | .8 |
| Lateral E′ (cm/s) | 8.9 ± 3.1 | 8.1 ± 2.4 | 9.4 ± 2.3 | 9-4 ± 3.0 | 8.5 ± 5.6 | .75 |
| Lateral E/E′ | 11.3 ± 5.4 | 13.1 ± 5.4 | 10.1 ± 3.9 | 7.3 ± 2.1 | 14.0 ± 7.8 | .75 |
| Rest gradient (mm Hg) | 9 (0-111) | 10 (0-111) | 17 (0-1000) | 0 (0-6) | 0 (0-76) | .78§ |
| Valsalva gradient (mm Hg) | 17 (0-144) | 12 (0-117) | 31 (0-144) | 3 (0-6) | 14 (2-73) | .50§ |
| Exercise gradient (mm Hg) | 26 (0-213) | 60 ± 59 | 62 ± 53 | 4 ± 6 | 42 ± 42 | .43§ |
| ΔRest-peak (mm Hg) | 20 (0-189) | 23 (0-162) | 28 (0-189) | 0 (0-9) | 19 (0-115) | .56† |
| HR during postexercise gradient (beat/min) | 105 ± 35 | 89 ± 25 | 107 ± 22 | 105 ± 27 | 114 ± 29 | .13 |
*P < .05 between apical versus proximal and reverse HCM. |
†P < .05 between reverse curvature versus other groups. |
‡P < .05 between concentric versus others. |
§P value obtained after exclusion of apical group from analysis. |
Maximal LV thickness was significantly higher in the reverse curvature group. The LV cavity dimensions were significantly greater in apical HCM and patients with concentric HCM demonstrated the most severe LVPW hypertrophy (Table IV). Rest SAM was significantly more frequent in proximal and classic HCM. No significant differences between groups were noted in LA sizes and all markers of diastolic function. Excluding apical HCM, gradients were also not significantly different among groups.
Exercise test responses
Mean estimated METs for the entire group was 10.8 ± 4.1 (Table V). Chronotropic incompetence was present in 23 patients and an abnormal BP response occurred in 12 patients, without significant differences between groups. Occasional premature ventricular contractions (PVC)s were noted in 15 patients with most presenting <6 PVCs per minute. Among subgroups, no significant differences were noted in hemodynamic responses.
Table V. Exercise data
| Entire population | Patterns | |||||
|---|---|---|---|---|---|---|
| Variables | n = 63 | Proximal (n = 11) | Reverse Curvature (n = 32) | Apical (n = 7) | Concentric (n = 13) | P |
| Borg's score | 17 (16-18) | 18 (15-19) | 18 (17-19) | 16 (15-20) | 17 (15-19) | .48 |
| Rest HR (beat/min) | 71 ± 13 | 66 ± 10 | 72 ± 13 | 66 ± 16 | 75 ± 14 | .21 |
| Peak HR (beat/min) | 142 ± 29 | 133 ± 25 | 138 ± 28 | 162 ± 33 | 149 ± 32 | .13 |
| HR reserve (beat/min) | 71 ± 28 | 68 ± 26 | 66 ± 26 | 96 ± 29* | 73 ± 29 | .06 |
| Chronotropic incompetence (no [%]) | 23 (36.5) | 3 (28.3) | 15 (46.9) | 1 (14.3) | 4 (30.8) | .31 |
| Resting SBP (mm Hg) | 120 ± 18 | 123 ± 21 | 118 ± 18 | 127 ± 12 | 118 ± 20 | .63 |
| Maximal SBP (mm Hg) | 160 ± 27 | 160 ± 33 | 156 ± 26 | 176 ± 27 | 159 ± 24 | .37 |
| BP rise (mm Hg) | 40 ± 23 | 37 ± 26 | 38 ± 23 | 50 ± 29 | 40 ± 16 | .66 |
| Abnormal BP response (no [%]) | 12 (19.1) | 3 (27.3) | 8 (25.0) | 0 | 1 (7.7) | .27 |
| Maximal exercise capacity (METs) | 10.8 ± 4.1 | 10.9 ± 5.0 | 9.9 ± 3.6 | 14.8 ± 3.2 | 10.8 ± 4.1 | .07 |
| HR at 1 min into recovery (beat/min) | 28 ± 16 | 34 ± 25 | 25 ± 13 | 36 ± 17 | 27 ± 10 | .23 |
| Arrhythmia (no [%]) | .25 | |||||
| <6 PVCs/min | 13 (22.8) | 2 (18.2) | 8 (28.6) | 1 (20.0) | 2 (15.4) | |
| >6 PVCs/min | 2 (3.5) | 0 | 0 | 0 | 2 (15.4) | |
| Peak Vo2 (mL/kg per min) | 26.2 ± 10.1 | 24.7 ± 8.2 | 24.8 ± 9.1 | 34.1 ± 15.1 | 26.8 ± 10.2 | .16 |
| % Predicted Vo2max | 81 ± 26 | 93 ± 30 | 78 ± 22 | 97 ± 30 | 69 ± 21† | .04 |
| Maximal RER | 1.13 ± 0.07 | 1.11 ± 0.08 | 1.13 ± 0.06 | 1.12 ± 0.07 | 1.17 ± 0.09 | .23 |
| VE/Vco2 slope | 29 ± 6 | 31 ± 6 | 30 ± 6 | 25 ± 2 | 28 ± 6 | .12 |
| % Vo2 at VT | 71 ± 46 | 98 ± 105 | 68 ± 21 | 60 ± 13 | 62 ± 20 | .27 |
| Saturation O2% at peak | 97 ± 3 | 98 ± 3 | 97 ± 3 | 99 ± 1 | 97 ± 2 | .59 |
*P < .05 between proximal and classic reverse versus apical group. |
†P < .05 between proximal and apical versus concentric group. |
For the entire group, peak Vo2 was 26.2 ± 10.1 mL/kg per minute (81 ± 26 %predicted peak Vo2), VE/Vco2 was 29 ± 6, %Vo2 at VT was 71 ± 46% and maximal RER was 1.13 ± 0.07. Peak Vo2 was not significantly different between groups. Although no differences were noted in external work between groups, patients with concentric HCM achieved a significantly lower percent predicted peak Vo2 (Figure 3).
Figure 3.
Plots of A) maximal exercise capacity and B) %predicted maximal Vo2 by patterns.
Discussion
This study demonstrated a significant association between diastolic dysfunction and exercise capacity in HCM, whereas no significant relationships between exercise capacity and dimensions or gradients were found. Although subjects with a concentric pattern were more likely to have impaired exercise tolerance, morphology overall did not predict exercise capacity.
Our findings suggest that diastolic dysfunction contributes significantly to the objective functional evaluation of HCM. Previously, HCM patients have been shown to have lower E wave velocity, prolonged E wave and DT, higher A-wave velocity, and E/A ration <1.0.18 Studies with HCM using noninvasive indices have mostly failed to show significant correlations between transmitral inflow velocities and exercise capacity,8, 11 or have done so with considerable overlap.17 The lack of association between conventional indices of diastolic dysfunction and exercise capacity can be partly explained by its dependence on factors unrelated to intrinsic myocardial diastolic function, such as loading conditions.19 Our findings are therefore consistent with previous studies.7, 20
In contrast, TDI-derived indexes are less preload-dependent.21 Moreover, high E/E′ ratios22 have been associated with increased LV filling pressures and poor prognosis in CAD and HF populations. Lateral and septal E/E′ have also been correlated with peak Vo2 in various HCM populations.7, 8 However, none of the studies combined the use of exercise echocardiography with CPX. Thus, the association between exercise capacity and dynamic gradient was not analyzed.
Reflecting the chronicity and severity of increased LA pressure, enlarged LA diameter has been suggested to be a marker of chronic diastolic dysfunction and a predictor of adverse events.23 In clinical practice, LA volume is preferred because it is a more accurate for asymmetric remodeling and has a stronger association with adverse events.24 In our study, we found a previously unreported strong negative correlation between indexed LA volume and peak Vo2.
With the exception of patients with concentric HCM who exhibited a lower than predicted functional capacity, we did not find morphology to be a strong predictor of any expired gas variable. This is consistent with previous studies suggesting that LV morphology and dimensions are not major determinants of exercise capacity in HCM.11 More surprising perhaps, no significant association was observed between peak Vo2 and gradients in patients with and without resting gradients. The importance of mechanical obstruction underlying exercise intolerance is controversial. HCM is known as a predominantly obstructive disease in which gradients are frequently associated with HF symptoms often identified only with exercise.3 However, in studies that have demonstrated such associations, investigators have not included the evaluation of diastolic function with TDI-derived indices.3, 11 More recently, in a large study combining CPX and exercise echocardiography, patients who developed dynamic gradients achieved a higher %predicted peak Vo2 compared to those in the non-obstructive group.25 Interestingly, invasive management of obstruction with septal reduction therapy markedly improved their symptoms without changes in percent predicted peak Vo2. Moreover, the group with dynamic gradient had a higher peak exercise BP. The authors suggested that patients with exercise gradients may have higher cardiac output at peak exercise and that patients without dynamic obstruction may have more severe diastolic dysfunction.25 However, other studies have demonstrated clear coexistence of these two variables. In our study, patients with a concentric HCM achieved a lower %predicted peak Vo2 than others. We speculate that those patients had more severe diastolic dysfunction. The relationship, or lack thereof, between gradient and exercise capacity remains to be further elucidated by studies that evaluate the cardiac output response to exercise.
Study limitations
Exercise testing was carried out on a treadmill with immediate supine echocardiography. Thus, instantaneous changes in hemodynamics at the cessation of exercise cannot be accounted for. Upright treadmill exercise is however more physiological than supine bike exercise, which would allow such measurements at peak exertion. The relationship between mitral annular velocity measurements and LA pressure is complex and although there is a clear correlation, its predictive accuracy for LA pressure estimation is low.26
Conclusion
Lateral E′ and indexed LA volume are significantly associated with functional capacity in HCM. Although patients with concentric HCM achieved the lowest percent predicted maximal Vo2, gradient and morphology did not predict exercise capacity. This suggests that diastolic dysfunction is an important and underappreciated factor limiting exercise capacity in HCM. Diastolic indices may represent effective surrogates for clinical progression and may guide management decisions. While interventional decisions with respect to septal reduction focus on gradients and subjective and objective limitations, the present data argue for a more prominent role for markers of intrinsic myocardial stiffness. Although no current therapies directly target the underlying disease process of HCM, future studies should clarify the complex ventricular-vascular coupling relationships and in particular the exercise cardiac output response.
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PII: S0002-8703(09)00448-7
doi:10.1016/j.ahj.2009.06.006
© 2009 Mosby, Inc. All rights reserved.
