Although exercise echocardiography may assess left ventricular (LV) function and LV outflow tract (LVOT) gradients during exercise in patients with hypertrophic cardiomyopathy (HCM), its value for predicting outcomes has not been studied. The aim of this study was to determine whether exercise echocardiography predicts outcomes in patients with HCM.
LV function and LVOT gradients were evaluated during exercise echocardiography in 239 patients with HCM.
Sixty patients (25.1%) had LVOT obstruction at rest, and 43 (18%) developed exercise-induced LVOT obstruction. The mean resting LV ejection fraction was 69 ± 9%, and the mean resting wall motion score index was 1.00 ± 0.06. Wall motion abnormalities during exercise were seen in 19 patients (7.9%). During follow-up of 4.1 ± 2.6 years, 19 patients had hard events (cardiac death, cardiac transplantation, appropriate discharge of a defibrillator, stroke, myocardial infarction, or hospitalization for heart failure), and 41 patients had composite end points of hard or soft events (including atrial fibrillation and syncope). Exercise wall motion abnormalities occurred in 31.5% of patients with hard events compared with 5.9% of patients without hard events ( P < .001). After adjustment, LV wall thickness (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.05–1.21; P = .002), resting wall motion score index (HR, 21.59; 95% CI, 2.38–196.1, P = .006), and metabolic equivalents (HR, 0.74; 95% CI, 0.63–0.88; P = .001) remained independent predictors of hard events. Change in wall motion score index was also independently associated with hard events (HR, 52.30; 95% CI, 3.81–718.5; P = .003) and with the composite end point (HR, 39.51; 95% CI, 3.79–412.4; P = .002). LVOT obstruction was not associated with either end point.
Assessment of exercise capacity and LV systolic function during exercise echocardiography may have a role in risk stratification of patients with HCM.
Outcomes in patients with hypertrophic cardiomyopathy (HCM) are not easily predictable. Several risk factors have been proposed in an approach similar to that for patients with coronary artery disease, namely, familial history of sudden death, previous syncope, demonstrated ventricular tachycardia, severe hypertrophy, obstructive left ventricular (LV) outflow tract (LVOT) gradient, and abnormal blood pressure (BP) during exercise. Although exercise is commonly performed in patients with HCM for functional evaluation and demonstration of obstruction, the precise role of exercise echocardiography in these patients is not well known. Exercise-induced wall motion abnormalities (WMAs) has been associated to poor outcomes in several other cardiac diseases (i.e., coronary artery disease), but this association has not been investigated in HCM. We hypothesized that some patients with HCM may have WMAs during exercise and that this finding may be related to worse prognosis. We also explored the relationship between WMAs, LV obstruction, exercise mitral regurgitation (MR), abnormal BP response, and events during follow-up.
A group of 255 consecutive patients with clinical diagnoses of HCM who were being followed in our HCM research unit were referred for exercise echocardiography according to an institutional research protocol. HCM was diagnosed by the presence of a nondilated and hypertrophied left ventricle (wall thickness > 15 mm in adult index patients or > 13 mm plus abnormal electrocardiographic results in relatives of patients with HCM) in the absence of another cardiac or systemic disease capable of producing the magnitude of LV hypertrophy observed. Patients with resting LV systolic dysfunction, defined as a resting LV ejection fraction (LVEF) < 50% ( n = 11), and those who had either a history of coronary artery disease or evidence of coronary lesions on angiography ( n = 5) were excluded from the analysis. Therefore, the final study group consisted of 239 patients, including 204 index patients and 35 affected relatives. Clinical patient characteristics are listed in Table 1 .
|Parameter||All patients||No events |
( n = 220)
|Hard events |
( n = 19)
|Age (y)||52 ± 15||52 ± 15||58 ± 13||.046|
|Men||145 (61)||138 (63)||7 (37)||.03|
|Family history of HCM||76 (32%)||70 (32%)||6 (32%)||.98|
|Maximal LV thickness (mm)||20 ± 5||20 ± 5||24 ± 6||.007|
|Left atrial diameter (mm)||44 ± 7||44 ± 7||48 ± 6||.006|
|NYHA functional class ≥ II||132 (55%)||116 (53%)||16 (84%)||.008|
|History of atrial fibrillation||32 (13%)||29 (13%)||3 (16%)||.73|
|History of syncope||26 (11%)||25 (11%)||1 (5%)||.7|
|History of angina||90 (38%)||80 (36%)||10 (53%)||.16|
|NSVT||35 (15%)||28 (13%)||7 (37%)||.004|
|SVT/CRA||3 (1%)||2 (1%)||1 (5%)||.22|
|Implanted defibrillator||2 (1%)||1 (0.5%)||1 (5%)||.15|
|Resting ECG (%)|
|Atrial fibrillation||18 (8%)||15 (7%)||3 (16%)||.16|
|LBBB/pacemaker||14 (6%)||13 (6%)||1 (5%)||1.0|
|ST-segment abnormalities||109 (46%)||98 (45%)||11 (58%)||.26|
|β-blockers||93 (39%)||84 (38%)||9 (47%)||.43|
|Calcium channel blockers||29 (12%)||26 (12%)||3 (16%)||.71|
|Disopyramide||10 (4%)||8 (4%)||2 (11%)||.18|
|Amiodarone||20 (8%)||16 (7%)||4 (21%)||.06|
|ACE inhibitors/ARBs||49 (21%)||43 (20%)||6 (32%)||.21|
|Diuretics||45 (19%)||37 (17%)||8 (42%)||.007|
Medications were not withdrawn before the tests. Heart rate and BP were measured and 12-lead electrocardiography was performed at baseline and at each stage of the exercise protocol. Patients were encouraged to perform a treadmill exercise test (Bruce protocol in 86%, modified Bruce protocols in 14%). End points included significant arrhythmia, severe hypertension (systolic BP > 240 mm Hg or diastolic BP > 110 mm Hg), hypotensive response (decrease > 20 mm Hg from baseline), or limiting symptoms. Two-dimensional echocardiography using a Vivid 5 machine (GE Vingmed Ultrasound AS, Horten, Norway) was performed in standard parasternal and apical views at baseline and peak exercise. Peak exercise echocardiography was performed when signs of exhaustion were present or an end point was reached. LVOT and intraventricular gradients by continuous Doppler and MR by color Doppler (jet area in the four-chamber apical view) were measured at rest and during the immediate postexercise period (within 1 min). LV obstruction was defined as a gradient > 30 mm Hg at rest or after exercise. MR severity was assessed by total jet area and graded as trace, mild (1–4 cm 2 ), moderate (4–8 cm 2 ), or severe (>8 cm 2 ), as described previously. Significant MR was defined as at least moderate MR at rest or after exercise. Early and late LV inflow waves at rest and during exercise were measured in the last 152 studies performed. Abnormal BP response was defined as a failure to increase systolic BP by ≥20 mm Hg during exercise or an initial increase in systolic BP with a subsequent fall of >20 mm Hg compared with peak BP. Informed consent was obtained for each patient.
Rest and exercise two-dimensional echocardiographic analysis was performed on a digital quad-screen display system. The left ventricle was divided into 16 segments. A wall motion score index (WMSI) at rest and during exercise was calculated (1 = normal, 2 = hypokinetic, 3 = akinetic, and 4 = dyskinetic). LVEFs at rest and at peak exercise were measured using the biplane Simpson’s rule. For assessment of interobserver and intraobserver variability (presence or absence of WMAs), 20 studies (eight with exercise WMAs in the initial assessment and 12 without) were chosen in a random manner.
Follow-up and events were determined by revisiting the patients and reviewing medical records and death certificates. No patients were lost during follow-up. Hard events included cardiac death, cardiac transplantation, appropriate implantable cardioverter-defibrillator discharge, sustained ventricular tachycardia, stroke in the context of atrial fibrillation or flutter, myocardial infarction, and heart failure requiring hospitalization. Cardiac death was defined as death due to acute myocardial infarction, congestive heart failure, life-threatening arrhythmias, or cardiac arrest; unexpected, otherwise unexplained sudden death was also considered cardiac death. Combined hard and soft events were defined as a hard event or new-onset atrial fibrillation or syncope. Myectomy, septal ablation, defibrillator implantation, and demonstration of nonsustained ventricular tachycardia on 24-hour electrocardiographic monitoring were not considered events.
Continuous variables are reported as mean ± SD and categorical variables as percentages. Event-free survival was estimated using the Kaplan-Meier method using a time–to–first event approach. Patients who died of noncardiac causes were censored at the time of death. Interobserver and intraobserver variability for assessing WMAs was measured. The percentage of intraobserver and interobserver agreement and κ values are given. Univariate associations of clinical, exercise testing, and exercise echocardiographic variables with events were assessed using Cox proportional-hazards modeling. P values < .05 were considered significant. The hazard ratios and 95% confidence intervals are given. Variables that were significantly associated with the end points on univariate analyses were considered for entry in the multivariate model. The value of exercise echocardiography over clinical and exercise testing data was assessed in steps, as is usually done in clinical practice. The first step was based on clinical data. The second step consisted of resting echocardiography. In the third step, the exercise testing variables were added. The fourth step consisted of the addition of exercise LV function. Continuous variables were used instead of dichotomous variables with similar meaning. Variables that were significant ( P < .05) at each step were allowed to remain in the model. To clarify whether exercise WMAs provided incremental prognostic information compared with other established markers of adverse outcomes in patients with HCM, we also assessed a model in which we included the clinical predictors of adverse outcome in patients with HCM in step 1, then resting LVEF in step 2, then achieved metabolic equivalents (METs) in step 3, then exercise LVEF in step 4, and finally exercise WMSI in the last step. Clinical variables in step 1 in this model were family history of sudden death, previous cardiac arrest or history of sustained ventricular tachycardia, documented nonsustained ventricular tachycardia on 24-hour electrocardiographic monitoring, previous syncope, blunted BP during exercise testing, maximal LV wall thickness, and resting LV obstruction. The incremental value between steps was measured using the χ 2 method.
Exercise echocardiography was performed without serious complications in all patients. Exhaustion was the most common reason for stopping the test (90%). Faintness and hypotension were the reasons for stopping the test in six patients. Thirteen patients experienced dyspnea, and 19 had angina during exercise.
WMAs during Exercise
Exercise WMAs occurred in 19 of the 239 patients (7.9%) and were more frequent in patients who developed hard events (31.5% vs 5.9%, P < .001) and combined events (17% vs 6%, P = .018). Exercise WMAs were described as a global phenomenon in five of the 19 patients (global LV dysfunction) and as a regional phenomenon in 14 patients, involving predominantly the anteroseptal region (13 of 14). The frequency of hypotensive response was similar between patients with and those without exercise WMAs (58% vs 40%, P = NS), as was the presence of significant MR either at rest (16% vs 17%, P = NS) or during exercise (37% vs 27%, P = NS). Maximal LV wall thickness and left atrial diameter were also similar in patients with and those without exercise WMAs (20 ± 5 vs 21 ± 5 mm and 45 ± 6 vs 44 ± 7 mm, respectively, P = NS for both). LV obstruction was similar between groups at rest (LVOT gradient, 19 ± 24 vs 26 ± 33 mm Hg; P = NS), although it was lower during exercise in patients with WMAs (LVOT gradient, 28 ± 34 vs 52 ± 55 mm Hg, P = .008). LVEF was lower at rest and during exercise in patients with exercise WMAs (63 ± 9% vs 70 ± 9% and 61 ± 8% vs 74 ± 10%, P = .001 and P < .001, respectively), as were achieved METs (7.6 ± 2.4 vs 10 ± 3.4, P = .004). Coronary angiography performed in 13 of the 19 patients with exercise WMAs and in 37 of the 220 patients without WMAs showed absence of coronary lesions in all, although the milking phenomenon was described in seven of the 37 studies of patients without WMAs. Coronary risk factors were also similar in patients with and those without exercise WMAs (hypertension, 37% vs 39%; hypercholesterolemia, 32% vs 34%; diabetes mellitus, 11% vs 7%; smoking, 16% vs 24%; number of coronary risk factors, 0.9 ± 0.8 vs 1 ± 0.9; P = NS for all). Among the six patients with WMAs who did not undergo angiography, there were three women (aged 65, 66, and 73 years) and three men (aged 36, 52, and 59 years). Only one had a history of angina, although the exercise testing was clinically silent in all six. The pretest probability of coronary artery disease was very low (<5%) in two patients, low (<10%) in three, and intermediate (10%–90%) in one. The mean 10-year Framingham risk score in these six patients was 11 ± 9% (range, 1%–25%).
Variability for the Assessment of WMAs
Interobserver and intraobserver variability values for exercise WMAs were 90% and 85%, with κ values of 0.80 and 0.69, respectively. Figure 1 and Videos 1 and 2 are examples of normal exercise echocardiographic responses in two patients, and Figure 2 and Video 3 show exercise-induced global WMAs in another patient.
LV Obstruction at Rest and during Exercise
At rest, LVOT gradients of >30 and >50 mm Hg were found in 25% and 16% of the patients, whereas during exercise, these percentages were 43% and 35%, respectively. Most of the 60 patients who already had significant obstruction at rest developed high grades of obstruction during exercise, up to 109 ± 41 mm Hg, being >50 mm Hg in 52 patients (87%). Development of significant LV obstruction during exercise in patients who did not have obstruction at rest occurred in 44 patients (18%). In 88 of the 104 patients (85%) with significant gradients either at rest or during exercise, systolic anterior motion (SAM) of the mitral valve was seen, whereas in four patients, midventricular gradients were obtained. An abnormal BP response was more common in patients with severe obstruction at rest (i.e., gradient > 50 mm Hg; 62% vs 37%, P = .004), although this association was not significant for patients with gradients > 50 mm Hg during exercise (47% vs 38%, P = NS).
MR at Rest and during Exercise
Significant MR was observed at rest in 40 patients (16%), being severe in 12, whereas during exercise it was seen in 67 patients (28%), being severe in 23. New significant MR developed in 30 patients (13%) during exercise, whereas resting MR diminished in three patients. The main cause of significant MR during exercise was mitral valve SAM, which was reported in 48 of the 69 patients (70%). MR secondary to LV dysfunction and dilation during exercise accounted for four patients and degenerative disease for one patient. As expected, significant MR during exercise was associated with LV obstruction. Thus, more patients with significant exercise MR had exercise LVOT gradients > 30 mm Hg and >50 mm Hg than those without exercise MR (72% vs 32% and 64% vs 23%, respectively, P < .001 for both). Abnormal BP was also more prevalent in patients with significant exercise MR (72% vs 32%, P < .001).
Events during Follow-Up
During a mean follow-up period of 4.1 ± 2.6 years, 19 patients had hard cardiovascular events (cardiac death in five patients, cardiac transplantation in one, appropriate discharge of a defibrillator in two, stroke in one, myocardial infarction in two, and hospitalization due to heart failure in eight), and 41 patients had combined events (hard events in 19, new atrial fibrillation in 17, and syncope in five). Tables 1 and 2 show the clinical characteristics and resting and exercise results of the 239 patients with HCM, according to the presence or absence of hard events during follow-up. Univariate and multivariable predictors of events are listed in Table 3 . Septal ablation or myectomy were performed in only seven patients (3.2%) who did not have any hard events during follow-up, and defibrillator implantation was performed in 13 (6%) and three (16%) patients without and with hard events, respectively. However, these therapeutic procedures were not considered events, as the results of the exercise testing may have influenced them. Exercise WMAs were associated with a higher likelihood of hard events in univariate analysis (hazard ratio, 7.68; 95% confidence interval, 2.88–20.46; P < .001). Resting or exercise-induced LVOT obstruction was not significantly associated with either end point. After multivariate adjustment, LV wall thickness, resting WMSI, and achieved METs remained independent predictors of hard events. Change in WMSI was associated with greater likelihood of hard events. Change in WMSI was also associated with combined events, along with maximal achieved METs. Figure 3 shows the Kaplan-Meier event-free survival curves according to the presence or absence of exercise WMAs. Figure 4 shows how exercise WMAs increased the prediction of hard events over traditional clinical risk assessment, resting LVEF, achieved METs, and exercise LVEF.
|Parameter||All patients||No events ( n = 220)||Hard events ( n = 19)||P|
|Clinical symptoms during test||32 (13%)||27 (12%)||5 (26%)||.09|
|Positive results on electrocardiographic exercise testing||34 (14%)||32 (15%)||2 (11%)||1.00|
|LV gradient at rest (mm Hg)||25 ± 32||24 ± 30||38 ± 50||.07|
|LV gradient >30 mm Hg at rest||60 (25%)||52 (24%)||8 (42%)||.08|
|LV gradient with exercise (mm Hg)||50 ± 54||49 ± 53||64 ± 67||.37|
|LV gradient with exercise > 30 (mm Hg)||103 (43%)||92 (42%)||11 (58%)||.18|
|LV gradient with exercise > 50 (mm Hg)||83 (35%)||74 (34%)||9 (47%)||.23|
|LV end-diastolic volume at rest (mL)||55 ± 16||55 ± 16||54 ± 13||.83|
|LV end-diastolic volume during exercise (mL)||55 ± 19||54 ± 19||59 ± 15||.28|
|LV end-systolic volume at rest (mL)||16 ± 7||16 ± 7||17 ± 6||.73|
|LV end-systolic volume during exercise (mL)||15 ± 8||14 ± 8||15 ± 8||.81|
|Resting LVEF (%)||69 ± 9||70 ± 9||65 ± 10||.09|
|Exercise LVEF (%)||73 ± 10||74 ± 10||70 ± 12||.27|
|Regional WMAs at rest||5 (2%)||2 (0.9%)||3 (15.8%)||.004|
|Regional WMAs during exercise||19 (7.9%)||13 (5.9%)||6 (31.5%)||<.001|
|Resting WMSI||1.00 ± 0.06||1.00 ± 0.3||1.07 ± 0.20||<.001|
|Peak WMSI||1.03 ± 0.11||1.02 ± 0.9||1.13 ± 0.23||<.001|
|MR moderate or greater at rest||40 (17%)||35 (16%)||5 (26%)||.24|
|MR moderate or greater during exercise||67 (28%)||58 (26%)||9 (47%)||.05|
|E/A ratio at rest||1.13 ± 0.47||1.12 ± 0.48||1.18 ± 0.42||.82|
|E/A ratio during exercise||1.18 ± 0.45||1.18 ± 0.45||1.12 ± 0.49||.79|
|METs||9.8 ± 3.4||10 ± 3.3||7.2 ± 2.8||<.001|
|Peak heart rate (beats/min)||144 ± 28||146 ± 27||130 ± 26||.02|
|Peak BP (mm Hg)||161 ± 31||162 ± 31||148 ± 28||.04|
|Peak rate-pressure product (beats/min · mm Hg)||23,483 ± 6,939||23,831 ± 6,890||19,449 ± 6,350||.009|
|% maximum achieved peak heart rate||86 ± 14||86 ± 14||80 ± 17||.08|
|Abnormal BP response||99 (41%)||86 (39%)||13 (68%)||.013|