Patients with hypertrophic cardiomyopathy (HC) have coronary microvascular dysfunction, which is an independent predictor of adverse left ventricular remodeling, systolic dysfunction, and mortality in these patients. Whether these defects in vasomotor function are localized to the coronary arteries or whether systemic vasomotor dysfunction is present in patients with HC has not yet been adequately examined. The aim of this study was to test the hypothesis that patients with HC have altered peripheral vascular endothelial function. Subjects without coronary artery disease (CAD) and those with CAD served as negative and positive controls, respectively. Conduit artery endothelium-dependent vasomotion was assessed with ultrasound by measuring flow-mediated dilation of the brachial artery. Flow-mediated dilation was lower in patients with HC compared with those without CAD (p <0.05) but was similar in patients with CAD (p = NS). In conclusion, vasomotor dysfunction in HC is not restricted to the coronary vasculature. Patients with HC have impaired peripheral conduit vessel endothelial function, and the magnitude of impairment is similar to that seen in older patients with advanced CAD.
Patients with hypertrophic cardiomyopathy (HC) have abnormalities of the intramural coronary arteries characterized by structurally atypical coronary endothelial cells and thickening of the intima and/or medial layers of the vessel wall associated with decreased luminal cross-sectional area. These abnormalities of the intramural coronary vessels likely represent the primary morphologic substrate contributing to microvascular dysfunction (i.e., abnormal vasodilatory capacity) and its functional consequences, namely, blunted myocardial blood flow during stress. Coronary microvascular dysfunction is an independent predictor of adverse left ventricular (LV) remodeling, systolic dysfunction, and mortality in patients with HC. Whether these defects in vasomotor function in HC are localized to the coronary arteries or whether systemic vasomotor dysfunction is present has not been adequately examined. The primary purpose of this study was to examine vascular endothelial function in patients with HC to better characterize systemic vascular physiology and pathophysiology in this population.
Methods
We prospectively evaluated 46 consecutive patients with HC without known coronary artery disease (CAD). The diagnosis of HC was based on the echocardiographic demonstration of a focal area of LV hypertrophy (wall thickness ≥15 mm), associated with a nondilated cavity in the absence of another cardiac or systemic disease that could produce the magnitude of hypertrophy evident. In addition, patients without HC but with CAD (n = 46) and those without HC or CAD (n = 46) were retrospectively selected and served as positive and negative controls, respectively. Exclusion criteria included severe valvular disease, recent myocardial infarction or unstable cardiac symptoms, congestive heart failure or an LV ejection fraction <40%, severe arrhythmia, coexistent aortic stenosis, or Raynaud disease. In addition, patients with HC were excluded if they had histories of septal myectomy or alcohol septal ablation.
The presence or absence of the following cardiovascular risk factors was assessed in each patient: male gender, hypertension (taking antihypertensive medication or systolic blood pressure >140 mm Hg and/or diastolic blood pressure >90 mm Hg), hypercholesterolemia (taking lipid-lowering medication or total serum cholesterol >200 mg/dl), diabetes mellitus (taking medication or fasting glucose level >126 mg/dl), smoking (having smoked ≥5 cigarettes per day within the previous month), and family history of CAD (having first- or second-degree relatives with premature CAD). CAD was defined as the presence of ischemia or infarction on single-photon emission computed tomographic nuclear myocardial perfusion imaging or >50% stenosis of an epicardial coronary artery by angiography. All subjects gave written informed consent, and this study was approved by the institutional review board at Tufts Medical Center.
Brachial artery diameter was assessed using high-resolution ultrasonography. Briefly, the right brachial artery was longitudinally imaged 2 cm above the antecubital fossa using a 10-MHz linear-array vascular ultrasound transducer (Philips Medical Systems, Andover, Massachusetts). Diameters were measured during end-diastole (gated with electrocardiographic R waves) using ultrasonic calipers. The average of 5 evenly spaced measures (distance between the anterior and posterior intima-blood interfaces) obtained within a 5-cm segment of the vessel was used for subsequent analysis. After baseline arterial diameter measurement, reactive hyperemia was induced by an ischemic stimulus (rapid inflation of a blood pressure cuff around the upper arm to a suprasystolic pressure for 5 minutes). Immediately after cuff release, reactive hyperemia was confirmed by qualitatively assessing blood velocity for 10 seconds using spectral Doppler. Sixty seconds after the release of the occlusion cuff, brachial diameter was once again measured as aforementioned. Responses were calculated as percentage change in brachial artery diameter from baseline and taken as a measure of conduit vessel endothelial function.
Cardiac dimensions and the ejection fraction were assessed using standard 2-dimensional echocardiographic techniques. The presence and magnitude of LV outflow tract (LVOT) obstruction was assessed as previously described at rest, with the Valsalva maneuver and during exercise. LVOT obstruction was defined as a peak instantaneous outflow gradient of ≥30 mm Hg by continuous-wave Doppler echocardiography. Systolic anterior motion and mitral regurgitation were assessed semiquantitatively (on a scale ranging from 0 to 4), as previously described.
All data are reported as mean ± SE. Group differences were assessed using analysis of variance with Tukey’s method for post hoc comparisons. Analysis of covariance was performed with variables known to influence flow-mediated dilation (FMD) entered as covariates. Chi-square tests were used to compare categorical variables. Pearson’s and Spearman’s correlation coefficients were used to assess relations between variables of interest. Significance was set at p <0.05. All data analysis was carried out using SPSS version 16.0 (SPSS, Inc., Chicago, Illinois).
Results
Controls with HC and without CAD did not differ in age, body mass index, gender, and the prevalence of cardiovascular risk factors ( Table 1 ). Compared to controls with HC and without CAD, patients with CAD were older and had a greater prevalence of hypertension, hyperlipidemia, and diabetes mellitus (p <0.05; Table 1 ). Characteristics of patients with HC are listed in Table 2 .
| Variable | Patients With HC | Patients Without CAD | Patients With CAD |
|---|---|---|---|
| (n = 46) | (n = 46) | (n = 46) | |
| Age (years) | 46 ± 2 ⁎ | 48 ± 2 ⁎ | 56 ± 1 |
| Body mass index (kg/m 2 ) | 28 ± 1 | 29 ± 1 | 30 ± 1 |
| Men | 22 (48%) | 20 (43%) | 24 (52%) |
| Hypertension | 14 (30%) ⁎ | 16 (35%) ⁎ | 26 (57%) |
| Hyperlipidemia | 19 (41%) ⁎ | 14 (30%) ⁎ | 31 (67%) |
| Diabetes mellitus | 3 (7%) ⁎ | 3 (7%) ⁎ | 17 (37%) |
| Smokers | 10 (22%) | 8 (17%) | 15 (33%) |
| Family history of CAD | 14 (30%) | 16 (35%) | 22 (48%) |
| Variable | Value |
|---|---|
| Ejection fraction (%) | 64 ± 1 |
| Maximum left ventricular thickness (mm) | 20.5 ± 0.7 |
| Left ventricular end-diastolic dimension (mm) | 40.4 ± 1.0 |
| Left atrial size (mm) | 39.6 ± 1.2 |
| Systolic anterior motion (scale 0–4) | 2.2 ± 0.2 |
| Mitral regurgitation (scale 0–4) | 1.5 ± 0.1 |
| Family history of hypertrophic cardiomyopathy | 19 (41%) |
| Gradient at rest | 18 (39%) |
| Exercise gradient | 24 (52%) |
| New York Heart Association Class | |
| I | 26 (56%) |
| II | 10 (22%) |
| III | 10 (22%) |
| Implantable Cardioverter-Defibrillator | 19 (41%) |
| Medications | |
| β blocker | 29 (63%) |
| Calcium channel blocker | 14 (30%) |
| Diuretic | 7 (15%) |
| Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker | 4 (9%) |
| Antiarrhythmic | 3 (6%) |
| Statin | 11 (24%) |
FMD was impaired in patients with HC compared to controls without CAD (p <0.05; Figure 1 ), to levels similar to that in patients with CAD (p = NS; Figure 1 ). After adjusting for potential confounders that were different between groups (age and the prevalence of hypertension, hyperlipidemia, and diabetes mellitus), FMD was still similarly impaired in patients with HC and CAD compared to controls without CAD (adjusted means: patients with HC 8.4 ± 0.9%, controls with CAD 9.1 ± 0.9%, controls without CAD 12.3 ± 0.9%; p <0.05).
