American Journal of Cardiology
Volume 105, Issue 1 , Pages 112-115, 1 January 2010

Peripheral Vascular Endothelial Function in Patients With Hypertrophic Cardiomyopathy

The Vascular Function Study Group, The Hypertrophic Cardiomyopathy Center, Division of Cardiology, Tufts Medical Center, Boston, Massachusetts

Received 30 June 2009; received in revised form 12 August 2009; accepted 12 August 2009.

Article Outline

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.1, 2, 3, 4 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.1, 2, 3, 4 Coronary microvascular dysfunction is an independent predictor of adverse left ventricular (LV) remodeling, systolic dysfunction, and mortality in patients with HC.5, 6, 7 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.

Back to Article Outline

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.8 LVOT obstruction was defined as a peak instantaneous outflow gradient of ≥30 mm Hg by continuous-wave Doppler echocardiography.8 Systolic anterior motion and mitral regurgitation were assessed semiquantitatively (on a scale ranging from 0 to 4), as previously described.8

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).

Back to Article Outline

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.

Table 1. Patient characteristics
VariablePatients With HCPatients Without CADPatients With CAD
(n = 46)(n = 46)(n = 46)
Age (years)46±2⁎48±2⁎56±1
Body mass index (kg/m2)28±129±130±1
Men22(48%)20(43%)24(52%)
Hypertension14(30%)⁎16(35%)⁎26(57%)
Hyperlipidemia19(41%)⁎14(30%)⁎31(67%)
Diabetes mellitus3(7%)⁎3(7%)⁎17(37%)
Smokers10(22%)8(17%)15(33%)
Family history of CAD14(30%)16(35%)22(48%)

Data are expressed as mean ± SEM or as number (percentage).

⁎Significantly different from patients with CAD (p <0.05).

Table 2. Hypertrophic cardiomyopathy patient characteristics (n = 46)
VariableValue
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 cardiomyopathy19(41%)
Gradient at rest18(39%)
Exercise gradient24(52%)
New York Heart Association Class
I26(56%)
II10(22%)
III10(22%)
Implantable Cardioverter-Defibrillator19(41%)
Medications
β blocker29(63%)
Calcium channel blocker14(30%)
Diuretic7(15%)
Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker4(9%)
Antiarrhythmic3(6%)
Statin11(24%)

Data are expressed as mean ± SEM or as number (percentage).

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).

  • View full-size image.
  • Figure 1. 

    FMD (%) in patients with HC. FMD was lower in patients with HC and those with CAD (CAD+) compared to those without CAD (CAD-). *Significantly different from patients without CAD (p <0.05).

There was no association between FMD and age in patients with HC (r = 0.10, p = NS). There was a significant inverse association between FMD and age in controls (r = −0.35, p <0.05). There was no association between FMD and the absolute number of cardiovascular risk factors in patients with HC (r = −0.12, p = NS). There was a significant inverse association between FMD and the absolute number of cardiovascular risk factors in controls (r = −0.22, p <0.05). Medication use had no effect on FMD in patients with HC. FMD was not different in patients with HC taking β blockers (p >0.05), calcium channel blockers (p >0.05) angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (p >0.05), diuretics (p >0.05), or statins (p >0.05) compared to patients with HC not taking these agents.

In the HC cohort, 24 patients had evidence of LVOT obstruction, with an average gradient at rest for all patients of 30 ± 6 mm Hg. Patients with LVOT obstruction were older than those without obstruction (51 ± 3 vs 39 ± 4 years, p <0.05). Patients with and without obstruction did not differ in cardiovascular risk factors, gender, body mass index, or cardiac structures (LV end-diastolic dimension, LV wall thickness, left atrial size). FMD was similar between patients with HC with obstruction and those without obstruction (9.2 ± 1.4% vs 8.3 ± 1.1%, p = NS). FMD was not correlated with absolute LVOT gradient at rest (r = 0.045, p = NS). Adjusting for age had no effect on the lack of a group difference in FMD (p >0.05).

Back to Article Outline

Discussion 

The novel findings of this investigation are that (1) patients with HC had reduced peripheral vascular endothelial function compared to controls without CAD, and the level of impairment was similar to that seen in patients with CAD, and (2) peripheral vascular endothelial impairment with HC is not related to the presence or magnitude of LVOT obstruction. Our findings suggest that vascular endothelial dysfunction in HC is systemic and may not be influenced by other attributes of the disease pathology, namely, LVOT obstruction.

Patients with HC have coronary vascular dysfunction contributing to low coronary flow reserve, ischemia, systolic dysfunction, fibrosis, LV remodeling, and ultimately death. The extent to which vascular dysfunction with HC is systemic has been sparsely examined. Previous studies in small select populations of patients with HC have reported heightened forearm resistance vessel vasoconstriction and blunted resistance vessel vasodilation to pharmacologic and physiologic perturbations.9, 10, 11, 12 Patients with HC also have elevated levels of plasma biomarkers associated with endothelial dysfunction, such as C-reactive protein, interleukin-6, soluble cluster of differentiation 40 ligand, tissue factor pathway inhibitor, soluble thrombomodulin, β-thromboglobulin, asymmetric dimethylarginine (the endogenous inhibitor of nitric oxide), and endothelin-1.13, 14, 15 Our finding of reduced conduit vessel FMD in a larger HC cohort is consistent with the notion that there is global vascular endothelial dysfunction in patients with HC.

Peripheral vascular endothelial dysfunction is associated with coronary endothelial dysfunction16 and predicts future cardiovascular events.17, 18, 19 A novel finding of the present study was that the degree of impairment of peripheral vascular endothelial function in HC was similar in magnitude to the degree of impairment in CAD. It has been previously established that this level of impairment in CAD holds important prognostic implications.20 Whether the vascular endothelial dysfunction witnessed in patients with HC also carries with it prognostic utility will require further study.

The accumulation of cardiovascular risk factors contributes to a deterioration of endothelial function in various clinical cohorts, and this was seen in our patients with and without CAD. However, in the present study, FMD was not associated with cardiovascular risk factor burden in patients with HC. Endothelial function has also been shown to deteriorate with advancing age,21 as seen in our patients with and without CAD, but this too was not evident in patients with HC. Therefore, the pathogenesis of endothelial dysfunction in HC does not appear to be due to the accumulation of cardiovascular atherosclerotic risk factors with aging, as may occur in patients without and those with CAD.

Prognoses in patients with HC are worse when LVOT obstruction is present, and recent studies have suggested that >1/2 of patients with HC have obstruction.8, 22 Moreover, many of the morbidities associated with HC have been attributed to presence of LVOT obstruction. To our knowledge, this is the first study to examine the impact of LVOT obstruction on peripheral vascular endothelial function in HC. The presence and/or magnitude of outflow gradient has been associated with von Willebrand factor dysfunction (a glycoprotein synthesized by endothelial cells necessary for normal hemostasis), elevated asymmetric dimethylarginine, and increased inflammation.13, 14, 15 Thus, it has been suggested that LVOT obstruction contributes to endothelial damage through the creation of high sheer forces on the vascular wall.23 Although patients with HC have higher circulating biomarkers of endothelial damage, we noted that in vivo peripheral vasomotor reactivity was not influenced by the presence or magnitude of obstruction, suggesting that factors unrelated to obstruction are responsible for noted differences.

Limitations of this study should be noted. Clinical correlates of endothelial dysfunction in patients with HC were not investigated. Whether low FMD in patients with HC carries with it the same clinical significance as is seen in other cohorts needs to be demonstrated empirically. Endothelium-independent vasodilation was not assessed. Thus, it remains plausible that patients with HC may have a primary defect in smooth muscle vasomotor dysfunction contributing to blunted dilation.

Back to Article Outline

References 

  1. Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA. 2002;287:1308–1320
  2. Cannon RO, Rosing DR, Maron BJ, Leon MB, Bonow RO, Watson RM, et al. Myocardial ischemia in patients with hypertrophic cardiomyopathy: contribution of inadequate vasodilator reserve and elevated left ventricular filling pressures. Circulation. 1985;71:234–243
  3. Petersen SE, Jerosch-Herold M, Hudsmith LE, Robson MD, Francis JM, Doll HA, et al. Evidence for microvascular dysfunction in hypertrophic cardiomyopathy: new insights from multiparametric magnetic resonance imaging. Circulation. 2007;115:2418–2425
  4. Dimitrow PP, Krzanowski M, Nizankowski R, Szczeklik A, Dubiel JS. Comparison of the effect of verapamil and propranolol on response of coronary vasomotion to cold pressor test in symptomatic patients with hypertrophic cardiomyopathy. Cardiovasc Drugs Ther. 2000;14:643–650
  5. Cecchi F, Olivotto I, Gistri R, Lorenzoni R, Chiriatti G, Camici PG. Coronary microvascular dysfunction and prognosis in hypertrophic cardiomyopathy. N Engl J Med. 2003;349:1027–1035
  6. Olivotto I, Cecchi F, Gistri R, Lorenzoni R, Chiriatti G, Girolami F, et al. Relevance of coronary microvascular flow impairment to long-term remodeling and systolic dysfunction in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2006;47:1043–1048
  7. Krams R, Kofflard MJ, Duncker DJ, Von Birgelen C, Carlier S, Kliffen M, et al. Decreased coronary flow reserve in hypertrophic cardiomyopathy is related to remodeling of the coronary microcirculation. Circulation. 1998;97:230–233
  8. Maron MS, Olivotto I, Zenovich AG, Link MS, Pandian NG, Kuvin JT, et al. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation. 2006;114:2232–2239
  9. Dimitrow PP, Krzanowski M, Surdacki A, Nizankowski R, Szczeklik A, Dubiel JS. Impaired response of the forearm resistance but not conductance vessels to reactive hyperemia in hypertrophic cardiomyopathy. Angiology. 1999;50:267–272
  10. Imaizumi T, Takeshita A, Yamamoto K, Nakamura M, Sueishi K. Limited maximal vasodilator capacity of forearm resistance vessels in patients with hypertrophic cardiomyopathy. Heart Vessels. 1990;5:159–165
  11. Kawano S, Iida K, Nishi I, Iwasaki Y, Masumi T, Sugishita Y, et al. Impaired peripheral vasoconstriction in response to alpha-adrenergic stimulation in patients with idiopathic hypertrophic cardiomyopathy. Jpn Circ J. 1998;62:903–908
  12. Pedrinelli R, Spessot M, Chiriatti G, Gistri R, Salvadori P, Catapano G, et al. Evidence for a systemic defect of resistance-sized arterioles in hypertrophic cardiomyopathy. Coron Artery Dis. 1993;4:67–72
  13. Dimitrow PP, Undas A, Bober M, Tracz W, Dubiel JS. Plasma biomarkers of endothelial dysfunction in patients with hypertrophic cardiomyopathy. Pharmacol Rep. 2007;59:715–720
  14. Dimitrow PP, Undas A, Bober M, Tracz W, Dubiel JS. Obstructive hypertrophic cardiomyopathy is associated with enhanced thrombin generation and platelet activation. Heart. 2008;94:e21
  15. Hasegawa K, Fujiwara H, Koshiji M, Inada T, Ohtani S, Doyama K, et al. Endothelin-1 and its receptor in hypertrophic cardiomyopathy. Hypertension. 1996;27:259–264
  16. Anderson TJ, Uehata A, Gerhard MD, Meredith IT, Knab S, Delagrange D, et al Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol. 1995;26:1235–1241
  17. Guazzi M, Reina G, Gripari P, Tumminello G, Vicenzi M, Arena R. Prognostic value of flow-mediated dilatation following myocardial infarction. Int J Cardiol. 2009;132:45–50
  18. Yeboah J, Crouse JR, Hsu FC, Burke GL, Herrington DM. Brachial flow-mediated dilation predicts incident cardiovascular events in older adults: the Cardiovascular Health Study. Circulation. 2007;115:2390–2397
  19. Yeboah J, Folsom AR, Burke GL, Johnson C, Polak JF, Post W, Lima JA, Crouse JR, Herrington DM. Predictive value of brachial flow-mediated dilation for incident cardiovascular events in a population-based study. The Multi-Ethnic Study of Atherosclerosis. Circulation. In press.
  20. Kuvin JT, Patel AR, Sliney KA, Pandian NG, Rand WM, Udelson JE, et al. Peripheral vascular endothelial function testing as a noninvasive indicator of coronary artery disease. J Am Coll Cardiol. 2001;38:1843–1849
  21. Celermajer DS, Sorensen KE, Spiegelhalter DJ, Georgakopoulos D, Robinson J, Deanfield JE. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol. 1994;24:471–476
  22. Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA, et al. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med. 2003;348:295–303
  23. Le Tourneau T, Susen S, Caron C, Millaire A, Marechaux S, Polge AS, et al. Functional impairment of von Willebrand factor in hypertrophic cardiomyopathy: relation to rest and exercise obstruction. Circulation. 2008;118:1550–1557

PII: S0002-9149(09)02223-1

doi:10.1016/j.amjcard.2009.08.658

American Journal of Cardiology
Volume 105, Issue 1 , Pages 112-115, 1 January 2010

Article Tools

* Image Usage & Resolution