Utility of both carotid intima-media thickness and endothelial function for cardiovascular risk stratification in patients with angina-like symptoms.

BACKGROUND: Myocardial perfusion scintigraphy (MPS) is used widely to assess cardiovascular risk in patients with chest pain. The utility of carotid intima-media thickness (CIMT) and endothelial function as assessed by reactive hyperemia-peripheral arterial tonometry index (RHI) in risk stratifying patients with angina-like symptoms needs to be defined. We investigated whether the addition of CIMT and RHI to Framingham Cardiovascular Risk Score (FCVRS) and MPS improves comprehensive cardiovascular risk prediction in patients presenting with angina-like symptoms. METHODS: We enrolled 343 consecutive patients with angina-like symptoms suspected of having stable angina. MPS, CIMT, and RHI were performed and patients were followed for cardiovascular events for a median of 5.3 years (range 4.4-6.2). Patients were stratified by FCVRS and MPS. RESULTS: During the follow-up, 57 patients (16.6%) had cardiovascular events. Among patients without perfusion defect, low RHI was significantly associated with cardiovascular events in the intermediate and high FCVRS groups (hazard ratio (HR) [95% confidence interval (CI)] of RHI ≤ 2.11 was 6.99 [1.34-128] in the intermediate FCVRS group and 6.08 [1.08-114] in the high FCVRS group). Furthermore, although MPS did not predict, only RHI predicted hard cardiovascular events (cardiovascular death, myocardial infarction, and stroke) independent from FCVRS, and adding RHI to FCVRS improved net reclassification index (20.9%, 95% CI 0.8-41.1, p = 0.04). Especially, RHI was significantly associated with hard cardiovascular events in the high FCVRS group (HR [95% CI] of RHI ≤ 1.93 was 5.66 [1.54-36.4], p = 0.007). CONCLUSIONS: Peripheral endothelial function may improve discrimination in identifying at-risk patients for future cardiovascular events when added to FCVRS-MPS-based risk stratification.

Comparison of the effect of the metabolic syndrome and multiple traditional cardiovascular risk factors on vascular function.

OBJECTIVE: To assess the effect of the metabolic syndrome (MetS) on endothelial function and compare these findings to those in individuals with a similar burden of traditional cardiovascular (CV) risk factors (≥ 3) without MetS. PATIENTS AND METHODS: Both MetS and multiple CV risk factors were identified from 1103 individuals who underwent the evaluation of endothelial function at the Mayo Clinic, in Rochester, Minnesota, from July 1, 2000, through July 31, 2011. Endothelial function was measured using digital arterial tonometry by assessing reactive hyperemia-induced vasodilation in one arm and adjusting for changes in the contralateral arm (reactive hyperemia index [RHI]). RESULTS: A total of 316 individuals with MetS and 210 with multiple risk factors were assessed. Endothelial dysfunction was more pronounced in the MetS group compared with the multiple risk factor group (mean ± SD natural logarithmic RHI, 0.61 ± 0.25 and 0.68 ± 0.28, respectively; P=.006). Leukocyte count (7.00 ± 1.89 × 10(9)/L vs 6.41 ± 1.76 × 10(9)/L, respectively; P=.001) and high-sensitivity C-reactive protein level (1.78 ± 1.53 mg/L vs 1.48 ± 1.42 mg/L, respectively; P=.01) were higher in the MetS group compared with the multiple risk factor group. After adjustment for covariates and 6 traditional CV risk factors in a multivariate regression model, MetS had a significant and independent influence on natural logarithmic RHI (ß=-.11; P=.01). CONCLUSION: The current study found that individuals with MetS have a higher degree of endothelial dysfunction and inflammation compared with individuals with multiple CV risk factors and may therefore have an increased CV risk beyond the contributions of multiple traditional risk factors.

Normal vascular function as a prerequisite for the absence of coronary calcification in patients free of cardiovascular disease and diabetes.

BACKGROUND: The absence of coronary artery calcium (CAC) is a marker of very low cardiovascular risk. Endothelial cells may have an effect on the initiation and propagation of arterial calcification. We aimed to identify the relationship between the absence of CAC and endothelial function in individuals without cardiovascular disease and diabetes. METHODS AND RESULTS: CAC was assessed using electron-beam computed tomography and the calcium score was then computed. Endothelial function was measured by assessing reactive hyperemia-induced vasodilation and expressed by the reactive hyperemia index (RHI). Of 82 patients, 39 had non-detectable calcium (CAC score=0) and 43 had a CAC score >0. In the CAC score=0 group, the prevalence of normal endothelial function was 84.6%, compared to 48.8% in the CAC score >0 group, P=0.001. The absence of CAC was highly correlated with normal endothelial function (γ=0.704, P<0.001). On average, endothelial function was significantly better in the CAC score=0 group than in the CAC score >0 group (RHI 2.2±0.6 vs. 1.8±0.5, P=0.002). In a multivariate logistic regression model, only normal endothelial function (odds ratio [OR] 5.03, 95% confidence interval [CI] 1.55-16.27, P=0.007) and age (years) (OR 0.91, 95% CI 0.86-0.96, P=0.002) were independently associated with the absence of CAC. CONCLUSIONS: Normal functional status of the vasculature may be important for the prevention of coronary calcification and may partly account for the low cardiovascular risk of absent CAC.

Comparing EndoPAT and BIOPAC measurement of vascular responses to mental stress.

There are currently no comparison measurements of stress-induced changes in vascular function during acute mental stress tests to measurements made by BIOPAC MP150 systems technology, a standard polygraph device used to detect deception during polygraph examinations in military or law enforcement applications. Vascular responses to reactive hyperaemia and acute mental stress in 25 healthy subjects were measured by both peripheral arterial tonometry (EndoPAT) and a blood pressure cuff attached to a pressure transducer (BIOPAC) and compared. Reactive hyperaemia was performed at baseline and following three acute mental stress tests. There was no difference in vascular reactivity at baseline and following acute mental stress, as measured by EndoPAT or BIOPAC systems (p > 0·05). Mental stress ratios measured by EndoPAT were significantly different than those measured by BIOPAC (p < 0·01). These data suggest that EndoPAT measurements of vascular responses to acute mental stress may be more specific and sensitive than measurements using the BIOPAC system.

Long-term administration of endothelin receptor antagonist improves coronary endothelial function in patients with early atherosclerosis.

BACKGROUND: Endothelin (ET-1) is one of the most potent vasoconstrictors and plays a seminal role in the pathogenesis of atherosclerosis. The present study was designed to test the hypothesis that long-term treatment with an endothelin-A (ET(A)) receptor antagonist improves coronary endothelial function in patients with early coronary atherosclerosis. METHODS AND RESULTS: Forty-seven patients with multiple cardiovascular risk factors, nonobstructive coronary artery disease, and coronary endothelial dysfunction were randomized in a double-blind manner to either the ET(A) receptor antagonist atrasentan (10 mg) or placebo for 6 months. Coronary endothelium-dependent vasodilation was examined by infusing acetylcholine (10(-6) to 10(-4) mol/L) in the left anterior descending coronary artery. N(G)-monomethyl-l-arginine was administered to a subgroup of patients. Endothelium-independent coronary flow reserve was examined by use of intracoronary adenosine and nitroglycerin. Baseline characteristics and incidence of adverse effects were similar between the 2 groups. There was a significant improvement in percent change of coronary blood flow in response to acetylcholine at 6 months from baseline in the atrasentan group compared with the placebo group (39.67%, 95% confidence interval 23.23% to 68.21%, versus -2.22%, 95% confidence interval -27.37% to 15.28%; P<0.001). No significant difference in the percent change of coronary artery diameter or change in coronary flow reserve was demonstrated. Coronary blood flow, coronary artery diameter, and the effect of N(G)-monomethyl-l-arginine were similar between the groups at baseline and at 6 months. CONCLUSIONS: This study demonstrates that 6-month treatment with atrasentan improves coronary microvascular endothelial function and supports the role of the endogenous endothelin system in the regulation of endothelial function in early atherosclerosis in humans. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00271492.

Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events.

AIMS: There is growing need for the identification of novel non-invasive methodologies for the identification of individuals at risk for adverse cardiovascular (CV) events. We examined whether endothelial dysfunction, as detected by non-invasive peripheral arterial tonometry (EndoPAT), can predict late CV events. METHODS AND RESULTS: Reactive hyperaemia (RH) was induced following upper arm occlusion of systolic blood pressure in 270 outpatients (54 +/- 12 years, 48% female). The natural logarithmic scaled RH index (L_RHI) was calculated from the ratio between the digital pulse volume during RH and at baseline. The patients were followed for CV adverse events (AE: cardiac death, myocardial infarction, revascularization or cardiac hospitalization) during a 7-year follow-up (inter-quartile range = 4.4-8). Cox models were used to estimate the association of EndoPAT results with AE adjusted for age. During the follow-up, AE occurred in 86 patients (31%). Seven-year AE rate was 48% in patients with L_RHI < 0.4 vs. 28% in those with L_RHI >or= 0.4 (P = 0.03). Additional univariate predictors of AE were advancing age (P = 0.02) and prior coronary bypass surgery (P = 0.01). The traditional Framingham risk score was not higher in patients with AE. Multivariate analysis identified L_RHI < 0.4 as an independent predictor of AE (P = 0.03). CONCLUSION: A low RH signal detected by EndoPAT, consistent with endothelial dysfunction, was associated with higher AE rate during follow-up. L_RHI was an independent predictor of AE. Non-invasive assessment of peripheral vascular function may be useful for the identification of patients at risk for cardiac AEs.

Efficacy and safety of atrasentan in patients with cardiovascular risk and early atherosclerosis.

Endothelin plays an important role in the pathogenesis of atherosclerosis. The aim of the study was to evaluate the safety and hemodynamic and metabolic responses to 6 months treatment with atrasentan, the selective endothelin-A receptor antagonist. Seventy-two patients with multiple cardiovascular risk factors and nonobstructive coronary artery disease on coronary angiogram were randomly assigned in a double-blind manner to atrasentan or placebo. Mean aortic blood pressure decreased from 92+/-10 to 80+/-10 mm Hg (P<0.001) in the atrasentan group and did not change in the placebo group (93+/-10 and 92+/-11 mm Hg; P=0.84). The difference between the groups was significant (P<0.001). No effect on heart rate was observed. In a subgroup of patients not treated with angiotensin-converting enzyme inhibitor, creatinine level decreased in the atrasentan versus the placebo group (P=0.011). Fasting glucose (P=0.026), glycosylated hemoglobin level (P=0.041), triglyceride l (P=0.013), lipoprotein-A (P=0.046), and uric acid levels (P=0.048) decreased significantly in the atrasentan group compared with the placebo group. No progression of angiographic coronary disease was observed. The most common adverse effects with atrasentan were nasal stuffiness, headache, and edema. In conclusion, 6 months of treatment with atrasentan results in a reduction of blood pressure and improvement in glucose and lipid metabolism. These findings suggest the beneficial role of atrasentan in the treatment of hypertension and metabolic syndrome.

Circulating CD34+ cell subsets in patients with coronary endothelial dysfunction.

BACKGROUND: Endothelial dysfunction is an early manifestation of atherosclerotic disease. Circulating cells that express CD34, including endothelial and hematopoietic progenitor cells, might play a part in the development and progression of atherosclerosis. The aim of this study was to evaluate the association between coronary endothelial dysfunction and concentrations of circulating CD34+ cell subsets. METHODS: Intracoronary acetylcholine challenge was used to test for coronary endothelial dysfunction in 57 consecutive patients scheduled to undergo diagnostic coronary angiography and with no signs of substantial obstructive lesions. Mononuclear cells were extracted from whole blood samples taken from all patients, analyzed by flow cytometry for CD14, CD34, CD133, CD45, and vascular endothelial growth factor receptor 2 (VEGFR2), and cultured for functional analysis. RESULTS: Compared with patients with normal coronary endothelial function, in those with coronary endothelial dysfunction, the number of circulating CD34+/CD45(dim)/VEGFR2- cells, CD34+/CD45(dim)/CD133+/VEGFR2- cells and colony-forming units were reduced. Concentrations of CD34+/CD45-/VEGFR2+ cells did not differ between groups. CONCLUSIONS: Regulation of CD34+ cell subsets seems to differ between patients with coronary endothelial dysfunction and those with normal coronary endothelial function. Changes in specific circulating progenitor cell subsets might, therefore, be an early manifestation of atherosclerosis.

Coronary endothelial dysfunction is associated with erectile dysfunction and elevated asymmetric dimethylarginine in patients with early atherosclerosis.

AIMS: Coronary endothelial dysfunction (CED) precedes atherosclerosis and is associated with cardiovascular events. Both CED and erectile dysfunction (ED) are partly mediated by impairment in the nitric oxide pathway. ED is associated with established coronary atherosclerosis, but its relationship with early coronary atherosclerosis and CED is unknown. This study was designed to test the hypothesis that CED is associated with ED in men with early coronary atherosclerosis. Moreover, the role of the nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) was investigated; ADMA is a novel endogenous competitive inhibitor of nitric oxide synthase and has been shown to be an independent marker for cardiovascular disease. METHODS AND RESULTS: Fifty-six men without obstructive coronary artery disease (CAD) who underwent coronary endothelial function testing were studied. ADMA levels were determined and all men were asked to complete the International Index of Erectile Function-5 questionnaire to assess erectile function. Patients were divided according to the presence (n = 32) or absence (n = 24) of CED. Men with CED had significant impairment of erectile function (P = 0.008) and significantly higher ADMA levels (0.50 +/- 0.06 vs. 0.45 +/- 0.07 ng/mL, P = 0.017) compared with men with normal endothelial function. Erectile function positively correlated with coronary endothelial function. This correlation was independent of age, body mass index, high-density lipoprotein, C-reactive protein, homeostasis model assessment of insulin resistance index, and smoking status. CONCLUSION: CED is independently associated with ED and plasma ADMA concentration in men with early coronary atherosclerosis. This study further supports the role of the endothelium in systemic vascular diseases and the role of ADMA in the systemic manifestations of endothelial dysfunction.