Jeffrey T. Kuvin

Assessment of peripheral vascular endothelial function with finger arterial pulse wave amplitude.

BACKGROUND Abnormalities in pulse wave amplitude (PWA) have been described in subjects with atherosclerosis and may be a marker of future cardiac events. We evaluated the relationship between changes in PWA of the finger and peripheral endothelial function. METHODS We performed measurements of PWA with a novel finger plethysmograph (peripheral arterial tonometry [PAT]) and compared the findings with a simultaneous noninvasive measurement of peripheral endothelial function with brachial artery ultrasound scanning (BAUS) in 89 subjects. The PAT hyperemia ratio was defined as the ratio of PWA during reactive hyperemia relative to the baseline. Flow-mediated dilation (FMD) was defined by BAUS as the ratio of the brachial artery diameter during reactive hyperemia relative to the baseline. Sixty-eight subjects underwent exercise myocardial perfusion imaging (ExMPI). RESULTS Fifty-four men and 35 women were examined. There was a linear relationship between the PAT hyperemia ratio and FMD during the same episode of reactive hyperemia (r = 0.55, P <.0001). Subjects in the lowest FMD quartile had the lowest PAT hyperemia ratio, whereas subjects in the highest FMD quartile had the highest PAT hyperemia ratio (P <.001 for trend). Similar to BAUS, the PAT hyperemia ratio was more impaired in subjects with cardiovascular risk factors and in subjects with ExMPI studies that were indicative of coronary artery disease. CONCLUSIONS Assessment of PWA with PAT demonstrates patterns of abnormality similar to that of BAUS assessment of FMD. PWA during reactive hyperemia is influenced by factors known to affect endothelial function, including cardiovascular risk factors and coronary artery disease. These findings support the concept that analysis of PWA with PAT during reactive hyperemia may be used to study peripheral vascular endothelial function.

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.

Enhanced external counterpulsation improves endothelial function in patients with symptomatic coronary artery disease.

OBJECTIVES The goal of this study was to examine the effect of enhanced external counterpulsation (EECP) on endothelial function. BACKGROUND Enhanced external counterpulsation improves symptoms and exercise tolerance in patients with symptomatic coronary artery disease (CAD). However, the exact mechanisms by which this technique exerts its clinical benefit are unclear. METHODS Reactive hyperemia-peripheral arterial tonometry (RH-PAT), a noninvasive method to assess peripheral endothelial function by measuring reactive hyperemic response in the finger, was performed in 23 patients with refractory angina undergoing a 35-h course of EECP. In each patient RH-PAT measurements were performed before and after the first, at midcourse, and the last EECP session. In addition, RH-PAT response was assessed one month after completion of EECP therapy; RH-PAT index, a measure of reactive hyperemia, was calculated as the ratio of the digital pulse volume during reactive hyperemia divided by that at rest. RESULTS Enhanced external counterpulsation led to symptomatic improvement (>/=1 Canadian Cardiovascular Society class) in 17 (74%) patients; EECP was associated with a significant immediate increase in average RH-PAT index after each treatment (p < 0.05). In addition, average RH-PAT index at one-month follow-up was significantly higher than that before EECP therapy (p < 0.05). When patients were divided by their clinical response, RH-PAT index at one-month follow-up increased only in those patients who experienced clinical benefit. CONCLUSIONS Enhanced external counterpulsation enhances peripheral endothelial function with beneficial effects persisting at one-month follow-up in patients with a positive clinical response. This suggests that improvement in endothelial function may contribute to the clinical benefit of EECP in patients with symptomatic CAD.

Peripheral vascular endothelial function testing as a noninvasive indicator of coronary artery disease

OBJECTIVES We studied whether assessment of endothelium-dependent vasomotion (EDV) with brachial artery ultrasound (BAUS) imaging predicts the presence or absence of coronary artery disease (CAD) as defined by exercise myocardial perfusion imaging (ExMPI). BACKGROUND Abnormalities in EDV can be detected in arteries before the development of overt atherosclerosis, and its presence may predict poor long-term prognosis. Brachial artery ultrasound during reactive hyperemia is a noninvasive method of assessing peripheral EDV. METHODS Clinically-indicated ExMPI along with BAUS were performed in 94 subjects (43 women, 51 men). Coronary artery disease was defined by myocardial ischemia or infarction on single photon emission computed tomography images. Flow-mediated dilation (FMD) after upper arm occlusion was defined as the percent change in arterial diameter during reactive hyperemia relative to the baseline. RESULTS Subjects with CAD by ExMPI (n = 23) had a lower FMD (6.3 +/- 0.7%) than those without CAD by ExMPI (n = 71) (10.5 +/- 0.6%; p = 0.0004). Flow-mediated dilation was highly predictive for CAD with an odds ratio of 1.32 for each percent decrease in FMD (p = 0.001). Based on a receiver-operator analysis, an FMD of 10% was used as a cut-point for further analysis. Twenty-one of 23 subjects who were positive for ExMPI had an FMD < 10% (sensitivity 91%), whereas only two of 40 subjects with an FMD > or =10% were ExMPI-positive (negative predictive value: 95%). There was a correlation between the number of cardiac risk factors and FMD. Individuals with an FMD < 10% exercised for a shorter duration than those with an FMD > or =10% (456 +/- 24 vs. 544 +/- 31 s, respectively; p = 0.02). CONCLUSIONS Assessment of EDV with BAUS has a high sensitivity and an excellent negative predictive value for CAD and, thus, has the potential for use as a screening tool to exclude CAD in low-risk subjects. Further standardization of BAUS is required, however, before specific cut-points for excluding CAD can be established.

The Safety of Rosuvastatin as Used in Common Clinical Practice A Postmarketing Analysis

Background—Statins are currently the mainstay of dyslipidemia management for the primary and secondary prevention of cardiovascular disease. Controversial concerns about the safety of the newly marketed statin rosuvastatin have been raised on the basis of premarketing studies and a few postmarketing reports. Methods and Results—We reviewed rosuvastatin-associated adverse events reported to the US Food and Drug Administration over its first year of marketing. On the basis of prescription data obtained from IMS Health, rates of adverse event reports (AERs) per million prescriptions were calculated. Rates of rosuvastatin-associated AERs over its first year of marketing were compared with those seen with atorvastatin, simvastatin, and pravastatin over the concurrent timeframe and during their respective first years of marketing. Comparison was also made to the first year of marketing of cerivastatin. The primary analysis examined the composite end point of AERs of rhabdomyolysis, proteinuria, nephropathy, or renal failure. With either timeframe comparison, rosuvastatin was significantly more likely to be associated with the composite end point of rhabdomyolysis, proteinuria, nephropathy, or renal failure AERs. Reported cases of rhabdomyolysis, proteinuria, or renal failure tended to occur early after the initiation of therapy and at relatively modest doses of rosuvastatin. The increased rate of rosuvastatin-associated AERs relative to other widely used statins was also observed in secondary analyses when other categories of AERs were examined, including adverse events with serious outcomes, liver toxicity, and muscle toxicity without rhabdomyolysis. Conclusions—The present analysis supports concerns about the relative safety of rosuvastatin at the range of doses used in common clinical practice in the general population.

Clinical Utility of Endothelial Function Testing Ready for Prime Time

“…Arteriosclerosis…is the expression of the natural wear and tear to which the tubes are subjected…the onset of arteriosclerosis depends on the quality of arterial tissue (vital rubber)…in the make up of the machine, bad material was used for the tubing…”1 — William Osler, The Principles and Practice of Medicine, 1892 The arterial endothelium comprises cells resting on a basement membrane that exert autocrine, paracrine, and endocrine functions. This monolayer of endothelial cells plays a crucial role in the regulation of vascular tone in part by the release of vasoactive substances, notably NO, endothelin, prostacyclin, and angiotensinogen.2–4 In addition, endothelial cells are involved in the modulation of platelet activation, leukocyte adhesion, and thrombosis. The endothelium, therefore, delicately balances the counterregulatory pathways that control vasomotion, cell proliferation, thrombosis, inflammation, and oxidation. Endothelial function becomes impaired early in the atherogenic process, and this diminishes the normal vasodilator response. Impaired endothelium-dependent vasorelaxation can be detected by measuring the response to pharmacological and physiological stressors before the development of angiographically significant atherosclerotic plaque in the coronary5,6 and peripheral vasculature.7 Well-known cardiac risk factors, including age, gender, hypertension, hyperlipidemia, diabetes mellitus, and smoking, as well as novel risk factors, such as inflammation and hyperhomocystinemia, have been associated with abnormal vasorelaxation. Pharmacological therapies and lifestyle changes aimed at improving cardiovascular risk, in many instances, may also improve vasomotor function.8 Because atherosclerosis is a diffuse disease process, endothelial function can be assessed in either the coronary or the peripheral circulation. Coronary artery endothelial function is most commonly assessed by intracoronary infusion of acetylcholine, which, acting via muscarinic receptors on endothelial cells, causes release of NO and coronary artery dilation. In patients with risk factors for atherosclerosis and in those with overt coronary artery disease, infusion of acetylcholine results in a diminished vasodilatory response …

Assessment of peripheral vascular endothelial function in the ambulatory setting

Until now, peripheral vascular endothelial function testing has been performed in research laboratories under highly controlled conditions, thus limiting its clinical applicability. In this study, we evaluated endothelial function in two peripheral vascular beds before and during reactive hyperemia in an outpatient clinic setting. The brachial artery was imaged with a portable ultrasound device and changes in vessel diameter were expressed as percent flow-mediated dilation (%FMD). Pulse wave amplitude of the finger was detected by peripheral arterial tonometry (PAT) and PAT hyperemia was defined as the maximal plethysmographic recording compared to baseline. Sixty individuals (43 men) were enrolled with an average age 53 ± 2 years (mean ± SE). The 31 individuals with more than two cardiac risk factors (CRF) had lower FMD (7.0 ± 1.1%) and PAT hyperemia (2.1 ± 0.9) compared to the 29 individuals with 0—2 CRF (FMD 11.3 ± 0.8%, PAT hyperemia 2.4 ± 0.1; p < 0.05 for both). The 32 individuals with coronary artery disease (CAD) had lower FMD (6.8 ± 1.1%) and PAT hyperemia (2.0 ± 0.1) compared to the 28 individuals without CAD (FMD 11.5 ± 0.8%, PAT hyperemia 2.4 ± 0.1; p < 0.05 for both). Thus, peripheral vascular endothelial function testing in the ambulatory setting correlates with the extent of CAD risk and the presence or absence of CAD. In conclusion, these data suggest that peripheral vascular endothelial function testing is feasible in ambulatory patients, and this is an important next step in bringing this technology to clinical applicability.

Postoperative cardiac tamponade in the modern surgical era

BACKGROUND Pericardial effusions resulting in cardiac tamponade (CT) are uncommon after open heart surgery (OHS) and are associated with significant morbidity and mortality. Characteristics and outcomes of patients who develop postoperative CT are poorly defined. Our objective was to further analyze the population at risk for developing postoperative CT, identify potential perioperative and surgical risk factors, and evaluate the impact of CT on patient outcomes. METHODS A retrospective analysis of 4,561 consecutive patients undergoing OHS at our institution was performed. Patients with clinical suspicion of pericardial effusion following surgery were evaluated by transthoracic or transesophageal echocardiography, and clinical parameters were analyzed. RESULTS Forty-eight (1%) of the 4,561 patients were found to have echocardiographic evidence of a moderate or large pericardial effusion, of whom 36 (74%) had evidence of CT. The mean age of the patients with CT was 61 years. Coronary artery bypass grafting (CABG) had been performed in 24% of these patients, valve +/- CABG in 73%, and other OHS procedures in 3%. The incidence of CT following CABG alone was 0.2%, whereas it was 0.6% after valve +/- CABG. Females had a higher risk for developing CT, and this occurred earlier in the postoperative period when compared with men. Aspirin, heparin, or warfarin were given to 84% of patients within 3 days of surgery. Mean time to diagnosis of CT was 10 +/- 1 days after OHS. Prior to diagnosis of CT, the maximum international normalized ratio (INR) and partial thromboplastin time (PTT) were 2.7 +/- 0.3 and 68 +/- 5 seconds, respectively. Forty-nine percent of pericardial effusions were posterior and 46% were circumferential; one-third of the effusions were considered large by echocardiography. There was one in-hospital cardiovascular death. CONCLUSIONS CT after OHS is more common following valve surgery than CABG alone and may be related to the preoperative use of anticoagulants. Females appear to be at higher risk for developing early postoperative CT. When diagnosed and treated promptly, postoperative CT should not significantly increase mortality.

Chronic Heart Failure in Congenital Heart Disease: A Scientific Statement from the American Heart Association

### Introduction The past 60 years have brought remarkable advancements in the diagnosis and treatment of congenital heart disease (CHD). Early diagnosis and improvements in cardiac surgery and interventional cardiology have resulted in unprecedented survival of patients with CHD, even those with the most complex lesions. Despite remarkable success in treatments, many interventions are palliative rather than curative, and patients often develop cardiac complications, including heart failure (HF). HF management in the setting of CHD is challenged by the wide range of ages at which HF occurs, the heterogeneity of the underlying anatomy and surgical repairs, the wide spectrum of HF causes, the lack of validated biomarkers for disease progression, the lack of reliable risk predictors or surrogate end points, and the paucity of evidence demonstrating treatment efficacy. The purposes of this statement are to review the literature pertaining to chronic HF in CHD and to elucidate important gaps in our knowledge, emphasizing the need for specific studies of HF mechanisms and improving outcomes for those with HF. In this document, the definition of CHD severity is the definition common in CHD documents, including the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines1 for the management of adults with CHD (Table 11–3). The definition of HF corresponds to that found in the multiple guidelines on diagnosis and management of HF. Although nuances and specific details may be controversial,4 the broad definition from the Heart Failure Society of America guidelines states the following: “In physiologic terms, HF is a syndrome characterized by either or both pulmonary and systemic venous congestion and/or inadequate peripheral oxygen delivery, at rest or during stress, caused by cardiac dysfunction.”5 The definition of chronic HF in this document concurs with that of the European Society of Cardiology guidelines, which emphasize chronic HF …

Relation between high-density lipoprotein cholesterol and peripheral vasomotor function

Low levels of high-density lipoprotein (HDL) cholesterol are one of the most common lipid abnormalities in patients with coronary artery disease. Endothelial dysfunction is also highly prevalent in patients with coronary artery disease. We sought to determine whether HDL cholesterol levels are correlated with endothelium-dependent vasomotion in patients being evaluated for atherosclerosis. Peripheral vascular endothelial function was assessed by high-resolution brachial artery ultrasound. Flow-mediated dilation (FMD) during reactive hyperemia was defined as the percent change in arterial diameter following 5-minute arterial occlusion. All patients underwent stress testing with nuclear single-photon emission computed tomographic imaging to determine percent left ventricular ejection fraction and define the presence or absence of coronary artery disease. One hundred fifty-one subjects (87 men, 64 women) were enrolled (average age 58 +/- 11 years). Total cholesterol, HDL cholesterol, low-density lipoprotein cholesterol, and triglyceride levels were 188 +/- 48, 47 +/- 13, 108 +/- 37 and 154 +/- 88 mg/dl, respectively. The mean FMD for the entire group was 9.9 +/- 5.2%. Subjects with an HDL cholesterol of <40 mg/dl (n = 39) had lower FMD (7.4 +/- 3.6%) compared with those with an HDL cholesterol >/=40 mg/dl (11.0 +/- 5.5%, p <0.001). There was a significant correlation between FMD and HDL cholesterol level (linear regression, p <0.001), and in multivariate analysis, HDL cholesterol was an independent predictor of FMD. Peripheral endothelial function was abnormal in subjects with low HDL cholesterol and well-preserved in those with high HDL cholesterol. These data suggest that impaired endothelial function associated with low HDL cholesterol may be an additional, previously unrecognized mechanism contributing to the increased risk of atherosclerosis in these patients.