Citations

Background Quantification of coronary artery calcified plaques by electron-beam CT (EBCT) may predict cardiovascular events. However, whereas advanced coronary atherosclerotic plaques can be identified, mildly stenotic lipid-rich (soft) plaques may be difficult to detect. The value of EBCT in a subgroup of patients has therefore been questioned. To investigate this, we evaluated patients with acute coronary syndromes by EBCT and compared the results with coronary angiography and, in patients with an indeterminate angiogram, intracoronary ultrasound (ICUS). Methods and Results EBCT was performed in 118 consecutive patients (57±11 years of age) with previous myocardial infarction (n=101) or unstable angina (n=17). A standard protocol requiring a CT density >130 Hounsfield units in an area ≥1.03 mm 2 was used for the definition of coronary artery calcium. We found that 110 patients had moderate to severe coronary artery disease by coronary angiography, and 8 had either mildly stenotic plaques at a single site (4 patients, confirmed by ICUS) or nonatherosclerotic causes of the unstable coronary syndrome (4 patients). One hundred and five of the 110 patients (96%) with moderate to severe angiographic disease but only 1 of the 8 other patients (13%) had a positive EBCT. Patients with acute coronary syndromes and negative EBCTs were significantly younger than patients with positive EBCTs (46±12 versus 58±10 years, P <.001), and a higher percentage was actively smoking (100% of the smokers versus 46%, P <.05). Conclusions The vast majority of patients with acute coronary syndromes and at least moderate angiographic disease have identifiable coronary calcium by EBCT. Those patients with negative EBCTs have minimal or no atherosclerotic plaque formation. They are younger and tend to be active cigarette smokers.

Background Elevated lipoprotein(a) [Lp(a)] levels have been associated with the presence of atherosclerotic disease. However, the results of prospective studies of Lp(a) and cardiovascular disease have been contradictory. Methods and Results From 1968 through 1982, lipoprotein analysis was performed in 11 335 Olmsted County residents. Quantitative cholesterol and triglycerides were obtained along with semiquantitative Lp(a) levels based on electrophoretic pattern. Lp(a) bands were scored from 0 (absent) to 3 (increased). A cohort of 4967 men and 4968 women with no prior history of atherosclerotic disease who had baseline Lp(a) determinations were followed up for 14 years for development of coronary artery disease (CAD) and cerebrovascular disease (CVD). During 131 330 person-years of follow-up, there were 1848 CAD events and 841 CVD events. Age, diabetes, hypertension, cholesterol, and triglycerides were significantly and independently associated with an increased risk of CAD and CVD in men and women. There was a significant increase in the adjusted hazards ratio for CAD with increasing Lp(a) levels for men and women. For Lp(a) level 3, the hazard ratio was 1.9 (range, 1.3 to 2.9) in women and 1.6 (range, 1.0 to 2.5) in men. The adjusted hazard ratio for CVD showed an irregular association with Lp(a) levels in men and no association in women. Conclusions In this cohort of 9936 men and women initially free of cardiovascular disease who were followed up for 14 years, Lp(a) was a significant predictor of risk of future CAD. Lp(a) was a weak risk factor for CVD in men and was not a significant predictor of CVD risk in women.

BackgroundQuantitative Doppler echocardiography and proximal flow convergence methods are validated techniques for quantifying mitral regurgitation. However, the clinical interpretation of the values calculated is hindered by the absence of calibration of ranges of severity in large numbers of patients.Methods and ResultsIn 180 consecutive patients (men, 62%; mean age±SD, 66±11 years), the results of Doppler quantification of isolated mitral regurgitation were calibrated by use of left ventricular angiographic grading performed within 3 months in routine practice and without intervening events. The thresholds of the quantitative variables corresponding to the angiographic grades were identified by maximizing the sum of sensitivity and specificity and minimizing their difference. The mitral regurgitation grade by angiography was 2.7±1.3. The mean value and correlation with angiographic grades for effective regurgitant orifice were 43±37 mm andr=.79 (P<.0001); for regurgitant volume, 62±45 mL andr=.80 (P<.0001); and for regurgitant fraction, 45±17% andr=.78 (P<.0001). Despite some overlap, differences between mitral regurgitation grades were all significant (allP<.05). The thresholds for severe mitral regurgitation (grade 4) were 60 mL, 50%, and 40 mm2for regurgitant volume, regurgitant fraction, and orifice, respectively.ConclusionsIn routine practice in large numbers of patients in a clinical laboratory, Doppler echocardiographic quantification of mitral regurgitation shows highly significant correlation with qualitative angiographic grades. Despite an expected overlap between classes, the calibration by angiography of grading ranges for the quantitative variables provides a framework for their interpretation and allows the definition in clinical practice of thresholds for severe mitral regurgitation.

Background Coronary endothelial dysfunction may occur in patients with minimally obstructive coronary artery disease and angina, and potentially may cause myocardial ischemia. Methods and Results Coronary endothelium-dependent vasodilation was examined in patients with angina and <50% coronary artery diameter (CAD) stenosis by selectively infusing acetylcholine (10 −6 mol/L to 10 −4 mol/L) into the left anterior descending coronary artery (LAD). Percent change in CAD (%ΔCAD) was measured by quantitative coronary angiography, and percent change in coronary blood flow (%ΔCBF) was calculated using intracoronary flow Doppler. Coronary endothelium-independent vasodilation was examined using intracoronary adenosine and nitroglycerin. 99m Tc sestamibi was injected intravenously just prior to the infusion of the highest dose of acetylcholine. Patients were divided blindly into three groups: Perfusion defects in non-LAD territory (group 1, n=6), no perfusion defects (group 2, n=7), and perfusion defects in the LAD territory (group 3, n=7). All patients had intact endothelium-independent vasodilation. In group 1, perfusion defects outside the LAD territory reflected an increase in %ΔCAD and %ΔCBF by 24±5% and 241±46% in the LAD. In group 2, %ΔCAD decreased by 26±5%, but %ΔCBF increased by 54±17%. In group 3, perfusion defects were within the LAD territory, reflecting a decrease in %ΔCAD and %ΔCBF by 35±5% and 51±14%, respectively. Conclusions This study demonstrates that coronary endothelial dysfunction in humans may be temporally associated with myocardial perfusion defects and supports a role for the coronary epicardial and microcirculation endothelium in regulating myocardial perfusion. Myocardial ischemia may occur in humans with impaired endothelium-dependent coronary flow reserve of the coronary epicardial and microcirculation.

Background Hyperglycemia is a primary cause of premature vascular disease. Endothelial cell dysfunction characterized by diminished endothelium-dependent relaxations is likely to be involved. Little is known about the molecular mechanisms of hyperglycemia-induced endothelial dysfunction. Methods and Results This study was designed to determine the effect of hyperglycemia on the l -arginine/nitric oxide (NO) pathway. Expression of endothelial nitric oxide synthase (eNOS) mRNA and production of NO were studied in human aortic endothelial cells exposed to control levels (5.5 mmol/L) and high levels (22.2 mmol/L) of glucose for 5 days. We examined the effect of glucose on NO release by measuring changes in nitrite (NO 2 − ) levels by Griess reaction. Superoxide anion (O 2 − ) production was also examined by the ferrocytochrome c assay. NOS mRNA and protein expression, which were evaluated by reverse transcription–polymerase chain reaction and Western blotting, were approximately twofold greater in endothelial cells exposed to high glucose. Elevated glucose levels increased NO 2 − production by only 40% but increased the release of O 2 − by more than threefold. Conclusions The present study demonstrates that prolonged exposure to high glucose increases eNOS gene expression, protein expression, and NO release. However, upregulation of eNOS and NO release is associated with a marked concomitant increase of O 2 − production. These results provide the molecular basis for understanding how chronic exposure to elevated glucose leads to an imbalance between NO and O 2 − . This may explain impaired endothelial function and be important for diabetic vascular disease.

Background Although retrospective analyses have revealed an association between survival and coronary angiography and angioplasty in patients with acute myocardial infarction complicated by cardiogenic shock, the degree to which bias in the selection of patients to undergo these procedures contributes to this observation remains unclear. Methods and Results We studied 2200 patients in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) trial with acute myocardial infarction complicated by cardiogenic shock (systolic blood pressure <90 mm Hg for ≥1 hour) who survived ≥1 hour after the onset of shock to determine the influence of an aggressive strategy of early angiography (within 24 hours of shock onset) and coronary angioplasty or bypass surgery, if appropriate, on survival. Revascularization was not protocol mandated but was selected by the attending physicians. Shock was present on admission in 11% and developed after admission in 89% of shock patients. The 30-day mortality was 38% in the 406 patients who underwent early angiography and were referred within 24 hours for angioplasty (n=175), bypass surgery (n=36), angioplasty and bypass surgery (n=22), or neither (late or no revascularization, n=173) compared with 62% in the 1794 patients who did not ( P =.0001). However, there were important differences in the baseline characteristics of the two groups, including younger age (63 versus 68 years, P =.0001), less prior infarction (19% versus 27%, P =.001), and a shorter time to thrombolytic therapy (2.9 versus 3.2 hours, P =.0001) in patients treated with an aggressive strategy. Using multivariate logistic regression analysis to adjust for differences in baseline characteristics, an aggressive strategy was independently associated with reduced 30-day mortality (odds ratio, 0.43 [confidence interval, 0.34 to 0.54], P =.0001). Conclusions An aggressive strategy of early angiography (and revascularization when appropriate) is associated with a reduction in mortality in patients with acute myocardial infarction and cardiogenic shock who receive thrombolytic therapy.

BackgroundRight heart failure is an important cause of morbidity and mortality in primary pulmonary hypertension. In a recent prospective, randomized study of severely symptomatic patients, treatment with prostacyclin (epoprostenol) produced improvements in hemodynamics, quality of life, and survival. This article describes the echocardiographic characteristics of participants in this trial; the relationships of echocardiographic variables to hemodynamic parameters, exercise capacity, and quality of life; and the echocardiographic changes associated with prostacyclin therapy.Methods and ResultsThe 81 patients enrolled in this multicenter trial were randomized to treatment with a long-term infusion of prostacyclin in addition to conventional therapy (n=41) or conventional therapy alone (n=40) for 12 weeks. Echocardiograms and assessments of hemodynamics, exercise capacity, and quality of life were performed before and after the treatment phase. On baseline evaluation, patients had marked right ventricular dilatation and dysfunction, abnormal septal curvature, and significant tricuspid regurgitation with a high regurgitant velocity. Pericardial effusions were common. More pronounced abnormalities in right heart structure and function were associated with higher pulmonary arterial and mean right atrial pressures, lower cardiac index, and impaired exercise capacity but had no predictable relationship to quality-of-life indicators. The 12-week infusion of prostacyclin had beneficial effects on right ventricular size, curvature of the interventricular septum, and maximal tricuspid regurgitant jet velocity.ConclusionsThe echocardiographic manifestations of severe primary pulmonary hypertension reflect abnormalities in hemodynamics and exercise capacity. Prostacyclin has beneficial effects on right heart structure and function that may contribute to the clinical improvement and prolonged survival observed with this drug.

Background The use of exercise echocardiography for the diagnosis of coronary artery disease (CAD) has been validated in pilot studies but is not documented in clinical practice and in women comparatively with men. The objectives of this study were to determine the effects of sex and of test verification bias on the diagnostic performance of exercise echocardiography. Methods and Results Three thousand six hundred seventy-nine consecutive patients (1714 women, 1965 men) who underwent an exercise echocardiographic study were studied; the observed sensitivity, specificity, and correct classification rate were calculated among 340 patients (244 men, 96 women) who underwent angiography; to study the effect of test verification bias, sensitivity and specificity were estimated for all patients who underwent exercise echocardiography including those not referred to angiography. In the angiographic group, the prevalence of CAD was 60% in women and 80% in men. The observed sensitivity and specificity of exercise echocardiography was 78% and 44% in men and 79% and 37% in women. After adjustment for test verification bias, the estimated sensitivity was lower in women (32% versus 42% in men), whereas specificity was similar in both sexes. The positive predictive value was lower in women (66%) compared with men (84%). Conclusions In clinical practice, test verification bias results in a lower observed specificity and a higher sensitivity of exercise echocardiography. In women, positive predictive value and adjusted sensitivity are lower compared with that in men.

Background Endothelin-1 (ET-1) is an endothelium-derived vasoactive peptide with mitogenic properties. In vitro, vascular release of ET-1 is increased in response to mechanical stress. The goal of the present study was to examine whether ET-1 is released from human atherosclerotic coronary arteries in vivo in response to mechanical pressure and stretch and to characterize immunoreactivity for ET-1 and its precursor, big ET-1, within the atheromatous plaque. Methods and Results Circulating ET-1 levels were measured in 20 patients before and after coronary angioplasty for stable angina at three sampling sites: the femoral artery and the coronary artery segments proximal and distal to the lesion dilated. In addition, atheromatous tissue obtained from 20 patients undergoing directional coronary atherectomy for stable angina were analyzed for immunoreactivity for ET-1 and big ET-1. In patients undergoing angioplasty, ET-1 levels in the distal coronary artery increased after balloon dilatation (8.4±0.9 to 16.4±2 pg/mL, P <.05); proximal coronary artery and systemic ET-1 levels were unchanged. The degree of mechanical stress applied (product of duration and pressure of balloon inflation) correlated with the change in distal coronary artery ET-1 levels ( r =.71, P <.01). Immunoreactivity for big ET-1 and ET-1 was ubiquitous in the extracellular space and the intracellular compartment (macrophages, myointimal cells, myofibroblasts, and endothelial cells) of human coronary atheromatous tissue. Conclusions Big ET-1 and ET-1 immunoreactivity is ubiquitous within the intracellular and extracellular compartments of coronary atherosclerotic tissue. ET-1 is released from these sites in response to mechanical stress. These findings support a role for endothelins in the evolution and progression of coronary atherosclerosis in humans.