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Rationale: Transthoracic Doppler echocardiography is recommended for screening for the presence of pulmonary hypertension (PH). However, some recent studies have suggested that Doppler echocardiographic pulmonary artery pressure estimates may frequently be inaccurate.Objectives: Evaluate the accuracy of Doppler echocardiography for estimating pulmonary artery pressure and cardiac output.Methods: We conducted a prospective study on patients with various forms of PH who underwent comprehensive Doppler echocardiography within 1 hour of a clinically indicated right-heart catheterization to compare noninvasive hemodynamic estimates with invasively measured values.Measurements and Main Results: A total of 65 patients completed the study protocol. Using Bland-Altman analytic methods, the bias for the echocardiographic estimates of the pulmonary artery systolic pressure was -0.6 mm Hg with 95% limits of agreement ranging from +38.8 to -40.0 mm Hg. Doppler echocardiography was inaccurate (defined as being greater than +/-10 mm Hg of the invasive measurement) in 48% of cases. Overestimation and underestimation of pulmonary artery systolic pressure by Doppler echocardiography occurred with a similar frequency (16 vs. 15 instances, respectively). The magnitude of pressure underestimation was greater than overestimation (-30 +/- 16 vs. +19 +/- 11 mm Hg; P = 0.03); underestimates by Doppler also led more often to misclassification of the severity of the PH. For cardiac output measurement, the bias was -0.1 L/min with 95% limits of agreement ranging from +2.2 to -2.4 L/min.Conclusions: Doppler echocardiography may frequently be inaccurate in estimating pulmonary artery pressure and cardiac output in patients being evaluated for PH. [ABSTRACT FROM AUTHOR]

Rationale: Right ventricular (RV) function is an important determinant of prognosis in pulmonary hypertension. However, noninvasive assessment of the RV function is often limited by complex geometry and poor endocardial definition. Objectives: To test whether the degree of tricuspid annular displacement (tricuspid annular plane systolic excursion [TAPSE]) is a useful echo-derived measure of RV function with prognostic significance in pulmonary hypertension. Methods: We prospectively studied 63 consecutive patients with pulmonary hypertension who were referred for a clinically indicated right heart catheterization. Patients underwent right heart catheterization immediately followed by transthoracic echocardiogram and TAPSE measurement. Results: In the overall cohort, a TAPSE of less than 1.8 cm was associated with greater RV systolic dysfunction (cardiac index, 1.9 vs. 2.7 L/min/m2; RV % area change, 24 vs. 33%), right heart remodeling (right atrial area index, 17.0 vs. 12.1 cm(2)/m), and RV-left ventricular (LV) disproportion (RV/LV diastolic area, 1.7 vs. 1.2; all p < 0.001), versus a TAPSE of 1.8 cm or greater. In patients with pulmonary arterial hypertension (PAH; n = 47), survival estimates at 1 and 2 yr were 94 and 88%, respectively, in those with a TAPSE of 1.8 cm or greater versus 60 and 50%, respectively, in subjects with a TAPSE less than 1.8 cm. The unadjusted risk of death (hazard ratio) in patients with a TAPSE less than 1.8 versus 1.8 cm or greater was 5.7 (95% confidence interval, 1.3-24.9; p = 0.02) for the PAH cohort. For every 1-mm decrease in TAPSE, the unadjusted risk of death increased by 17% (hazard ratio, 1.17; 95% confidence interval, 1.05-1.30; p = 0.006), which persisted after adjusting for other echocardiographic and hemodynamic variables and baseline treatment status. Conclusions: TAPSE powerfully reflects RV function and prognosis in PAH. [ABSTRACT FROM AUTHOR]

Objectives: Our objective was to determine if long-term daily administration of phytonutrient supplements can prevent the immediate adverse impact of a high-fat meal and increase the production of nitric oxide.Background: Ingestion of a high-fat meal impairs flow-mediated vasodilation of the brachial artery for at least 4 h; however, co-ingestion of vitamin antioxidants or a green salad has been shown to prevent this effect.Methods: Flow-mediated brachial artery reactivity test (BART) both before and 3 h after a 900 calorie 50 g fat meal was evaluated in 38 healthy volunteers (age 36.4 +/- 10.1 years). Subjects were randomized to four weeks of daily supplementation with a powdered fruit vegetable juice concentrate (Juice Plus [JP]) along with a complex supplement providing nutritional antioxidants and various herbal extracts (Vineyard [V]), JP alone, or a matching placebo. At three and four weeks, BART was repeated both before and after the high-fat meal. Serum nitrate/nitrite concentrations were measured at baseline and at four weeks.Results: Four weeks of the JP-V combination blunted the detrimental effect of the high-fat meal (-47.5 +/- 23.4% at baseline vs. -1.7 +/- 9.7% at four weeks [p < 0.05]). Four weeks of JP alone had a similar beneficial effect (-45.1 +/- 19.7% at baseline vs. -16.6 +/- 10.3% at four weeks [p < 0.05]), whereas there was no substantial effect of the placebo. In the subjects treated with supplements, concentrations of serum nitrate/nitrite increased from 78 +/- 39 to 114 +/- 62 microm/l (p < 0.02).Conclusions: Daily ingestion of modest amounts of a fruit/vegetable juice concentrate with or without adjunctive phytonutrient supplementation can reduce the immediate adverse impact of high-fat meals on flow-mediated vasoactivity and increase nitrate/nitrite blood concentration. [ABSTRACT FROM AUTHOR]

Endothelial function is thought to be an important factor in the pathogenesis of atherosclerosis, hypertension and heart failure. In the 1990s, high-frequency ultrasonographic imaging of the brachial artery to assess endothelium-dependent flow-mediated vasodilation (FMD) was developed. The technique provokes the release of nitric oxide, resulting in vasodilation that can be quantitated as an index of vasomotor function. The noninvasive nature of the technique allows repeated measurements over time to study the effectiveness of various interventions that may affect vascular health. However, despite its widespread use, there are technical and interpretive limitations of this technique. State-of-the-art information is presented and insights are provided into the strengths and limitations of high-resolution ultrasonography of the brachial artery to evaluate vasomotor function, with guidelines for its research application in the study of endothelial physiology. [ABSTRACT FROM AUTHOR]

Peripheral arterial disease (PAD) is a major cause of morbidity and mortality. Endothelial function, which is a measure of vascular health, is impaired in patients with PAD. We examined the effects of 6 months of aerobic exercise rehabilitation on brachial artery endothelial function, assessed using high-frequency ultrasonography, and calf blood flow in 19 older PAD patients (age 69 +/- 1 years, mean +/- SEM) with intermittent claudication (ankle to brachial artery index of 0.73 +/- 0.04). After exercise, the time to onset of claudication pain increased by 94%, from 271 +/- 49 to 525 +/- 80 seconds (p <0.01), and the time to maximal claudication pain increased by 43%, from 623 +/- 77 to 889 +/- 75 seconds (p <0.05). Exercise rehabilitation increased the flow-mediated brachial arterial diameter by 61%, from 0.18 +/- 0.03 to 0.29 +/- 0.04 mm (p <0.005), as well as the relative change in brachial arterial diameter from the resting state by 60%, from 4.81 +/- 0.82% to 7.97 +/- 1.03% (p <0.005). Maximal calf blood flow (14.2 +/- 1.0 vs 19.2 +/- 2.0 ml/100 ml/min; p = 0.04), and postocclusive reactive hyperemic blood flow (9.8 +/- 0.8 vs 11.3 +/- 0.7 ml/100 ml/min; p = 0.1) increased 35% and 15%, respectively. In conclusion, exercise rehabilitation improved ambulatory function, endothelial-dependent dilation, and calf blood flow in older PAD patients with intermittent claudication. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction is a key early mechanism in a variety of cardiovascular diseases and can be observed in larger conduit arteries as well as smaller resistance vessels (microvascular dysfunction). The presence of endothelial dysfunction is a strong prognosticator for cardiovascular events and mortality, and assessment of endothelial function can aid in selecting therapies and testing their response. While the gold standard method of measuring coronary endothelial function remains invasive angiography, several non-invasive imaging techniques have emerged for investigating both coronary and peripheral endothelial function. In this review, we will explore and summarize the current invasive and non-invasive modalities available for endothelial function assessment for clinical and research use, and discuss the strengths, limitations and future applications of each technique., Competing Interests: AA-Z has received research support from Canon Medical Systems. AL serves as a consultant for Itamar Medical. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Minhas, Goerlich, Corretti, Arbab-Zadeh, Kelle, Leucker, Lerman and Hays.)

Aortic insufficiency is commonly observed in rheumatologic diseases such as ankylosing spondylitis, systemic lupus erythematosus, antiphospholipid syndrome, Behçet's disease, granulomatosis with polyangiitis, and Takayasu arteritis. Aortic insufficiency with an underlying rheumatologic disease may be caused by a primary valve pathology (leaflet destruction, prolapse or restriction), annular dilatation due to associated aortitis or a combination of both. Early recognition of characteristic valve and aorta morphology on cardiac imaging has both diagnostic and prognostic importance. Currently, echocardiography remains the primary diagnostic tool for aortic insufficiency. Complementary use of computed tomography, cardiac magnetic resonance imaging and positron emission tomography in these systemic conditions may augment the assessment of underlying mechanism, disease severity and identification of relevant non-valvular/extracardiac pathology. We aim to review common rheumatologic diseases associated with aortic insufficiency and describe their imaging findings that have been reported in the literature., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Choi, Mathews, Paik, Corretti, Wu, Michos, Hays and Mukherjee.)

Stress cardiomyopathy (Takotsubo syndrome) is a reversible syndrome stemming from myocardial injury leading to systolic dysfunction and is usually noted in the setting of a stressful event, be it an emotional or physical trigger. While the exact pathophysiology behind stress cardiomyopathy is yet unknown, there is ample evidence suggesting that neurocardiogenic mechanisms may play an important role. Although historically stress cardiomyopathy was generally thought to be a relatively benign condition, there is growing recognition of the cardiovascular complications associated with it despite its reversibility. Our review aims to shed light onto key cardiovascular imaging modalities used to diagnose stress cardiomyopathy while highlighting the role that imaging plays in assessing disease severity, identifying complications, dictating treatment approaches, and in short-term and long-term prognosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zghyer, Botheju, Kiss, Michos, Corretti, Mukherjee and Hays.)

Echocardiography is the foundation for diagnostic cardiac testing, allowing for direct identification and management of various conditions. Point-of-care ultrasound (POCUS) has emerged as an invaluable tool for bedside diagnosis and management. The objective of this review is to address the current use and clinical applicability of POCUS to identify, triage, and manage a wide spectrum of cardiac conditions. POCUS can change diagnosis and management decisions of various cardiovascular conditions in a range of settings. In the outpatient setting, it is used to risk stratify and diagnose a variety of medical conditions. In the emergency department (ED) and critical care settings, it is used to guide triage and critical care interventions. Furthermore, the skills needed to perform POCUS can be taught to noncardiologists in a way that is retained and allows identification of normal and grossly abnormal cardiac findings. Various curricula have been developed that teach residents and advanced learners how to appropriately employ point-of-care ultrasound. In conclusion, POCUS can be a useful adjunct to the physical exam, particularly in critical care applications., (Copyright © 2018. Published by Elsevier Inc.)

Background: Physicians spend less time at the bedside in the modern hospital setting which has contributed to a decline in physical diagnosis, and in particular, cardiopulmonary examination skills. This trend may be a source of diagnostic error and threatens to erode the patient-physician relationship. We created a new bedside cardiopulmonary physical diagnosis curriculum and assessed its effects on post-graduate year-1 (PGY-1; interns) attitudes, confidence and skill., Methods: One hundred five internal medicine interns in a large U.S. internal medicine residency program participated in the Advancing Bedside Cardiopulmonary Examination Skills (ACE) curriculum while rotating on a general medicine inpatient service between 2015 and 2017. Teaching sessions included exam demonstrations using healthy volunteers and real patients, imaging didactics, computer learning/high-fidelity simulation, and bedside teaching with experienced clinicians. Primary outcomes were attitudes, confidence and skill in the cardiopulmonary physical exam as determined by a self-assessment survey, and a validated online cardiovascular examination (CE)., Results: Interns who participated in ACE (ACE interns) by mid-year more strongly agreed they had received adequate training in the cardiopulmonary exam compared with non-ACE interns. ACE interns were more confident than non-ACE interns in performing a cardiac exam, assessing the jugular venous pressure, distinguishing 'a' from 'v' waves, and classifying systolic murmurs as crescendo-decrescendo or holosystolic. Only ACE interns had a significant improvement in score on the mid-year CE., Conclusions: A comprehensive bedside cardiopulmonary physical diagnosis curriculum improved trainee attitudes, confidence and skill in the cardiopulmonary examination. These results provide an opportunity to re-examine the way physical examination is taught and assessed in residency training programs.

Dilation of the sinus of Valsalva (SoV) has been increasingly observed after repaired tetralogy of Fallot (TOF). We estimate the prevalence of SoV dilation in adults with repaired TOF and analyze possible factors related to aortic disease. Adults with TOF [n = 109, median age 33.2 years (range 18.1 to 69.5)] evaluated at Johns Hopkins Hospital from 2001 to 2009 were reviewed in an observational retrospective cohort study. Median follow-up was 27.3 (range 0.1-48.8) years. SoV dilation was defined as >95 % confidence interval adjusted for age and body surface area (z-score > 2). The prevalence of SoV dilation was 51 % compared with that of a normal population with a mean z-score of 2.03. Maximal aortic diameters were ≥ 4 cm in 39 % (42 of 109), ≥ 4.5 cm in 21 % (23 of 109), ≥ 5 cm in 8 % (9 of 109), and ≥ 5.5 cm in 2 % (2 of 109). There was no aortic dissection or death due contributable to aortic disease. Aortic valve replacement was performed in 1.8 % and aortic root or ascending aorta (AA) replacement surgery in 2.8 % of patients. By multivariate logistic regression analysis, aortic regurgitation (AR) [odds ratio (OR) = 3.09, p = 0.005], residual ventricular septal defect (VSD) (OR = 4.14, p < 0.02), and TOF with pulmonary atresia (TOF/PA) (OR = 6.75, p = 0.03) were associated with increased odds of dilated aortic root. SoV dilation after TOF repair is common and persists with aging. AR, residual VSD, and TOF/PA are associated with increased odds of dilation. AA evaluation beyond the SoV is important. Indexed values are imperative to avoid bias on the basis of age and body surface area.

A three-stage approach was undertaken using genome-wide, case-control, and case-only association studies to identify genetic variants associated with heart failure mortality. In an Amish founder population (n = 851), cardiac hypertrophy, a trait integral to the adaptive response to failure, was found to be heritable (h² = 0.28, p = 0.0002) and GWAS revealed 21 candidate hypertrophy SNPs. In a case (n = 1,610)-control (n = 463) study in unrelated Caucasians, one of the SNPs associated with hypertrophy (rs2207418, p = 8 × 10⁻⁶), was associated with heart failure, RR = 1.85(1.25-2.73, p = 0.0019). In heart failure cases rs2207418 was associated with increased mortality, HR = 1.51(1.20-1.97, p = 0.0004). There was consistency between studies, with the GG allele being associated with increased ventricular mass (~13 g/m²) in the Amish, heart failure risk, and heart failure mortality. This SNP is in a gene desert of chromosome 20p12. Five genes are within 2.0 mbp of rs2207418 but with low LD between their SNPs and rs2207418. A region near this SNP is highly conserved in multiple vertebrates (lod score = 1,208). This conservation and the internal consistency across studies suggests that this region has biologic importance in heart failure, potentially acting as an enhancer or repressor element. rs2207418 may be useful for predicting a more progressive form of heart failure that may require aggressive therapy., (© 2011 Wiley Periodicals, Inc.)

Introduction: Multidetector CT (MDCT) is used prior to atrial fibrillation ablation (AFA) to anatomically guide ablation procedures. Whether 64-slice MDCT also can be used to diagnose left atrial thrombus is not known., Methods: We sought to determine the accuracy and interobserver variability of MDCT in the evaluation of left atrial thrombus prior to AFA. We enrolled 50 patients scheduled for AFA who underwent 64-slice MDCT scan and transesophageal echocardiography prior to the procedure. Three experienced observers reviewed all the MDCT images for the presence of a left atrial thrombus, and two different readers interpreted the transesophageal echocardiograms (TEE), which were used as the gold standard. All observers were blinded to clinical data and each other., Results: Interobserver variability between the three MDCT readers was poor (highest kappa statistic 0.43, P = 0.001). Diagnostic accuracy was highly variable, with sensitivities ranging from 100% to 50% and specificities ranging from 85% to 44%. TEE reader agreement was 98%., Conclusion: MDCT demonstrates high interobserver variability and has only modest diagnostic accuracy for the detection of left atrial thrombus in patients undergoing AFA procedure. Potential factors affecting the accuracy of MDCT include image quality and the difficulty of distinguishing clot from pectinate muscle. MDCT likely is not the optimal method to detect left atrial thrombus using current techniques and standards of interpretation.

Aerobic activity performed on a regular basis is 1 of several lifestyle recommendations endorsed to reduce risk of coronary disease. However, 1 potential concern of arduous aerobic activity is exercise-induced hypertension. This is the first case to our knowledge, of accelerated coronary calcification in an otherwise asymptomatic middle-aged male marathon runner devoid of traditional cardiovascular risk factors. As a consequence of exercise-induced hypertension and associated oxidative stress, improvement of endothelial dysfunction occurred after antioxidant supplementation. In conclusion, vigorous aerobic activity in susceptible individuals may promote oxidative stress and coronary atherosclerosis.

Epidemiologic and experimental reports suggest that female hormones protect against the development of colorectal cancer, but studies are limited. We describe a patient in the placebo arm of a 4-year primary chemoprevention trial who developed adenomatous polyps and then had eradication of polyps after the administration of oral contraceptives. No change in the prostaglandin levels in the colonic mucosa was noted after polyp elimination, making nonsteroidal anti-inflammatory drug ingestion unlikely as a cause. This report represents the regression of colorectal adenomas with the use of estrogen/progesterone compounds.

Objectives: This study investigated the postprandial effect of components of the Mediterranean diet on endothelial function, which may be an atherogenic factor., Background: The Mediterranean diet, containing olive oil, pasta, fruits, vegetables, fish, and wine, is associated with an unexpectedly low rate of cardiovascular events. The Lyon Diet Heart Study found that a Mediterranean diet, which substituted omega-3-fatty-acid-enriched canola oil for the traditionally consumed omega-9 fatty-acid-rich olive oil, reduced cardiovascular events., Methods: We fed 10 healthy, normolipidemic subjects five meals containing 900 kcal and 50 g fat. Three meals contained different fat sources: olive oil, canola oil, and salmon. Two olive oil meals also contained antioxidant vitamins (C and E) or foods (balsamic vinegar and salad). We measured serum lipoproteins and glucose and brachial artery flow-mediated vasodilation (FMD), an index of endothelial function, before and 3 h after each meal., Results: All five meals significantly raised serum triglycerides, but did not change other lipoproteins or glucose 3 h postprandially. The olive oil meal reduced FMD 31% (14.3 +/- 4.2% to 9.9 +/- 4.5%, p = 0.008). An inverse correlation was observed between postprandial changes in serum triglycerides and FMD (r = -0.47, p < 0.05). The remaining four meals did not significantly reduce FMD., Conclusions: In terms of their postprandial effect on endothelial function, the beneficial components of the Mediterranean and Lyon Diet Heart Study diets appear to be antioxidant-rich foods, including vegetables, fruits, and their derivatives such as vinegar, and omega-3-rich fish and canola oils.

Background: The ultrasound assessment of brachial artery flow-mediated vasodilation provides a noninvasive means for measuring endothelial function. The test is performed using either upper or lower arm blood pressure cuff arterial occlusion to induce hyperemia. Upper arm occlusion produces a greater hyperemic stimulus. Brachial artery flow-mediated vasodilation is abnormal in the presence of coronary risk factors., Hypothesis: The study sought to compare the ability of the upper and lower arm occlusion techniques to differentiate endothelial function in subjects with and without risk factors., Methods: We measured brachial artery flow-mediated vasodilation in 20 subjects, 10 without and 10 with a single risk factor (hypertension, hypercholesterolemia, or cigarette smoking) using both the upper and lower arm occlusion techniques (5 min blood pressure cuff occlusion). Using 11 MHz ultrasound, Doppler blood flow velocities were measured before and immediately after cuff deflation. Brachial artery vasodilation was measured 1 min after cuff deflation, compared with baseline, and expressed as a percent increase., Results: The immediately postocclusion hyperemia (% increase in flow) was significantly greater (p < 0.01) using the upper versus the lower arm technique in both the normal (530 +/- 152 vs. 383 +/- 51%) and the risk factor (583 +/- 153 vs. 409 +/- 114%) groups. Flow-mediated vasodilation was significantly greater (p < 0.01) using the upper arm versus the lower arm occlusion technique in both the normal (13.4 +/- 5.3 vs. 5.6 +/- 3.4%) and risk factor (7.9 +/- 3.6 vs. 3.9 +/- 2.2%) groups. Vasodilation was significantly greater (p < 0.01) in the normal subjects than in the risk factor subjects (13.4 +/- 5.3 vs. 7.9 +/- 3.6%) using the upper arm technique, but was not statistically different in the two groups using the lower arm technique., Conclusions: Our study demonstrates that upper arm compared with lower arm cuff occlusion undertaken to induce hyperemia for the assessment of brachial artery flow-mediated vasodilation results in significantly greater hyperemia and vasodilation. Flow-mediated vasodilation obtained using the upper arm technique better separates subjects with and without coronary risk factors.

Peripheral arterial disease (PAD) is a major cause of morbidity and mortality. Endothelium-dependent vasoreactivity, which is advocated as a measure of vascular health, is impaired in persons with cardiac risk factors and coronary artery disease. Few studies have examined the degree of endothelial dysfunction in patients with PAD. Using high-resolution external vascular ultrasound, we measured brachial artery diameter and flow at rest, and in response to reactive hyperemia (flow-mediated dilation) in 50 older patients (age 69 +/- 1 year) with PAD (ankle-to-brachial artery index of 0.67 +/- 0.03), and 50 age-matched non-PAD patients. Coronary artery disease was more prevalent in PAD than in non-PAD patients (40% vs 4%, p <0.001). Systolic blood pressure (153 +/- 4 vs 141 +/- 3 mm Hg, p <0.01), fasting glucose (129 +/- 6 vs 109 +/- 5 mg/dl, p <0.001), and pack-years smoked (54 +/- 7 vs 25 +/- 3, p <0.01) were higher in the PAD than in non-PAD patients. There were no differences in baseline brachial artery diameter, blood velocity, or flow between the 2 groups. However, the 1-minute postocclusion percent change in diameter (6.5 +/- 0.7% vs 9.8 +/- 0.7%, p <0.001) and the change in diameter (0.22 +/- 0.02 vs 0.33 +/- 0.02 mm, p <0.001) were lower in PAD than in non-PAD patients, suggesting impaired endothelium-dependent dilation. The postocclusion hyperemic velocity and blood flow were also lower in PAD than in non-PAD patients. In multiple regression analyses the low-density lipoprotein-to-high-density lipoprotein cholesterol ratio, elevated fasting glucose, and high systolic blood pressure were independent predictors of percent change in brachial artery diameter (r2 = 0.37, p <0.001). Thus, older patients with PAD had impaired endothelial dependent vasodilation compared with controls that was associated with the presence of cardiac risk factors. The effect of cardiac risk factor intervention on endothelial function in patients with PAD remains to be determined.

A strong relationship between hypercholesterolemia and atherosclerosis has been established through epidemiological, experimental, and clinical trial data. Traditional theories on the pathophysiology of this relationship involve the deposition, modification, and cellular uptake of cholesterol, and the release of inflammatory and growth factors resulting in smooth muscle cell proliferation and collagen matrix production. The vasculature has recently been found to be an active and complex organ, with the endothelium playing a controlling role in vascular tone, lipid breakdown, thrombogenesis, inflammation, and vessel growth. In the presence of risk factors such as hypercholesterolemia, the endothelium promotes vasoconstriction, monocyte and platelet adhesion, thrombogenesis, and growth factor release. A high-fat diet also directly impairs endothelial function and increases coagulation factors. Endothelial dysfunction is associated with decreased availability of the predominant vasodilator nitric oxide, possibly by increased destruction by oxygen free radicals. This dysfunctional state appears before the earliest anatomic evidence of atherosclerosis and may represent an important initial step in its development. Several studies have shown improvements in endothelial function with cholesterol lowering in both normal individuals and those with coronary heart disease. Short-term improvements in endothelial-dependent vasodilation and adhesion molecule expression have also been reported with antioxidant therapy. These observations suggest that atherosclerosis is at least in part caused by endothelial dysfunction that favors cellular proliferation. This new understanding helps to explain the early and substantial reductions in major cardiovascular events associated with cholesterol lowering.

To elucidate whether or not Ca channel blockers have an intrinsic benefit that cannot be attributed to the reduction of Ca2+ entry by pretreatment, time-averaged intracellular Ca2+ concentration ([Ca2+]i) and energy-related phosphates were measured in isolated ferret hearts using nuclear magnetic resonance. In the drug-free ischemic group, [Ca2+]i increased significantly during 30 min of global ischemia at 30 degrees C and during 0-5 min of reperfusion. After 30 min of reperfusion, isovolumic left ventricular developed pressure recovered only to 63+/-7% of the pre-ischemic level (mean+/-SEM; N=5). Pretreatment with the Ca channel blocker clentiazem (10(-7) mol/L) itself depressed developed pressure by 53+/-9%. In the clentiazem group, [Ca2+]i showed no significant changes during ischemia or reperfusion. Recovery of developed pressure (87+/-8% of untreated level) was significantly higher than in the non-treated group (p<0.05). Nevertheless, when the negative inotropism of clentiazem was offset by increasing [Ca]o from 2 to 3 mmol/L, no beneficial effects of clentiazem were observed; [Ca2+]i increased significantly during 0-5 min of reperfusion, and developed pressure recovered only 60+/-7% of untreated level. These results indicate that reduction of Ca2+ entry from the extracellular space to the myocyte, as reflected by negative inotropism during pretreatment, is required for clentiazem to protect myocardium in a model of global ischemia and reperfusion.

Impaired endothelial function is observed as altered vasomotion in both the peripheral and coronary circulation in the presence of cardiovascular risk factors and early atherogenesis. An improvement in endothelium-dependent vasoactivity has been reported with both cholesterol reduction and smoking cessation. This study was performed to determine whether smoking status in coronary artery disease (CAD) effects both flow-mediated and cold pressor vasoactivity. We studied 25 men (ages 30-59), 12 smokers and 13 nonsmokers with angiographically documented coronary artery disease and cardiac risk factors who were grouped as smokers and nonsmokers. Using 7.5 MHz ultrasound, we measured brachial artery diameter and Doppler flow velocity at baseline, following 5 mins of ipsilateral blood pressure cuff occlusion and release (flow-mediated), during contralateral ice water hand immersion (cold pressor test) and after sublinqual nitroglycerin administration (an endothelium-independent vasodilator). Flow-mediated percent diameter change was significantly less in the smokers than nonsmokers (1.9 +/- 5.7% vs 11.4 +/- 7.2%, p < 0.001). Both smokers and nonsmokers responded similarly to the cold pressor test (-3.9 +/- 2.3 vs -1.2 +/- 0.2%) and nitroglycerin (15.1 +/- 7.6 vs 17.5 +/- 8.3%). Cholesterol level did not appear to be an independent determinant of flow-mediated vasoactivity when smoking status was taken into account. Flow-mediated vasoactivity is associated with smoking status in the presence of coronary artery disease but cold pressor induced vasoactivity is not.

Context: Much has been written about the potential role of antioxidants in the prevention of atherosclerosis., Objective: To assess the short-term effect of a single high-fat meal with and without pretreatment with antioxidant vitamins on endothelial function in healthy, normocholesterolemic subjects., Design: Observer-blinded randomized trial., Setting: University hospital., Participants: Twenty healthy, normocholesterolemic (total and low-density lipoprotein cholesterol <5.2 mmol/L and <3.4 mmol/L [<200 mg/dL and <130 mg/ dL], respectively), male (7) and female (13) hospital employee volunteers, aged 24 to 54 years., Intervention: Three randomly administered breakfasts: (1) a high-fat meal (3766 J [900 calories], 50 g of fat); (2) a low-fat meal (3766 J [900 calories], 0 g of fat); and (3) a high-fat meal and pretreatment with oral administration of vitamins C (1 g) and E (800 IU) (high-fat meal with vitamins). A subgroup of 10 subjects also ate the low-fat meal with the same vitamin pretreatment (low-fat meal with vitamins)., Main Outcome Measure: High-resolution ultrasound assessed flow-mediated (endothelium-dependent) brachial artery vasodilation measured as percent diameter change before and hourly for 6 hours following each meal., Results: Flow-mediated vasodilation fell from a mean+/-SD of 20%+/-8% before to 12%+/-6%, 10%+/-6%, and 8%+/-9% at 2, 3, and 4 hours, respectively, after the high-fat meal (P<.001). No significant changes in flow-mediated vasodilation occurred after the low-fat meal, high-fat meal with vitamins, or low-fat meal with vitamins. The change in flow-mediated vasodilation after the low-fat and high-fat meals correlated inversely with the 2-hour postprandial change in triglyceride levels (r=-0.54; P<.001)., Conclusion: A single high-fat meal transiently reduces endothelial function for up to 4 hours in healthy, normocholesterolemic subjects, probably through the accumulation of triglyceride-rich lipoproteins. This decrease is blocked by pretreatment with antioxidant vitamins C and E, suggesting an oxidative mechanism.

Although there is a well-established relation between serum cholesterol and coronary artery disease risk, individual and national variations in this association suggest that other factors are involved in atherogenesis. High-fat diet associated triglyceride-rich lipoproteins have also been suggested to be atherogenic. To assess the direct effect of postprandial triglyceride-rich lipoproteins on endothelial function, an early factor in atherogenesis--10 healthy, normocholesterolemic volunteers--were studied before and for 6 hours after single isocaloric high- and low-fat meals (900 calorie; 50 and 0 g fat, respectively). Endothelial function, in the form of flow-mediated vasoactivity, was assessed in the brachial artery using 7.5-MHz ultrasound as percent arterial diameter change 1 minute after 5 minutes of upper-arm arterial occlusion. Serum lipoproteins and glucose were determined before eating and 2 and 4 hours postprandially. Serum triglycerides increased from 94 +/- 55 mg/dl preprandially to 147 +/- 80 mg/dl 2 hours after the high-fat meal (p = 0.05). Flow-dependent vasoactivity decreased from 21 +/- 5% preprandially to 11 +/- 4%, 11 +/- 6%, and 10 +/- 3% at 2, 3, and 4 hours after the high-fat meal, respectively (all p <0.05 compared with low-fat meal data). No changes in lipoproteins or flow-mediated vasoactivity were observed after the low-fat meal. Fasting low-density lipoprotein cholesterol correlated inversely (r = -0.47, p = 0.04) with preprandial flow-mediated vasoactivity, but triglyceride level did not. Mean change in postprandial flow-mediated vasoactivity at 2, 3, and 4 hours correlated with change in 2-hour serum triglycerides (r = -0.51, p = 0.02). These results demonstrate that a single high-fat meal transiently impairs endothelial function. These findings identify a potential process by which a high-fat diet may be atherogenic independent of induced changes in cholesterol.

Current National Cholesterol Education Program guidelines consider desirable total and low-density lipoprotein cholesterol levels to be < 200 and < 160 mg/dl, respectively, for healthy individuals without multiple coronary risk factors. To determine the extent to which these levels affect vascular function, we assessed flow-mediated (endothelium-dependent) brachial artery vasoactivity noninvasively before, during, and after cholesterol lowering (simvastatin 10 mg/day) in 7 healthy middle-aged men with cholesterol levels meeting current recommendations. Flow-mediated brachial artery vasoactivity was measured using 7.5 MHz ultrasound and expressed as percent diameter change from baseline to hyperemic conditions (1 minute following 5 minutes of blood pressure cuff arterial occlusion). Flow-mediated vasoactivity rose from 5.0 +/- 3.6% at baseline to 10.5 +/- 5.6%, 13.3 +/- 4.3%, and 15.7 +/- 4.9% (all p < 0.05) as cholesterol fell from 200 +/- 12 to 161 +/- 18, 169 +/- 16, and 153 +/- 11 mg/dl after 2, 4, and 12 weeks, respectively, of cholesterol-lowering therapy. Vasoactivity and cholesterol returned to baseline levels 12 weeks after simvastatin discontinuation. Overall, vasoactivity was found to correlate inversely with cholesterol levels (r = -0.47, p = 0.004). These data suggest that flow-mediated brachial artery vasoactivity responds rapidly to changes in cholesterol levels and that endothelial function improves by lowering cholesterol levels below recommendations of current guidelines.

This study investigated whether there is an association between the degree of interatrial shunting across a patent foramen ovale, as determined by saline contrast transesophageal echocardiography, and the risk of subsequent systemic embolic events, including stroke. Thirty-four patients found to have foramen ovale during transesophageal echocardiography were divided into two groups on the basis of the maximum number of microbubbles in the left heart in any single frame after intravenous saline contrast injection: group 1 (n = 16) with a "large" degree of shunt ( > or = 20 microbubbles) and group 2 (n = 18) with a "small" degree of shunt ( > or = 3 microbubbles). Patients were followed up over a mean period of 21 months for subsequent systemic embolic events, including transient ischemic attack and stroke. Five (31%) of the patients with large shunts had subsequent ischemic neurologic events, whereas none of the patients with small shunts had embolic events (p = 0.03). These events occurred in spite of antiplatelet or anticoagulant therapy. We conclude that patients with a large degree of shunt across a patient foramen ovale, as determined by contrast transesophageal echocardiography, are at a significantly higher risk of subsequent adverse neurologic events compared with patients with a small degree of shunt.

Impaired endothelium-dependent vasomotion in response to flow-mediated, cholinergic, and cold pressor stimulation has been demonstrated in the presence of both atherosclerosis and cardiac risk factors. This study investigated the effects of different vasoactive stimuli on brachial artery vasomotion with respect to age and gender. Forty healthy subjects (20 men and 20 women), ages 23 to 52 years, were studied. Using 7.5 MHz ultrasound, brachial artery diameter and Doppler flow velocity at baseline, following 5 min of ipsilateral blood pressure cuff occlusion (flow-mediated), during contralateral hand immersion in ice (cold pressor) and after sublingual nitroglycerin administration, were measured in older subjects (> 40 yrs) and younger subjects (< 40 yrs). Among normal subjects, % diameter change in response to the flow-mediated stimulus was less in older men than in younger men (6.8 +/- 3.2% vs. 11.5 +/- 7.4%, p < 0.05); older and younger women had comparable responses (10.0 +/- 5.3% vs. 11.6 +/- 4.3%, p = NS). With cold pressor, normal older men and older women vasoconstricted (-1.2 +/- 0.9%, -2.2 +/- 4.7%) compared with younger subjects who vasodilated (1.4 +/- 2.5%, 0.6 +/- 2.3%, p < 0.02). The cold pressor test elicited comparable responses among older normal subjects. Nitroglycerin, a non-endothelium-mediated stimulus, induced significant vasodilatation in all the groups. In conclusion, endothelium-mediated responses in subjects of varying age and gender are stimulus-dependent. Flow-mediated vasodilatation could not differentiate older premenopausal women from younger women; cold pressor stimulus could.

Flow-mediated brachial and coronary artery vasoactivity are abnormal in patients with coronary artery disease (CAD) and cardiac risk factors. Cold pressor coronary artery vasoactivity is abnormal in patients with CAD, but brachial artery responses have not been studied. This study assesses whether cold pressor and flow-mediated brachial artery vasoactivity correlate independently with the presence of CAD. We studied 50 men (27 who were clinically normal, 23 with angiographically proven CAD) aged 23 to 59 years. With use of 7.5 MHz ultrasound, we measured brachial artery diameter and Doppler flow velocity at baseline, during contralateral ice water hand immersion (cold pressor), after 5 minutes of ipsilateral blood pressure cuff occlusion (flow-mediated), and after nitroglycerin administration. During cold pressor stimulation, mean brachial artery diameter increased 0.36 +/- 2.93% in normal subjects but decreased 2.38 +/- 3.32% in the CAD subjects (p = 0.006). Mean flow-mediated diameter increased 9.11 +/- 6.01% and 6.58 +/- 7.50% in normal and CAD subjects, respectively (p = NS). Responses to sublingual nitroglycerin were the same in the 2 groups. Multiple stepwise regression analysis revealed that cold pressor vasoactivity was found to correlate with smoking status (p = 0.0002) and the presence of CAD (p = 0.04). In the 32 nonsmokers undergoing assessment, only the presence of CAD correlated with cold pressor vasoactivity (p = 0.02). The associations of brachial artery vasoactivity with cardiac risk factors and CAD appear to be stimulus-dependent. Cold pressor vasoactivity correlates more closely with the presence of CAD than does flow-mediated vasoactivity.

Previous studies using thallium-201 scintigraphy have suggested that angiographic coronary collaterals can protect against the development of stress-induced perfusion abnormalities, but the effect of collaterals on stress echocardiography (SECHO) has not been determined. In this study, 21 consecutive patients referred for cardiac catheterization underwent SECHO and coronary angiography. Of the 21 study patients, there was a total of 16 significantly obstructed coronary arteries (> or = 70% stenosis) in 14 patients. SECHO revealed stress-induced wall motion abnormalities in the distribution of seven of nine obstructed coronary vessels without angiographic collaterals, but in only one of seven vessels with collaterals (p < 0.05). Six of eight obstructed vessels not associated with a stress-induced wall motion abnormality had collaterals, whereas only one of eight obstructed vessels associated with a stress-induced wall motion abnormality had collaterals. We conclude that (1) angiographically demonstrated coronary collaterals can protect against the development of stress-induced wall motion abnormalities despite the presence of a high-grade coronary artery obstruction, and (2) the lack of a stress-induced wall motion abnormality on SECHO in the perfusion territory of an obstructed vessel may suggest the presence of adequate collateral perfusion.

Flow-mediated brachial artery vasoactivity has been recently proposed as a noninvasive means for assessing endothelial function. To better characterize this technique, we measured brachial artery diameter and flow using 7.5-MHz ultrasound following 1, 3, and 5 min of upper arm blood pressure cuff occlusion in 19 normal volunteers and 13 patients with coronary artery disease (CAD). Although similar flow increases were observed with each protocol, statistically significant vasodilatation (12.6 +/- 5.7%) was observed in the normals only after 5 min of occlusion. With the use of this protocol, postocclusion blood flow increased 528 +/- 271 and 481 +/- 247% in the normals and CAD patients, respectively (P = NS). More vasodilatation was observed in the normals compared with the CAD patients (11.3 +/- 5.4 vs. 1.6 +/- 5.2%, P < 0.001). Interestingly, vasodilatation persisted for 20 min despite return of blood flow to baseline in 2 min. With the use of lower arm occlusion, arterial diameter was found to decrease 4.4 +/- 3.9% in response to a 85 +/- 7% decrease in flow. We conclude that 1) longer brachial artery occlusion results in more vasodilatation despite similar hyperemic responses, 2) vasodilatation persists substantially beyond hyperemia, and 3) CAD patients have impaired flow-mediated vasodilatation using this noninvasive technique.

Free radicals have been implicated in the pathogenesis of reperfusion injury, but it is unclear how they exert their deleterious effects on cellular metabolism. Several lines of indirect evidence suggest that free radicals elevate intracellular Ca2+ concentration ([Ca2+]i) and inhibit glycolysis as part of their mechanism of injury. We tested these ideas directly in hearts subjected to hydroxyl radicals produced by the Fenton and Haber-Weiss reactions. Nuclear magnetic resonance spectra were obtained from Langendorff-perfused rabbit hearts before, during, and after 4 min of perfusion with H2O2 (0.75 mM) and Fe(3+)-chelate (0.1 mM). Isovolumic left ventricular pressure exhibited progressive functional deterioration and contracture after exposure to H2O2 + Fe3+. Phosphorus nuclear magnetic resonance (NMR) spectra revealed partial ATP depletion and sugar phosphate accumulation indicative of glycolytic inhibition. To measure [Ca2+]i, fluorine NMR spectra were acquired in a separate group of hearts loaded with the Ca2+ indicator 5F-BAPTA [5,5'-difluoro derivative of 1,2-bis-(o-aminophenoxy)ethane- N,N,N',N'-tetraacetic acid]. Mean time-averaged [Ca2+]i increased from 347 +/- 14 nM in control to 1,026 +/- 295 nM 4 min after free radical generation (means +/- SEM, n = 7), and remained elevated thereafter. We conclude that free radicals induce clear-cut, specific derangements of cellular metabolism in the form of glycolytic inhibition and calcium overload. The observed increase in [Ca2+]i suggests that the deleterious effects of free radicals are at least partially mediated by secondary changes in cellular calcium homeostasis.

The basis of early ischemic contractile failure was investigated in perfused ferret hearts at 27 degrees C. Isovolumic left ventricular developed pressure fell by more than 50% within 30 seconds of the onset of total global ischemia and reached zero by 5 minutes. Monophasic action potential recordings revealed no decrease in excitability during this period. Phosphorus nuclear magnetic resonance spectra obtained at 30-second resolution showed no significant changes in inorganic phosphate or phosphocreatine during the first 30 seconds of ischemia. Intracellular pH (pHi) and ATP changed even more slowly; therefore, none of these metabolites could account for the rapid fall in force. To gauge the contribution of intravascular pressure, we compared ordinary aortic flow occlusion with tissue-level ischemia induced by massive coronary microembolization at the level of the precapillary arterioles. Functional depression developed significantly more slowly in the microembolized hearts, despite accumulation of inorganic phosphate and protons comparable with that in ordinary ischemia. After microembolization, the time course of functional depression reflected much more closely the concomitant inorganic phosphate and pHi changes. Thus, our results provide novel evidence supporting the importance of vascular collapse in the mechanism of early ischemic contractile failure.