Jon G. Keevil

Purple Grape Juice Improves Endothelial Function and Reduces the Susceptibility of LDL Cholesterol to Oxidation in Patients With Coronary Artery Disease

BACKGROUND In vitro, the flavonoid components of red wine and purple grape juice are powerful antioxidants that induce endothelium-dependent vasodilation of vascular rings derived from rat aortas and human coronary arteries. Although improved endothelial function and inhibition of LDL oxidation may be potential mechanisms by which red wine and flavonoids reduce cardiovascular risk, the in vivo effects of grape products on endothelial function and LDL oxidation have not been investigated. This study assessed the effects of ingesting purple grape juice on endothelial function and LDL susceptibility to oxidation in patients with coronary artery disease (CAD). METHODS AND RESULTS Fifteen adults with angiographically documented CAD ingested 7.7+/-1.2 mL. kg(-1). d(-1) of purple grape juice for 14 days. Flow-mediated vasodilation (FMD) was measured using high-resolution brachial artery ultrasonography. Susceptibility of LDL particles to oxidation was determined from the rate of conjugated diene formation after exposure to copper chloride. At baseline, FMD was impaired (2.2+/-2. 9%). After ingestion of grape juice, FMD increased to 6.4+/-4.7% (P=0.003). In a linear regression model that included age, artery diameter, lipid values, and use of lipid-lowering and antioxidant therapies, the effect of grape juice on FMD remained significant (mean change 4.2+/-4.4%, P<0.001). After ingestion of grape juice, lag time increased by 34.5% (P=0.015). CONCLUSIONS Short-term ingestion of purple grape juice improves FMD and reduces LDL susceptibility to oxidation in CAD patients. Improved endothelium-dependent vasodilation and prevention of LDL oxidation are potential mechanisms by which flavonoids in purple grape products may prevent cardiovascular events, independent of alcohol content.

Effect of ingestion of purple grape juice on endothelial function in patients with coronary heart disease

T “French Paradox” refers to the observation that the coronary heart disease mortality rate is lower in France than in other industrialized countries with similar prevalences of coronary risk factors.1,2 This paradox has been attributed to frequent consumption of alcohol-containing beverages, which increase highdensity lipoprotein (HDL) cholesterol levels and inhibit platelet function.1–7 Several epidemiologic studies suggest that ingestion of red wine, which contains several hundred different types of flavonoids, is more cardioprotective than beer or spirits.1–4 Indeed, the flavonoids found in red wine and purple grape juice (GJ) also inhibit platelet aggregation, and in 1 study, were shown to be powerful antioxidants that improved endothelial function.8–10 In that study, however, most subjects were taking vitamin E, so it is unclear if the observed results were due solely to the flavonoids in GJ or a combination of vitamin E and GJ.10 Furthermore, a high dose of GJ was administered (approximately 8 ml/kg/day) for only 2 weeks. The purpose of this study was to assess the endothelial function and antioxidant effects of 2 doses of purple GJ alone and in combination with vitamin E for 8 weeks. • • • The institutional review board of the University of Wisconsin Medical School approved this study. All subjects provided informed consent before participation. Twenty-two adults with angiographically documented coronary artery disease were recruited for this study. Subjects were not allowed to take vitamin supplements for 4 weeks before enrollment or during this study, except as prescribed by the research protocol. Subjects also were prohibited from consuming fruit products, tea, or alcoholic beverages during this study. Medications could not be changed during the study. All subjects ingested purple GJ (Welch’s 100% Concord Grape, Concord, Massachusetts) for 56 days. The first 11 subjects were instructed to drink 8.0 ml/kg of GJ, twice daily. For an average 80-kg person, this was approximately 640 ml/day (21 ounces) of GJ, which contained approximately 112 g of carbohydrate. The next 11 subjects were instructed to drink 4.0 ml/kg of purple GJ, once daily (low-dose group). After 28 days, subjects added vitamin E (d,l-a-tocopheryl) 400 IU to their daily intake of GJ. Subjects’ diaries indicated .90% compliance with GJ and vitamin E. Endothelial function was evaluated by measuring flow-mediated vasodilation (FMD) of the brachial artery using B-mode ultrasound. Studies were performed at baseline and at subsequent visits on the morning of phlebotomy, after a 12-hour fast. Subjects were instructed to drink their daily dose of GJ at least 2 hours before testing. Brachial artery diameters and blood flows were measured with a 7.5-MHz linear array vascular ultrasound transducer and an Agilent Technologies 5500 Sonos ultrasound system (Palo Alto, California). Increased forearm blood flow was induced by inflating a blood pressure tourniquet around the widest part of the forearm to a systolic blood pressure of 250 mm Hg for 4.5 minutes. Repeat brachial artery diameter and blood flow scans were obtained immediately and 1 minute after deflation of the tourniquet. Resting brachial artery diameter and blood flow scans were repeated 15 minutes later. Sublingual nitroglycerin (400 mg) was administered and final scans were performed after 3 minutes. The brachial artery was imaged in longitudinal sections 2 to 15 cm above the elbow. Images were recorded using the digital storage and retrieval software of the ultrasound system. Vessel diameters were measured in triplicate using digital calipers (Freeland Systems, Westfield, Indiana). Measurements were performed and interpreted by investigators who were blinded to subject information and study date. The brachial artery diameter was measured at end-diastole, using intima-media interfaces, or if they could not be visualized, media-adventitia interfaces, as landmarks. FMD was calculated as the ratio of the brachial artery diameter after reactive hyperemia to the baseline diameter, expressed as a percent change. Nitroglycerinmediated vasodilation was calculated in an analogous fashion. In this laboratory, intraobserver reliability for measurement of the brachial artery diameter is 0.987, reflecting an interclass correlation coefficient across all readings and conditions.10 Lipid and glucose levels were measured using enzymatic techniques on a Hitachi 747 analyzer (Tokyo, Japan) using standard reagents (Roche, Mannheim, Germany). Insulin levels were measured by radioimmunoassay. Low-density lipoprotein (LDL) particles were isolated from serum by sequential density ultracentrifugation between densities of 1.006 and 1.063 g/ml using a Beckman Optima ultracentrifuge (Fullerton, California) at 100,000 rpm (.400,000 g). The LDL-containing fraction was desalted with a 2-ml column of preswollen 12% cellulose and 0.1 mol/L From the University of Wisconsin Medical School, Madison, Wisconsin. This study was supported by an unrestricted grant from Welch’s Foods, Inc., Concord, Massachusetts. Dr. Stein’s address is: Section of Cardiovascular Medicine, University of Wisconsin Medical School, 600 Highland Avenue, H6/315 CSC (MC 3248), Madison, Wisconsin 53792. E-mail: jhs@medicine.wisc.edu. Manuscript received February 21, 2001; revised manuscript received and accepted April 10, 2001.

Implications of cardiac risk and low-density lipoprotein cholesterol distributions in the United States for the diagnosis and treatment of dyslipidemia: data from National Health and Nutrition Examination Survey 1999 to 2002.

Background— Updated guidelines from the National Cholesterol Education Program Adult Treatment Panel III stratify patients into 5 groups of coronary heart disease (CHD) risk that determine intensity of lipid-lowering therapy. The present study assesses the distribution of low-density lipoprotein cholesterol (LDL-C) in the United States across the 5 groups of CHD risk as defined in the updated guidelines. Methods and Results— Subjects included 7399 individuals 20 to 79 years of age in the 1999 to 2002 National Health and Nutrition Examination Survey representing 171 million individuals in the United States. CHD risk, LDL-C levels, and goal achievement were determined per Adult Treatment Panel III guidelines. CHD risk assessment incorporated a medical condition review, risk factor summation, and Framingham Risk Score calculation. Percentages were weighted to represent population estimates, and SEs were adjusted for the survey design. The distribution of individuals by CHD risk included 61.1% at lower risk, 10.6% at high risk, and 5.7% at very high risk. From Adult Treatment Panel III criteria, only 5.4% of the population was at “intermediate” risk. Two thirds (66.3%) met their Adult Treatment Panel III–defined LDL-C goal. Of those at high and very high risk, 23% and 26%, respectively, met the goal of LDL-C <100 mg/dL, whereas only 3.1% and 4.6% had an LDL-C <70 mg/dL (or non–high-density lipoprotein C <100 mg/dL). Conclusions— Most adult US residents are at lower 10-year CHD risk and meet risk-adjusted LDL-C goals. However, large portions of the high-risk population are undertreated. The commonly described population at intermediate risk is small. A novel method of identifying patients who might benefit from additional testing to determine their treatment strategy is provided.

Treatment with sildenafil and treprostinil allows successful liver transplantation of patients with moderate to severe portopulmonary hypertension

Portopulmonary hypertension (PoPH) refers to pulmonary arterial hypertension associated with portal hypertension with or without evidence of an underlying liver disease. Despite the potential for curing PoPH with liver transplantation, the presence of moderate or severe PoPH is associated with increased morbidity and mortality and is, therefore, a contraindication to transplantation. Previous studies have predominantly used intravenous epoprostenol for treatment in order to qualify patients for liver transplantation. In this retrospective case series, we describe the clinical course of 11 patients whom we successfully treated (predominantly with oral sildenafil and subcutaneous treprostinil) in order to qualify them for liver transplantation. The mean pulmonary artery pressure significantly improved from 44 to 32.9 mm Hg, and the pulmonary vascular resistance decreased from 431 to 173 dyn second cm−5. There were significant improvements in the cardiac output and the transpulmonary gradient with these therapies as well. All 11 patients subsequently received liver transplants with a 0% mortality rate to date; the duration of follow‐up ranged from 7 to 60 months. After transplantation, 7 of the 11 patients (64%) were off all pulmonary vasodilators, and only 2 patients required transiently increased doses of prostacyclins. In conclusion, an aggressive approach to the treatment of PoPH with sildenafil and/or treprostinil and subsequent liver transplantation may be curative for PoPH in some patients. Liver Transpl 18:686–695, 2012.

Trends in low-density lipoprotein cholesterol goal achievement in high risk United States adults: longitudinal findings from the 1999-2008 National Health and Nutrition Examination Surveys.

Background Previous studies have demonstrated gaps in achievement of low-density lipoprotein-cholesterol (LDL-C) goals among U.S. individuals at high cardiovascular disease risk; however, recent studies in selected populations indicate improvements. Objective We sought to define the longitudinal trends in achieving LDL-C goals among high-risk United States adults from 1999–2008. Methods We analyzed five sequential population-based cross-sectional National Health and Nutrition Examination Surveys 1999–2008, which included 18,656 participants aged 20–79 years. We calculated rates of LDL-C goal achievement and treatment in the high-risk population. Results The prevalence of high-risk individuals increased from 13% to 15.5% (p = 0.046). Achievement of LDL-C <100 mg/dL increased from 24% to 50.4% (p<0.0001) in the high-risk population with similar findings in subgroups with (27% to 64.8% p<0.0001) and without (21.8% to 43.7%, p<0.0001) coronary heart disease (CHD). Achievement of LDL-C <70 mg/dL improved from 2.4% to 17% (p<0.0001) in high-risk individuals and subgroups with (3.4% to 21.4%, p<0.0001) and without (1.7% to 14.9%, p<0.0001) CHD. The proportion with LDL-C ≥130 mg/dL and not on lipid medications decreased from 29.4% to 18% (p = 0.0002), with similar findings among CHD (25% to 11.9% p = 0.0013) and non-CHD (35.8% to 20.8% p<0.0001) subgroups. Conclusion The proportions of the U.S. high-risk population achieving LDL-C <100 mg/dL and <70 mg/dL increased over the last decade. With 65% of the CHD subpopulation achieving an LDL-C <100 mg/dL in the most recent survey, U.S. LDL-C goal achievement exceeds previous reports and approximates rates achieved in highly selected patient cohorts.

National improvements in low-density lipoprotein cholesterol management of individuals at high coronary risk: National Health and Nutrition Examination Survey, 1999 to 2002

BACKGROUND This study sought to evaluate national levels of elevated low-density lipoprotein cholesterol (LDL-C) before and after publication of the Adult Treatment Panel III (ATP III). The ATP III guidelines intensified LDL-C targets and defined additional high-risk conditions. These recommendations are expected to have a noticeable impact on US cholesterol levels. METHODS Coronary heart disease (CHD) risk was determined per ATP III guidelines for US residents aged 20 to 79 years in the 1999 to 2000 and 2001 to 2002 surveys. For those at high risk, the LDL-C mean percentage <100 mg/dL and percentage > or =130 mg/dL, although not taking lipid-lowering therapy, were compared between the 2 surveys. In addition, subsets with and without CHD were evaluated. RESULTS Of all high-risk US residents, the mean LDL-C dropped from 129 mg/dL in 1999 to 2000 to 120 mg/dL in 2001 to 2002 (P = .003). Those <100 mg/dL increased from 23% to 32% (P = .003). Those > or =130 mg/dL and not on medication dropped from 36% to 27% (P = .001). Goal achievement and improvements were more favorable in the subset with CHD compared with those at high risk due to high-risk equivalent conditions. CONCLUSIONS The sharp increase in high-risk US residents at the goal and the drop in the untreated percentage of those above treatment threshold illustrate national improvements in the management of LDL-C for those at high coronary risk. High-risk subjects without CHD displayed less significant improvements, suggesting an opportunity for better recognition and management of these individuals.

A Case Series of Real-Time Hemodynamic Assessment of High Output Heart Failure as a Complication of Arteriovenous Access in Dialysis Patients

Congestive heart failure (CHF) is an important source of morbidity and mortality in end‐stage renal disease patients. Although CHF is commonly associated with low cardiac output (CO), it may also occur in high CO states. Multiple conditions are associated with increased CO including congenital or acquired arteriovenous fistulae or arteriovenous grafts. Increased CO resulting from permanent AV access in dialysis patients has been shown to induce structural and functional cardiac changes, including the development of eccentric left ventricle hypertrophy. Often, the diagnosis of high output heart failure requires invasive right heart monitoring in the acute care setting such as a medical or cardiac intensive care unit. The diagnosis of an arteriovenous access causing high output heart failure is usually confirmed after the access is ligated surgically. We present for the first time, a case for real‐time hemodynamic assessment of high output heart failure due to AV access by interventional nephrology in the cardiac catheterization suite.

Intracranial arterial four-dimensional flow is associated with metrics of brain health and Alzheimer's disease

Although cerebrovascular disease has long been known to co‐occur with Alzheimers disease (AD), recent studies suggest an etiologic contribution to AD pathogenesis. We used four dimensional (4D)‐flow magnetic resonance imaging (MRI) to evaluate blood flow and pulsatility indices in the circle of Willis. We hypothesized decreased mean blood flow and increased pulsatility, metrics indicative of poor vascular health, would be associated with cerebral atrophy and an AD cerebrospinal fluid (CSF) profile.

Successful Computed Tomography Angiogram Through Tibial Intraosseous Access: A Case Report

BACKGROUND Intraosseous access has been used increasingly with proven efficacy in emergent situations for adults when intravenous access could not be obtained. OBJECTIVE Our aim was to demonstrate if tibial intraosseous (IO) is an effective route for iodinated contrast administration and pulmonary vasculature visualization. CASE REPORT We report on an obtunded patient requiring a computed tomography angiogram to help with diagnosis and tibial IO was the only viable access appropriate to withstand the pressure of a computed tomography iodinated contrast load. Tibial IO access was used successfully for administration of iodinated contrast to evaluate for massive pulmonary embolism in an obtunded patient in extremis secondary to cardiovascular instability. CONCLUSIONS The pulmonary arteries were opacified and demonstrated a high-quality CT angiogram can be done via tibial IO device.

Women up, men down: the clinical impact of replacing the Framingham Risk Score with the Reynolds Risk Score in the United States population.

Background The Reynolds Risk Score (RRS) is one alternative to the Framingham Risk Score (FRS) for cardiovascular risk assessment. The Adult Treatment Panel III (ATP III) integrated the FRS a decade ago, but with the anticipated release of ATP IV, it remains uncertain how and which risk models will be integrated into the recommendations. We sought to define the effects in the United States population of a transition from the FRS to the RRS for cardiovascular risk assessment. Methods Using the National Health and Nutrition Examination Surveys, we assessed FRS and RRS in 2,502 subjects representing approximately 53.6 Million (M) men (ages 50–79) and women (ages 45–79), without cardiovascular disease or diabetes. We calculated the proportion reclassified by RRS and the subset whose LDL-C goal achievement changed. Results Compared to FRS, the RRS assigns a higher risk category to 13.9% of women and 9.1% of men while assigning a lower risk to 35.7% of men and 2% of women. Overall, 4.7% of women and 1.1% of men fail to meet newly intensified LDL-C goals using the RRS. Conversely, 10.5% of men and 0.6% of women now meet LDL-C goal using RRS when they had not by FRS. Conclusion In the U.S. population the RRS assigns a new risk category for one in six women and four of nine men. In general, women increase while men decrease risk. In conclusion, adopting the RRS for the 53.6 million eligible U.S. adults would result in intensification of clinical management in 1.6 M additional women and 2.10 M fewer men.