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Purpose: Previous research identified decreased overall and cardiovascular mortality for National Football League (NFL) players from the 1959-1988 era. The present study explored the mortality risk among recent NFL players who played in an era of heavier linemen and nearly year-round physical conditioning., Methods: This cohort study included 9778 former NFL players with at least 1 yr in the NFL whose last season was between 1986 and 2012. Players' pension fund records were matched to the National Death Index to determine vital status, date of death, and cause of death. Standardized mortality ratios (SMR) compared player mortality through 2014 with US men of the same age, race, and calendar year. Cox proportional hazards models assessed the effect of player characteristics on overall and cardiovascular mortality., Results: Two percent (n = 227) of players were deceased, with a median age at death of 38 yr (range, 23-61 yr). The most common major causes of death were diseases of the heart (n = 47; 21%), violence (n = 39; 17%), and transportation injuries (n = 34; 15%). Risk of death was significantly lower than the general population for overall mortality (SMR, 0.46, 95% confidence interval (CI), 0.40-0.52), cardiovascular disease (SMR, 0.65; 95% CI, 0.50-0.84), and other major causes. Players with playing-time body mass index (BMI) of >35 kg·m had significantly higher cardiovascular disease mortality (SMR, 2.20; 95% CI, 1.32-3.44) than did the general population and higher overall mortality risk (standardized rate ratio, 3.84; 95% CI, 2.66-5.54) than did players with a BMI of <30 kg·m., Conclusions: Consistent with an earlier NFL cohort and other elite athlete populations, the overall and cardiovascular mortality risk of this NFL cohort was significantly lower than that of the general US male population, likely attributable to a healthy worker effect and less smoking.However, players with the highest playing-time BMI exhibited elevated cardiovascular mortality risk.

Purpose: Limited data from former National Football League (NFL) players suggest that obstructive sleep apnea (OSA) may be highly prevalent after retirement. It remains unclear whether the high prevalence of OSA in retired players is comparable to nonathletes. This retrospective analysis compared sleep apnea (SA) risk in retired NFL players to a community cohort (CARDIA Sleep study), and examined associations between SA risk and cardiovascular risk factors, including subclinical atherosclerosis., Materials and Methods: Retired NFL players (n=122) were matched to CARDIA Sleep participants by age ±2 years (range 37-55 years), body mass index ±2 kg/m 2 , race, and male sex. Participants underwent electron-beam computed tomography to measure coronary artery calcium (CAC) and completed the Berlin Questionnaire to determine SA risk. The presence of CAC was defined as an Agatston score >0., Results: Retired NFL players had a greater prevalence of high SA risk than the matched CARDIA Sleep participants (27% vs 11.5%, P =0.002). Compared to the CARDIA Sleep participants, retired players were less likely to smoke, and had higher blood pressure, lower fasting glucose levels, and higher cholesterol levels. However, there was no difference in the prevalence of detectable CAC (30% vs 30%, P =1). In both players and the community cohort, SA risk was not significantly associated with CAC after controlling for age, race, and body mass index., Conclusion: Retired NFL players have a greater prevalence of high SA risk but similar prevalence of CAC compared with a well-matched community cohort., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Previous findings suggest that professional American football players have higher blood pressures (BP) and a higher prevalence of pre-hypertension and hypertension than the general population. We sought to determine whether race is associated with differences in BP and prevalence of pre-hypertension and hypertension among a large sample of professional football players. BP was measured at 2009 team mini-camps for 1484 black (n = 1007) and white (n = 477) players from 27 National Football League (NFL) teams. Players were categorized into three position groups based on body mass index (BMI). There was no racial difference in mean systolic or diastolic BP in any of the three position groups. There were no racial differences in prevalence of hypertension (99 [9.8%] black players vs. 39 [8.2%] white players; P = .353) or pre-hypertension (557 [55.3%] black players vs. 264 [55.3%] white players; P = 1.0). Contrary to findings in the general population, BP and prevalence of pre-hypertension/hypertension did not vary with race in a large population of active NFL players., (Copyright © 2015 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Retired National Football League (NFL) linemen have an increased prevalence of risk factors for atherosclerosis and have an increased risk of cardiovascular death compared with nonlinemen and the general population. We evaluated whether playing in lineman position is independently associated with an increased risk of the presence and severity of subclinical atherosclerosis. Players were categorized as linemen if they reported playing on the offensive or defensive line during their careers. Subclinical atherosclerosis was assessed using coronary artery calcium (CAC) scores in 931 retired NFL players (310 linemen, 621 nonlinemen). CAC scores were evaluated for absence of subclinical atherosclerosis (CAC = 0), presence of mild subclinical atherosclerosis (CAC 1 to 100), and moderate to severe subclinical atherosclerosis (CAC ≥100). We performed multivariate logistic regression to determine whether the lineman position is independently associated with the presence and severity of subclinical atherosclerosis. Linemen were noted to have a lesser likelihood of absence of subclinical atherosclerosis (CAC = 0, 33.8% vs 41.7%, p = 0.02), a similar likelihood of mild subclinical atherosclerosis (CAC 1 to 100, 33.2% vs 31.8%, p = 0.7), and a greater likelihood of moderate to severe subclinical atherosclerosis (CAC >100, 32.9% vs 26.4%, p = 0.04) compared with nonlinemen. Adjusting for demographic and metabolic covariates, lineman status remained independently associated with mild subclinical atherosclerosis (CAC 1 to 100, odds ratio [OR] 1.41, 95% confidence interval [CI] 1.05 to 2.2, p = 0.04) and moderate to severe subclinical atherosclerosis (CAC ≥100, OR 1.67, 95% CI 1.05 to 2.2). The association was attenuated after adjustment for race (CAC 1 to 100, OR 1.24, 95% CI 0.82 to 1.8; CAC >100, OR 1.59, 95% CI 1.01 to 2.49). In conclusion, lineman status in retired NFL players is associated with presence and severity of subclinical atherosclerosis, which is partly explained by race., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: It is unknown which measure of adiposity (body mass index [BMI] or waist circumference [WC]) is associated with subclinical atherosclerosis in retired National Football League (NFL) players and whether this relation is attenuated after adjusting for components of the metabolic syndrome (elevated triglycerides, fasting glucose, and low levels of high-density lipoprotein-cholesterol [HDL-C]) that frequently coexist with obesity., Methods: Coronary artery calcium (CAC) was measured in 926 retired NFL players. BMI was calculated as weight (in kilograms)/height (in meters)(2) and WC was measured in inches. Logistic regression analyses adjusting for age, race, systolic blood pressure, high sensitivity C-reactive protein, triglycerides, HDL-C, and fasting blood glucose were performed to evaluate whether BMI or WC was independently associated with the presence of CAC (CAC score >0)., Results: The median age, BMI and WC were 54 years, 31 kg/m(2), and 40 inches, respectively. CAC was present in 61% (n = 562) of retired players. Adjusting for age, race, systolic blood pressure, high sensitivity C-reactive protein, triglycerides, HDL-C, and fasting blood glucose, each standard deviation increase in BMI (4.85 kg/m(2)) was significantly associated with CAC (odds ratio [OR] 1.25, 95% confidence interval [CI] 1.03-1.50), but each standard deviation increase in WC (10.53 inches) was not significantly associated with CAC (OR 1.18, 95% CI 0.96-1.45). There was a significant association for the presence of CAC for highest versus lowest quartiles of both BMI (OR 1.93, 95% CI 1.13-3.28) and WC (OR 1.75, 95% CI 1.05-2.92), although the trend for the presence of CAC was significant only across increasing BMI quartiles, even in models that included WC., Conclusions: In retired NFL players both BMI and WC were associated with CAC. Higher BMI may be associated with an increasing trend for the presence of CAC independent of WC.

Despite the efficacy of statin therapy, patients treated with these agents face substantial residual risk that is associated with achieved levels of LDL cholesterol (LDL-C). These observations suggest a potential benefit of additional strategies to promote further LDL-C reduction. Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as an attractive target in this regard. Abrogation of PCSK9 function prevents PCSK9-mediated catabolism of LDL receptors, increases cell surface LDL receptor density, and promotes clearance of LDL and other atherogenic lipoproteins from the circulation. Thus far, the most advanced approaches to block PCSK9 action are monoclonal antibodies and anti-sense oligonucleotides. Among statin-treated patients, these agents may produce additional LDL-C lowering exceeding 50 %. In rare genetic experiments of nature, individuals with dominant negative or dual loss of function mutations of PCSK9 appear to have no adverse health effects resulting from lifelong, very low levels of LDL-C. In short-term trials, PCSK9 antibodies have been generally well-tolerated. However, evidence to support long-term safety and efficacy of PCSK9 therapy to reduce cardiovascular risk awaits the results of large cardiovascular outcome trials.

A daily routine of physical activity is highly beneficial in the prevention and treatment of many prevalent chronic diseases, especially of the cardiovascular (CV) system. However, chronic, excessive sustained endurance exercise may cause adverse structural remodeling of the heart and large arteries. An evolving body of data indicates that chronically training for and participating in extreme endurance competitions such as marathons, ultra-marathons, Iron-man distance triathlons, very long distance bicycle racing, etc., can cause transient acute volume overload of the atria and right ventricle, with transient reductions in right ventricular ejection fraction and elevations of cardiac biomarkers, all of which generally return to normal within seven to ten days. In veteran extreme endurance athletes, this recurrent myocardial injury and repair may eventually result in patchy myocardial fibrosis, particularly in the atria, interventricular septum and right ventricle, potentially creating a substrate for atrial and ventricular arrhythmias. Furthermore, chronic, excessive, sustained, high-intensity endurance exercise may be associated with diastolic dysfunction, large-artery wall stiffening and coronary artery calcification. Not all veteran extreme endurance athletes develop pathological remodeling, and indeed lifelong exercisers generally have low mortality rates and excellent functional capacity. The aim of this review is to discuss the emerging understanding of the cardiac pathophysiology of extreme endurance exercise, and make suggestions about healthier fitness patterns for promoting optimal CV health and longevity.

Objectives: We assessed whether low-density lipoprotein particle concentration (LDL-P) and high-sensitivity C-reactive protein [hs-CRP] can identify subclinical atherosclerosis better than traditional cholesterol parameters in retired National Football League (NFL) players., Background: It is not known whether LDL-P and the biomarker hs-CRP can identify subclinical atherosclerosis better than low-density lipoprotein cholesterol (LDL-C) or non-high-density-lipoprotein cholesterol (non-HDL-C) in retired NFL players, given high prevalence of metabolic syndrome in these players., Methods: Carotid artery plaque screening was performed with traditional lipids, LDL-P, and hs-CRP in 996 retired players. Logistic regression analyses comparing highest with the lowest quartile were performed., Results: Carotid artery plaques were seen in 41%. LDL-C (odds ratio [OR] 1.66, 95% confidence interval [CI] 1.06-2.59), non-HDL-C (OR 1.67, 95% CI 1.04-2.67), and LDL-P (OR 2.21, 95% CI 1.35-3.62) were associated with plaques in adjusted models. Among 187 retired players with metabolic syndrome, LDL-C (OR 1.40, 95% CI 0.53-3.72) was not associated with carotid plaques, whereas LDL-P (OR 3.71, 95% CI 1.16-11.84) and non-HDL-C (OR 2.63, 95% CI 0.91-7.63, p=0.07; borderline significant) were associated with carotid plaques. hs-CRP (OR 1.13, 95% CI 0.71-1.79) was not associated with carotid plaques., Conclusion: Carotid artery plaques were common in retired NFL players and were strongly associated with LDL-P, especially among those with metabolic syndrome. hs-CRP was not associated with carotid plaques in this cohort., (Published by Elsevier Ireland Ltd.)

A routine of regular exercise is highly effective for prevention and treatment of many common chronic diseases and improves cardiovascular (CV) health and longevity. However, long-term excessive endurance exercise may induce pathologic structural remodeling of the heart and large arteries. Emerging data suggest that chronic training for and competing in extreme endurance events such as marathons, ultramarathons, ironman distance triathlons, and very long distance bicycle races, can cause transient acute volume overload of the atria and right ventricle, with transient reductions in right ventricular ejection fraction and elevations of cardiac biomarkers, all of which return to normal within 1 week. Over months to years of repetitive injury, this process, in some individuals, may lead to patchy myocardial fibrosis, particularly in the atria, interventricular septum, and right ventricle, creating a substrate for atrial and ventricular arrhythmias. Additionally, long-term excessive sustained exercise may be associated with coronary artery calcification, diastolic dysfunction, and large-artery wall stiffening. However, this concept is still hypothetical and there is some inconsistency in the reported findings. Furthermore, lifelong vigorous exercisers generally have low mortality rates and excellent functional capacity. Notwithstanding, the hypothesis that long-term excessive endurance exercise may induce adverse CV remodeling warrants further investigation to identify at-risk individuals and formulate physical fitness regimens for conferring optimal CV health and longevity., (Copyright © 2012 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

The US Air Force Patient-Centered Precision Care Genomic Medicine Research Program hosted a symposium entitled 'Changing the Health Care Paradigm' on 27 September 2011 in Laurel, MD, USA. The program provided a unique opportunity for subject matter experts to participate in critical discussions on the current and potential outlook for the implementation of genome-informed healthcare. The implications for patient privacy, data management and security revealed the ethical, legal and social issues faced by clinicians, patients and policy-makers. Highlights from these discussions are summarized in this article.

Circulating levels of inflammatory markers predict the risk of cardiovascular disease (CVD), mediated perhaps in part by dietary fat intake, through mechanisms only partially understood. To evaluate post-fat load changes in inflammatory markers and genetic influences on these changes, we administered a standardized high-fat meal to 838 related Amish subjects as part of the Heredity and Phenotype Intervention (HAPI) Heart Study and measured a panel of inflammatory markers, including C-reactive protein (CRP), interleukin-1beta (IL-1beta), matrix metalloproteinase-1 and -9 (MMP-1 and MMP-9), and white blood cell (WBC) count, before and 4 h after fat challenge (CRP prechallenge only). Heritabilities (h(2) +/- s.d.) of basal inflammatory levels ranged from 16 +/- 8% for MMP-9 (P = 0.02) to 90 +/- 7% for MMP-1 (P < 0.0001). Post-fat load, circulating levels of WBC, MMP-1, and MMP-9 increased by 16, 32, and 43% (all P < 0.0001), with no significant changes in IL-1beta. Postprandial changes over the 4-h period were modestly heritable for WBC (age- and sex-adjusted h(2) = 14 +/- 9%, P = 0.04), but the larger MMP-1 and MMP-9 changes appeared to be independent of additive genetic effects. These results reveal that a high-fat meal induces a considerable inflammatory response. Genetic factors appear to play a significant role influencing basal inflammatory levels but to have minimal influence on post-fat intake inflammatory changes.

Study Objectives: Prior studies have suggested that the prevalence of sleep disordered breathing (SDB) among players in the National Football League (NFL) is disproportionately high. SDB can increase cardiovascular disease risk and is correlated with hypertension. NFL players have a higher prevalence of hypertension, and we sought to determine the prevalence of SDB among players the NFL and the associations of SDB with anthropometric measures and cardiovascular risk factors., Design: Cross-sectional cohort study., Setting: NFL athletic training facilities from April to July 2007., Participants: A total of 137 active veteran players from 6 NFL teams., Measurements: This evaluation of SDB among players in the NFL used a single-channel, home-based, unattended, portable, sleep apnea monitor. Multiple domains of self-reported sleep were assessed. Weight, body mass index, body fat percentage, neck circumference, waist circumference, and waist-to-hip ratio, as well as blood pressure, cholesterol, and fasting glucose concentrations were measured., Results: The mean respiratory disturbance index was 4.7 (+/- 12), with a median (interquartile range) of 2 (1,4). The prevalence of at least mild SDB (RDI > or = 5) was 19% (95% confidence interval, 12.8%-26.6%). Only 4.4% (95% confidence interval, 1.6%-9.2%) of participants had respiratory disturbance index of 15 or greater. Linemen and non-linemen were not different in their prevalence or severity of SDB. No single anthropometric measure was highly associated with SDB, and SDB was not well correlated with cardiovascular risk factors., Conclusions: The prevalence of SDB in active NFL players was modest, predominately mild, and positively associated with several measures of adiposity. SDB did not account for excess cardiovascular risk factors.

Objective: To evaluate the extent to which music may affect endothelial function. In previous research, a link between music and physiologic parameters such as heart rate and blood pressure has been observed., Methods: Randomized four-phase crossover and counterbalanced trial in ten healthy, nonsmoking volunteers (70% male; mean age, 35.6 years) that included self-selections of music evoking joy or provoking anxiety. Two additional phases included watching video clips to induce laughter and listening to audio tapes to promote relaxation. To minimize emotional desensitization, subjects were asked to refrain from using self-selected tapes and images for at least 2 weeks before the assigned study phase. Endothelial function was assessed by brachial artery flow-mediated dilation (FMD) and measured as percent diameter change after an overnight fast. After baseline FMD measurements, subjects were randomized to a 30-minute phase of the testing stimulus followed by poststudy FMD; they returned a minimum of 1 week later for the subsequent task. A total of 160 FMD measurements were obtained., Results: Compared with baseline, music that evoked joy was associated with increases in mean upper arm FMD (2.7% absolute increase; p < .001), whereas reductions in FMD were observed after listening to music that elicited anxiety (0.6% absolute decrease; p = .005 difference between joyful and anxiety-provoking music). Self-selected joyful music was associated with increased FMD to a magnitude previously observed with aerobic activity or statin therapy., Conclusion: Listening to joyful music may be an adjunctive life-style intervention for the promotion of vascular health.

Aims: We characterized the size of active National Football League (NFL) players by multiple criteria and analyzed their relation to traditional cardiovascular disease (CVD) risk factors with the objective of further clarifying the occurrence of cardiovascular risk factors in different player positions., Methods: This cross-sectional study was conducted in professional athletic training facilities. The participants were 504 active veteran players from a convenience sample of 12 NFL teams, grouped as interior linemen (IL) or all others (AO). Comparisons were made between the NFL groups and an age-equivalent general population database., Results: The IL group was significantly larger than AO by all size measures. Both groups were significantly larger than the Coronary Artery Risk Development in Young Adults (CARDIA) group. Mean percent body fat measurements in AO (mean, 13.4%; 95% confidence interval [CI], 12.9%-14%) and IL (mean, 25.2%; 95% CI, 24.4%-26%) groups were lower than estimates for the general population. Systolic blood pressure (BP) was higher in IL (mean, 131 mm Hg; 95% CI, 129-133 mm Hg) than AO (mean, 126 mm Hg; 95% CI, 125-127 mm Hg) and greater in both groups compared with the CARDIA group (mean, 112 mm Hg; 95% CI, 111-112 mm Hg). Mean low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (HDL-C), total cholesterol, triglycerides, and glucose were within the normal range for both IL and AO. Interior linemen had significantly lower HDL-C than AO and the CARDIA group. Both NFL groups had significantly lower fasting glucose than CARDIA., Conclusion: Body fat in active NFL players was lower than predicted by standard measures of obesity. Although the players were large, they were in the normal range for most CVD risk factors. Mean BP in the prehypertensive range was found in both NFL position groups, but was significantly higher in IL than in AO. Prehypertension in these athletes warrants vigilance.

Context: Concern exists about the cardiovascular health implications of large size among professional football players and those players who aspire to professional status., Objectives: To assess cardiovascular disease (CVD) risk factors in active National Football League (NFL) players and to compare these findings with data from the Coronary Artery Risk Development in Young Adults (CARDIA) study., Design, Setting, and Participants: A cross-sectional study of 504 active, veteran football players from a convenience sample of 12 NFL teams at professional athletic training facilities between April and July 2007. Data were compared with men of the same age in the general US population (CARDIA study, a population-based observational study of 1959 participants aged 23 to 35 years recruited in 1985-1986)., Main Outcome Measures: Prevalence of CVD risk factors (hypertension, dyslipidemia, glucose intolerance, and smoking)., Results: The NFL players were less likely to smoke when compared with the CARDIA group (0.1% [n = 1]; 95% confidence interval [CI], 0%-1.4%; vs 30.5% [n = 597]; 95% CI, 28.5%-32.5%; P < .001). Despite being taller and heavier, NFL players had significantly lower prevalence of impaired fasting glucose (6.7% [n = 24]; 95% CI, 4.6%-8.7%; vs 15.5% [n = 267]; 95% CI, 13.8%-17.3%; P < .001). The groups did not differ in prevalence of high total cholesterol and low-density lipoprotein cholesterol (LDL-C), low high-density lipoprotein cholesterol (HDL-C), or high triglycerides. Hypertension (13.8% [n = 67]; 95% CI, 11.0%-16.7%; vs 5.5% [n = 108]; 95% CI, 4.6%-6.6%) and prehypertension (64.5% [n = 310]; 95% CI, 58.3%-70.7%; vs 24.2% [n = 473]; 95% CI, 22.3%-26.1%) were significantly more common in NFL players than in the CARDIA group (both P < .001). Large size measured by body mass index (BMI) was associated with increased blood pressure, LDL-C, triglycerides, and fasting glucose, and decreased HDL-C., Conclusions: Compared with a sample of healthy young-adult men, a sample of substantially larger NFL players had a lower prevalence of impaired fasting glucose, less reported smoking, a similar prevalence of dyslipidemia, and a higher prevalence of hypertension. Increased size measured by BMI was associated with increased CVD risk factors in this combined population.

Although popular diets focus on weight loss and their favorable biochemical and physiological effects, fewer investigations have evaluated the biological impact of these diets during weight maintenance. To study this issue, three popular diets-Atkins, South Beach, and Ornish-were tested in a randomized and counterbalanced crossover study between January and December 2006. Participants completed each of the three 4-week isocaloric dietary intervention phases followed by a 4-week washout period. They were weighed weekly and caloric adjustments made if weight change exceeded 1 kg. At the completion of each dietary phase, 3-day food records were analyzed, fasting blood sampled, and brachial artery reactivity testing performed. Eighteen adults completed all three isocaloric dietary phases. During the South Beach and Ornish maintenance phase, there were significant reductions in low-density lipoprotein cholesterol (11.8%; P=0.01, 16.6%; P=0.0006, respectively) compared to prediet baseline. In addition, in contrast to the Atkins maintenance phase, significant reductions in low-density lipoprotein cholesterol and apolipoprotein B levels were observed after the South Beach (P=0.003, P=0.05; repeated measures analyses of variance) and Ornish maintenance phases (P=0.0004, P=0.006, repeated measures analyses of variance). Brachial artery testing revealed an inverse correlation between flow-mediated vasodilatation and intake of saturated fat (r=-0.33; P=0.016). These data suggest that during weight maintenance, less favorable biological effects are observed during a simulated, high-fat Atkins diet when compared to the South Beach and Ornish diet. The findings support additional study in subjects with visceral obesity and the metabolic syndrome, in whom an increased risk of coronary disease at baseline may be accentuated with chronic consumption of a diet that exhibits unfavorable effects on lipids and endothelial function.

Objective: Recent clinical trials and observational studies have suggested that reduction in low-density lipoprotein cholesterol (LDL-C) does not account for all differences among statins' effects on cardiovascular (CV) events, but that these effects may vary with time. Using a large US managed-care claims data set for 2002-2005, we assessed whether a difference in the rate of inpatient CV event rates could be observed between new atorvastatin and simvastatin users taking doses with comparable LDL-C-lowering potency, when prior risk factors are controlled and varying observation periods are employed., Research Design and Methods: Eligible patients had a 6-month period of no statin use prior to the initial statin prescription, an initial statin dosage of either 20 or 40 mg of simvastatin or 10 or 20 mg of atorvastatin (the most commonly used doses of both drugs), a 0 to 3-month 'qualifying period' after the first prescription to allow for varying minimum lengths of statin use, and no statin switches. In the primary analysis, patients were observed until an event or significant non-adherence occurred, up to 3.5 years; in secondary analyses, maximum 3-month, 6-month and 1-year observation periods were used. The primary endpoint was the first inpatient admission due to a CV event after the end of the qualifying period; multivariate Cox regression analysis controlled for a variety of demographic and CV risk characteristics and statin type., Results: At baseline, simvastatin users had significantly higher observed risk factors and higher subsequent, unadjusted CV event rates. In the primary Cox regression analyses, the CV event hazard rates for atorvastatin ranged from 0.899 (1-month qualifying period, p = 0.027) to 0.936 (3-month qualifying period, p = 0.33) versus simvastatin. Cox-based hazard rates for atorvastatin during 3-month to 1-year observation periods ranged from 0.908 to 0.915 for the 0-day qualifying period and from 0.851 to 0.884 for the 1-month qualifying period cohort (all p < 0.05); rates for the 3-month qualifying period cohort remained non-significant., Limitations: Since this was not a prospective randomized study, there is the potential for unobserved risk factors to be responsible for some or all of the differences observed., Conclusions: These results indicate an association between atorvastatin use and lower CV event rates, particularly in the first year of use, when observable risk factor differences are controlled. The implied absolute risk reduction of 2-3 events per 1000 patients per year may be considered clinically significant when viewed relative to major clinical trial results.

Endothelial dysfunction is an important factor in the pathogenesis of atherosclerosis, hypertension, and heart failure. The endothelium mediates vascular tone, structure, and function by the release and regulation of multiple vasoactive substances that promote or inhibit vasodilation, vasoconstriction, cell growth, and other mechanisms. The effect of antihypertensive drugs on endothelial function may be an important indicator of their ability to reduce risks for cardiovascular morbidity and mortality. Endothelium-dependent vasodilation induced by various antihypertensive drugs is accurately measured with high-resolution ultrasound of flow-mediated dilation of the brachial artery. Calcium channel blockers and angiotensin-converting enzyme inhibitors have been shown to reverse endothelial dysfunction. The benefits of angiotensin-converting enzyme inhibitors and calcium channel blockers on the endothelium are believed to derive from their effects on nitric oxide production and antioxidant effects, possibly independent of blood pressure reduction. Due to their complementary mechanisms of action, it has been hypothesized that the combination of an angiotensin-converting enzyme inhibitor and a calcium channel blocker will provide superior cardiovascular protection, in part by producing an additive effect of increased nitric oxide availability, when compared with either agent alone.

Evidence suggests that renin-angiotensin-aldosterone system inhibition ameliorates endothelial dysfunction. The authors examined the effect of amlodipine besylate/benazepril HCl combination treatment compared with amlodipine besylate monotherapy in modulating endothelial dysfunction. This multicenter, double-blind, 12-week study randomized 70 hypertensive subjects with at least one other endothelial dysfunction risk factor to amlodipine besylate/benazepril HCl (5/20 mg/d force-titrated to 5/40 mg/d) or amlodipine besylate monotherapy (5 mg/d force-titrated to 10 mg/d). Both the combination and monotherapy produced significant median increases from baseline in percentage flow-mediated vasodilation (2.0% and 1.2%, respectively) and percentage change in percent flow-mediated vasodilation (25% and 16%, respectively). These improvements were numerically larger with combination treatment, but between-group differences did not achieve statistical significance. Reductions in systolic and diastolic blood pressure were significantly greater (P=.0452/P=.0297) with combination treatment (-18.6/-12.3 mm Hg) than with monotherapy (-14.8/-9.1 mm Hg). A highly positive correlation between change in systolic blood pressure and change in percent of flow-mediated vasodilation was demonstrated only for combination treatment.

Context: Statin drugs reduce both atherogenic lipoproteins and cardiovascular morbidity and mortality. However, the optimal strategy and target level for lipid reduction remain uncertain., Objective: To compare the effect of regimens designed to produce intensive lipid lowering or moderate lipid lowering on coronary artery atheroma burden and progression., Design, Setting, and Patients: Double-blind, randomized active control multicenter trial (Reversal of Atherosclerosis with Aggressive Lipid Lowering [REVERSAL]) performed at 34 community and tertiary care centers in the United States comparing the effects of 2 different statins administered for 18 months. Intravascular ultrasound was used to measure progression of atherosclerosis. Between June 1999 and September 2001, 654 patients were randomized and received study drug; 502 had evaluable intravascular ultrasound examinations at baseline and after 18 months of treatment., Interventions: Patients were randomly assigned to receive a moderate lipid-lowering regimen consisting of 40 mg of pravastatin or an intensive lipid-lowering regimen consisting of 80 mg of atorvastatin., Main Outcome Measures: The primary efficacy parameter was the percentage change in atheroma volume (follow-up minus baseline)., Results: Baseline low-density lipoprotein cholesterol level (mean, 150.2 mg/dL [3.89 mmol/L] in both treatment groups) was reduced to 110 mg/dL (2.85 mmol/L) in the pravastatin group and to 79 mg/dL (2.05 mmol/L) in the atorvastatin group (P<.001). C-reactive protein decreased 5.2% with pravastatin and 36.4% with atorvastatin (P<.001). The primary end point (percentage change in atheroma volume) showed a significantly lower progression rate in the atorvastatin (intensive) group (P =.02). Similar differences between groups were observed for secondary efficacy parameters, including change in total atheroma volume (P =.02), change in percentage atheroma volume (P<.001), and change in atheroma volume in the most severely diseased 10-mm vessel subsegment (P<.01). For the primary end point, progression of coronary atherosclerosis occurred in the pravastatin group (2.7%; 95% confidence interval [CI], 0.2% to 4.7%; P =.001) compared with baseline. Progression did not occur in the atorvastatin group (-0.4%; CI -2.4% to 1.5%; P =.98) compared with baseline., Conclusions: For patients with coronary heart disease, intensive lipid-lowering treatment with atorvastatin reduced progression of coronary atherosclerosis compared with pravastatin. Compared with baseline values, patients treated with atorvastatin had no change in atheroma burden, whereas patients treated with pravastatin showed progression of coronary atherosclerosis. These differences may be related to the greater reduction in atherogenic lipoproteins and C- reactive protein in patients treated with atorvastatin.

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.

Among postmenopausal women, 38% use hormone replacement therapy (HRT)- the leading brand of conjugated equine estrogen is the second most prescribed drug in the United States. Although adverse effects of this therapy have been recognized, it was traditionally reasoned that HRT could be broadly recommended to postmenopausal women because coronary heart disease was their most significant health risk. Evolving vascular biologic understanding, however, suggests that HRT, in direct opposition to the existing observational study data, does not reduce coronary heart disease risk. During the summer of 2002, three important studies on HRT dramatically changed our view of this widespread treatment. These trials provide clear, new, guidelines for patients and physicians contemplating HRT therapy.

Observational data suggest that moderate alcohol consumption is associated with reduced all-cause mortality compared with that associated with either abstinence or heavy drinking. Alcohol consumption reduces cardiovascular disease risk primarily by increasing production of high-density lipoprotein cholesterol, and possibly by increasing plasminogen, tissue plasminogen activator, and endothelial function, and decreasing platelet aggregability, fibrinogen, and lipoprotein(a). Red wine, containing antioxidants, has been purported to be especially cardioprotective. However, red wine consumption is not associated with reduced all-cause mortality in European countries, and American studies have found no relationship between the type of alcohol consumed and cardiovascular risk. Alcohol appears to be more cardioprotective if consumed with meals (possibly owing to protection against postprandial endothelial protection) and in moderation daily (as opposed to binge drinking). Despite the wealth of observational data, it is not absolutely clear that alcohol reduces cardiovascular risk, because no randomized controlled trials have been performed. Alcohol should never be recommended to patients to reduce cardiovascular risk as a substitute for the well-proven alternatives of appropriate diet, exercise, and drugs. Alcohol remains the number three cause of preventable premature death in this country, and the risk of alcohol habituation, abuse, and adverse effects must be considered in any patient counseling.

Conventional cardiac risk factors do not fully explain the incidence of coronary artery disease and coronary events. Risk stratification and therapy based solely on these conventional risk factors may exclude a population who would otherwise benefit from lifestyle and risk factor modification. Recent efforts to improve our ability to recognize individuals and populations at increased risk of coronary events have focused on the noninvasive imaging of atherosclerosis, both in coronary and extracoronary arterial beds, or the identification of "non-traditional" serum markers. We review the complimentary role of these newer methods of risk stratification in the context of conventional risk factor evaluation.

In response to physical and chemical stimuli, the endothelium regulates vascular tone through the release of vasodilators, such as nitric oxide, and vasoconstrictors, such as endothelin. Increased blood flow is an important stimulus for endothelium-mediated vasodilation (flow-mediated vasodilation). Brachial artery flow-mediated vasodilation can be assessed using high-frequency ultrasound assessment of changes in brachial artery diameter after a 5-minute blood pressure cuff arterial occlusion. Endothelial dysfunction is demonstrated as reduced vasodilation, which is usually associated with the presence of coronary risk factors. Brachial artery flow-mediated vasodilation correlates with coronary artery flow-mediated vasodilation. Both indexes have been shown to predict long-term cardiovascular events. Whereas the clinical applicability of brachial artery flow-mediated vasodilation is unclear, it has become a frequently employed measure of endothelial function.