Further information: Endocrine Disorders and the Heart (see p2295) and Cardiovascular Complications of Obesity and the Metabolic Syndrome (see p2693) from Cardiovascular Medicine, 3rd Edn*

Although published in the two separate papers listed above, the effects of Valsartan and Nateglinide were studied in the same trial entitled, “Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR)” [1, 2]. The double-blind, randomized clinical trial with a two-by-two factorial design was conducted from January 2002 through January 2004, with recruitment occurring at 806 centers in 40 countries. Eligible patients had impaired glucose tolerance, a fasting plasma glucose level of at least 95 mg/dl, but less than 126 mg/dl, and one or more cardiovascular risk factors or known cardiovascular disease, and 9306 participants were enrolled. Patients were randomized to receive either nateglinide, up to 60 mg three times a day, or a matching placebo, and valsartan, up to 160 mg daily, or a matching placebo. In addition, patients were required to participate in a lifestyle program, and a goal was set to maintain a 5% weight loss, an increase in physical activity to an average of 30 min five days a week, and adherence to a low-fat diet. Valsartan, an angiotensin-receptor blocker (ARB), is used to treat high blood pressure, heart failure (HF), and long-term consequences of a heart attack. Valsartan was selected for this trial to evaluate the use of an ARB in the delay or prevention of diabetes and to determine the possibility of its helping the cardiovascular system. In the valsartan group, the cumulative incidence of diabetes was 33.1%, as compared with 36.8% in the placebo group (hazard ratio (HR) with valsartan, 0.86; 95% confidence interval [CI], 0.80–0.92; P<0.001). Compared with placebo, valsartan did not significantly reduce the incidence of either the extended CV outcome (14.5% vs. 14.8%; hazard ratio [HR], 0.96; 95% CI, 0.86–1.07; P=0.43) or the core CV outcome (8.1% vs. 8.1%; HR, 0.99; 95% CI, 0.86–1.14; P=0.85). Although nateglinide is in a class of drugs previously shown to lower post prandial glycemia, the hoped-for effect did not occur in NAVIGATOR, nor was the incidence of cardiovascular disease reduced. Nateglinide compared with placebo did not reduce cumulative incidence of diabetes (36% and 34% respectively; HR, 1.07; 95% CI, 1.00–1.15; P=0.05), the core composite CV outcome (7.9% and 8.3% respectively; HR, 0.94, 95% CI, 0.82–1.09; P=0.43), or the extended composite CV outcome (14.2% and 15.2%, respectively; HR, 0.93%, 95% CI, 0.83–1.03; P=0.16).

In an accompanying editorial [3], the author opined that effective lifestyle interventions should be used to combat the current diabetes epidemic, a critical public health concern, but for now, neither drug evaluated in the NAVIGATOR should be used.

[1] The NAVIGATOR study group.Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med 2010;362(16):1477-90

[2] The NAVIGATOR study group.Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med 2010;362(16):1463-76

[3] Navigating the choices for diabetes prevention. Nathan DM. N Engl J Med 2010;362:1533-35

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Further information: Coronary Risk Factors: An Overview (see p2609) and Management of Cholesterol Disorders (see p2667) from Cardiovascular Medicine, 3rd Edn*

In a presentation of results from a controversial late-breaking clinical trial at the November 2009 American Heart Association Scientific Sessions in Orlando, Florida, Dr. Allen Taylor reported that the ARBITER6-HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies) trial had been terminated early. The full results are summarized in the first paper [1]. The study, which enrolled 363 patients, involved using either ezetimibe or extended-release niacin. The patients had at a high risk for atherosclerotic vascular disease and were already receiving statin therapy. They also had a serum LDL cholesterol level (<100 mg/dL), as well as a low serum HDL level (mean, 42 mg/dL). The patients in this open-label randomized trial of two adjunctive medications were randomly assigned to receive either extended-release niacin (target dose was 2000 mg/day) or ezetimibe (10 mg/day). A surrogate marker for the progression of atherosclerosis (identified as a change in the common-carotid intima-media thickness) was the primary endpoint.

Because the trial was terminated early on the basis of efficacy, data from only 208 patients were available for analysis. However, on the basis of the small sample size and the with the use of a surrogate marker, both of which created controversy, the authors reported the following conclusions. In the niacin group, the mean HDL cholesterol level increased by 18.4%, and the mean LDL cholesterol and triglyceride level were significantly reduced. In the ezetimibe group, LDL cholesterol was reduced by 19.2%. A paradoxical finding regarding ezetimibe indicated that an association between reduction in the patient’s LDL level was accompanied by an increased carotid intima-media thickness. Based on these results the authors concluded that niacin therapy was superior to ezetimibe.

Two editorials were published with the article. Blumenthal and Michos [2] raised four major concerns regarding the trial and expressed the opinion that premature termination of the trial, a small number of patients, and limited follow-up precluded a statement of decisive conclusions. Kastelein and Bots [3] expressed that although the trial had several limitations, the results were likely to be correct. Both editorials pointed to additional studies currently underway that, when concluded, will produce results likely to aid in the evaluation of the use of niacin and statin therapies.

[1] Taylor AJ, Villines TC, Stanek EJ, et al. Extended release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med 2009;361:2113-22

[2] Blumenthal RS, Michos ED. The HALTS trial—halting atherosclerosis or halting too early? N Engl J Med 2009;361:2178-80

[3] Kastelein JJP, Bots ML. Statin therapy with ezetimibe or niacin in high-risk patients. N Engl J Med 2009;361:2180-83

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Further information: Coronary Risk Factors: An Overview (see p2609) from Cardiovascular Medicine, 3rd Edn*

The Clinical Guidelines section of the October 6, 2009 issue of Annals of Internal Medicine contained three articles reporting the recommendations of the United States Preventive Services Task Force (USPSTF) regarding the addition of non-traditional risk factors in determining patients’ risk for coronary heart disease (CHD). This review summarizes the paper reporting on the use of C-reactive protein (CRP) [1].

Forty percent of deaths in the US can be attributed to cardiovascular (CV) disease  and, although Framingham risk factors can be attributed to most of the excessive risk for coronary heart disease (CHD), an estimated 40% of CHD deaths occur in people who do not have high cholesterol or other elements of the Framingham risk score. With increasing awareness, chronic inflammation in CHD has been targeted as a major factor in CHD risk, and therefore, the role of inflammatory marker, CRP, has come under scrutiny. In particular, the current article addresses whether or not the routine measurement of CRP is a beneficial marker for risk of death from CHD.

From articles published between 1966 and November 2007, the authors of this study selected prospective, cohort, case-cohort, and nested case-cohort studies that pertained to the independent predictive ability of CRP used in intermediate-risk patients. The review was conducted to help the USPSTF determine whether a test for a patient’s CRP level should be incorporated into guidelines for CV risk assessment in primary care testing. Investigators concluded that although the study found evidence that CRP is associated with CHD, the evidence that proves reducing CRP prevents CHD is not conclusive.

[1] Buckley DL, Fu R, Freeman M, et al. C-reactive protein as a risk factor for coronary artery disease: a systematic review and meta-analyses for the U.S. preventive Services task force. Ann Intern Med 2009;151:483-95.

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Further information: Cardiovascular Complications of Obesity and the Metabolic Syndrome (see p2693) from Cardiovascular Medicine, 3rd Edn*

The goal of investigators in this study [1] was to determine the mechanisms by which leptin, an adipocyte-derived hormone that is increased in most forms of obesity, affects cardiovascular function. In addition to leptin’s communicating to the central nervous system in regard appetite and metabolism, its signaling pathways communicate to the sympathetic nervous system. Protein tyrosine phosphate 1B (PTP1B), as a regulator of this signaling pathway, constrains the metabolic activity of leptin. Pharmacological efforts are underway to develop PTP1B inhibitors for the treatment of metabolic disorders, but in the present study, the PTP1B knockout mice under observation had lower body fat, but higher mean arterial pressure from an increased sympathetic affect on blood pressure.

In an accompanying Editorial [2], Dr Mark comments on the recent identification of new pathways that regulate appetite and metabolism, pathways that also affect the regulation of sympathetic neural activity and arterial pressure. In relationship to the current study [1] that shows adverse sympathetic and arterial pressure responses to genetic deletion of the leptin and insulin inhibitor PTP1B in knockout mice, Dr. Mark explains that while leptin does act in the brain to decrease adiposity, its pleiotropic effect also influences arterial pressure regulation. Therefore, he noted that this complicated the safety of antiobesity drugs and emphasized the importance of evaluating the cardiovascular actions of these potentially emerging drugs.

[1] Belin de Chantemele EJ, Muta K, Mintz J, et al. Protein tyrosine phosphatase 1B, a major regulator of leptin-mediated control of cardiovascular function. Circulation 2009;120:753-63

[2] Mark AL. Cardiovascular side effects of antiobesity drugs. Circulation 2009;120:719-21

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* To view the online text from the book, please navigate to SpringerLink or use the DVD to access electronic content. SpringerLink is a subscription service. For further information, click here.

Further information: Coronary Risk Factors: An Overview (see p2609), Preventive Cardiology: The Effects of Exercise (see p2631), Smoking, Secondhand Smoke, and Cardiovascular Disease (see p2649), and  Cardiovascular Complications of Obesity and the Metabolic Syndrome (see p2693) from Cardiovascular Medicine, 3rd Edn*

The Physicians Health Study1 (PHS 1), conducted from 1982–2008, included a cohort of 20,900 apparently healthy male physicians. The current study [1] used data from the cohort to compare the relationship of modifiable lifestyle factors to the risk of heart failure (HF) for the period of lifetime remaining after 40 years of age. Lifestyle factors that were the focus of this study included adiposity, smoking, physical activity, alcohol consumption, and diet (i.e. consumption of cereals, fruits, and vegetables). Modification of these factors has been shown to reduce heart attacks and strokes, and it is estimated that by age 40, one in every five adults will develop HF. However, it is not clear if a healthy lifestyle could lead to a reduction in the possibility of HF in years of life that remained after 40. Results of the study showed that at 40 years of age, an overall lifetime risk of HF was 13.8% (95% confidence interval [CI], 12.9–14.7%) and remained constant through 70 years of age. Then, between 70 and 80 years of age, the lifetime risk was 10.6% (95% CI, 9.4–11.7%).

The results of the study showed that the lifetime risk of HF was 21% in men who adhere to none of the six desirable factors versus 10% in those men who followed a healthy lifestyle in four or more of the desirable factors, and the greater reduction in risk occurred after age 70.

An editorial [2] was also published that addresses the issues of increased health care expenses and the increased need for individuals and society to assume responsibility for prevention of disease (covered in a previous update http://bit.ly/SP5sD). The original study by Djoussé et al [1] emphasizes that adherence to a healthy lifestyle will help prevent cardiovascular disease, and that the responsibility for such a lifestyle must be assumed by the individual.

[1] Djoussé L, Driver JA, Gaziano JM. Relation between modifiable lifestyle factors and lifetime risk of heart failure. JAMA 2009;302:394-400
[2] Roger VL. Lifestyle and cardiovascular health: Individual and societal choices. JAMA 2009;302:437-439

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* To view the online text from the book, please navigate to SpringerLink or use the DVD to access electronic content. SpringerLink is a subscription service. For further information, click here.

Further information: Preventive Cardiology: The Effects of Exercise (see p2631), Smoking, Secondhand Smoke, and Cardiovascular Disease (see p2649), and  Cardiovascular Complications of Obesity and the Metabolic Syndrome (see p2693) from Cardiovascular Medicine, 3rd Edn*

The Nurses’ Health Study II began in 1989 and is an ongoing prospective study of 116,671 female registered nurses. This study [1] was limited to 83,882 women from the original cohort who were 27–44 years old and used a baseline year of 1991. At that time, the women did not have hypertension, cardiovascular disease, diabetes, or cancer. Hypertension is responsible for more deaths in women than any other preventable risk factor. The risk factors for the development of hypertension that can be controlled by the individual include being overweight or obese, not being physically active, and having a poor diet. This study sought to determine whether or not adherence to a lifestyle where weight, activity, and diet were controlled could prevent the onset of incident hypertension. To help in the calculation of data from this study, a hypothetical population attributable risk (PAR) was developed to estimate the percentage of new incident hypertension cases that occurred in this population that could have been prevented if all of the women in the study had adhered to the six low-risk factors for prevention of hypertension, i.e. a body mass index (BMI) of less than 25, a daily mean of 30 minutes of vigorous exercise, a high score on the Dietary Approaches to Stop Hypertension (Dash) diet, moderate intake of alcohol, use of nonnarcotic analgesics less than once per week, and 400 µg/d or more of supplemental folic acid.

In total, 12,319 cases of incident hypertension were reported. In an analysis of the data, the authors concluded that a significantly lower incidence of hypertension was associated with adherence to low-risk dietary and lifestyle factors.

An editorial [2] was also published that addresses the issues of increased health care expenses and the increased need for individuals and society to assume responsibility for prevention of disease. The study by Forman et al [1] emphasizes that adherence to a healthy lifestyle will help prevent cardiovascular disease, and that the responsibility for such a lifestyle must be assumed by the individual.

[1] Forman JP, Stampfer MJ, Curham GC. Diet and lifestyle risk factors associated with incident hypertension and women. JAMA 2009;302:401-411
[2] Roger VL. Lifestyle and cardiovascular health: Individual and societal choices. JAMA 2009;302:437-439

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* To view the online text from the book, please navigate to SpringerLink or use the DVD to access electronic content. SpringerLink is a subscription service. For further information, click here.

Further information: Coronary Risk Factors: An Overview (see p2609) from Cardiovascular Medicine, 3rd Edn*

Data collected in The Framingham Heart Study [1] that began in 1948 with an original cohort of 5209 patients culminated in the identification of specific common risk factors that contributed to the development of cardiovascular disease (CVD) in patients who had never suffered a heart attract or had experienced symptoms. Algorithms were constructed of standard risk factors (male sex, age, systolic blood pressure, antihypertensive treatment, cholesterol levels, smoking, and diabetes) for risk assessment over a ≤10-year period for doctors to use in a primary care setting. Authors of the current study [2] believe that in order to understand today’s public health burden of CVD, the longer-term risk factors of CVD must be evaluated. Using data collected from the Offspring of the Framingham Heart Study [3], 2333 women and 2173 men (free of CVD and cancer at enrollment) were followed for possible development of “hard” CV events that included coronary death, myocardial infarction, or stroke. Although the results of this study found that the standard risk factors currently in use were still effective in predicting CVD risk over a 30-year follow-up period, the same was not true for the impact of body mass index (BMI) over a 30-year follow-up period. The authors developed a longer-term algorithm that quantified a 30-year risk as a direct function of risk factors that applied to younger individuals and women, accounted for the competing cause of non-CVD mortality, and could be used by the patient’s primary care doctor.

[1] Dawber TR, Meadors GF, Moore FE Jr. Epidemiological approaches to heart disease: the Framingham Study. Am J Public Health 1951; 41:279-286.

[2] Pencina MJ, D’Agostino RB, Larson MG, et al. Predicting the 30-year risk of cardiovascular disease. The Framingham Heart Study. Circulation 2009;109:3078-3084

[3] Kannel WB, Feinleib M, McNamara PM, et al. An investigation of coronary heart disease in families: the Framingham Offspring Study. Am J Epidemiol 1979;110:281-290.

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* To view the online text from the book, please navigate to SpringerLink or use the DVD to access electronic content. SpringerLink is a subscription service. For further information, click here.

Further information: Stem Cell Therapy for Cardiac Disease (see p2754) from Cardiovascular Medicine, 3rd Edn*

The BALANCE Study provides the first 5-year data available on autologous bone-marrow cell (BMC) therapy in patients with acute myocardial infarction (AMI) [1] . It has been termed a “milestone paper” because it reports results of the first long-term BMC transplantation after AMI, and the results showed significant clinical benefit.

A major cause of infarct-related heart failure and death following AMI is ventricular remodeling. The remodeling of the myocardium can be treated medically or by revascularization to improve ventricular function, but not to restore damaged tissue. To evaluate the amount of improvement achieved by BMC therapy, 124 patients with AMI were enrolled into the study, and 62 patients received autologous BMC infused directly into the infarct-related artery 7±2 days post AMI. The control group consisted of 62 patients. Within three months, the therapy group showed significant improvement in ejection fraction (EF), the infarct size was reduced by 8%, and there was improvement in contractility in the infarct zone. In addition, exercise capacity was increased in the treated group, and mortality was significantly reduced.

[1] Yousef M, Schannwell CM, Kostering M, et al. The BALANCE study: Clinical benefit and long-term outcome after intracoronary autologous bone marrow cell transplantation in patients with acute myocardial infarction. J Am Coll Cardiol 2009; 53:2262-2269.

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Further information: Management of Cholesterol Disorders (see p2667) from Cardiovascular Medicine, 3rd Edn*

This paper [1] presents a prospective, subanalysis study using the data obtained from 15,548 initially healthy men and women who participated in the Justification for the Use of statins in Prevention: an Interventional Trial Evaluating Rosuvastatin (JUPITER) trial (87% of the total number), and was intended to examine the effects of rosuvastatin 20 mg versus placebo on rates of non-fatal myocardial infarction, non-fatal stroke, admission for unstable angina, arterial revascularization, or cardiovascular death during follow-up of 5 years.

Investigators sought to validate the hypothesis that asymptomatic individuals with normal LDL cholesterol concentrations, but with evidence of increased inflammation by measurement of C-reactive protein, would benefit from a statin. Compared with placebo, men and women who achieved LDL cholesterol less than 1.8 mmol/l had a 55% reduction in vascular events (event rate [ER] 1.11 vs. 0.51 per 100 person-years; hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.34–0.60, P<0.0001), and those achieving hsCRP less than 2 mg/l a 62% reduction (ER 0.42 per 100 person-years; HR 0.38, 95% CI 0.26–0.56, P<0.0001). LDL cholesterol and hsCRP reductions were only weakly correlated in individual patients (r<0.15), but we recorded a 65% reduction in vascular events in patients who received rosuvastatin who achieved both LDL cholesterol less than 1.8 mmol/l and hsCRP less than 2 mg/l (ER 0.38 per 100 person-years; adjusted HR 0.35, 95% CI 0.23–0.54) versus a 33% reduction in those who achieved one or neither target (ER 0.74 per 100 person-years; HR 0.67, 95% CI 0.52–0.87) (across treatment groups P<0.0001). Individuals who achieved LDL cholesterol less than 1.8 mmol/l and hsCRP less than 1 mg/l had a 79% reduction (ER 0.24 per 100 person-years; HR 0.21, 95% CI, 0.09–0.52). Achieved hsCRP concentrations were predictive of event rates irrespective of the lipid endpoint used, including the apolipoprotein B to apolipoprotein A1 ratio.

The mechanism by which statins reduce cholesterol is known to be the inhibition of the hydroxymethyl-glutaryl-coenzyme A (HMG-CoA) reductase pathway. The data from this study have now shown insight into the mechanism of a statin’s ability to reduce inflammation. Statins reduce inflammatory cell adhesion and monocyte recruitment to endothelial cells, change smooth muscle migration in developing plaques, and favorably affect matrix metalloproteinases, leading to plaque stabilization, and the extent to which these inflammatory properties affect clinical outcomes, and whether or not they are independent of LDL cholesterol, still must be evaluated in future studies.

[1] Ridker PM, Danielson E, Fonseca FAH et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 2009; 373:1175-1182

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* To view the online text from the book, please navigate to SpringerLink or use the DVD to access electronic content. SpringerLink is a subscription service. For further information, click here.

Further information: Smoking, Secondhand Smoke, and Cardiovascular Disease (see p2649) and Cardiovascular Complications of Obesity and the Metabolic Syndrome (see p2693) from Cardiovascular Medicine, 3rd Edn*

In an effort to evaluate the effects of both obesity and smoking in late adolescence on adult mortality, the investigators conducted a study based on a cohort of 49,321 Swedish men in a required nationwide military enrollment who registered from 1969–1970 at 16-19 years of age and were followed for 38 years [1]. The investigators’ primary hypothesis was that the effect of obesity and smoking in late adolescence increased the risk of adult mortality, and the secondary hypothesis was that excess risk of mortality in underweight people was due to smoking. In the cohort studied, 2897 men died.

Compared with normal weight men, risk of mortality was increased in overweight men (hazard ratio [HR] 1.33 [1.15–1.53]; incidence rate [IR] 23 [20–26]) and obese men (HR 2.14 [1.61–2.85], IR 38, 27 to 48), with similar relative estimates in separate analyses of smokers and non-smokers. No increased risk was detected in underweight men (HR 0.97 [0.86–1.08]; IR 18 [16–19]). The relative excess risk due to interaction between BMI and smoking status was not significant in any stratum. Additionally, all estimates of interaction were of small magnitude, except for the combination of obesity and heavy smoking (RR 1.5 [-0.7–3.7]). Compared with non-smokers (IR 14 [13–15]), risk was increased in both light (HR 1.54 [1.41–1.70]; IR 15 [14–16]) and heavy smokers (HR 2.11, 1.92 to 2.31; IR 26 [24–27]).

The results showed that regardless of smoking status, adult mortality increased when men were overweight or obese as adolescents. In addition, smoking was as hazardous to the men as being obese or overweight. There was no interaction between smoking and obesity status. These findings indicate the need for public health initiatives to target obesity and smoking in the adolescent years.

[1] Neovius M, Sundtrom J, Rasmussen F et al. Combined effects of overweight and smoking in late adolescence on subsequent mortality: nationwide cohort study. BMJ 2009:338:b496

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