Physical Activity, Weight Loss, and Cardiac Rehabilitation to Reduce Recurrent Cardiovascular Events

Contemporary studies now suggest that multifactorial risk factor modification—especially smoking cessation, more intensive dietary modifications, pharmacotherapies to control hyperlipidemia, antihypertensive regimens, weight reduction, and regular moderate-to-vigorous physical activity—may reduce the risk of recurrent cardiovascular events. Although better outcomes for cardiovascular and all-cause mortality have been reported in some overweight and moderately obese cohorts of patients with cardiovascular disease (the “obesity paradox”), numerous reports now support purposeful weight reduction in this escalating patient population. Moreover, cardiorespiratory fitness is one of the strongest prognostic indicators in persons with coronary disease, irrespective of traditional risk factors, body habitus, and left ventricular function. Accordingly, sedentary patients should be counseled to become more physically active and/or fit by starting an exercise program, increasing lifestyle activity, or both. Despite the effectiveness and safety of cardiac rehabilitation, these services remain vastly underutilized. Cardiac rehabilitation has been shown to markedly improve the cardiovascular risk factor profile and is associated with significant reductions in all-cause and cardiac mortality.     

Glycemic control to prevent cardiovascular disease in type 2 diabetes

Epidemiologists have found relationships between diabetes and cardiovascular disease and between the degree of hyperglycemia and cardiovascular disease. Clinical trials, however, have been less successful in providing convincing evidence to support changes in clinical care. Observational data from the DCCT and interventional data—notably, results related to metformin use from the UKPDS—support glucose lowering. Several ongoing studies in individuals with diabetes and “pre-diabetes” and in those with and without existing cardiovascular disease seek a definitive answer. If positive, these studies will justify even greater efforts toward glycemic control, and they may support blood glucose lowering in individuals without diabetes.     

Genomics and the efficacy of aspirin in the treatment of cerebrovascular disease

Opinion statement  Aspirin has been shown to reduce the risk of stroke, myocardial infarction, and death in patients with a history of cardiovascular disease or at high risk for cardiovascular disease. However, many individuals suffer a stroke or other cardiovascular event despite aspirin therapy. Data suggest that heritability contributes importantly to the antiplatelet and clinical responses to aspirin. Candidate genes for influencing aspirin response include those involved in platelet aggregation and in modulating cardiovascular disease risk and progression. Although several studies have examined genetic determinants of platelet responsiveness to aspirin, the results are largely inconsistent. Few studies have examined genetic association with clinical outcomes, including reductions in stroke risk, with aspirin. In perhaps the most significant pharmacogenomic study with aspirin to date, a large primary prevention trial showed that the apolipoprotein A genotype was associated with risk of stroke and other cardiovascular events in women and that aspirin eliminated this risk. These data suggest that ultimately, it may be possible to tailor aspirin therapy based on an individual’s genotype, at least for primary prevention of stroke and cardiovascular events in women. Data on genetic determinants of response to aspirin in secondary stroke prevention are far less advanced. Future pharmacogenomic studies should focus on elucidating the role of genotyping in choosing appropriate antiplatelet therapy (ie, aspirin alone versus a thienopyridine or combination antiplatelet therapy) for secondary disease prevention.     

Platelet glycoprotein Ibα polymorphisms and function evaluated by the platelet function analyzer PFA-100 in patients with lupus anticoagulant: the association with thromboembolic disease

Lupus anticoagulants (LA) are a surrogate marker for the risk of thromboembolic disease (TE). However, not all individuals with LA acquire TE, and it is desirable to distinguish those at risk for TE from those without. Platelets polymorphisms may contribute to the risk of TE, mainly those of glycoprotein (GP)Ibα: these are the variable number of tandem repeats (VNTR) and a dimorphism in the Kozak region, which affect platelet plug formation in healthy individuals under high shear stress rates. We determined polymorphisms within the GPIbα in individuals with persistent LA and a history of TE (LA/TE+) and in those without TE (LA/TE-). Further, we measured platelet function, as estimated by the collagen-epinephrine closure time (CEPI-CT) of the platelet function analyzer PFA-100 and compared all data with healthy controls. There was no difference of the VNTR alleles compared to healthy controls. The (−5)C allele of the Kozak dimorphism was significantly more frequent in LA patients compared to controls (p = 0.04), as a result of its increased frequency in LA/TE+ (vs controls p = 0.04), but there was no difference between LA/TE+ and LA/TE−. The increased frequency of the (−5)C allele resulted in an overrepresentation of (−5)TC genotype in the LA/TE+ group (p = 0.02) but not in a subgroup of 18 patients with arterial disease. The CEPI-CT of the PFA-100 was shorter in LA/TE+ than in LA/TE− (p = 0.044), but this difference did not persist after exclusion of patients with low platelet counts or low ristocetin cofactor activity. Unlike in healthy individuals, the CEPI-CT was not related to any Kozak dimorphism, neither in LA/TE−, nor in LA/TE+. Thus, the Kozak dimorphism may just contribute to stronger factors disposing individuals with LA towards TE without any discernible effect on their in vitro platelet function estimated by the PFA-100.     

Effects of circadian disruption on the cardiometabolic system

The presence of day–night variations in cardiovascular and metabolic functioning is well known. However, only recently it has been shown that cardiovascular and metabolic processes are not only affected by the behavioral sleep/wake cycle but are partly under direct control of the master circadian pacemaker located in the suprachiasmatic nucleus (SCN). Heart rate, cardiac autonomic activity, glucose metabolism and leptin—involved in appetite control—all show circadian variation (i.e., under constant behavioral and environmental conditions). This knowledge of behavioral vs. circadian modulation of cardiometabolic function is of clinical relevance given the morning peak in adverse cardiovascular incidents observed in epidemiological studies and given the increased risk for the development of diabetes, obesity, and cardiovascular disease in shift workers. We will review the evidence for circadian control of cardiometabolic functioning, as well its sensitivity to light and melatonin, and discuss potential implication for therapy.     

Measuring plasma fibrinogen to predict stroke and myocardial infarction: an update.

Plasma fibrinogen is a major determinant of platelet aggregation and blood viscosity. The decrease in plasma fibrinogen by bezafibrate is associated with a decrease in the risk of reinfarctions. To strengthen the predictive value of plasma fibrinogen with respect to cardiovascular risk, we performed a meta-analysis of studies conducted between 1984 and 1998. Emphasis has been put on the relationship between high levels of plasma fibrinogen and fatal and/or nonfatal cardiovascular events in both the general population and in patients with previous cardiovascular events. Twenty-two studies (13 prospective, 5 cross-sectional, and 4 case-control) addressing the association between fibrinogen plasma concentrations and cardiovascular disease were analyzed. The overall estimate of risk of cardiovascular event in subjects with plasma fibrinogen levels in the higher tertile, was twice as high as that of subjects in the lower one (odds ratio, 1.99; 95% confidence interval, 1.85 to 2.13). High plasma fibrinogen levels were associated with an increased risk of cardiovascular disease in healthy as much as in high-risk individuals. A metaregression showed no confounding effects attributable to selected characteristics of retrieved studies. A subgroup analysis (study design, follow up, mean fibrinogen levels, percentage of smokers, and mean age) allowed us to conclude that fibrinogen is an independent risk factor for cardiovascular disease; that it interacts with major determinants of myocardial and cerebrovascular ischemia; and that, in secondary prevention studies, it enhances by 8% the prediction of future events by established risk factors. Thus, fibrinogen measurements should be encouraged to refine the overall risk profiles of individuals and to better tailor preventive interventions.     

Update on the Safety of Thiazolidinediones

Diabetic patients are at increased risk for developing cardiovascular disease, and they constitute a large proportion of the global cardiovascular disease burden. Although multiple drugs exist for treating the hyperglycemia associated with diabetes, few have been shown to reduce cardiovascular risk. Great hope surrounded the arrival of the thiazolidinediones—drugs that favorably affect insulin sensitivity, inflammation, and some aspects of lipid profiles in diabetic patients. However, the cardiovascular effects of these agents are varied, and studies have suggested that they may be associated with increases in ischemic heart disease and heart failure, as well as with an increased risk for bone fracture. The following article provides a summary of important studies that have been published regarding the safety profiles of these agents. Findings from two recently published trials, RECORD and BARI 2D, are emphasized in this paper.     

C-reactive protein, inflammation, and coronary risk

Advancements in understanding of the pathobiology of atherothrombosis have implicated inflammation as a central contributor to the progression of atherosclerotic vascular disease. Epidemiologic data demonstrate an association between the inflammatory marker hs-CRP and risk for future cardiovascular morbidity and mortality among those at high risk or with documented vascular disease. Moreover, a series of prospective studies provides consistent data documenting that mild elevation of baseline levels of hs-CRP among apparently healthy individuals is associated with higher long-term risk for future cardiovascular events. Among men and women, this predictive capacity of hs-CRP is independent of traditional cardiovascular risk factors and offers a prognostic advantage over measurement of lipids alone. Further, observations from the PHS and CARE trial suggest that the increased risk associated with systemic inflammation may be modified with certain preventive therapies and that inflammatory markers such as hs-CRP may help to identify those who would benefit most from these pharmacologic interventions. Given that high-throughput assays for inflammatory markers, including hs-CRP, are likely to become available for clinical use, carefully designed studies are needed to evaluate the clinical efficacy of hs-CRP as a new marker to stratify cardiovascular risk. Further, prospective, randomized trials are important to test directly the value of inflammatory markers in targeting specific preventive therapies. Finally, it is still undetermined as to whether elevation of these inflammatory markers reflects the degree of underlying atherosclerosis or plaque vulnerability or rather results from some other environmental or infectious stimulus or even has direct effects on platelet aggregation or coagulation [1]. Ongoing and future investigation will clarify the specific pathophysiologic relationships through which these markers correlate with adverse prognosis.     

Obesity and lipids

Obesity increases cardiovascular risk through multiple mechanisms. Abdominal (visceral) adiposity is metabolically active and is largely responsible for the atherogenic dyslipidemia, hyperinsulinemia, hypertension, chronic inflammatory state, and prothrombotic state that constitute the metabolic syndrome, and the subsequent increased risk for cardiovascular disease and acute coronary events. Cholesterol guidelines for assessing cardiovascular risk have traditionally focused on low-density lipoprotein (LDL) levels, and reduction of plasma LDL has been shown to reduce cardiovascular events and total mortality. However, the cardiovascular risks associated with the dyslipidemia of obesity—characterized by low levels of high-density lipoprotein; increased triglycerides; increased subfractions of small, dense LDL; and increased levels of apolipoprotein B-100—are also now well recognized.     

Does Self-Reported Physical Activity Underestimate the Importance of Activity in Cardiovascular Disease Prevention?

Engagement in regular exercise or physical activity (PA) is known to protect against cardiovascular disease. Evidence for this strong association comes from both epidemiologic studies in which individuals self-report their level of PA and randomized controlled trials in which individuals increase their level of PA to a pre-defined level for a specific duration. Misclassification biases associated with self-reported PA may underestimate the true reduction in cardiovascular disease (CVD) risk obtained through regular engagement in PA, particularly at high levels. Given the strong dose–response relationship observed between objectively measured PA and changes in CVD risk factors in randomized controlled trials, the estimated risk reduction associated with high levels of PA (> 2,000 kcal/wk) would be predicted to be larger than current estimates (30% risk reduction) derived from epidemiologic studies. Self-reported PA may underestimate the true risk reduction in CVD produced through engagement in high levels of PA, although definitive evidence is not available.     

Flavonoids for reduction of atherosclerotic risk

Flavonoids are polyphenolic compounds found in fruits, vegetables, and beverages derived from plants. Foods thought historically by many societies to have healing properties—cocoa, red wine, and tea—are particularly rich in flavonoids. A majority of prospective cohort studies demonstrate a significant inverse association between flavonoid consumption and cardiovascular risk. Short-term studies demonstrate numerous plausible mechanisms by which flavonoids may confer cardiovascular protection: they inhibit low-density lipoprotein oxidation, reduce thrombosis, improve endothelial function, and reduce inflammation. No long-term, randomized, controlled trials of flavonoids with hard clinical endpoints have been conducted. Although there are no recommended daily intake goals for flavonoids, the data presented provide additional rationale to eat a diet containing a variety of flavonoid-rich foods and beverages.     

Selecting optimal antiplatelet therapy based on platelet function monitoring in patients with coronary artery disease

Opinion statement  Results from pharmacodynamic and translational research studies assessing platelet reactivity have highlighted the limitations of current oral antiplatelet therapy. The data from translational research studies present strong arguments against the “one-size-fits-all” approach that has been used in large-scale clinical trials. At one end of the spectrum, selected patients with excessively low on-treatment platelet reactivity may have unnecessary bleeding, whereas patients with high platelet reactivity may experience ischemic events. Current evidence suggests that high on-treatment platelet reactivity will become a major risk factor determined as standard of care in patients with cardiovascular diseases. Future translational research holds the promise of identifying a therapeutic window for antiplatelet therapy based on objective measurement of platelet physiology. The main aim of this therapeutic window is to effectively attenuate ischemic events while avoiding bleeding risk with excessive platelet inhibition in selected patients with optimal antiplatelet therapeutic strategies involving current or novel antiplatelet agents. Preliminary findings suggest there may be thresholds predictive of adverse ischemic events. Ongoing studies such as GRAVITAS (Gauging Responsiveness With a Verify Now Assay—Impact on Thrombosis and Safety) and the S.T.E.N.T. Thrombosis Study and future research will likely support the current concepts and lead to personalized treatment regimens that will optimize antiplatelet therapy.     

Insulin-like growth factors and coronary heart disease

Insulin-like growth factor-1 (IGF-I), the primary mediator of growth hormone (GH) effects, is an important regulator of cell growth, differentiation, and apoptosis. GH and IGF-I deficiency is known to be associated with premature atherosclerosis and elevated cardiovascular disease mortality. Recent evidence suggests that cardiovascular disease risk may also be elevated among apparently healthy individuals who have serum IGF-I levels in the low-normal range. In this review, we appraise the epidemiologic and clinical studies implicating low IGF-I level as a risk factor for incident myocardial infarction and other manifestations of coronary heart disease. Potential mechanisms that may underlie this association include beneficial effects of IGF-I on myocyte survival after ischemia, stability of atherosclerotic lesions, and endothelial function. We conclude that additional confirmatory data from prospective studies are needed to confirm low IGF-I level as an independent cardiovascular risk factor. However, if this finding is confirmed, this would support the rationale for intervention trials aimed at reducing cardiovascular disease morbidity and mortality among older adults by targeting the GH/IGF-I pathway.     

Platelet response to low-dose enteric-coated aspirin in patients with stable cardiovascular disease.

OBJECTIVES: We investigated whether use of low-dose enteric-coated (EC) aspirin for secondary prevention of cardiovascular events has sufficient bioavailability to achieve complete platelet cyclooxygenase (COX) inhibition in all individuals. BACKGROUND: Aspirin reduces cardiovascular morbidity and mortality in patients with pre-existing vascular disease; however, there is variability in the way individuals respond. Persistent normal platelet function despite therapy, referred to as "aspirin resistance," is associated with an increased risk of major cardiovascular events. METHODS: We studied 131 stable cardiovascular patients between March and September 2002 who were taking 75 mg EC aspirin. Serum thromboxane (TX) B2 levels were assayed as a measure of COX activity. Mean arachidonic acid (AA)-induced platelet aggregation > or =20% was deemed evidence of persistent platelet activity and an incomplete aspirin response. RESULTS: Patients of median age 63 years (61% men) were enrolled. Forty-four percent of patients had elevated serum TX B2 levels (>2.2 ng/ml). Arachidonic acid-induced platelet aggregation occurred more frequently in these patients (21% vs. 3%; p = 0.004). In all cases addition of exogenous aspirin during the assay abolished platelet aggregation. Patient weight and age were significant independent predictors of an incomplete response to EC aspirin (p = 0.025 and p < 0.001, respectively). These patients were also more likely to have a history of myocardial infarction (MI) (p = 0.038). CONCLUSIONS: Many patients who are prescribed low-dose EC aspirin for secondary prevention of cardiovascular events have persistent uninhibited platelet COX activity. Younger and heavier patients and those with a previous MI are most likely to have an inadequate response to treatment.     

The role of nutrition therapy and dietitians in the management of the metabolic syndrome

Nutrition therapy interventions for the metabolic syndrome include weight reduction or maintenance, physical activity, whole grains and fiber, and type and amount of food fats. Interventions related to carbohydrate—amount and type—and alcohol are controversial. The role of the dietitian is to assist persons with the metabolic syndrome to make lifestyle changes that modify the factors that increase risk of diabetes and cardiovascular disease.     

Flavonoids from Fruit and Vegetables: A Focus on Cardiovascular Risk Factors

Epidemiological studies suggest that high intakes of dietary flavonoids are associated with decreased cardiovascular disease mortality and risk factors. Less is known about the cardioprotective effects of flavonoids from fruit and vegetables. This review summarizes data from studies which examine the effects of commonly consumed fruit and vegetables on cardiovascular disease risk biomarkers in healthy volunteers or at-risk individuals. Although flavonoids from apples, berries, and onions appear to impact positively on blood pressure, vascular function, and serum lipid levels, further research is required to find out the optimal quantity and food matrix for conferring substantial clinical benefit. The benefits from citrus flavonoids are still inconclusive. Further robust, longer-term dietary intervention studies, with the inclusion of placebo or control arms, are required to improve the credibility of the findings and confirm current observations. An improved understanding of the impact of flavonoids from fruit and vegetables can help one make discerning food choices for optimal cardiovascular health.     

Exercise and thrombosis

Long-term moderate or strenuous physical activity is associated with a considerable reduction in cardiovascular morbidity and mortality. This article reviews the evidence to suggest that part of the effect is mediated through the effects on thrombogenic factors. Fibrinogen has been convincingly shown to be an independent cardiovascular risk factor. Other hemostatic and fibrinolytic parameters that are predictive of coronary events include factor VII, platelet hyperreactivity, plasminogen activator inhibitor-1, and tissue-plasminogen activator. The effects of exercise on fibrinogen have been studied intensively. One randomized, controlled trial, two other intervention studies and a large number of population-based cross-sectional studies have consistently found an inverse relationship between various measures of sport activity or leisure activity and plasma levels of fibrinogen. The magnitude of the effect might be associated with a sizeable reduction in major coronary events. Relatively few data are available on endurance exercise and markers of the fibrinolytic system. Acute exercise leads to a transient activation of the coagulation system, which is accompanied by an increase in the fibrinolytic capacity in healthy subjects. However, patients with ischemic heart disease, who cannot increase their fibrinolytic potential, may be at considerable risk for acute ischemic events if they are exposed to unaccustomed strenuous physical exertion. It is concluded that physical activity has profound effects on thrombogenic factors and that these mechanisms could contribute to its beneficial cardiovascular effects.     

Alcohol and cardiovascular disease

Alcohol in moderation is associated with lower risk of coronary heart disease in healthy men and women. New evidence suggests that this association, described in over 70 epidemiologic studies, is causal and can be explained, in part, by alcohol’s beneficial effects on serum lipids and clotting factors. Recently, the inverse association between alcohol and cardiovascular disease also has been reported in populations with adult-onset diabetes and among individuals with previous cardiovascular disease. Although mounting evidence strongly supports the cardiovascular benefits of moderate alcohol consumption in most populations, clinical advice to abstainers to initiate daily alcohol consumption has not yet been substantiated in the literature and must be taken with caution and given on an individual basis.     

Metabolic Syndrome and Heart Failure—The Risk,Paradox, and Treatment

The constellation of obesity, hypertension, dyslipidemia, and insulin resistance—together referred to as metabolic syndrome (MetS)—is increasing in prevalence in the American population and also worldwide. The individual components of MetS and MetS as a whole increase the risk of heart failure, cardiovascular mortality, and all-cause mortality. Despite this adverse association, numerous studies have documented an obesity paradox, in which overweight and obese people with established cardiovascular disease, including hypertension, coronary heart disease, heart failure, and peripheral arterial disease, have a better prognosis than patients who are not overweight or obese. Current treatment strategies for these patients include weight loss, control of blood pressure and cholesterol levels, and treatment of hyperglycemia. Because of increasing evidence for the obesity paradox, some physicians question whether obesity should be treated when it is associated with heart failure. Several studies have shown improvement in left ventricular function and decreased mortality and morbidity from heart failure with weight loss and treatment of elevated blood pressure, cholesterol, and hyperglycemia. The most reasonable approach at this time appears to be weight loss and exercise, lowering blood pressure to less than 130/80 mm Hg, low-density lipoprotein (LDL) cholesterol to less than 100 mg/dL, and glycosylated hemoglobin levels to less than 7%.     

Diabetic cardiomyopathy: do women differ from men?

Although many aspects of cardiovascular disease are similar between women and men, it is becoming increasingly obvious that there are significant differences as well. Premenopausal women ususally have a lower risk of cardiovascular diseases than age-matched men and postmenopausal women. However, the “female advantage” disappears once women are affilicted with diabetes mellitus. Heart diseases are twice as common in diabetic men and five times as common in diabetic women. It is believed that differences in sex hormones and intrinsic myocardial and endothelial functions between men and women may be responsible for this female “advantage” and “disadvantage” in normal and diabetic conditions. Most experimental and clinical studies on diabetes only included male subjects and failed to address this important gender difference in diabetic heart complications. Although female hearts may be better tolerated to stress (such as ischemia) insults than their male counterparts, female sex hormone such as estrogen may interact with certain risk factors under diabetes which may compromise the overall cardiac function. The benefit versus risk of estrogen replacement therapy on cardiac function and overall cardiovascular health in diabetes remains controversial. This review will focus on gender-related difference in diabetic heart complication—diabetic cardiomyopathy—and if gender differences in intrinsic myocardial contraction, polyol pathway metabolism, and advanced glycation endproduct formation and other neuroendocrinal regulatory mechanisms to the heart may contribute to disparity in diabetic cardiomyopathy between men and women.