Novel biomarkers for cardiovascular risk prediction

Cardiovascular disease (CVD) is the leading cause of death and disability worldwide. The primary prevention of CVD is dependent upon the ability to identify high-risk individuals long before the development of overt events. This highlights the need for accurate risk stratification. An increasing number of novel biomarkers have been identified to predict cardiovascular events. Biomarkers play a critical role in the definition, prognostication, and decision-making regarding the management of cardiovascular events. This review focuses on a variety of promising biomarkers that provide diagnostic and prognostic information. The myocardial tissue-specific biomarker cardiac troponin, high- sensitivity assays for cardiac troponin, and heart-type fatty acid binding proteinall help diagnose myocardial infarction (MI) in the early hours following symptoms. Inflammatory markers such as growth differentiation factor-15, high-sensitivity C-reactive protein, fibrinogen, and uric acid predict MI and death. Pregnancy-associated plasma protein A, myeloperoxidase, and matrix metalloproteinases predict the risk of acute coronary syndrome. Lipoprotein-associated phospholipase A2 and secretory phospholipase A2 predict incident and recurrent cardiovascular events. Finally, elevated natriuretic peptides, ST2, endothelin-1, mid-regional-pro-adrenomedullin, copeptin, and galectin-3 have all been well vali?dated to predict death and heart failure following a MI and provide risk stratification information for heart failure. Rapidly developing new areas, such as assessment of micro-RNA, are also explored. All the biomarkers reflect different aspects of the development of atherosclerosis.     

Preventing cardiovascular disease in women: an update

Coronary heart disease (CHD) continues to be the leading cause of death among women in the United States. Evidence-based guidelines of the American Heart Association (AHA) offer clinicians recommendations for preventing CHD in women delineating particular lifestyle, risk factor, and pharmacologic interventions. Cigarette smoking, physical inactivity, inappropriate diet, dyslipidemia, hypertension, diabetes mellitus, and metabolic syndrome contribute to the risk of CHD in women, as in men. Lifestyle interventions substantially reduce that risk. Many women, however, require pharmacotherapy to control hypertension, dyslipidemia, and diabetes to levels required for decreasing risk. New findings from clinical trials featuring women may enhance their CHD risk prediction and treatment. However, high coronary risk in many women continues to be underrecognized, and women remain undertreated with statins and other therapeutic agents.     

Novel biomarkers for risk stratification and identification of lifethreatening cardiovascular disease: troponin and beyond

Chest pain and other symptoms that may represent acute coronary syndromes (ACS) are common reasons for emergency department (ED) presentations, accounting for over six million visits annually in the United States [1]. Chest pain is the second most common ED presentation in the United States. Delays in diagnosis and inaccurate risk stratification of chest pain can result in serious morbidity and mortality from ACS, pulmonary embolism (PE), aortic dissection and other serious pathology. Because of the high morbidity, mortality, and liability issues associated with both recognized and unrecognized cardiovascular pathology, an aggressive approach to the evaluation of this patient group has become the standard of care. Clinical history, physical examination and electrocardiography have a limited diagnostic and prognostic role in the evaluation of possible ACS, PE, and aortic dissection, so clinicians continue to seek more accurate means of risk stratification. Recent advances in diagnostic imaging techniques particularly computed-tomography of the coronary arteries and aorta, have significantly improved our ability to diagnose life-threatening cardiovascular disease. In an era where health care utilization and cost are major considerations in how disease is managed, it is crucial to riskstratify patients quickly and efficiently. Historically, biomarkers have played a significant role in the diagnosis and risk stratification of several cardiovascular disease states including myocardial infarction, congestive heart failure, and pulmonary embolus. Multiple biomarkers have shown early promise in answering questions of risk stratification and early diagnosis of cardiovascular pathology however many do not yet have wide clinical availability. The goal of this review will be to discuss these novel biomarkers and describe their potential role in direct patient care.     

Novel cardiovascular biomarkers in unexplained syncopal attacks: the SYSTEMA cohort

Objectives

The aim of the study was to investigate the resting levels of novel cardiovascular biomarkers in common types of noncardiac syncope.

Design and setting

An observational study was conducted including 255 patients (mean age 60 years, range 15–93; 45% men) with unexplained syncopal attacks. Subjects underwent an expanded head‐up tilt test including carotid sinus massage, and nitroglycerin provocation if indicated. Using logistic regression, we explored the associations between specific diagnoses of syncope and resting levels of circulating biomarkers: C‐terminal pro‐arginine vasopressin (CT‐proAVP), C‐terminal endothelin‐1 precursor fragment (CT‐proET‐1), midregional fragments of pro‐atrial natriuretic peptide (MR‐proANP) and pro‐adrenomedullin (MR‐proADM).

Results

A total of 142 (56%) patients were diagnosed with vasovagal syncope (VVS), 85 (33%) with orthostatic hypotension (OH) and 47 (18%) with carotid sinus hypersensitivity (CSH); in addition, 74 (29%) patients had more than one diagnosis. Thirty‐five patients (14%) demonstrated a cardioinhibitory reflex. The probability of VVS was highest in the first quartile of MR‐proANP [Q1 vs. Q4: odds ratio (OR) 5.57, 95% confidence interval (CI) 1.86–16.74; P < 0.001] and CT‐proET‐1 (OR 7.17, 95% CI 2.43–21.13; P < 0.001). By contrast, the probability of OH was highest in the fourth quartile of CT‐proET‐1 (Q4 vs. Q1: OR 8.66, 95% CI 2.49–30.17; P < 0.001). Furthermore, CSH was most frequently observed in the first quartile of MR‐proANP (Q1 vs. Q4: OR 6.57, 95% CI 1.62–26.62; P = 0.008) among those over 60 years of age, whereas the cardioinhibitory reflex was strongly associated with low CT‐proET‐1 levels (Q1 vs. Q4: OR 69.7, 95% CI 6.97–696.6; P < 0.001). Moreover, in patients with VVS, a high concentration of CT‐proET‐1 was predictive of OH (OR per 1 SD 2.4, 95% CI 1.15–5.02; P = 0.02), whereas low CT‐proET‐1 suggested involvement of the cardioinhibitory reflex (OR per 1SD 0.42, 95% CI 0.25–0.70; P = 0.001).

Conclusions

The levels of MR‐proANP and CT‐proET‐1 are markedly changed in common forms of syncope, suggesting the involvement of novel neurohormonal mechanisms in syncopal attacks.     

Fibrinogen and cardiovascular disease: genetics and biomarkers

Several prospective epidemiological studies and clinical observations provided evidence regarding fibrinogen and coronary artery disease (CAD). Many of these studies firmly correlate fibrinogen with CAD. However, it is uncertain whether this relation is causal or reflects genetic variability and residual confounding by other risk factors. Several polymorphisms on fibrinogen chain genes affect its levels, however only few of the genetic variants are associated with increased cardiovascular risk. As regards the role of fibrinogen in myocardial infarction (MI) studies indicate that genetic variations have at best a modest impact on the process resulting in MI. Therefore, the screening of fibrinogen genes might not be useful for the assessment of the risk of MI. However, the findings that specific genotypes lead to specific differences in fibrinogen levels, but may not be linked to cardiovascular risk, complicates the hypothesis of causality of fibrinogen in the pathogenesis of cardiovascular disease.     

Platelet inhibitor agents in cardiovascular disease: an update

Platelets interact with the coagulation and fibrinolytic systems in the maintenance of hemostasis. However, these physiologic mechanisms may become pathologic, requiring prevention and treatment. In this review, the following clinical developments are analyzed: 1) the role of platelets in thrombogenesis; 2) the pharmacology of platelet inhibitory agents; and, most important, 3) the results of recent randomized trials of platelet inhibitor agents in different cardiovascular disorders. Aspirin reduces mortality and infarction rates in unstable angina and significantly decreases vascular mortality in acute myocardial infarction. Platelet inhibitors decrease mortality and recurrent cardiovascular events in the chronic phase after myocardial infarction. They also decrease vein graft occlusion rates after coronary bypass surgery. Although platelet inhibitors are beneficial in preventing acute vessel occlusion during coronary angioplasty, they are ineffective in preventing chronic restenosis. Antiplatelet agents, combined with warfarin, reduce thromboembolic events in patients with a mechanical prosthesis. Platelet inhibitors are also effective in secondary prevention of vascular events in patients with cerebrovascular disease. Finally, the use of aspirin for primary prevention of cardiovascular disease is still evolving, particularly in individuals at high risk. In conclusion, platelet inhibitors are effective in patients with a variety of cardiovascular disorders. The best studied, most inexpensive and least toxic agent is aspirin at a daily dose of 160 to 325 mg. Studies using new platelet inhibitor agents with different mechanisms of action are currently underway.     

Vascular biomarkers and surrogates in cardiovascular disease

Cardiovascular biomarker research efforts have resulted in the identification of new risk factors and novel drug targets, as well as the establishment of treatment guidelines. Government agencies, academic research institutions, diagnostic industries, and pharmaceutical companies all recognize the importance of biomarkers in advancing therapies to improve public health. In drug development, biomarkers are used to evaluate early signals of efficacy and safety, to select dose, and to identify the target population. The United States Food and Drug Administration has relied on biomarkers to support clinical applications in many therapeutic fields, including cardiovascular disease. The appropriate application of cardiovascular biomarkers requires an understanding of disease natural history, the mechanism of the intervention, and the characteristics and limitations of the biomarker. Channels of communication among researcher, developer, and regulator must remain open to maximize the success of future biomarker efforts. In 2003, 2004, and 2005, an international panel of cardiovascular biomarker experts convened at the "Cardiovascular Biomarker and Surrogate Endpoints Symposia" held in Bethesda, Md, to discuss the use of biomarkers in the development of improved cardiovascular diagnostics and therapeutics. The information presented in the present report summarizes the authors' perspective distilled from these proceedings.     

Obesity and cardiovascular disease risk: research update

The obesity epidemic has reached unprecedented proportions in Western society. Evidence continues to accumulate that obesity is associated with significant morbidity and mortality and in particular that it is an independent risk factor for cardiovascular disease (CVD). The association of obesity with CVD and its risk factors, including hypertension, dyslipidemia, glucose intolerance, and impaired hemostasis is becoming more clearly understood. An increasing body of data indicates that risk factors tend to cluster in obese individuals and may act synergistically to increase these people's risk for CVD. Individuals with disproportionate visceral adiposity are at significantly greater risk for CVD. Adult weight gain also underlies the development of many risk factors and augments the risk of CVD. Physicians can play a vital and active role in the prevention and treatment of obesity and overweight and thereby reduce patients' CVD risk.     

Novel biomarkers of fibrosis in Crohn's disease

Fibrosis represents a major challenge in Crohn's disease(CD),and many CD patients will develop fibrotic strictures requiring treatment throughout their lifetime.There is no drug that can reverse intestinal fibrosis,and so endoscopic balloon dilatation and surgery are the only effective treatments.Since patients may need repeated treatments,it is important to obtain the diagnosis at an early stage before strictures become symptomatic with extensive fibrosis.Several markers of fibrosis have been proposed,but most need further validation.Biomarkers can be measured either in biological samples obtained from the serum or bowel of CD patients,or using imaging tools and tests.The ideal tool should be easily obtained,costeffective,and reliable.Even more challenging is fibrosis occurring in ulcerative colitis.Despite the important burden of intestinal fibrosis,including its detrimental effect on outcomes and quality of life in CD patients,it has received less attention than fibrosis occurring in other organs.A common mechanism that acts via a specific signaling pathway could underlie both intestinal fibrosis and cancer.A comprehensive overview of recently introduced biomarkers of fibrosis in CD is presented,along with a discussion of the controversial areas remaining in this field.     

Novel concepts in radiation-induced cardiovascular disease

Radiation-induced cardiovascular disease(RICVD) is the most common nonmalignant cause of morbidity and mortality among cancer survivors who have undergone mediastinal radiation therapy(RT).Cardiovascular complications include effusive or constrictive pericarditis,cardiomyopathy,valvular heart disease,and coronary/vascular disease.These are pathophysiologically distinct disease entities whose prevalence varies depending on the timing and extent of radiation exposure to the heart and great vessels.Although refinements in RT dosimetry and shielding will inevitably limit future cases of RICVD,the increasing number of long-term cancer survivors,including those treated with older higher-dose RT regimens,will ensure a steady flow of afflicted patients for the foreseeable future.Thus,there is a pressing need for enhanced understanding of the disease mechanisms,and improved detection methods and treatment strategies.Newly characterized mechanisms responsible for the establishment of chronic fibrosis,such as oxidative stress,inflammation and epigenetic modifications,are discussed and linked to potential treatments currently under study.Novel imaging modalities may serve as powerful screening tools in RICVD,and recent research and expert opinion advocating their use is introduced.Data arguing for the aggressive use of percutaneous interventions,such as transcutaneous valve replacement and drug-eluting stents,are examined and considered in the context of prior therapeutic approaches.RICVD and its treatment options are the subject of a rich and dynamic body of research,and patients who are at risk or suffering from this disease will benefit from the care of physicians with specialty expertise in the emerging field of cardiooncology.     

Triglycerides and risk of atherosclerotic cardiovascular disease: An update

Regulation of triglyceride-rich lipoprotein (TGRL) metabolism. Serum triglyceride concentration identifies the presence of potentially atherogenic TGRLs. Human genetics strongly support remnants of TGRLs as a causal cardiovascular risk factor. Remnants of TGRLs play a role in residual risk on statin therapy. Apo: apolipoprotein; ANGPTL: angiopoietin-like protein; LPL: lipoprotein lipase; RLP: remnant lipoprotein.