Current Cardiology Reviews - Volume 6, Issue 2, 2010

Endothelium plays a crucial role in the maintenance of vascular tone and structure. Endothelial dysfunction is known to precede overt coronary artery disease. A number of cardiovascular risk factors, as well as metabolic diseases and systemic or local inflammation cause endothelial dysfunction. Nitric oxide (NO) is one of the major endothelium derived vaso-active substances whose role is of prime importance in maintaining endothelial homeostasis. Low levels of NO are associated with impaired endothelial function. Asymmetric dimethylarginine (ADMA), an analogue of L-arginine, is a naturally occurring product of metabolism found in human circulation. Elevated levels of ADMA inhibit NO synthesis and therefore impair endothelial function and thus promote atherosclerosis. ADMA levels are increased in people with hypercholesterolemia, atherosclerosis, hypertension, chronic heart failure, diabetes mellitus and chronic renal failure. A number of studies have reported ADMA as a novel risk marker of cardiovascular disease. Increased levels of ADMA have been shown to be the strongest risk predictor, beyond traditional risk factors, of cardiovascular events and all-cause and cardiovascular mortality in people with coronary artery disease. Interventions such as treatment with Larginine have been shown to improve endothelium-mediated vasodilatation in people with high ADMA levels. However the clinical utility of modifying circulating ADMA levels remains uncertain.

Cardiovascular malformations are the most common type of birth defect and result in significant mortality worldwide. The etiology for the majority of these anomalies remains unknown but genetic factors are being recognized as playing an increasingly important role. Advances in our molecular understanding of normal heart development have led to the identification of numerous genes necessary for cardiac morphogenesis. This work has aided the discovery of an increasing number of monogenic causes of human cardiovascular malformations. More recently, studies have identified single nucleotide polymorphisms and submicroscopic copy number abnormalities as having a role in the pathogenesis of congenital heart disease. This review discusses these discoveries and summarizes our increasing understanding of the genetic basis of congenital heart disease.

Coronary artery disease (CAD) is the most prevalent form of cardiovascular disease affecting about 13 million Americans, while more than one million percutaneous transluminal intervention (PCI) procedures are performed annually in the USA. The relative high occurrence of restenosis, despite stent implementation, seems to be the primary limitation of PCI. Over the last decades, single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI), has proven an invaluable tool for the diagnosis of CAD and patients' risk stratification, providing useful information regarding the decision about revascularization and is well suited to assess patients after intervention. Information gained from post-intervention MPI is crucial to differentiate patients with angina from those with exo-cardiac chest pain syndromes, to assess peri-intervention myocardial damage, to predict-detect restenosis after PCI, to detect CAD progression in non-revascularized vessels, to evaluate the effects of intervention if required for occupational reasons and to evaluate patients' long-term prognosis. On the other hand, chest pain and exercise electrocardiography are largely unhelpful in identifying patients at risk after PCI. Although there are enough published data demonstrating the value of myocardial perfusion SPECT imaging in patients after PCI, there is still debate on whether or not these tests should be performed routinely.

The pathophysiology of several conditions including heart failure is partly attributable to a failure of the cell energy metabolism. Studies have shown that exercise training (ET) improves quality of life (QOL) and is beneficial in terms of reduction of symptoms, mortality and duration of hospitalization. Increasingly, ET is now achieving acceptance as complimentary therapy in addition to routine clinical practice in patients with chronic heart failure (CHF). However, the mechanisms underlying the beneficial effects of ET are far less understood and need further evaluation. Evidence suggests that while CHF induces generalized metabolic energy depletion, ET largely enhances the overall function of the heart muscle. Hence, research efforts are now aiming to uncover why ET is beneficial as a complimentary treatment of CHF in the context of improving endothelial function and coronary perfusion, decreasing peripheral resistance, induction of cardiac and skeletal muscle cells remodeling, increasing oxygen uptake, substrate oxidation, and resistance to fatigue. Here we discuss the current evidence that suggest that there are beneficial effects of ET on cardiac and skeletal muscle cells oxidative metabolism and intracellular energy transfer in patients with CHF.

Given evidence of increasing prevalence in developed and developing countries, as a result of obesity trends and sedentary lifestyles, the metabolic syndrome represents an increasing burden on healthcare systems. Management guidelines for dyslipidaemia have primarily focused on LDL-C reduction; however, this approach fails to sufficiently address other lipid abnormalities associated with the metabolic syndrome. Atherogenic dyslipidaemia (characterized by elevated triglycerides and low HDL-C) is strongly associated with insulin-resistant states, such as type 2 diabetes and the metabolic syndrome, and is also a common finding among patients receiving treatment for dyslipidaemia. Intervening against atherogenic dyslipidaemia may address a substantial modifiable fraction of residual cardiovascular risk that remains after treatment with a statin. Recent findings from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study support this view. Fenofibrate treatment was shown to be especially effective in treating marked atherogenic dyslipidaemia, with a significant 27% relative risk reduction for cardiovascular events (P=0.0005, vs. 11%, P=0.035 for all patients) relative to placebo. These data, together with the earlier demonstration of significant microvascular benefits associated with this treatment, suggest a role for fenofibrate, in addition to statin therapy and lifestyle intervention, for reducing global vascular risk in type 2 diabetes patients and for impacting atherogenic dyslipidaemia associated with the metabolic syndrome.

Resistant hypertension is a major opportunity for prevention of cardiovascular disease. Despite widespread dissemination of consensus guidelines, most patients are uncontrolled with approaches that assume that all patients are the same. Causes of resistant hypertension include 1) non-compliance 2) consumption of substances that aggravate hypertension (such as salt, alcohol, nonsteroidal anti-inflammatory drugs, licorice, decongestants) and 3) secondary hypertension. Selecting the appropriate therapy for a patient depends on finding the cause of the hypertension. Once rare causes have been eliminated (such as pheochromocytoma, licorice, adult coarctation of the aorta), the cause will usually be found by intelligent interpretation (in the light of medications then being taken) of plasma renin and aldosterone. If stimulated renin is low and the aldosterone is high, the problem is primary aldosteronism, and the best treatment is usually aldosterone antagonists (spironolactone or eplerenone; high-dose amiloride for men where eplerenone is not available). If the renin is high, with secondary hyperaldosteronism, the best treatment is angiotensin receptor blockers or aliskiren. If the renin and aldosterone are both low the problem is over-activity of renal sodium channels and the treatment is amiloride. This approach is particularly important in patients of African origin, who are more likely to have low-renin hypertension.

The emergence of new platforms for the discovery of innovative therapeutics has provided a means for diagnosing cardiac disease in its early stages. Taking into consideration the global health burden of cardiac disease, clinicians require innovations in medical diagnostics that can be used for risk stratification. Proteomic based studies offer an avenue for the discovery of proteins that are differentially regulated during disease; such proteins could serve as novel biomarkers of the disease state. For instance, in clinical practice, the abundance of such biomarkers in blood could be correlated with the severity of the disease state. As such, early detection of biomarkers would enable an improvement in patient prognosis. In this review, we outline advancements in various proteomic platforms used to study the disease proteome and their applications to the field of clinical medicine. Specifically, we highlight the contributions of proteomicbased profiling experiments to the analysis of cardiovascular diseases.

Cardiac MR imaging is an effective method for noninvasive imaging of the heart. The technology has been limited in the past because of imaging difficulties associated with cardiac motion. In recent years, however, cardiac MR imaging has broadened its spectrum of applications in cardiovascular disease with impressive advances in spatial and temporal resolution and increased imaging speeds. This review presents the current clinical applications of cardiac MR imaging for evaluation of cardiac disease in infiltrative disorders such as amyloidosis, hemochromatosis, and sarcoidosis.