Current Cardiology Reviews - Volume 3, Issue 2, 2007

Uric acid is produced by the degradation of purines, a process catalysed by xanthine oxidase, which is also responsible for the production of toxic free radicals. This provides a central link to the association between serum uric acid and myocardial ischemia, myocardial dysfunction and also non-cardiac dysfunction in patients with heart disease, mainly due to an impaired peripheral circulation. Uric acid can thus be considered a marker for pathophysiological mechanisms in patients with heart disease, and thus an explanation for S-uric acid's prognostic importance. Inhibition of xanthine oxidase by allopurinol may possibly be used as a therapy for patients with heart disease in the future.

Cardiovascular disease is the major cause of morbidity and mortality in patients with chronic kidney disease (CKD). Cardiac event rate rises as the glomerular filtration rate decreases, particularly below 60 ml/min/1.73m2. This risk remains even after adjustment for traditional risk factors. In patients with end stage renal failure (ESRF), death rates from cardiovascular disease are 20 to 40 times higher than in the general population and make up 40% of all-cause mortality. Furthermore, 72% patients with ESRF who suffer an acute myocardial infarction are dead within 2 years. Interestingly, whilst coronary artery atherosclerosis is more common in patients with CKD and risk of plaque rupture greater, only a third of the cardiac events in dialysis patients are associated with myocardial infarction; two thirds are due to sudden cardiac death or cardiac failure. Taken together, these observations suggest there is a more complex pattern of cardiovascular injury in patients with kidney disease. We propose to review the current understanding of vascular disease in CKD, the relation of vascular disease to cardiac disease and outcomes, using accumulating data regarding both acute and chronic inflammation. We postulate that the complex pattern of cardiovascular injury is due to these processes, which are understudied and under-recognized and are likely to be modified in the context of CKD. We suggest a direction of study, which may help to identify the nature of the vascular injury in CKD, understand the impact of this on cellular and clinical events, and ultimately help to design interventional studies targeted at specific patient groups.

Well developed coronary collateral arteries in patients with coronary artery disease (CAD) mitigate myocardial infarcts with less ventricular aneurysm formation and improved ventricular function, they reduce future cardiovascular events, and improve survival. Myocardial infarct size is a product of coronary artery occlusion time, area at risk for infarction and the inverse of collateral supply. Collateral arteries preventing myocardial ischemia during brief vascular occlusion are present in 1/3 of patients with CAD. Collateral flow sufficient to prevent myocardial ischemia during coronary occlusion amounts to ≥25% of the normal flow through the open vessel. Among individuals without relevant coronary stenoses, there are preformed collateral arteries preventing myocardial ischemia in 20-25%. Coronary collateral flow can be assessed only during vascular occlusion of the collateral-receiving artery. Presently, the gold standard for clinical coronary collateral assessment is the measurement of intracoronary occlusive pressure- or velocity- derived collateral flow index which expresses collateral as a fraction of flow during vessel patency. Clinical variables predicting the development of collateral arteries are the hemodynamic severity of coronary stenoses and the duration of myocardial ischemic symptoms. One fifth to one third of patients with CAD cannot be revascularized by percutaneous coronary intervention or coronary artery bypass grafting; therapeutic promotion of collateral growth appears to be a valuable treatment strategy in those patients. Promotion of collateral growth should aim at inducing the development of large conductive collateral arteries (i.e. arteriogenesis) and not so much the sprouting of capillary like vessels (i.e. angiogenesis). So far, the largest, controlled clinical angiogenesis trials on the efficacy of VEGF and basic FGF have been negative with regard to treadmill exercise time and myocardial scintigraphic data. Large conductive collateral arteries (i.e. arteriogenesis) appear to be effectively promoted via the activation of monocytes / macrophages, which release VEGF, FGF, tumor necrosis factor alpha, granulocyte colony stimulating factors and other growth and remodelling-associated factors.

Post infarction left ventricular remodeling is a compensatory response to an acute myocardial infarction that is characterized by left ventricular dilation and myocardial hypertrophy. Although stable left ventricular remodeling may be achieved for a period of time, progressive myocardial dysfunction usually develops and ultimately leads to overt congestive heart failure. Heart failure is considered an end-stage, irreversible clinical condition for which current medical management strategies merely relieve symptoms, slow deterioration, and prolong life modestly. In recent years, stem cell transplantation has emerged as a potential “preventive” therapy for detrimental ventricular remodeling and progression to heart failure. The therapeutic approach is based on the notion that stem or progenitor cells can be delivered to the site of injury to directly or indirectly instigate repair of the damaged myocardium. This novel approach offers an unprecedented opportunity to treat the underlying loss of myocytes, restore function to the scar tissue in the infarct region and inhibit the cascade of events leading to congestive heart failure. This review focuses on recent research in the field of adult stem cell-based cellular therapy. In addition, stem cell mobilization with cytokines and growth factors to initiate endogenous repair of the infarct region is briefly discussed. Although cellular therapy shows great clinical promise, many hurdles remain before the possibility of widespread clinical use. However, the intense research efforts will likely lead to the development of effective cellular therapies against cardiovascular and other degenerative diseases.

The diagnosis of Takotsubo cardiomyopathy (TC) must be considered in all patients who develop transient left ventricular apical (or mid ventricular) ballooning in the absence of obstructive coronary artery disease (CAD). Although the prevalence of TC remains unknown, approximately 2% of all patients presenting with a presumed diagnosis of ST elevation myocardial infarction have been found to have this syndrome. TC usually occurs in the setting of physical or emotional stress associated with excessive sympathetic stimulation and catecholamine release. A literature review and illustrative case report are provided.

Heat Shock Proteins (HSPs) are intracellular molecular chaperones, which preserve protein folding and protect cells from injury. Intracellularly, their normal location, HSPs are protective. HSPs can also be found in the extracellular compartment, either after necrotic cell death or independent of cell death. The physiologic function of exogenous HSPs remains elusive. However, extracellular as well as membrane- localized HSPs have been implicated in the pathogenesis of a number of diseases including type I diabetes, Crohn's, atherosclerosis and juvenile chronic arthritis. It is thought that HSPs can provoke an immune response either by directly activating the innate immune system, or through the adaptive immune response leading to production of antibodies, possibly as a result of prior exposure to the bacterial HSPs, which have great sequence similarity. Extracellular HSPs can activate Toll-like receptors (TLR), and induce the production of cytokines; but, intracellular HSPs can downregulate cytokine production and mediate myocardial protection. Production of nitric oxide may trigger HSPs, ameliorating cardiotoxic effects of cytokines. Apoptosis has come into focus as a contributing factor for ischemia/reperfusion injury, and conflicting data exist about a potentially beneficial or deleterious role of HSPs. Although novel therapeutic strategies include elevation of specific HSPs, the interplay of HSPs in the clinical setting is poorly understood.

In this review, the enhanced activity of the cardiac Na+/H+ exchanger is considered to be a key step in the intracellular signaling pathway leading to cardiac hypertrophy, and the inhibition of the exchanger is a pharmacological tool to prevent or regress it. This enhanced activity has been demonstrated after stretching neonatal rat cardiomyocytes and cat papillary muscles. In the latter preparation, the activation of the exchanger results in a mechanical counterpart, the slow force response to stretch. The chain of events triggered by a stretch begins with the release of angiotensin II (Ang II), which in turn releases endothelin (ET) and ends with the increase in [Ca2+]i through the Na+/Ca2+ exchanger (NCX) in its reverse mode and the activation of the calcineurin/NFAT pathway. It should be emphasized that the link proposed herein between myocardial stretch and Ang II/ET relies upon the release of small amounts of these peptides. Higher concentrations of either of them may trigger Ca2+ influx through mechanisms other than NCX, and induce cardiac hypertrophy by the activation of widely recognized intracellular signaling pathways.