Current Cardiology Reviews - Volume 2, Issue 3, 2006

There is growing clinical and epidemiological evidence supporting the concept that regular exercise training reduces the incidence of coronary events and increases the chance of survival after myocardial infarction. This protection is achieved through the reduction of many risk factors relating to cardiovascular disease, such as high blood pressure, high cholesterol, obesity etc. Moreover, exercise has been found capable of reproducing the phenomenon known as ischemic preconditioning (IP). This term identifies the capacity of short periods of ischemia to render the myocardium more resistant to a subsequent ischemic insult. Classically, the IP phenomenon refers to the ability to limit the infarct size. However, IP is a complex phenomenon which, along with infarct size reduction, can also provide protection against ischemia- and reperfusion-induced arrhythmia and myocardial stunning. There are several indications demonstrating that exercise may directly induce preconditioning, thus putting the heart in a protection status without the need for a prior ischemia. It appears that exercise acts as a physiological stress that induces beneficial myocardial adaptive responses at cellular level. The purpose of the present paper is to review the latest data on the role played by exercise in inducing myocardial preconditioning.

Matricellular proteins are extracellular matrix proteins that do not play a direct structural role but act contextually modulating cell function and activity. These structurally diverse proteins include Thrombospondin (TSP)-1 and -2, tenascin-C and -X, Osteonectin/SPARC (Secreted protein, acidic and rich in cysteine) and osteopontin (OPN). Matricellular proteins show low level expression in normal adult tissues, but are markedly upregulated in wound healing and tissue remodeling. Our review examines our current knowledge of the expression and role of the matricellular proteins in the infarcted heart. TSP-1 and tenascin-C are upregulated in the border zone of healing infarcts. TSP-1 null mice exhibit enhanced and prolonged inflammation and extension of the inflammatory infiltrate into the non-infarcted areas, suggesting a role for TSP-1 in containment of the inflammatory response. These defects are probably due to impaired TGF-β activation and lead to increased adverse remodeling. OPN is markedly upregulated in healing infarcts and is predominantly localized in a subset of macrophages. OPN -/- mice show increased left ventricular dilation and defective collagen deposition in the infarct. SPARC is also markedly induced in experimental models of infarction; however, its role in the healing process remains unknown. Matricellular proteins play an important role in the orchestration of the molecular events involved in infarct healing by modulating a wide range of cellular responses. Understanding the role of specific functional domains of the matricellular proteins in infarct healing may result in identification of novel therapeutic strategies aiming at optimizing cardiac repair.

Several inflammatory proteins intervene with endothelium and haemostatic factors leading to plaque formation and rupture. Of these, C-reactive protein (CRP), monocyte/macrophage colony-stimulating factor (MCSF) and interleukin- 6 (IL-6) promote atherogenesis by inducing monocyte-macrophage activation, foam cell formation, platelet activation, tissue factor expression, release of other procoagulant cytokines or downregulation of atheroprotective cytokines, namely interleukin 10 and transforming growth factor b-1 (TGF-b1). CRP, MSCF and IL-6 are interrelated and have been found increased in circulation in both chronic CAD and acute coronary syndromes. IL-6 is also related to the extent and duration of LV dysfunction following reversible myocardial ischaemia. TGF-b1 has been found decreased in patients with CAD and inversely related with MCSF. More importantly, increased levels of CRP or MCSF and low levels of TGFb-1 predict adverse cardiovascular events in CAD patients independently of traditional risk factors. Moreover, in patients with chronic CAD, the predictive value of MCSF is additive and beyond that of CRP suggesting the need of a "multimarker approach" in assessing cardiovascular risk. Although several therapeutic strategies like vaccination against antigens promoting atherogenesis, cyclooxygenase inhibitors (aspirin, coxibs), statins, and ACE inhibitors may reduce the levels of these inflammatory markers, the impact on cardiovascular risk resulting from these changes is unknown. Thus, inflammatory markers may serve as independent prognostic markers as well as therapeutic targets.

Vascular alterations in diabetes cause or contribute to the etiology of microvascular complications such as nephropathy, neuropathy, and retinopathy. The endothelium controls the vascular smooth muscle tone through the production of vasodilator mediators such as nitric oxide, prostacyclin, and a still-elusive endothelium-derived hyperpolarizing factor (EDHF). Although EDHF is a prominent vasodilator, particularly in smaller arteries, little attention has been paid to the potential role of EDHF responses in diabetes. EDHF function may involve the participation of mediators, including several diffusible factors and non-diffusible factors, (e.g., conduction of hyperpolarization via myoendothelial gap junctions). Indeed, in several vessels, cyclic adenosine 3',5'-monophosphate (cAMP) facilitates EDHF responses by enhancing electrotonic conduction via gap junctions. It has been demonstrated that the alterations in EDHF relaxation seen in mesenteric arteries from diabetic rats may be attributable to an increase in phosphodiesterase3 (PDE3) activity, leading to a reduction in the action of cAMP, and moreover the activity of protein kinase A (PKA) is decreased in such arteries. Although an improvement in EDHF responses has not been, as yet, the subject of any direct pharmaceutical effort, increasing cAMP/PKA signaling (e.g., by inhibiting PDE3 activity) has potential as an interesting therapeutic target in diabetic microvascular disease.

Nitric oxide (.NO) regulates mitochondrial oxygen uptake through reversible high-affinity binding to heme and Cu2+ centers of cytochrome oxidase, and sets adaptive responses to changes in blood flow, O2 availability and hypoxia, thyroid disorders, endotoxemia and cold adaptation. Moreover, subcellular traffic of.NO synthases (NOS) participates in the adjustment of mechanical cardiac efficiency. In isolated beating rat hearts,.NO and bradykinin promote a dosedependent decrease of myocardial O2 uptake and coronary perfusion pressure, without significant variations of the developed left ventricular pressure. Also, in human hearts.NO from NOS isoforms tunes mechanical performance. On these bases, NOS traffic to mitochondria acquires physiological significance. In liver and heart, mitochondrial NOS (mtNOS) was identified as the neuronal isoform (nNOSα) with postranslational modifications. This new class of NOS spatial confinement leads cells to save energy under particular circumstances. Likewise, thyroid status reciprocally regulates mtNOS expression and.NO yield, while it linearly regulates mitochondrial respiration and systemic oxygen uptake. In rats exposed to cold, a clear contribution of.NO from mtNOS to modulation of.VO2 and redistribution of energy expenditure was reported. We conclude that.NOS traffic and mtNOS activity are natural mechanisms to link mitochondria and cardiovascular responses to environmental and endogenously mediated challenges

The distressed personality (Type D) is an emerging risk factor in cardiovascular disease (CVD) that incurs a risk on par with left ventricular dysfunction in patients with ischemic heart disease. Type D is defined as the co-occurring tendencies to experience increased negative emotions and to inhibit self-expression in social interactions. Evidence is accumulating that Type D may also be a risk factor for adverse outcome across CVD patient groups, including patients undergoing revascularization with drug-eluting stent implantation or bypass surgery, patients with heart failure, peripheral arterial disease, and arrhythmia. In these patient groups, Type D personality has been associated with a 2-5 fold increased risk of adverse prognosis, impaired quality of life and symptoms of anxiety and depression independent of traditional biomedical risk factors, including disease severity. Although little is known about the pathways responsible for the detrimental effects of Type D on clinical outcome, the immune system and health-related behaviors, such as smoking and noncompliance, are likely candidates. Further research is warranted to investigate whether Type D personality is here to stay as a risk factor for CVD, but weighing current evidence on Type D against a set of external criteria shows that Type D personality fulfills the majority of these criteria. Importantly, Type D can easily be assessed in clinical research and practice with the standardized and validated DS14.

Despite the recent advances in the treatment of atherosclerotic vascular disease, more effective measures should be provided for the primary prevention in high-risk individuals. Serious adverse vascular events can be seen in individuals with low risk calculations based on standard cardiovascular risk factors including age, sex, history of smoking, low density lipoprotein, high density lipoprotein, diabetes and hypertension. These findings suggest the necessity of additional risk parameters. Recently, characterization of the clear association between atherosclerosis and inflammation lead to the use of several circulatory inflammatory markers for cardiovascular risk stratification. Among these markers high-sensitivity CRP is the most studied one. There are several studies reporting the value of high-sensitivity CRP in defining cardiac adverse events both in patients with acute coronary syndromes and those without known cardiovascular disease. Moderately elevated high-sensitivity CRP levels are associated with increased cardiovascular event rates independent from the other risk factors. Highsensitivity CRP adds more information to the risk defined by lipid levels, so helps to define the candidates for statin therapy. This review summarizes high-sensitivity CRP, factors affecting high-sensitivity CRP, its role in risk stratifications and suggestions for its clinical use.

Human epidemiological studies have shown a clear association of adverse intrauterine environment and an increased risk of ischemic heart disease in later adult life. Although adult lifestyle adds to the effects developed during intrauterine life, compelling evidence indicates that the association of ischemic heart disease with adverse intrauterine environment does not reflect confounding variables linked to adult lifestyle. It is suggested that epigenetic programming in the gene expression pattern caused by adverse intrauterine environments at a critical period of development in early life plays an important role in the heart development, and its lifelong pathophysiological consequences in the adult heart. Potential fetal programming of adult disease has been shown in maternal undernutrition and fetal exposure to glucocorticoids, hypoxia, alcohol, tobacco smoking, and cocaine. Although early epidemiological studies suggest that small body size at birth is associated with an increased risk of death from ischemic heart disease in the adult, it is becoming clear that fetal growth restriction is not a prerequisite of adult disease. Recent animal studies suggest that adverse intrauterine environments suppress fetal cardiac function, alter cardiac gene expression pattern, increase apoptosis of cardiomyocytes, cause a premature exit of the cell cycle of cardiomyocytes and myocyte hypertrophy, and result in an increase in susceptibility of the adult heart to ischemia-reperfusion injury. This review discusses recent epidemiological evidence in humans, as well as evidence from studies in experimental animals, of an association of adverse intrauterine environments and an increased risk of ischemic heart disease in the adult, and the possible molecular mechanisms of epigenetic programming involved in fetal gene expression pattern, which is essential in explaining many fundamental biological processes by which a variety of cardiovascular dysfunctions and disease emerge and evolve.