Current Cardiology Reviews - Volume 2, Issue 4, 2006

Postischemic reperfusion causes microvascular endothelial cell dysfunction characterized by low shear stress, excessive oxidative stress and a reduced nitric oxide (NO) release. Recent studies have demonstrated that reduced shear forces are responsible for the impairment of endothelium-dependent vasodilation after ischemia reperfusion (I/R) injury. Preconditioning is an endogenous phenomenon whereby intermittent periods of ischemia provide protection against subsequent periods of I/R. Several models show that intermittent hypoxia (IH, brief periods of systemic hypoxia and reoxygenation), treatment with erythropoietin (EPO) and ultrasound exposure are methods of preconditioning. This chapter explores the hypothesis that these procedures that improve tolerance to subsequent I/R are directly related to shear stress. It acts as a biochemical mechanotransducer by modulating the production of vasoactive substances by endothelial cells. The adaptation of endothelial cells to high shear stress during the preconditioning period is crucial to ensure vasodilation and capillary perfusion during subsequent periods of I/R. Both IH and EPO treatment increase blood viscosity thus increasing shear stress associated with a reduced oxidative stress during postischemic reperfusion. Ultrasound treatment can also improve tolerance to I/R and normale shear stress during postischemic reperfusion by pulsatile mechanism acting on endothelial cells.

There is growing evidence that oxidative stress is involved in the pathogenesis of atrial fibrillation. Many known triggers of oxidative stress, such as age, diabetes, smoking, inflammation, and renin angiotensin system activation are linked with an increased risk of the arrhythmia. Blockers of angiotensin II signaling and other drugs with anti-oxidant properties can reduce the incidence of atrial fibrillation. Now, studies in animal models and human tissue have shown directly that atrial fibrillation is associated with increased atrial oxidative stress. We review the evidence for a role of oxidative stress in causing atrial fibrillation and propose a unifying hypothesis that multiple triggers elicit oxidative stress which acts to enhance the risk of atrial fibrillation through ion channel dysregulation.

The current knowledge of the development and progression of atherosclerotic lesions is largely owed to experimental studies carried out in animals fed a high cholesterol diet. Only a few studies have addressed the atherogenic effects of other important exogenous risk factor, namely cigarette smoking. The results of our research into the effects of cigarette smoking on the fetal arterial wall have demonstrated that the first reactive event is a severe alteration of the architecture of the tunica media, forming perpendicularly oriented columns of smooth muscle cells (SMCs), infiltrating the intima. These histopathological alterations go hand in hand with a marked change in the biological homeostasis of the SMCs. Our molecular biology research has shown that the first reaction of these cells to the nicotine is an intense activation of the c-fos proto-oncogene, followed by the transformation of the SMCs to “myofibroblasts”, characterized by the presence of β-actin and acquisition of both synthetic and ameboid activity. If the harmful effects of passive smoke persist, the myofibroblasts start to proliferate, as demonstrated by positivity of the PCNA, together with the onset of chromosomal alterations. These peculiar changes of the tunica media are the prerequisites for lipid accumulation that thereafter overwhelm the myofibroblast reaction.

The recently discovered protein family of NADPH oxidases (NOX) is a group of transmembrane proteins that generate reactive oxygen species (ROS) by transferring electrons from NADPH onto molecular oxygen. The NOX proteins are the catalytic subunits that assemble with several regulatory subunits to form the catalytically active enzyme complex. Of the regulatory subunits exist several isoforms that are differentially expressed in a wide range of tissues. In relation to the heart, low NOX1 expression has been described in the coronary vascular system, NOX2 expression in cardiomyocytes, vascular smooth muscle (VSMCs) and endothelial cells, and NOX4 seems to be present in VSMCs, fibroblasts and endothelial cells. While the prototypical NOX2 in phagocytes generates high bursts of superoxide that are needed to kill off invading pathogens, the other members of this family, as well as NOX2 in nonphagocytic tissues, are responsible for the generation of lower levels of ROS that are essential for cell signalling. Since the first demonstration of the basic principle of NADPH-oxidase-dependent redox signalling some ten years ago, NADPH-oxidase-derived ROS have been implicated in all major signalling pathways in most, if not all, tissue types. In the heart, ROS have been shown to play a role in cell proliferation, hypertrophy, apoptosis, differentiation and endothelial activation and adhesivity. Not surprisingly, therefore, NADPH oxidases have been implicated in the pathophysiologies of diabetes, hypertension, atherosclerosis, cardiac hypertrophy, heart failure, preconditioning and acute myocardial infarction, both by dysregulation of redox-based signalling pathways and by oxidative modification of a wide range of biomolecules. This review will briefly present the different NOX-family members and summarize our current knowledge concerning their regulation. Thereafter, we will give an overview of the expression patterns of the NOX-family members in the heart, both in health and disease, and will review their role in the (patho)physiology of the heart. Finally the present-day therapeutic opportunities in the form of the 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, will be critically assessed.

A quantitative assessment of regional cardiac performance is required for the diagnosis of disease, evaluation of severity and the quantification of treatment effect. MRI allows the noninvasive quantification of motion and deformation in the heart, including the precise assessment of all components of deformation in all regions of the heart throughout the cardiac cycle. In recent years, these imaging protocols have become standardized in both the research and clinical settings. However, adoption in the routine clinical environment has been hindered by the complex and time-consuming nature of the image post-processing. Model-based image analysis procedures provide a powerful mechanism for the fast, accurate assessment of cardiac MRI data and lend themselves to biophysical analysis and standardized functional mapping procedures. This paper reviews the current state of the art in MRI assessment of cardiac performance with an emphasis on mathematical modeling analysis procedures. Firstly, fast and accurate evaluation of mass and volume is discussed using interactive 4D modeling techniques. Analysis of tissue function, strain and strain rate is then reviewed. Mathematical models of regional tissue function and wall motion allow registration between cases and across groups, enabling quantification of multidimensional patterns of wall motion between disease and treatment groups. Finally, information on myocardial tissue kinematics can be incorporated into biophysical models of cardiac mechanics and used to gain an understanding of how physiological tissue parameters such as contractility, ventricular compliance and electrical activation combine to effect whole heart function.

Identification of high-risk patients for sudden cardiac death (SCD) remains difficult. Non-invasive markers evaluating changes in heart rate and ventricular repolarisation (VR) have been developed to stratify this risk. Most studies using VR analysis rely on static analysis of the QT interval which is poorly reproducible and heart rate dependent. Dynamic VR analysis assesses QT interval modification according to RR duration of the precedent heart cycle. This relation is characterized by the linear regression QT/RR (y = ax+b) thus defined by its slope (a) and the value of the QT for a virtual null RR cycle (b). Analysis can be made for QTa (apex) and QTe (end). In healthy subjects, the difference of QT/RR slopes observed between day and night highly suggest that the QT/RR slope is influenced by the autonomic tone. The QT/RR slope is also influenced by clinical, physiological, pharmacological and various diseases associated with an increased risk of SCD. The prognostic value of the QT/RR slope for SCD has been demonstrated after myocardial infarction and in chronic heart failure. These results suggest that QT dynamicity is a promising tool able to identify patients at risk of SCD.

Background: The coronary circulation in cyanotic congenital heart disease (CCHD) encompasses extramural coronary arteries, basal coronary blood flow, flow reserve, the coronary microcirculation, and coronary atherogenesis. Methods: Coronary arteriograms were analyzed in 59 adults with CCHD. Dilated extramural coronaries were examined histologically in 6 patients. Basal coronary blood flow was determined with N-13 positron emission tomography in 14 patients and in 10 controls. Hyperemic flow was induced by intravenous dipyridamole pharmacologic stress. Immunostaining of coronary arterioles against SM alpha-actin permitted microcirculatory morphometric analysis. Non-fasting total cholesterols were retrieved in 279 patients in four categories: Group A---143 cyanotic unoperated, Group B---47 acyanotic after reparative surgery, Group C---41 acyanotic unoperated, Group D---48 acyanotic before and after operation. Results: Extramural coronary arteries were mildly or moderately dilated to ectatic in 49/59 angiograms. Histologic examination disclosed loss of medial smooth muscle, increased medial collagen, and duplication of internal elastic lamina. Basal coronary flow was appreciably increased. Hyperemic flow was comparable to controls. Alterations in coronary arteriolar length, volume and surface densities indicated remodeling of the microcirculation. Coronary Atherosclerosis was not detected in the either arteriograms or necropsy specimens. Conclusions: Extramural coronary arteries dilate in CCHD in response to endothelial vasodilator substances coupled with mural attenuation caused by medial abnormalities. Basal coronary flow was appreciably increased, but hyperemic flow was normal. Remodeling of the microcirculation was the key mechanism for preservation of flow reserve. The coronaries were atheroma-free because of hypocholesterolemia, hypoxemia, upregulated nitric oxide, low platelet counts, and hyperbilirubinrmia.

Primary and secondary strategies for preventing cardiac events remain a major challenge in cardiovascular diseases. To date, there is robust evidence that inhibition of the renin-angiotensin system by angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists significantly improves the outcome and prevents cardiac events in patients with coronary risk factors. This beneficial effect may be explained both by the reduction of arterial pressure, and by arterial pressure non-dependent effects. This observation raises at least one question: why does inhibition of the reninangiotensin system improve cardiac outcome of patients with risk factors? One answer could be that the renin-angiotensin system is up-regulated in these patients. Then one may ask another question: why and how is the renin-angiotensin system stimulated by markedly different conditions such as hypertension, diabetes, dyslipidemia, cigarette smoking and obesity? In these conditions, is there a common pathway that leads to stimulation of the renin-angiotensin system and explains the beneficial effect of inhibiting this system? On the basis of previous experimental and clinical studies, this review proposes an integrative pathophysiological representation of the path leading from major coronary risk factors to renin-angiotensin system activation and cardiac events mainly due to complications of coronary artery disease. This allows us to understand how the renin-angiotensin system is involved in coronary artery disease, and why inhibition of this system has such beneficial effects in patients with cardiovascular risk factors.