Pre-load reduction decreases myocardial wall stress despite a small impact on blood pressure: a potential strategy to revert cardiac remodelling?
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In response to an increased afterload, the myocardium undergoes a complex adaptation by which wall stress is normalized and cardiac output is maintained. Although the consensus suggests that the increase of the myocardial mass is a necessary adaptive process to accommodate the increased workload, there is growing evidence that hypertrophy ultimately results in pathological remodeling and deterioration of cardiac function. Despite intense investigation, our understanding of the cellular mechanisms that are responsible for the initiation and the maintenance of this adaptation is largely incomplete and preventing or regressing left ventricular hypertrophy (LVH) is a major challenge. This chapter provides a detailed description of the procedures necessary to induce LVH by coarctation of the transverse aorta and to analyze the effects of the increased hemodynamic load on cardiac mass, cardiomyocyte size, and cardiac performance.
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Myocardial infarction (MI) is the common cause of heart failure, which happens following a myocardial ischemia. Left ventricular (LV) remodeling has been associated with the long-term outcomes following MI. The infarct region is growing and becoming stiffen over time as a result of remodeling, causing the LV to weaken and dilate. However, the evolution of the infarct growth starting from the shortage of the oxygen supply have not been extensively studied, thus further work involving a complete cardiac cycle is required to study the progressive effect of ischemic changes on both active and passive myocardial behaviors. This work aims to investigate the motion of the ischemic myocardial wall in a complete cardiac cycle using a 3D electro-chemical mechanical coupled mathematical model. The study on how the shortage of oxygen and different wall thickness affects the ischemic myocardium wall motion over time will also be examined. The finding shows a reduction in strain value at the early systole, which suggests a progressive stiffening of ischemic myocardium that contributes to the increase of the peak wall stress over time. Peak wall stress is an important determinant of myocardial oxygen consumption. Reduction of the wall thickness will increase the occurrence of the peak systolic wall stress.
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Myocardial hypertrophy in different cardiac diseases is considered to be an adaptive mechanism to the increase of hemodynamic load which might restore to normal radius/wall thickness ratio and consequently to normalize wall stress. However, it has been widely demonstrated that beside the hemodynamic load, other factors contribute to the development of myocardial hypertrophy. It has been shown that in hypertensive patients, functional abnormalities (increased contribution of atrial systole to total diastolic filling, increased isovolumic relaxation period, prolonged diastolic duration, slowed ventricular filling and altered diastolic distensibility) precede the development of myocardial hypertrophy. Thus, in hypertensive patients, sign and symptoms of heart failure could be manifested in absence of myocardial hypertrophy, and might be exclusively due to diastolic dysfunction (with normal systolic function). Systolic function might be involved and compromised late when focal myocardial cell death and fibrosis occur and consequently ¿adequate¿ hypertrophy is shifted to ¿inadequate¿. This evolution is accompanied by morphological and functional changes of the myocardium similar to those encountered in dilated cardiomyopathy. Impairment of systolic function in ¿inadequate¿ hypertrophy is also due to structural changes; altered ratio between sarcomers and mitochondria, increased intercapillary distance, sarcoplasmatic reticulum dysfunction, increase of collagene component with a consequent increment of wall rigidity, hypertrophy of arterial tunica media, which alters coronary flow and coronary reserve. The progression of these morpho-functional abnormalities is a very slow process, in which adaptive mechanism mediated by several enzymes and contractile protein, contribute to maintain myocardial viability. However, over the long course, disseminated focal myocardial cell necrosis and fibrosis, which is an evolving process, is considered to be the main responsible factor for the irreversible myocardial damage and systolic dysfunction in advanced myocardial inadequate hypertrophy.
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The terminal phases of volume-overload heart failure are characterised by eccentric ventricular hypertrophy. Relatively little attention has been directed to exploring the mechanisms involved in this development. The increase in diastolic wall stress leads to replication of the sarcomeres in series. The hypertrophied myocyte has a defective contractile ability that is due to an intrinsic depression of contractility; this is restored when failure is reversed. The development of appropriate hypertrophy is dependent upon adequacy of the coronary blood supply to the failing myocytes. Reduction of preload and after-load can be expected to be more effective in reducing systolic wall stress, and hence myocardial oxygen demands, in eccentric hypertrophy than in the nonfailing heart with concentric hypertrophy. However, there is no information available on the influence of anti-heart-failure drugs on the myocardial hypertrophy associated with severe volume-overload failure. The presence of such hypertrophy carries an ominous prognosis and may be associated with the high incidence of arrhythmic sudden deaths. The detection of myocardial hypertrophy in the patient with failure emphasises the urgency of adequate reduction of the elevated preload and afterload without impairment of the coronary perfusion gradient.
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An acute myocardial infarction, particularly one that is large and transmural, can produce expansion and alterations in the topography of both the infarcted and non-infarcted regions or the ventricle. This remodelling can importantly affect the function of the ventricle and the prognosis. Side-to-side slippage of myocytes in the myocardium occurring in association with ventricular dilatation is responsible for wall thinning. The increased internal load that is sustained through the cardiac cycle is thought to promote further stress, dilatation and hypertrophy of the non-infarcted area. The collagen network has been showed to be high responsible for the remodelling of the interstitium and therefore for the scar formation involved in the expansion. The process for ventricular enlargement can be influenced by infarct size, healing end ventricular wall stresses. The process of scarification can be interfered with during the acute infarct period by the administration of glucorticosteroids and non-steroidal anti-inflammatory agents, which results in thinner infarct and further expansion. A most effective way to prevent or minimize the increase in ventricular size is to limit the initial insult. Acute thrombolytic reperfusion therapy may work in this way. Finally early and long-term therapy with an angiotensin converting enzyme inhibitor can favorably alter the loading conditions of the left ventricle, reducing progressive enlargement with a prolongation in survival.
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Left ventricular hypertrophy is an adaptation of the cardiac fibre to the imposed mechanical overload. This adaptation is quantitative; increased numbers of contractile units with decreased wall stress. Qualitative changes in genomic expression allow the hypertrophied cardiac fibre to develop a normal active tension at the expense of its maximal shortening velocity. These changes are preceded by the temporary expression of proto-oncogenes, of genes of the proteins of thermal shock and by reorganisation of the cytoskeleton, all possible candidates of the regulation of the gene expression in cardiac hypertrophy. In the long-term, the hypertrophy becomes harmful: inadequate subendocardial vascular development; the lowering of the Vmax is beneficial at cellular level but eventually affects cardiac output; ventricular compliance decreases with the development of fibrosis; changes in calcium metabolism are arrhythmogenic. Modifying, prolonging and improving the natural process of adaptation is clearly the first therapeutic objective in order to decrease the hypertension and cause the hypertrophy to regress. Propranolol acts by reducing the cardiac work load. However, betablockers have the disadvantage of increasing the relative density of the subendocardial collagen. Rilmenidine decreases the quantity and density of the collagen. Vasodilators and diuretics induce regression of the myocytic hypertrophy by lowering the threshold of adaptation of these cells, but they have no effect on collagen synthesis. Angiotensin converting enzyme inhibitors which have been shown to be beneficial in controlling hypertension, induce a decrease in the hypertrophy of the myocytes and reduce fibrosis.
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