Left ventricular hypertrophy (LVH) is the major risk factor associated with myocardial failure. An explanation for why a presumptive adaptation such as LVH would prove pathological has been elusive. Insights into the impairment in contractility of the hypertrophied myocardium have been sought in the biochemistry of cardiac myocyte contraction. Equally compelling is a consideration of abnormalities in myocardial structure that impair organ contractile function while preserving myocyte contractility. For example, in the LVH that accompanies hypertension, the extracellular space is frequently the site of an abnormal accumulation of fibrillar collagen. This reactive and progressive interstitial and perivascular fibrosis accounts for abnormal myocardial stiffness and ultimately ventricular dysfunction and is likely a result of cardiac fibroblast growth and enhanced collagen synthesis. The disproportionate involvement of this nonmyocyte cell, however, is not a uniform accompaniment to myocyte hypertrophy and LVH, suggesting that the growth of myocyte and nonmyocyte cells is independent of each other. This has now been demonstrated in in vivo studies of experimental hypertension in which the abnormal fibrous tissue response was found in the hypertensive, hypertrophied left ventricle as well as in the normotensive, nonhypertrophied right ventricle. These findings further suggest that a circulating substance that gained access to the common coronary circulation of the ventricles was involved. This hypothesis has been tested in various animal models in which plasma concentrations of angiotensin II and aldosterone were varied. Based on morphometric and morphological findings, it can be concluded that arterial hypertension (i.e., an elevation in coronary perfusion pressure) together with elevated circulating aldosterone are associated with cardiac fibroblast involvement and the resultant heterogeneity in tissue structure. Nonmyocyte cells of the cardiac interstitium represent an important determinant of pathological LVH. The mechanisms that invoke short- (e.g., collagen metabolism) and long-term (e.g., mitosis) responses of cardiac fibroblasts require further investigation and integration of in vitro with in vivo studies. The stage is set, however, to prevent pathological LVH resulting from myocardial fibrosis as well as to reverse it.

Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system.

HYPERTENSIVE heart disease can be defined as the response of the heart to the afterload imposed on the left ventricle by the progressively increasing arterial pressure and total peripheral resistance produced by hypertensive vascular disease. Although the response sometimes appears to be out of proportion to the level of the arterial pressure, it is primarily the result of the hemodynamic overload. Hypertension can cause or is related to various cardiac manifestations, among them left ventricular hypertrophy, congestive heart failure, cardiac dysrhythmias, and ischemic heart disease. Although the risk of atherosclerotic coronary heart disease is related to the systolic and diastolic . . .

The heart in hypertension.

Time for primary review 24 days.

Animals have been used by humans for centuries to understand their own biology. In cardiovascular research, animal models have allowed the study of cardiovascular disease in the early stages, as well as the investigation of the mechanisms of the pathogenesis of cardiovascular disease and the effects of drug intervention. The aim of these studies is to provide clear concepts for selected investigations in humans. An ideal animal model for any cardiovascular disease in humans should have five characteristics: (i) mimic the human disease, (ii) allow studies in chronic, stable disease, (iii) produce symptoms which are predictable and controllable, (iv) satisfy economical, technical and animal welfare considerations, and (v) allow measurement of relevant cardiac, biochemical and haemodynamic parameters.

The use of rats as animal models is rational from the economic viewpoint and many techniques have been developed to measure relevant functional parameters. However, there is often insufficient consideration as to whether the other criteria, especially the mimicry of human disease, are satisfied with the choice of rat models of cardiovascular disease. Three examples illustrate the problems. Firstly, cardiovascular diseases such as hypertension and heart failure in humans are usually slowly developing with wide-ranging neurohumoral adaptations in contrast to the acute onset of symptoms in many surgical or drug-induced rat models of these important diseases. Secondly, cardiovascular disease is uncommon in young humans but markedly increases with age [1]yet most models of hypertension and heart failure only use young adult rats. Animal models of ageing have been recently reviewed [2]. Thirdly, the development of atherosclerosis is very unusual in most strains of rats, even in the presence of sustained high blood lipid levels, in contrast to humans where atherosclerosis is common and an important risk factor in hypertension and heart failure.

Although this review … 

* Corresponding author. Tel.: +64 (9) 373 7599 ext. 6418; Fax: +64 (9) 373 7556.

/pdf/rat-models-of-hypertension-cardiac-hypertrophy-and-failure-31gf392ido.pdf

Rat models of hypertension, cardiac hypertrophy and failure.

Heart failure with preserved ejection fraction (HFpEF) affects half of all patients with heart failure worldwide, is increasing in prevalence, confers substantial morbidity and mortality, and has very few effective treatments. HFpEF is arguably the greatest unmet medical need in cardiovascular disease. Although HFpEF was initially considered to be a haemodynamic disorder characterized by hypertension, cardiac hypertrophy and diastolic dysfunction, the pandemics of obesity and diabetes mellitus have modified the HFpEF syndrome, which is now recognized to be a multisystem disorder involving the heart, lungs, kidneys, skeletal muscle, adipose tissue, vascular system, and immune and inflammatory signalling. This multiorgan involvement makes HFpEF difficult to model in experimental animals because the condition is not simply cardiac hypertrophy and hypertension with abnormal myocardial relaxation. However, new animal models involving both haemodynamic and metabolic disease, and increasing efforts to examine human pathophysiology, are revealing new signalling pathways and potential therapeutic targets. In this Review, we discuss the cellular and molecular pathobiology of HFpEF, with the major focus being on mechanisms relevant to the heart, because most research has focused on this organ. We also highlight the involvement of other important organ systems, including the lungs, kidneys and skeletal muscle, efforts to characterize patients with the use of systemic biomarkers, and ongoing therapeutic efforts. Our objective is to provide a roadmap of the signalling pathways and mechanisms of HFpEF that are being characterized and which might lead to more patient-specific therapies and improved clinical outcomes.

Cellular and molecular pathobiology of heart failure with preserved ejection fraction.

Blood pressure-independent effect of angiotensin inhibition on vascular lesions of chronic renal failure.

An abnormal elevation in collagen concentration or myocardial fibrosis occurs in the hypertrophied left ventricle of the rat with renovascular hypertension (RHT). The structural nature and functional consequences of this fibrosis and the mechanisms involved in its appearance were reviewed for various phases of hypertrophy. Within days after the onset of renal ischemia, type I collagen messenger ribonucleic acid is expressed. An interstitial fibrosis follows, characterized by an increased dimension of existing perimysial fibers and the appearance of fibrillar collagen in spaces previously devoid of collagen, together with a perivascular fibrosis of intramyocardial coronary arteries. These expressions of myocardial fibrosis are associated with an increase in diastolic and systolic myocardial stiffness. Endomyocardial fibrosis serves to further increase diastolic stiffness while myocytes encircled by fibrillar collagen become atrophic. Each of these consequences of myocardial fibrosis reduce myocyte length-dependent force generation. At 32 weeks of RHT there is an obvious diastolic and systolic dysfunction of the ventricle together with heart failure that includes ventricular dilatation, wall thinning and reduced ejection fraction. The mechanisms involved in mediating fibrosis in RHT appear to be multiple. Myocyte necrosis and fibroblast proliferation have been associated with elevated circulating angiotensin II. Necrosis in RHT was not seen with captopril pretreatment or in the hypertension and hypertrophy that accompanied infrarenal aorta banding. An alteration in coronary artery permeability may be responsible for the perivascular fibrosis that is not seen with captopril pretreatment. Thus in RHT, the hemodynamic status of the ventricle determines myocyte hypertrophy while the elevation in circulating angiotensin II is responsible for the remodeling of nonmyocyte compartments, including the appearance of myocardial fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial fibrosis and pathologic hypertrophy in the rat with renovascular hypertension

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Myocardial fibrosis and pathologic hypertrophy in the rat with renovascular hypertension