Heart Failure in Aortic Regurgitation: The Role of Primary Fibrosis and Its Cellular and Molecular Pathophysiology

Borer²,

2013

Cardiology

Section: Vhd Interrelationshipsmentioning

confidence: 99%

Etiology of Valvular Heart Disease in the 21st Century

Borer²,

2013

Cardiology

Biomech Model Mechanobiol

“…It is now well recognized that mechanical forces play a fundamental role in the regulation of cell functions, including gene induction, protein synthesis, cell growth, death, and differentiation, which are essential to maintain tissue homeostasis. Conversely, abnormal mechanical loading conditions alter cellular function and change the structure and composition of the extracellular matrix (ECM), eventually leading to tissue or organ pathologies such as osteoporosis, osteoarthritis, tendinopathy, atherosclerosis, and fibrosis in the bone, cartilage, tendon, vessels, heart, lung, and skin (Ross 1986;Chicurel et al 1998;Grodzinsky et al 2000;Ireland et al 2001;Riley et al 2002;Ingber 2003;Bag et al 2004;Borer et al 2004;Eckes and Krieg 2004;Lammerding et al 2004).…”

mentioning

confidence: 99%

An Introductory Review of Cell Mechanobiology

Wang

Thampatty

2006

493

359

Mechanical loads induce changes in the structure, composition, and function of living tissues. Cells in tissues are responsible for these changes, which cause physiological or pathological alterations in the extracellular matrix (ECM). This article provides an introductory review of the mechanobiology of load-sensitive cells in vivo, which include fibroblasts, chondrocytes, osteoblasts, endothelial cells, and smooth muscle cells. Many studies have shown that mechanical loads affect diverse cellular functions, such as cell proliferation, ECM gene and protein expression, and the production of soluble factors. Major cellular components involved in the mechanotransduction mechanisms include the cytoskeleton, integrins, G proteins, receptor tyrosine kinases, mitogen-activated protein kinases, and stretch-activated ion channels. Future research in the area of cell mechanobiology will require novel experimental and theoretical methodologies to determine the type and magnitude of the forces experienced at the cellular and sub-cellular levels and to identify the force sensors/receptors that initiate the cascade of cellular and molecular events.

American Journal of Physiology-Heart and Circulatory Physiology

“…heart hypertrophy; gene expression; renin-angiotensin system; adrenergic system SEVERE AORTIC VALVE REGURGITATION (AR) is associated with a long asymptomatic period during which the left ventricle (LV) progressively dilates and hypertrophies in response to a chronic volume overload. This process is accompanied by a decrease in LV function, occurrence of symptoms, and eventually heart failure (4,7). No drug has yet been clearly shown in humans to be effective to slow LV dilation, hypertrophy, and loss of systolic function or to have any impact on morbidity or mortality in chronic AR (5,15).…”

mentioning

confidence: 99%

Gene profiling of left ventricle eccentric hypertrophy in aortic regurgitation in rats: rationale for targeting the β-adrenergic and renin-angiotensin systems

Champetier¹,

Bojmehrani²,

Beaudoin³

et al. 2009

profiling of left ventricle eccentric hypertrophy in aortic regurgitation in rats: rationale for targeting the ␤-adrenergic and renin-angiotensin systems. Am J Physiol Heart Circ Physiol 296: H669 -H677, 2009. First published December 26, 2008 doi:10.1152/ajpheart.01046.2008.-Aortic valve regurgitation (AR) imposes a severe volume overload to the left ventricle (LV), which results in dilation, eccentric hypertrophy, and eventually loss of function. Little is known about the impact of AR on LV gene expression. We, therefore, conducted a gene expression profiling study in the LV of rats with acute and severe AR. We identified 64 genes that were specifically upregulated and 29 that were downregulated out of 21,910 genes after 2 wk. Of the upregulated genes, a good proportion was related to the extracellular matrix. We subsequently studied a subset of 19 genes by quantitative RT-PCR (qRT-PCR) to see if the modulation seen in the LV after 2 wk persisted in the chronic phase (after 6 and 12 mo) and found that it did persist. Knowing that the adrenergic and renin-angiotensin systems are overactivated in our animal model, we were interested to see if blocking those systems using metoprolol (25 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) and captopril (100 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) would alter the expression of some upregulated LV genes in AR rats after 6 mo. By qRT-PCR, we observed that upregulations of LV mRNA levels encoding for procollagens type I and III, fibronectin, atrial natriuretic peptide, transforming growth factor-␤2, and connective tissue growth factor were totally or partially reversed by this treatment. These observations provide a molecular rationale for a medical strategy aiming these systems in the medical treatment of AR and expand the paradigm in the study of this form of LV volume overload. heart hypertrophy; gene expression; renin-angiotensin system; adrenergic system SEVERE AORTIC VALVE REGURGITATION (AR) is associated with a long asymptomatic period during which the left ventricle (LV) progressively dilates and hypertrophies in response to a chronic volume overload. This process is accompanied by a decrease in LV function, occurrence of symptoms, and eventually heart failure (4, 7). No drug has yet been clearly shown in humans to be effective to slow LV dilation, hypertrophy, and loss of systolic function or to have any impact on morbidity or mortality in chronic AR (5, 15).At the microscopic level, AR is associated with cardiomyocyte elongation and excessive but mostly noncollagen myocardial fibrosis (fibronectin) (6, 23). Although gene expression profiling in LV eccentric hypertrophy resulting from volume overload has been studied recently in an aortocaval fistula rat model (25), very little is known about the mechanisms of LV hypertrophy and extracellular matrix (ECM) remodeling associated with a more clinically common form of LV volume overload, namely AR. Aortocaval fistula models relate to a clinically rather rare complication of aortic aneurysm or secondary to abdominal trauma in humans (21). Moreover, aortocaval ...