Pathophysiologic mechanisms of calcific aortic stenosis (original) (raw)
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Calcification in Aortic Stenosis
Aortic stenosis is a common, potentially fatal condition that is set to become an increasing public health burden. Once symptoms develop, there is an inexorable deterioration with a poor prognosis. Despite this, there are no medical therapies capable of modifying disease progression, and the only available treatment is aortic valve replacement, to which not all patients are suited. Conventional teaching suggests that aortic stenosis is a degenerative condition whereby "wear and tear" leads to calcium deposition within the valve. Although mechanical stress and injury are important factors, it is becoming increasingly appreciated that aortic stenosis is instead governed by a highly complex, regulated pathological process with similarities to skeletal bone formation. This review discusses the pathophysiology of aortic stenosis with an emphasis on the emerging importance of calcification, how this can be visualized and monitored using noninvasive imaging, and how our improved knowledge may ultimately translate into novel disease-modifying treatments. (J Am Coll Cardiol 2015;66:561-77)
Calcific aortic stenosis: another face of atherosclerosis?
European Journal of Cardiovascular Prevention & Rehabilitation, 2006
ALCIFIC AORTIC STENOSIS has a lot in common with atherosclerotic coronary artery disease. So can lipid-lowering statin drugs stop it? Historically, calcific aortic stenosis was thought to result from aging and "wear and tear" of the aortic valve. 1,2 Hence it was designated "degenerative" or "senile-type." This perception is changing. Over the last decade, a growing understanding of the risk factors for calcific aortic stenosis and of its histologic characteristics have led to new insights into how it develops. Investigators have found histologic similarities between the lesion of aortic stenosis and atheromatous coronary artery disease 3,4 and have established an association between traditional atherosclerotic risk factors and the development of calcific aortic valve disease. 5-14 This condition is the most common reason for valve replacement in the United States, 15 and when it is severe it accounts for considerable disease and death, especially in older patients. Up to now, the only established treatment for symptomatic aortic valve stenosis has been to replace the valve. Newer therapies that may modify or reduce the likelihood of developing aortic valve disease are highly desirable and are currently under investigation. In this article we summarize what is known about the possible role of lipids, infection, and other risk factors in nonrheumatic calcific aortic sclerosis and stenosis and potential treatments. We use valve "sclerosis" to mean a thickening of the aortic valve leaflets, often with superimposed calcification, whereas valve "stenosis" implies a more advanced situation in which the leaflets stick and do not open normally.
Calcific Aortic Stenosis—A Review on Acquired Mechanisms of the Disease and Treatments
Frontiers in Cardiovascular Medicine, 2021
Calcific aortic stenosis is a progressive disease that has become more prevalent in recent decades. Despite advances in research to uncover underlying biomechanisms, and development of new generations of prosthetic valves and replacement techniques, management of calcific aortic stenosis still comes with unresolved complications. In this review, we highlight underlying molecular mechanisms of acquired aortic stenosis calcification in relation to hemodynamics, complications related to the disease, diagnostic methods, and evolving treatment practices for calcific aortic stenosis.
A comprehensive study of calcific aortic stenosis: from rabbit to human samples
Disease models & mechanisms, 2018
The global incidence of calcific aortic stenosis (CAS) is increasing due, in part, to a growing elderly population, and poses a great challenge to public health because of the multiple comorbidities of these patients. Using a rabbit model of CAS, we sought to characterize protein alterations associated with calcified valve tissue that can be ultimately measured in plasma as non-invasive biomarkers of CAS.Aortic valves from healthy and mild stenotic rabbits were analyzed by two-dimensional difference gel electrophoresis, and selected reaction monitoring was used to directly measure the differentially expressed proteins in plasma from the same rabbits to corroborate their potential as diagnostic indicators, and also in plasma from human subjects, to examine their translatability to the clinical setting.Eight proteins were found differentially expressed in CAS tissue, but only 3 were also altered in plasma samples from rabbits and humans: transitional endoplasmic reticulum ATPase, trop...
Aging Clinical and Experimental Research
Given the epidemiologic increase of aged population in the world, aortic stenosis (AS) represents now the most common valvular heart disease in industrialized countries. It is a very challenging disease, representing an important cause of morbidity, hospitalization and death in the elderly population. It is widely recognized that AS is the result of a very complex active process, driven by inflammation and involving multifactorial pathological mechanisms promoting valvular calcification and valvular bone deposition. Several evidence suggest that epicardial adipose tissue (EAT), the visceral fat depot of the heart, represents a direct source of cytokines and could mediate the deleterious effects of systemic inflammation on the myocardium. Importantly, obesity and metabolic disorders are associated with chronic systemic inflammation leading to a significant increase of EAT amount and to a pro-inflammatory phenotypic shift of this fat depot. It has been hypothesized that the EAT inflam...
2013
Aortic stenosis due to calcific aortic valve disease (CAVD) is currently the main indication for aortic valve replacement in developed countries (Iung et al, 2003). Due to an aging population and a decline in rheumatic heart disease, CAVD has become the most common heart valve disease in the Western countries, affecting approximately 25% of adults over 65 years, of which 2-3% has clinically significant aortic stenosis (Stewart et al, 1997). Even mild CAVD is associated with adverse outcomes, with a 50% increased risk of cardiovascular death (Lloyd-Jones et al, 2009). There are no known therapies that slow disease progression, and surgical valve replacement is the only effective treatment for aortic stenosis. More than 85,000 aortic valve replacement surgeries are done in the United States, and over 275,000 are performed worldwide. This numbers are expected to triple by 2050 (Takkenberg et al, 2008). These statistics emphasize the burden of aortic valve disease and the necessity of understanding its mechanisms, underscored recently by recommendations set out by The National Heart, Lung and Blood Institute Aortic Stenosis Working Group (http://www.nhlbi.nih.gov/meetings/workshops/cas.htm). CAVD is a progressive disease that starts with initial changes in the cell biology of the valve leaflets, which develop into atherosclerotic-like lesions and aortic sclerosis, and eventually lead to calcification of the valve, causing left ventricular outflow tract obstruction (Rajamannan et al, 2007, Otto, 2008). Although CAVD progresses with age, it is not an inevitable consequence of aging. CAVD traditionally has been considered a degenerative phenomenon, in which years of mechanical stress on an otherwise normal valve, cause calcium to deposit on the surface of the aortic valve leaflets. The evolving concept, however, is that CAVD is an actively regulated process that cannot be characterized simply as "senile" or "degenerative". The progressive calcification process involves lipid accumulation, increasing angiotensin-converting enzyme activity, inflammation, neovascularization, and extracellular matrix degradation. Furthermore, the risk factors for CAVD are similar to those for atherosclerosis: age, gender, hypercholesterolemia, diabetes, smoking, renal failure, and hypertension (Stewart et al, 1997). In addition, pathological studies of explanted human stenotic aortic valves have identified lesions similar to those in atherosclerotic plaques, which contain inflammatory cells and calcific deposits (Otto et al, 1994). The involvement of high cholesterol levels is corroborated by studies demonstrating that patients with familial hypercholesterolemia develop aortic valve lesions that calcify with age (Rajamannan et al, 2001). Furthermore, preclinical studies have demonstrated atherosclerotic-like lesions in aortic valve leaflets in www.intechopen.com Aortic Valve 134 atherosclerosis in rabbits and mice. From the notion that CAVD and atherosclerosis might share a similar mechanism, statins (3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors) emerged as a potential therapy for treating CAVD. Indeed, retrospective studies have demonstrated a reduction in disease progression when patients were treated with statins (Aronow et al, 2001, Novaro et al, 2001, Bellamy et al, 2002). In addition, animal studies confirmed that statin treatment inhibits calcificication (Rajamannan et al, 2005, Aikawa et al, 2007). Large prospective clinical trials, however have not shown slowed CAVD progression in patients treated with high doses of statins (Cowell et al, 2005, Rossebo et al, 2008). This may be due to the late implementation of the statins, after aortic valve calcification has progressed to the irreversible stage. The aortic valve consists of endothelial cells and valvular interstitial cells that maintain the health of the valve and are important in valvular disease. Valvular interstitial cells likely mediate the progression of CAVD (Mohler et al, 1999). Signals in aortic valve biology that trigger activation, differentiation, or pathological change are unclear. However, we know that in CAVD, valvular interstitial cells differentiate to myofibroblasts and osteoblast-like cells, which are eventually responsible for calcium deposition (Mohler et al, 2001). Possible pathological triggers include hemodynamic shear stress, solid tissue stresses, reactive oxygen species (ROS), inflammatory cytokines and growth factors, and physiological imbalances such as the metabolic syndrome, diabetes mellitus, end-stage renal disease, and calcium or phosphate imbalance (Schoen, 2008, New & Aikawa, 2011, Miller et al, 2010). The cellular and molecular factors involved in the development of aortic valve stenosis, however, remain largely obscure. The poor prognosis and increased mortality after the onset of symptoms provide a rationale for the pursuit of a better understanding of the disease process, which can lead to effective therapeutic strategies to prevent CAVD. This chapter discusses our current understanding of the pathophysiology, risk factors, cellular mechanisms, diagnosis, and clinical management of CAVD, and describes areas of future research vital for diagnosing, treating, and potentially preventing this disease.
American Journal of Physiology-heart and Circulatory Physiology, 2010
Recent epidemiologic studies have revealed the risk factors associated for vascular atherosclerosis, including the male sex, smoking, hypertension, and elevated serum cholesterol, similar to the risk factors associated with the development of AV stenosis. An increasing number of models of experimental hypercholesterolemia demonstrate features of atherosclerosis in the AV, which are similar to the early stages of vascular atherosclerotic lesions. Experimental and clinical studies demonstrate that the hypercholesterolemic AV develops an atherosclerotic lesion which is proliferative and expresses high levels of osteoblast bone markers which mineralize over time to form bone. Calcification, the end-stage process of the disease, is necessary to understand as a prognostic indicator in the modification of this cellular process before it is too late. In summary, these findings suggest that medical therapies may have a potential role in patients in the early stages of this disease process to slow the progression to severe aortic stenosis and to delay the timing of the need for surgery. The translation of these experimental studies to clinical practice will be important to understand the potential for medical therapy for this disease process.
The lipid theory in the pathogenesis of calcific aortic stenosis
Nutrition, metabolism, and cardiovascular diseases : NMCD, 2015
Biologically active phenomena, triggered by atherogenesis and inflammation, lead to aortic valve (AV) calcification. Lipids play an important role in activating the cell signaling leading to AV bone deposition. This review, based on evidence from animal and human studies, mainly focused on the involvement of lipids and atherogenic phenomena in the pathogenesis of calcific aortic stenosis (AS). The role of elevated low density lipoproteins for the risk of both vascular atherosclerosis and AS has been elucidated. Lipid disorders act synergistically with other risk factors to increase prevalence of calcific AS. Atherosclerosis is also involved in the pathogenesis of bone demineralization, a typical hallmark of aging, which is associated with ectopic calcification at vascular and valvular levels. Animal studies have recently contributed to demonstrate that lipids play an important role in AS pathogenesis through the activation of molecular cell signalings, such as Wnt/Lrp5 and RANK/RANK...
Calcific aortic valve disease and aortic atherosclerosis--two faces of the same disease?
Romanian journal of internal medicine = Revue roumaine de médecine interne
Calcific (degenerative) aortic valve disease is the most common etiology of acquired aortic valve stenosis. Historically, it was seen as a degenerative, "senile-like" process, resulting from aging--"wearing and tearing"--of the aortic valve. However, several lines of evidence suggest that calcific valve disease is not simply due to age-related degeneration but, rather, it is an active disease process with identifiable initiating factors, clinical and genetic risk factors, and cellular and molecular pathways that mediate disease progression. Histopathologically, the early lesions of aortic valve sclerosis resemble arterial atherosclerotic plaques. Furthermore, atherosclerotic risk factors and clinical atherosclerotic cardiovascular disease are independently associated with aortic sclerosis suggesting that it represents an atherosclerosis-like process involving the aortic valve. Until now, the only established treatment for symptomatic aortic valve stenosis has bee...