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Systemic sclerosis and aortic valve stenosis: therapeutic implications in two cases of aortic valve replacement.

Posted Nov 10 2010 6:41pm
Cardiac involvement is very frequent and underestimated in systemic sclerosis, but few reports have been published on the surgical treatment of patients with systemic sclerosis. We describe herein two cases of valve replacement because of aortic stenosis.

New Insights into Degenerative Aortic Valve Stenosis

Risk factors for aortic valve stenosis (AVS) are similar to those for atherosclerosis and include
Increasing age
Male sex
Hypercholesterolemia
Hypertension

More than 25% of patients over the age of 65 years have extensive aortic valve sclerosis, while as many as 10% of individuals in this age range have AVS.

In the past, AVS was considered a passive, degenerative process. This perspective has changed and AVS is now viewed as an active, dynamically regulated process. Within the past 15 years, 3 major discoveries have contributed to this shift
Detailed histopathologic studies have identified the presence of osteoblast-like cells, osteoclast-like cells, and actual bone matrix in tissue explanted during valve replacement surgery.

Studies in animals have demonstrated that pro-osteogenic pathways are activated early in valve disease and that calcification can be prevented by administering lipid-lowering therapy in the early stages of valve disease.

Investigations by Jordan D. Miller, Ph.D., a researcher in the Division of Cardiovascular Surgery at Mayo Clinic, have revealed that the initiation of lipid-lowering therapy in mild valve disease markedly reduces pro-osteogenic signaling in the aortic valve and halts progression to severe AVS.

Collectively, these data provide strong evidence that the progression of aortic valve disease — when caught early enough — is in fact a malleable process.

A particularly interesting observation has been that calcium deposition and pro-osteogenic signaling in stenotic valves are both associated with increases in oxidative stress. Subsequently, Dr. Miller and his colleagues demonstrated that increased oxidative stress in AVS is derived from 2 major sources:

A profound suppression antioxidant enzyme expression and activity in the calcified regions of the valve

Dysfunctional nitric oxide synthases, which produce superoxide instead of nitric oxide


Interestingly, this finding differs fundamentally from what has been described in atherosclerotic plaques, where increases in oxidative stress are attributed to increases in NAD(P)H oxidase activity (and are actually associated with increases in antioxidant enzyme expression). Consequently, a major focus of Dr. Miller's laboratory is to determine the role of increased oxidative stress in the initiation and progression of aortic valve disease and atherosclerosis and also to determine whether the alterations in antioxidant enzyme expression are adaptive or maladaptive.

Furthermore, recent studies have shown that the subcellular compartmentalization of reactive oxygen species plays a critical role in the biological effects of altering antioxidant mechanisms. For example, reducing the cytosolic isoform of superoxide dismutase slows the progression of atherosclerosis in mice, whereas reducing the mitochondrial isoform of superoxide dismutase accelerates the progression of atherosclerosis in mice.

To determine whether increases in mitochondrial oxidative stress are an independent contributor to the progression of AVS, Dr. Miller crossed mice that are deficient in a mitochondrial antioxidant enzyme with hypercholesterolemic mice that develop AVS.

At 18 months of age, wild-type mice have only modest AVS (peak velocity of about 2.7 m/s). Mice with increases in mitochondrial oxidative stress, however, have far greater impairments in aortic valve function (peak velocity of about 4.5 m/s).

These preliminary studies suggest that mitochondrial oxidative stress may play a critical role in determining the rate of progression of AVS. Dr. Miller is currently conducting studies to determine whether mitochondria-targeted antioxidant therapies slow the progression of AVS.

As AVS is most common in older patients, it is critical that interventions aimed at slowing the progression of valvular calcification do not alter skeletal ossification. Thus, Dr. Miller has also examined changes in skeletal ossification that occur with alterations in mitochondrial oxidative stress. In contrast to what has been observed in valvular tissue, losses in mitochondrial antioxidant enzyme activity markedly reduce bone mineral density and content in mice. Collectively, the use of mitochondria-targeted antioxidants appears to be a promising avenue to pursue to slow valvular calcification while increasing skeletal ossification.

While much effort is focused on understanding the role of oxidative stress in the development of cardiovascular disease, other work in Dr. Miller's laboratory involves screening human tissue to identify novel adaptive and maladaptive changes that occur with the progression of AVS.

Along these lines, a cardiovascular tissue biobank is being developed in the Division of Cardiovascular Surgery. Specifically, researchers will be acquiring blood and tissue samples for the isolation of DNA, RNA, and protein from patients undergoing surgery at Mayo Clinic. By conducting large-scale genomic, transcriptomic, and proteomic screening of human tissue, Dr. Miller hopes to
Identify novel mediators of valvular calcification and atherosclerosis

Thoroughly investigate the mechanisms of action of such mediators in genetically altered mice and in vitro

Deepen the understanding of fundamental differences between AVS and atherosclerosis
While it has been fascinating to unveil some of the major pro-osteogenic signaling pathways that regulate valvular and intimal plaque calcification, the greatest challenge is in the translation of these discoveries to clinically relevant interventions.

Although knocking down pro-osteogenic genes with gene therapy was once thought to be a useful tool to slow the progression of valvular calcification, it was quickly realized that the absence of a method to provide local, highly efficacious treatment will likely result in severe bone loss and worsened osteoporosis in affected patients. Thus, efforts have been directed toward identifying reciprocal regulators of ectopic and skeletal ossification.

Identification is particularly feasible in mouse models of AVS, where both soft tissue and skeletal tissue can be examined at various time points during the progression of disease. By using integrative systems approaches to understanding disease, Dr. Miller hopes his research will develop clinically relevant therapies that will not only slow the progression of cardiovascular disease, but also slow age-related reductions in bone mass and improve the quality of life for patients.


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