Calcific Valvular Disease Research Articles

Self-eating and Heart: The Emerging Roles of Autophagy in Calcific Aortic Valve Disease.

Autophagy is a self-degradative pathway by which subcellular elements are broken down intracellularly to maintain cellular homeostasis. Cardiac autophagy commonly decreases with aging and is accompanied by the accumulation of misfolded proteins and dysfunctional organelles, which are undesirable to the cell. Reduction of autophagy over time leads to aging-related cardiac dysfunction and is inversely related to longevity. However, despite the increasing interest in autophagy in cardiac diseases and aging, the process remains an undervalued and disregarded object in calcific valvular disease. Neither the nature through which autophagy is triggered nor the interplay between autophagic machinery and targeted molecules during aortic valve calcification are fully understood. Recently, the upregulation of autophagy has been shown to result in cardioprotective effects against cell death as well as its origin. Here, we review the evidence that shows how autophagy can be both beneficial and detrimental as it pertains to aortic valve calcification in the heart.

Abstract 44: Osteopontin, Cardiovascular Events, and Mortality: The Heart and Soul Study

Background: Osteopontin is a glycoprotein found primarily in bone which is also abundant in atherosclerotic plaques and calcified valves. Prior studies demonstrate that serum osteopontin levels are associated with cardiovascular (CV) mortality in subjects with stable angina, but the underlying mechanisms are unknown. Therefore, we investigated the relationship between osteopontin and CV events in outpatients with stable coronary heart disease (CHD). Methods: We measured osteopontin levels in 981 outpatients with prevalent CHD who were recruited between 2000 and 2002 from 12 clinics in the San Francisco Bay Area. We used proportional hazard models to evaluate the association between osteopontin and CV events. Results: During a mean follow-up of 6.4 ± 3.1 years, 300 subjects experienced the combined outcome of any CV event (myocardial infarction, heart failure, stroke or CV mortality). After adjustment for traditional CV risk factors, subjects with osteopontin in the highest quartile had 1.9 times the risk of a CV event compared to those in the lowest quartile (adjusted HR 1.9, 95% CI 1.3-2.9, p=0.001), and each standard deviation increase in osteopontin was associated with a 30% increase in risk (adjusted HR 1.3, 95% CI 1.1-1.5, p<0.001). This association was only minimally attenuated after adjustment for markers of calcific valvular disease (mitral annular calcification, aortic sclerosis), and other known markers of vascular calcification (calcium, phosphorus, FGF-23, MGP1, feturin A, adiponectin, leptin, and PTH), inflammation (C-reactive protein), and prognostic markers (NT-proBNP) (adjusted HR 1.2, 95% CI 1.1-1.4, p=0.007). Conclusions: Higher osteopontin levels are strongly associated with cardiovascular events in subjects with prevalent CHD. This association is not explained by extensive measures of inflammation, valvular disease, or vascular calcification.

Reduced Sox9 Function Promotes Heart Valve Calcification Phenotypes In Vivo

Calcification of heart valve structures is the most common form of valvular disease and is characterized by the appearance of bone-like phenotypes within affected structures. Despite the clinical significance, the underlying etiology of disease onset and progression is largely unknown and valve replacement remains the most effective treatment. The SRY-related transcription factor Sox9 is expressed in developing and mature heart valves, and its function is required for expression of cartilage-associated proteins, similar to its role in chondrogenesis. In addition to cartilage-associated defects, mice with reduced sox9 function develop skeletal bone prematurely; however, the ability of sox9 deficiency to promote ectopic osteogenic phenotypes in heart valves has not been examined. This study aims to determine the role of Sox9 in maintaining connective tissue homeostasis in mature heart valves using in vivo and in vitro approaches. Using histological and molecular analyses, we report that, from 3 months of age, Sox9(fl/+);Col2a1-cre mice develop calcific lesions in heart valve leaflets associated with increased expression of bone-related genes and activation of inflammation and matrix remodeling processes. Consistently, ectopic calcification is also observed following direct knockdown of Sox9 in heart valves in vitro. Furthermore, we show that retinoic acid treatment in mature heart valves is sufficient to promote calcific processes in vitro, which can be attenuated by Sox9 overexpression. This study provides insight into the molecular mechanisms of heart valve calcification and identifies reduced Sox9 function as a potential genetic basis for calcific valvular disease.

Antibiotic-resistant endocarditis in a hemodialysis patient.

A chronic dialysis patient developed persistent bacteremia as a result of infection with Enterococcus faecium. During the patient's illness, resistance to ampicillin, gentamicin, vancomycin, and teicoplanin developed. Despite arteriovenous (AV) graft removal and an extensive but inconclusive search for the source of the infection, bacteremia persisted. On autopsy, the patient was found to have had aortic-valve endocarditis. Endocarditis is a well-known complication in dialysis patients. Multidrug-resistant organisms are becoming more prevalent in hospitalized patients as well. Risk factors for the development of endocarditis in dialysis patients include catheters, AV grafts, and calcific valvular disease, all in conjunction with frequent access to the circulation. Avoidance of temporary catheter use by prompt placement of AV fistulas or grafts and consideration of their early use, the meticulous care of catheters once in place, and treatment of the nasal carriage of Staphylococcus aureus may lower the incidence of bacteremia and therefore endocarditis in dialysis patients. The removal of infected catheters and/or AV grafts if prompt clearing of the blood with antibiotics does not occur is the next step, followed by valve replacement in selected cases. The routine use of vancomycin in the dialysis population should be reevaluated in light of the development of high-level antibiotic-resistant organisms.

Surgical pathology of the aortic valve: gross and histological findings in 1120 excised valves

From January 1981 through December 1991, 1120 consecutive aortic valves were surgically explanted and their gross anatomy and histology studied at our university. Rheumatic disease (65%), dystrophic calcific valvular disease (23%), noninflammatory disease of the aortic root and/or floppy aortic valve (6.3%), and endocarditis (5.4%) were the causes of valve dysfunction. Among the total population the male sex predominated. The male to female ratio was 2.4 in the group with dystrophic calcific valvular disease and 1.6 in the group with bacterial endocarditis. The mean age was 37 ± 7.5 years in the group with non-inflammatory disease of the aortic root and/or aortic cusps. In the group with dystrophic calcific valvular disease, the mean age was 62 ± 6.3 years. Among the 1120 patients, 717 (64.03%) underwent surgery for aortic stenotic-incompetence, 250 (22.25%) for isolated aortic stenosis, and 153 (13.72%) for isolated aortic incompetence. In 449 cases (40.13%) a mitral pathology was associated. Chronic rheumatic aortic disease usually caused stenotic insufficiency (92.8%). Dystrophic calcific aortic disease caused pure stenosis in 84.8% of the cases. Among these, 46 patients (18.4%) had a congenitally bicuspidal aortic valve. Pure aortic incompetence was caused by noninflammatory aortic root and/or cusp disease in 44% of patients, infective endocarditis in 40%, and rheumatic disease in 16%. Patients with noninflammatory aortic root and/or cusp disease were divided into three groups: 29 patients with aortic root dilatation and normal cusps, 25 patients with aortic root dilatation and mixomatous infiltration of aortic cusps (floppy aortic valve), and 15 patients with floppy aortic valve and normal aortic root. Aortic incompetence was caused by cusp retraction caused by chronic rheumatic disease, cusp perforation or tears caused by infective endocarditis, and cusp prolapse for floppy aortic valve. Cusp diastasis has been the cause of aortic incompetence in patients with dilated aortic root. In patient with floppy aortic valve caused by the fibrous lamina disarray, the cusps prolapsed toward the left ventricle, causing valve regurgitation.

Degenerative calcific valvular disease and systolic murmurs in the elderly.

By use of echocardiographic and radiologic imaging, a prospective study was made of 98 elderly men, 65 to 102 years old, to define degenerative calcific valvular disease (DCVD)--its prevalence, morphologic features, functional significance, and relationship to systolic murmurs in the elderly. DCVD was diagnosed in 74 per cent of the group and murmurs were detected in 55 per cent, the incidences increasing with age. Fibrotic and calcific change of the aortic valve was the most common abnormality, occurring alone or together with alteration of the mitral valve. The murmurs were characteristically early systolic, of low intensity and medium pitch, and heard at more than one area. Of the group with valve degeneration, only 7 per cent was judged to be functionally significant and no more than moderate. It was concluded that DCVD is the cause of most systolic murmurs in the elderly and is usually hemodynamically unimportant. Echocardiographic criteria are important in identifying those subjects with possibly significant valvular dysfunction requiring invasive study.