Angiotensin II-converting enzyme inhibition improves survival, ventricular remodeling, and myocardial energetics in experimental aortic regurgitation.

BACKGROUND: Aortic valve regurgitation (AR) is a volume-overload disease causing severe eccentric left ventricular (LV) hypertrophy and eventually heart failure. There is currently no approved drug to treat patients with AR. Many vasodilators including angiotensin-converting enzyme inhibitors have been evaluated in clinical trials, but although some results were promising, others were inconclusive. Overall, no drug has yet been able to improve clinical outcome in AR and the controversy remains. We have previously shown in an animal model that captopril (Cpt) reduced LV hypertrophy and protected LV systolic function, but we had not evaluated the clinical outcome. This protocol was designed to evaluate the effects of a long-term Cpt treatment on survival in the same animal model of severe aortic valve regurgitation. METHODS AND RESULTS: Forty Wistar rats with AR were treated or untreated with Cpt (1 g/L in drinking water) for a period of 7 months to evaluate survival, myocardial remodeling, and function by echocardiography as well as myocardial metabolism by µ positron emission tomography scan. Survival was significantly improved in Cpt-treated animals with a survival benefit visible as soon as after 4 months of treatment. Cpt reduced LV dilatation and LV hypertrophy. It also significantly improved the myocardial metabolic profile by restoring the level of fatty acids metabolic enzymes and use. CONCLUSIONS: In a controlled animal model of pure severe aortic valve regurgitation, Cpt treatment reduced LV remodeling and LV hypertrophy and improved myocardial metabolic profile and survival. These results support the need to reevaluate the role of angiotensin-converting enzyme inhibitors in humans with AR in a large, carefully designed prospective clinical trial.

Influence of angiotensin-converting enzyme gene insertion/deletion polymorphism on rheumatic valve involvement, valve severity and subsequent valve calcification.

BACKGROUND AND AIM OF THE STUDY: The relationship between the severity of chronic rheumatic heart disease (RHD) and predisposing factors is unknown, and genetic predictors for severe scarring and calcification of the mitral valve are not well defined. A high angiotensin-converting enzyme (ACE) activity has been demonstrated in valve tissue. Thus, a case-control study was conducted to investigate any possible relationship between ACE gene polymorphisms and chronic mitral valve disease severity and calcification. METHODS: This case-control study included 82 patients (24 males, 58 females; mean age 40.3 +/- 14.7 years) with chronic rheumatic mitral valve, and 154 control subjects (53 males, 101 females; mean age 43.4 +/- 13.4 years). ACE gene insertion/deletion (I/D) polymorphisms were identified using polymerase chain reaction methods. RESULTS: Among RHD subjects, 31 (30.6%) were D/D, 25 (32.7%) were I/D, and 26 (18.8%) were I/I. Among controls, 57 (57.4%) were D/D, 69 (61.3%) were I/D, and 28 (35.2%) were I/I. The frequency of ACE I/I genotype was higher in RHD subjects than in controls (chi2 = 7.4, df = 2, p < 0.030; D/D versus I/D versus I/I), or (chi2 = 5.5, df = 1, p < 0.019; DD + ID versus II). Predisposition to RHD was significantly less frequent in the D/D genotype. There was no statistically significant difference in the genetic analysis of RHD with respect to mitral valve score, severity of mitral regurgitation and left atrial diameter. Mitral valve calcification was significantly associated with a higher frequency of I/I genotype and I/D genotype than D/D genotype alone (chi2 = 6.2, df = 2, p = 0.043). The ACE I/I genotype was associated with a predisposition to a greater risk of severe calcific valve disease. CONCLUSION: The ACE I/I genotype is more common in patients with rheumatic valve disease than in the normal population. This suggests that the ACE gene polymorphism may be involved in the pathogenesis of rheumatic heart disease.

Tissue microarray detection of matrix metalloproteinases, in diseased tricuspid and bicuspid aortic valves with or without pathology of the ascending aorta.

OBJECTIVE: The degeneration of bicuspid aortic valve and its frequent association with ascending aortic pathology, point to a still unidentified genetic tissue defect with unknown mediators. Metalloproteinases (MMPs) are lytic enzymes that have been strongly implicated in aneurysm formation. The purpose of this study was to detect the presence of these enzymes in aortic valvular tissue in healthy and diseased aortic valves with or without the presence of synchronous ascending aortic pathology. METHODS: Aortic valve specimens from 26 aortic valve replacement patients as well as 4 healthy control tricuspid aortic valves were included. 10 patients had bicuspid aortic valves, and 16 had tricuspid aortic valves. Half of our patient population had a concomitant aortic procedure for aortic pathology. The study detected MMPs 1,2 and 9 as well as their Tissue inhibitors (TIMPs) 1 and 2. MMP and TIMP detection was accomplished with the construction of a tissue micro array and immunohistochemistry. CONCLUSIONS: MMP-9 expression was significantly higher in bicuspid aortic valves compared to normal valves (P<0.05). When compared to the tricuspid valve group, MMP-9 mean value was significantly higher in bicuspid valves (P<0.05). When the entire rest of the valve group (n=4+16, i.e. control and tricuspid valve groups) was compared to the bicuspid valve group, bicuspid valves had significantly higher MMP-2, and MMP-9 (P<0.01) expression. TIMP expression also changed in diseased valves, among different patient groups. This increased proteolytic presence in bicuspid aortic valves may attribute to the observed decreased elastin and collagen content, and their resultant functional failure.

Semicarbazide-sensitive amine oxidase in annulo-aortic ectasia disease: relation to elastic lamellae-associated proteins.

Lysyl oxidases (Lox), which are members of the amine oxidase family, are involved in the maturation of elastic lamellae and collagen fibers. Modifications of amine oxidases in idiopathic annulo-aortic ectasia disease (IAAED) have never been investigated. Our aim was to examine the expression of several proteins that might interfere with elastic fiber organization in control (n=10) and IAAED (n=18) aortic tissues obtained at surgery. Expression of amine oxidases and semicarbazide-sensitive amine oxidase (SSAO), and cellular phenotypic markers were examined by immunohistopathology and confocal microscopy. The expression of these proteins was assessed in relation to clinical and histomorphological features of the arterial wall. In control aorta, SSAO staining was expressed along elastic lamellae, whereas in aneurysmal areas of IAAED, SSAO was markedly decreased, in association with severe disorganization of elastic lamellae. Smooth muscle myosin heavy chain was also decreased in IAAED compared with controls, indicating smooth muscle cell dedifferentiation. Multiple regression analysis showed that elastic lamellar thickness (ELT) was correlated positively with the SSAO:elastin ratio and negatively with the Lox:elastin ratio, and that the clinical features of IAAED (aneurysm, thoracic aorta diameter, and aortic insufficiency) were positively correlated with ELT but not with SSAO. The relationship between SSAO expression and ELT suggests that this amine oxidase may be involved in elastic fiber organization. However, in advanced IAAED, the deficit in SSAO expression could be secondary to the decrease and fragmentation of elastic fibers and/or to vascular smooth muscle cell dedifferentiation.