1067-140 Subnormal tissue inhibitor of metalloproteinase expression modulates matrix metalloproteinase-2 activity and fibrosis in aortic regurgitation

Karlheinz Schuleri, Eungsuk Lee, Lisa L Pitlor, Sharada L Truter, Jeffrey S Borer
2004 Journal of the American College of Cardiology  
Mitral regurgitation (MR) imposes a volume overload on the left ventricle (LV) during which LV ejection fraction remains normal, while LV contractility deteriorates. We have reported that LV contractile dysfunction is directly related to a decrease in responsivity of the β-adrenergic receptor (β-AR 1 ), but the mechanism for this reduced responsivity in chronic MR patients has not been explored. We hypothesized that this decrease in β-AR 1 responsivity may occur because of increased
more » ... receptor kinase (β-ARK 1 ) expression. Methods: Endomyocardial biopsy samples were obtained from four normal donor hearts and eight patients with chronic MR. Standard Affymetrix® chip technology was employed to analyze the samples for expression of β-ARK 1 , β-ARK 2 , β-AR 1 , β-AR 2 , and β-AR 3 . The expression data were optimized to the standard, probe-pairs were quantile normalized, and the data were expressed as a fold-change for the MR patients compared to the normal donor hearts. Then, simplified t-tests were applied to the log transformed data. Results: Seven of the eight MR patients had LV contractile dysfunction but normal LV ejection fractions. Compared to the normal donor heart data, β-ARK 1 expression was 1.82 fold greater (p = 0.03), while β-ARK 2 and ß-arrestin expression were unchanged (1.00 and 0.94 fold change, p=0.27 and 0.31, respectively). The β-AR expression was not different between the two groups with β-AR 1 changing 0.56 fold (p=0.11), β-AR 2 changing 0.93 fold (p=0.72); and β-AR 3 changing 1.05 fold (p=0.79). Conclusion: β-ARK 1 expression is elevated in chronic MR patients with LV contractile dysfunction but normal LV ejection fractions, while β-AR expression is relatively unchanged. These data support the hypothesis that the decrease in β-AR 1 responsivity in these chronic MR patients may, in large part, be due to modification of β-AR 1 functionality through β-ARK 1 overexpression. Background: Although afterload reduction is known to have favorable acute hemodynamic effects in patients with mitral regurgitation (MR), limited data exist concerning long-term effects. Our study examined whether afterload reduction slows progression of left ventricular (LV) dysfunction in stable asymptomatic patients with severe chronic MR. Methods: A retrospective cohort study was conducted in patients with moderate-severe MR (3-4+) and an LV ejection fraction (EF) of > 0.5, both determined by Dopplerechocardiographic visual estimate. The EF at 2 points in time from 48 patients not receiving afterload reduction during the interval (Group 1) and 45 patients receiving continuous afterload reduction both prior to and continuously during the observation period (Group 2) were compared. Results: Groups 1 and 2 differed in age (69±17 years vs. 77±10, respectively, p=0.01) and EF (below, p=0.02), but not by gender, etiology of MR, symptoms, proportion treated with digoxin and beta blockade, chamber dimensions, severity of MR, blood pressure and heart rate. The average interval between examinations was 17±12 months (Group 1) and 20±14 (Group 2) p=0.2. Afterload reduction included ACE inhibitors (78%), calcium blockers (42%), angiotensin receptor blockers (20%), and vasodilators (4%). In Group 1, EF decreased from 62.0±7.5% to 59.7±6.7% (p=0.02) while Group 2 increased from 58.7±5.8% to 59.4±7.6%, (p=0.84). The changes observed in Group 1 (-2.3% over 17 months) was significantly different from Group 2 (+0.7 over 20 months) p=0.05. LV dimensions, MR severity, blood pressure and heart rate did not change. Conclusions: In hemodynamically stable asymptomatic patients with severe chronic MR, long-term afterload reduction may halt progression of LV dysfunction.
doi:10.1016/s0735-1097(04)91818-9 fatcat:cky6zigzgvf55opyvodh3ocg4u