Chymase Inhibition Prevents Fibronectin and Myofibrillar Loss and Improves Cardiomyocyte Function and LV Torsion Angle in Dogs With Isolated Mitral Regurgitation

• Published in: Circulation (New York, N.Y.) Vol. 122; no. 15; pp. 1488 - 1495
• Main Authors: PAT, Betty, YUANWEN CHEN, DESAI, Ravi, WEI, Chih-Chang, HASE, Naoki, KOBAYASHI, Tsunefumi, SABRI, Abdelkarim, GRANZIER, Henk, DENNEY, Thomas, TILLSON, Michael, RAY DILLON, A, HUSAIN, Ahsan, KILLINGSWORTH, Cheryl, DELL'ITALIA, Louis J, GLADDEN, James D, KE SHI, JUNYING ZHENG, POWELL, Pamela C, WALCOTT, Greg, AHMED, Mustafa I, GUPTA, Himanshu
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 12-10-2010
• Subjects: Animals; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure - physiology; Bradykinin - metabolism; Cardiac Output - physiology; Cardiology. Vascular system; Cardiovascular system; Chymases - antagonists & inhibitors; Collagen - metabolism; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Dogs; Extracellular Matrix - metabolism; Female; Fibronectins - metabolism; Focal Adhesion Protein-Tyrosine Kinases - metabolism; Heart Rate - physiology; Investigative techniques of hemodynamics; Investigative techniques, diagnostic techniques (general aspects); Male; Medical sciences; Mitral Valve Insufficiency - metabolism; Mitral Valve Insufficiency - physiopathology; Models, Animal; Myocytes, Cardiac - cytology; Myocytes, Cardiac - physiology; Myofibrils - metabolism; Torsion Abnormality - metabolism; Torsion Abnormality - physiopathology; Ventricular Remodeling - physiology; Heart failure; Fissipedia; Carnivora; Mitral valve; heart contractility; Serine endopeptidases; Enzyme; Glycoprotein; Contractility; Cardiovascular disease; Fibronectin; Chymase; cardiac volume; Peptidases; Vertebrata; Mammalia; Angle; Cardiac valvular disease; Animal; Collagen; Mitral regurgitation; Hydrolases; Dog; Torsion
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.109.921619

The left ventricular (LV) dilatation of isolated mitral regurgitation (MR) is associated with an increase in chymase and a decrease in interstitial collagen and extracellular matrix. In addition to profibrotic effects, chymase has significant antifibrotic actions because it activates matrix metalloproteinases and kallikrein and degrades fibronectin. Thus, we hypothesize that chymase inhibitor (CI) will attenuate extracellular matrix loss and LV remodeling in MR.
We studied dogs with 4 months of untreated MR (MR; n=9) or MR treated with CI (MR+CI; n=8). Cine MRI demonstrated a >40% increase in LV end-diastolic volume in both groups, consistent with a failure of CI to improve a 25% decrease in interstitial collagen in MR. However, LV cardiomyocyte fractional shortening was decreased in MR versus normal dogs (3.71±0.24% versus 4.81±0.31%; P<0.05) and normalized in MR+CI dogs (4.85±0.44%). MRI with tissue tagging demonstrated an increase in LV torsion angle in MR+CI versus MR dogs. CI normalized the significant decrease in fibronectin and FAK phosphorylation and prevented cardiomyocyte myofibrillar degeneration in MR dogs. In addition, total titin and its stiffer isoform were increased in the LV epicardium and paralleled the changes in fibronectin and FAK phosphorylation in MR+CI dogs.
These results suggest that chymase disrupts cell surface-fibronectin connections and FAK phosphorylation that can adversely affect cardiomyocyte myofibrillar structure and function. The greater effect of CI on epicardial versus endocardial titin and noncollagen cell surface proteins may be responsible for the increase in torsion angle in chronic MR.