Passive Stiffness of Myocardium From Congenital Heart Disease and Implications for Diastole

• Published in: Circulation (New York, N.Y.) Vol. 121; no. 8; pp. 979 - 988
• Main Authors: CHATURVEDI, Rajiv R, HERRON, Todd, SIMMONS, Robert, SHORE, Darryl, KUMAR, Pankaj, SETHIA, Babulal, CHUA, Felix, VASSILIADIS, Efstathios, KENTISH, Jonathan C
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 02.03.2010
• Subjects: Adolescent; Adult; Aged; Biological and medical sciences; Biopsy; Blood and lymphatic vessels; Cardiology. Vascular system; Child; Child, Preschool; Collagen - metabolism; Connectin; Diastole - physiology; Dilatation, Pathologic - metabolism; Dilatation, Pathologic - physiopathology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Elasticity - physiology; Extracellular Matrix - metabolism; Female; Heart - physiopathology; Heart Diseases - congenital; Heart Diseases - metabolism; Heart Diseases - physiopathology; Humans; Hypertrophy, Left Ventricular - metabolism; Hypertrophy, Left Ventricular - physiopathology; Infant; Male; Medical sciences; Middle Aged; Muscle Proteins - metabolism; Myocardium - metabolism; Myocardium - pathology; Protein Kinases - metabolism; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Ventricular Dysfunction, Left - metabolism; Ventricular Dysfunction, Left - physiopathology; Young Adult; titin; volume overload; heart defects; Congenital; Diastole; Cardiovascular disease; Stiffness; Congenital cardiopathy; pressure overload
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.109.850677

In ventricular dilatation or hypertrophy, an elevated end-diastolic pressure is often assumed to be secondary to increased myocardial stiffness, but stiffness is rarely measured in vivo because of difficulty. We measured in vitro passive stiffness of volume- or pressure-overloaded myocardium mainly from congenital heart disease. Endocardial ventricular biopsies were obtained at open heart surgery (n=61; pressure overload, 36; volume-overload, 19; dilated cardiomyopathy, 4; normal donors, 2). In vitro passive force-extension curves and the stiffness modulus were measured in skinned tissue: muscle strips, strips with myofilaments extracted (mainly extracellular matrix), and myocytes. Collagen content (n=38) and titin isoforms (n=16) were determined. End-diastolic pressure was measured at cardiac catheterization (n=14). Pressure-overloaded tissue (strips, extracellular matrix, myocytes) had a 2.6- to 7.0-fold greater force and stiffness modulus than volume-overloaded tissue. Myocyte force and stiffness modulus at short stretches (0.05 resting length, L(0)) was pressure-overloaded >normal approximately volume-overloaded>dilated cardiomyopathy. Titin N2B:N2BA isoform ratio varied little between conditions. The extracellular matrix contributed more to force at 0.05 L(0) in pressure-overloaded (35.1%) and volume-overloaded (17.4%) strips than normal myocardium. Stiffness modulus increased with collagen content in pressure-overloaded but not volume-overloaded strips. In vitro stiffness modulus at 0.05 L(0) was a good predictor of in vivo end-diastolic pressure for pressure-overloaded but not volume-overloaded ventricles and estimated normal end-diastolic pressure as 5 to 7 mm Hg. An elevated end-diastolic pressure in pressure-overloaded, but not volume-overloaded, ventricles was related to increased myocardial stiffness. The greater stiffness of pressure-overloaded compared with volume-overloaded myocardium was due to the higher stiffness of both the extracellular matrix and myocytes. The transition from normal to very-low stiffness myocytes may mark irreversible dilatation.