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

Background—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. Methods and Results—Endocardial ventricular biopsies were obtained at open heart surgery (nϭ61; 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 (nϭ38) and titin isoforms (nϭ16) were determined. End-diastolic pressure was measured at cardiac catheterization (nϭ14). 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 ϾnormalϷvolume-overloadedϾdilated 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. Conclusions—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. A bnormal cardiac filling caused by altered diastolic chamber stiffness is often proposed as a contributor to the pathophysiology of a range of cardiac diseases, especially ventricular hypertrophy and dilatation. 1 However, quantifying diastolic chamber stiffness in vivo is extremely difficult and requires invasive measurement of the end-diastolic pressure-volume relationship (EDPVR). 2 This is particularly problematic in ventricles with complex geometry (eg, the right ventricle, congenital heart disease). Myocardial stiffness is usually a major determinant of ventricular chamber stiffness, although forces exerted by tissues and cavities surrounding the heart (eg, pericardium, pleura, intrathoracic pressure) can affect and even, in some clinical syndromes, dominate chamber stiffness. 3 An alternative to in vivo quantification of myocardial stiffness is direct in vitro measurement by stretching myocardial samples to different lengths and recording the force …