Circulation. 2002;106:1333-1341
Published online before print August 19, 2002, doi: 10.1161/01.CIR.0000029803.93022.93
Published online before print August 19, 2002, doi: 10.1161/01.CIR.0000029803.93022.93
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(Circulation. 2002;106:1333.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
Titin Isoform Switch in Ischemic Human Heart Disease
From the Institute of Physiology and Pathophysiology, University of Heidelberg, Germany (C.N., M.K., W.A.L.); the Cardiovascular Research Center, Massachusetts General Hospital, Boston (F.d.M., R.J.H.); the Boston University School of Medicine, Boston, Mass (J.K.G.); and the Department of Physiology and Biophysics, University of Illinois, Chicago (P.P.d.T.).
Correspondence to Wolfgang A. Linke, PhD, Institute of Physiology and Pathophysiology, University of Heidelberg, Im Neuenheimer Feld 326, D-69120 Heidelberg, Germany. E-mail wolfgang.linke{at}urz.uni-heidelberg.de
Background— Ischemia-induced cardiomyopathy usually is accompanied by elevated left ventricular end-diastolic pressure, which follows from increased myocardial stiffness resulting from upregulated collagen expression. In addition to collagen, a main determinant of stiffness is titin, whose role in ischemia-induced left ventricular stiffening was studied here. Human heart sarcomeres coexpress 2 principal titin isoforms, a more compliant N2BA isoform and a stiffer N2B isoform. In comparison, normal rat hearts express almost no N2BA titin.
Methods and Results— Gel electrophoresis and immunoblotting were used to determine the N2BA-to-N2B titin isoform ratio in nonischemic human hearts and nonnecrotic left ventricle of coronary artery disease (CAD) patients. The average N2BA-to-N2B ratio was 47:53 in severely diseased CAD transplanted hearts and 32:68 in nonischemic transplants. In normal donor hearts and donor hearts with CAD background, relative N2BA titin content was 
30%. The titin isoform shift in CAD transplant hearts coincided with a high degree of modifications of cardiac troponin I, probably indicating increased preload. Immunofluorescence microscopy on CAD transplant specimens showed a regular cross-striated arrangement of titin and increased expression of collagen and desmin. Force measurements on isolated myofibrils revealed reduced passive-tension levels in sarcomeres of CAD hearts with high left ventricular end-diastolic pressure compared with sarcomeres of normal hearts. In a rat model of ischemia-induced myocardial infarction (left anterior descending coronary artery ligature), 43% of animals, but only 14% of sham-operated animals, showed a distinct N2BA titin band on gels.
Conclusions— A titin isoform switch was observed in chronically ischemic human hearts showing extensive remodeling, which necessitated cardiac transplantation. The shift, also confirmed in rat hearts, caused reduced titin-derived myofibrillar stiffness. Titin modifications in long-term ischemic myocardium could impair the ability of the heart to use the Frank-Starling mechanism.
Key Words: preload • connectin • ischemia • diastole • coronary artery disease
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