Titin isoform switch in ischemic human heart disease

• Published in: Circulation (New York, N.Y.) N.Y.), 2002-09, Vol.106 (11), p.1333-1341
• Main Authors: NEAGOE, Ciprian, KULKE, Michael, DEL MONTE, Federica, GWATHMEY, Judith K, DE TOMBE, Pieter P, HAJJAR, Roger J, LINKE, Wolfgang A
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cardiology. Vascular system; Collagen - metabolism; Compliance; Connectin; Coronary Disease - metabolism; Coronary Disease - physiopathology; Coronary Disease - surgery; Coronary heart disease; Coronary Vessels - surgery; Desmin - metabolism; Female; Heart; Heart Failure - metabolism; Heart Transplantation; Humans; Ligation; Medical sciences; Muscle Proteins - metabolism; Myocardial Infarction - metabolism; Myocardial Ischemia - metabolism; Myocardial Ischemia - physiopathology; Myocardial Ischemia - surgery; Myocardium - metabolism; Myofibrils - metabolism; Myofibrils - physiology; Protein Isoforms - metabolism; Protein Kinases - metabolism; Rats; Rats, Sprague-Dawley; Troponin I - metabolism
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000029803.93022.93

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. 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 approximately 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. 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.