Giant molecule titin and myocardial stiffness.

Abstract

The beauty of the new titin hypothesis is that the heart is able to change its resting length-tension relationship under chronic stress conditions by isoform switching, thereby rehabilitating the old clinical paradigm of “diastolic tone.” The path from hypothesis to reality is rocky, however, as the articles by Wu and Neagoe in this issue of Circulation show.1,2⇓ See pp 1333 and 1384 Wu et al1 found that the titin isoforms N2BA/N2B ratio was decreased from a normal ratio of 1.0 to 0.8 in the paced dog heart. Because N2B represents the isoform with stiffer elastic properties, this resulted in an increased passive stiffness in isolated muscle strips. The authors suggest that this “titin-based” stiffness is acting in concert with “collagen-based” stiffness and that it may counteract ventricular dilatation in canine hearts failing because of chronic pacing. The results are somewhat in contrast with an earlier study by the same group in which a switch to the more extensible isoform N2BA was shown to occur in the subendocardium of canine hearts after 2 weeks of pacing. This seemingly contradictory result might reflect a different time course of titin isoform expression.3 Neagoe et al2 report a titin isoform shift from 30:70 (ratio 0.42) of N2BA/N2B in normal human myocardium to 47:53 (ratio 0.89) in nonischemic regions from human hearts transplanted because of coronary artery disease (CAD). Total passive tension was reduced in CAD compared with control, indicating a more compliant behavior of the myocardium. The authors, referring to the well-known increase in cardiac stiffness due to collagen in chronic heart failure, hypothesize that this isoform shift occurs to counteract the global stiffening caused by chronic preload elevation in CAD patients. The giant molecule titin, the “third sarcomeric filament system,” is the third most abundant (10%) of the …