Altered Titin Expression, Myocardial Stiffness, and Left Ventricular Function in Patients With Dilated Cardiomyopathy

Abstract

Background-The role of the giant protein titin in patients with heart failure is not well established. We investigated titin expression in patients with end-stage heart failure resulting from nonischemic dilated cardiomyopathy, in particular as it relates to left ventricular (LV) myocardial stiffness and LV function. Methods and Results-SDS-agarose gels revealed small N2B (stiff) and large N2BA (compliant) cardiac titin isoforms with a mean N2BA:N2B expression ratio that was significantly (PϽ0.003) increased in 20 heart failure patients versus 6 controls. However, total titin was unchanged. The coexpression ratio was highest in a subsample of patients with an impaired LV relaxation pattern (nϭ7), intermediate in those with pseudonormal filling (nϭ6), and lowest in the group with restrictive filling (nϭ7). Mechanical measurements on LV muscle strips dissected from these hearts (nϭ8) revealed that passive muscle stiffness was significantly reduced in patients with a high N2BA:N2B expression ratio. Clinical correlations support the relevance of these changes for LV function (assessed by invasive hemodynamics and Doppler echocardiography). A positive correlation between the N2BA:N2B titin isoform ratio and deceleration time of mitral E velocity, A wave transit time, and end diastolic volume/pressure ratio was found. These changes affect exercise tolerance, as indicated by the positive correlation between the N2BA:N2B isoform ratio and peak O 2 consumption (nϭ10). Upregulated N2BA expression was accompanied by increased expression levels of titin-binding proteins (cardiac ankyrin repeat protein, ankrd2, and diabetes ankyrin repeat protein) that bind to the N2A element of N2BA titin (studied in 13 patients). Conclusions-Total titin content was unchanged in end-stage failing hearts and the more compliant N2BA isoform comprised a greater percentage of titin in these hearts. Changes in titin isoform expression in heart failure patients with dilated cardiomyopathy significantly impact diastolic filling by lowering myocardial stiffness. Upregulation of titin-binding proteins indicates that the importance of altered titin expression might extend to cell signaling and regulation of gene expression.

Physiological Functions of the Giant Elastic Protein Titin in Mammalian Striated Muscle

“…[28]. tio increases in muscles from patients with end-stage heart failure [85]. In this study, a positive correlation was found between the N2BA:N2B titin isoform ratio and various clinical parameters, such as the ratio of end-diastolic volume to end-diastolic pressure.…”

Transmural Heterogeneity of Cellular Level Power Output Is Reduced in Human Heart Failure

“…This probably reflects a compensatory effect of titin isoform expression. Consistent with previous studies [15,16], samples from failing hearts had a greater relative content of the large N2BA isoform of titin (p=0.047, Figure S3B). This isoform shift tends to decrease passive stiffness and seems to counteract the mechanical effect of increased fibrosis in the samples from the failing hearts.…”

Gigantic Business

“…An increased proportion of the compliant N2BA variants was observed in end-stage failing human hearts, including those from ischemic cardiomyopathy, 105 nonischemic DCM, 109,110 and other patients with HFrEF, 111 compared with nonfailing donor hearts (45%-50% versus ≈30%). In patients with aortic stenosis, the N2BA:N2B expression ratio was somewhat higher than in healthy control hearts in one study, 111 but unaltered 112 or reduced 113 in other studies.…”

“…In contrast, characteristic for concentric remodeled hearts (compensated hypertrophy) with diastolic dysfunction following from hypertensive heart disease may be a decreased N2BA:N2B ratio causing elevated myocyte stiffness ( Figure 5A and 5B). Because the pattern of titin-isoform expression correlates with parameters of diastolic function, such as the end-diastolic volume, 110 it is likely that the titin-isoform ratio does affect overall myocardial passive stiffness. Not all relevant studies, however, have reported altered titin-isoforms in patients and HF models.…”