Mechanical Unloading During Left Ventricular Assist Device Support Increases Left Ventricular Collagen Cross-Linking and Myocardial Stiffness

Abstract

Background-Left ventricular assist devices (LVADs) induce reverse remodeling of the failing heart except for the extracellular matrix, which exhibits additional pathophysiological changes, although their mechanisms and functional consequences are unknown. Methods and Results-Hearts were obtained at transplant from patients with idiopathic dilated cardiomyopathy (DCM) not requiring LVAD support (nϭ30), patients requiring LVAD support (nϭ16; LVAD duration, 145Ϯ33 days), and 5 nonfailing hearts. Left (LV) and right ventricular (RV) ex vivo pressure-volume relationships were measured, and chamber and myocardial stiffness constants were determined. Myocardial tissue content of total and cross-linked collagen, collagen types I and III, MMP-1, MMP-9, TIMP-1, and angiotensin (Ang) I and II were measured. LV size, mass, and myocyte diameter decreased after LVAD compared with DCM without LVAD (PϽ0.05). Total and cross-linked collagen and ratio of type I to III collagen increased in DCM compared with nonfailing hearts and increased further after LVAD (PϽ0.05 versus DCM and nonfailing). Concomitantly, chamber and myocardial stiffness increased with LVAD. The ratio of MMP-1 to TIMP-1 increased in DCM and almost normalized after LVAD, favoring decreased collagen degradation. Tissue Ang I and II also increased during LVAD. There was no significant change in the RV of LVAD-supported heart compared with DCM. Conclusions-LVAD support increases LV collagen cross-linking and the ratio of collagen type I to III, which is associated with increased myocardial stiffness. Decreased tissue MMP-1-to-TIMP-1 ratio (decreased degradation) and increased Ang levels (stimulants of synthesis) are likely mechanisms for these changes. Lack of significant effects on the RV suggest that hemodynamic unloading of the LV (not provided to the RV) might be the primary factor that regulates these extracellular matrix changes. (Circulation. 2005;112:364-374.)Key Words: cardiomyopathy Ⅲ collagen Ⅲ heart-assist devices Ⅲ heart failure Ⅲ metalloproteinases L eft ventricular assist devices (LVADs) provide mechanical support for the end-stage failing human heart and have been used as a bridge to cardiac transplantation. We have demonstrated that LVAD support is associated with normalization of diastolic chamber properties as indexed by the passive pressure-volume relation. [1][2][3] This normalization of diastolic properties results from a regression of myocyte hypertrophy, including reduced LV mass, wall thickness, and myocyte diameter. 4,5 In addition, LVAD support has been associated with a trend toward normalization in cardiomyocyte function, 6 calcium cycling properties, 7 and expression of various genes. 8 In addition to changes in intrinsic myocardial properties, LVAD use is associated with changes in the characteristics and metabolism of the extracellular matrix (ECM). However, unlike almost all other aspects of reverse remodeling of the myocardium and ventricular chamber, the ECM changes do not uniformly reflect a return toward normal conditions. 9 -11...

Type IV collagen degradation in the myocardial basement membrane after unloading of the failing heart by a left ventricular assist device

“…The differences in this association between the BM and collagen fibers may be due to alterations of the BM but may also be caused by the changes in the ECM. 15,36,37 With IHC, we showed a significant reduction of type IV collagen immunoreactivity in the BM after LVAD support. However, laminin was still present in the BM after unloading of the heart.…”

“…[35][36][37] In a previous study of our group, 15 we have shown that reverse remodeling of type I and III collagen in the ECM follows a biphasic pattern. Initially, an increase of type I and III collagen turnover takes place, which is paralleled by an increase of the ECM volume.…”

Ventricular assist devices for heart failure: a focus on patient selection and complications

“…54 Secondly, myocardial fibrosis (antecedent scarring or localized injury induced by cannula placement) increases the propensity for arrhythmias. 59 Use of angiotensin-converting enzyme inhibitors may reduce levels of fibrosis and collagen deposition. The third aspect is the electrophysiological adaptation to LVAD support.…”

Altered Expression of mRNA and miRNA during Mechanical Support of the Failing Human Heart

“…The changes in ECM during this process of reverse remodeling resulted not only in a time-dependent change of type I and type III collagen protein (Goldsmith and Borg, 2002;Stamenkovic, 2003), but also in considerable changes in composition of the basal membrane. These included amongst others reduced collagen type IV content in the cardiomyocyte basal membrane, as a result of increased matrix metalloproteinase activity (Bruggink et al, 2007;Spinale, 2002;Li et al, 2001;Klotz et al, 2005). So, during LVAD support myocardial architecture and composition change at the level of both the cardiomyocytes and the ECM.…”