Alterations in the Determinants of Diastolic Suction During Pacing Tachycardia

Abstract

Abstract-In cardiomyocytes, generation of restoring forces (RFs) responsible for elastic recoil involves deformation of the sarcomeric protein titin in conjunction with shortening below slack length. At the left ventricular (LV) level, recoil and filling by suction require contraction to an end-systolic volume (ESV) below equilibrium volume (Veq) as well as large-scale deformations, for example, torsion or twist. Little is known about RFs and suction in the failing ventricle.We undertook a comparison of determinants of suction in open-chest dogs previously subjected to 2 weeks of pacing tachycardia (PT) and controls. To assess the ability of the LV to contract below Veq, we used a servomotor to clamp left atrial pressure and produce nonfilling diastoles, allowing measurement of fully relaxed pressure at varying volumes. We quantified twist with sonomicrometry. We also assessed transmural ratios of N2B to N2BA titin isoforms and total titin to myosin heavy chain (MHC) protein. In PT, the LV did not contract below Veq, even with marked reduction of volume (end-diastolic pressure [EDP], 1 to 2 mm Hg), whereas in controls ESV was less than Veq when EDP was less than Ϸ5 mm Hg. In PT, both systolic twist and diastolic untwisting rate were reduced, and there was exaggerated transmural variation in titin isoform and titin-to-MHC ratios, consistent with the more extensible N2BA being present in larger amounts in the subendocardium. Thus, in PT, determinants of suction at the level of the LV are markedly impaired. The altered transmural titin isoform gradient is consistent with a decrease in RFs and may contribute to these findings. Key Words: suction Ⅲ restoring forces Ⅲ diastole Ⅲ heart failure Ⅲ tachycardia D iastolic suction results from compression and/or deformation of elastic elements in the wall of the ventricle, with storage of potential energy generated during systole in the form of a restoring force (RF) that is converted to recoil and ultimately kinetic energy (mitral inflow) during filling. [1][2][3][4][5][6][7] Inherent in this definition is the requirement that the ventricle be the source of energy driving mitral flow, ie, it must actively lower its pressure below the atrium. Ventricular filling can also occur as a result of an atrioventricular pressure gradient dictated by the level of atrial pressure at the time the mitral valve opens. In this case, atrial pressure is higher than diastolic ventricular pressure whether or not suction is present.In the cardiomyocyte, deformation of the sarcomeric protein titin during contraction below slack length is the source of a RF. 8 Titin is a large, filamentous protein extending from Z-to M-line of the sarcomere, with the segment spanning from near the Z-line to the A-band acting as a molecular spring. Titin is the major determinant of passive mechanical properties of the cardiomyocyte in sarcomeres stretched above and shortened below slack length. 8,9 In large mammals, titin exists as 2 isoforms with differing mechanical properties. 9 The smaller, N2B, isoform is st...

Titin Isoform Switch in Ischemic Human Heart Disease

“…12 A shift toward higher N2BA titin levels lowers cellular passive stiffness, as shown in dog hearts exposed to pacing tachycardia. 16 In the present work, we investigated whether the titin isoform expression pattern can be altered in diseased HHs. Hearts from CAD patients were selected for the analysis because they frequently exhibit increased LV wall stiffness.…”

“…Only the anterolateral midwall region was analyzed, because titin isoform expression varies with location in the heart. 16 Transplant HHs were transported for Ϸ1 hour and donor HHs for 1 to 5 hours in cardioplegia (University of Wisconsin solution) before being stored at Ϫ80°C. The study was approved by the Subcommittee on Human Research at Massachusetts General Hospital.…”

Assessment of Left Ventricular Torsional Deformation by Doppler Tissue Imaging

“…11,12 In the past decade, tissue tagging magnetic resonance imaging (MRI) has enabled noninvasive measurement of LV myocardial deformation in 3D space [13][14][15] and prompted investigation of LV torsion in various cardiac diseases. 16 -20 More recently, it has been reported that LV torsion is closely related to alterations of sarcomeric proteins, like the transmural gradient of titin isoforms 21 or myosin regulatory light chain 22,23 in experimental cardiomyopathy models.…”

The early variation of left ventricular twisting function in patients with lymphoma received anthracycline therapy assessed by three-dimensional speckle tracking echocardiography

“…Depending on the extent and severity of cardiomyocyte loss as well as myocardial fibrosis induced by anthracycline [32], twisting movement and myocardial deformation may be reduced. Previous studies further demonstrated anthracycline-induced calpain-dependent titin proteolysis and necrosis in cardiomyocytes affected the fibers architecture and cardiac geometry which were verified to alter the cardiac torsion pattern [33,34].…”