Emerging mechanisms of T-tubule remodelling in heart failure

Abstract

Cardiac excitation-contraction coupling occurs primarily at the sites of transverse (T)-tubule/sarcoplasmic reticulum junctions. The orderly T-tubule network guarantees the instantaneous excitation and synchronous activation of nearly all Ca(2+) release sites throughout the large ventricular myocyte. Because of the critical roles played by T-tubules and the array of channels and transporters localized to the T-tubule membrane network, T-tubule architecture has recently become an area of considerable research interest in the cardiovascular field. This review will focus on the current knowledge regarding normal T-tubule structure and function in the heart, T-tubule remodelling in the transition from compensated hypertrophy to heart failure, and the impact of T-tubule remodelling on myocyte Ca(2+) handling function. In the last section, we discuss the molecular mechanisms underlying T-tubule remodelling in heart disease.

Figure 1

Ultrastructure and organization of T-tubules in cardiac muscle (myocytes). (A) Electron micrograph of a transverse section of cat cardiac muscle showing four T-tubules extending inward from the periphery of the fibre (×32 000). (B) Electron micrograph of a longitudinal section of cat papillary muscle showing two T-tubules and multiple junctional couplings between T-tubules and terminal cisternae of SR, as indicated by the arrows (×40 000; reproduced with permission from Fawcett and McNutt). (C) A confocal fluorescence image of the T-tubules in an isolated living rat ventricular myocyte stained with lipophilic membrane marker Di-8 ANEPPS. (D) 3D projection of the T-tubule network from 30 sequential sections (at 0.2 μm per section) of confocal images from the same myocyte. (E) Schematic drawing of the T-tubule system in a ventricular myocyte, viewed from the transverse section.

Figure 2

Cartoon of local Ca²⁺ micro-domain and major proteins concentrated in the dyadic junction. The local Ca²⁺ micro-domain includes primarily (L-type) Ca²⁺ channels and opposing RyRs within a 12–15 nm distance between T-tubule and SR membrane, forming functional Ca²⁺ release units (CRU). Other important components such as Na⁺/Ca²⁺ exchanger, Na⁺/K⁺-ATPase, and β-adrenergic receptor (β-AR) are also condensed on the T-tubules.

Figure 3

Synchrony of local Ca²⁺ release during E–C coupling. (A) Ca²⁺ spikes recorded in ventricular myocyte under whole-cell voltage-clamp condition, and 4 mM EGTA and 1 mM Oregon Green 488 BAPTA 5N in patch pipette solution. The confocal scan line was placed along the longitudinal axis of myocyte. Discrete Ca²⁺ spikes were evoked synchronously from all T-tubule/SR junctions upon membrane depolarization to 0 mV from a holding potential of −70 mV. (B) Surface plot of Ca²⁺ spikes shown in (A). (C and D) Sparklet–spark coupling—a direct visualization of local control of CICR. (C) LTCC Ca²⁺ influx mediated sparklets (the low-amplitude events, pink arrows) and triggered sparks (the high-amplitude events) recorded under loose-seal patch-clamp conditions. Note that not every sparklet can trigger a spark. (D) Surface plot of sparklet–spark coupling. The arrow indicates a sparklet foot that triggered a spark (from Wang et al.).

Figure 4

Ca²⁺ handling defects and T-tubule remodelling in failing myocytes. (A and B) Field-stimulated Ca²⁺ transients (1 Hz) in isolated myocytes from a control Wistar-Kyoto (WKY) rat and failing spontaneously hypertension rat (SHR/HF), respectively. Control healthy myocyte exhibits uniform, synchronous and stable Ca²⁺ transients from beat to beat. The failing myocyte displays dyssynchronous Ca²⁺ release at different regions of the cell. As shown by these arrows, Ca²⁺ releases are delayed at fixed locations on every beat. (C–F) T-tubule disorganization in a ventricular myocyte from a failing SHR heart (SHR/HF, D and F), compared with the organized T-tubule network from a WKY control myocyte (C and E). (From Song et al.)

Figure 5

3D reconstruction of epicardial myocyte T-tubule network in situ. Confocal images (25 confocal stacks at 0.2 μm interval) were acquired in situ from Langendorff-perfused intact healthy heart, demonstrating the periodically organized T-tubule structure in normal myocytes. (From Wei et al.)

Figure 6

Progressive T-tubule remodelling of left-ventricular myocytes in pressure overload rat cardiomyopathy. (A–D) Representative T-tubule images from left ventricle (LV) of age-matched sham-operated heart (A), hypertrophy (B), early HF (C), and advanced HF (D). At hypertrophy stage, discrete T-tubule loss (green arrows) was often observed with slight T-tubule disorganization (B). In moderately decompensated heart, LV myocytes exhibited widely impaired T-tubule system (C). At advanced HF stage, myocytes lost majority of T-tubules with striated pattern almost vanished (D). Each yellow framed inset is a zoom-in view of an area 40×40 μm² from associated images. (E) A gradual reduction in TT_power (an index of T-tubule regularity) with heart disease progression. (F) Cardiac global function (ejection fraction) correlates well with T-tubule integrity. LV, left ventricle; EF, ejection fraction. (From Wei et al.)

Figure 7

Schematic chart depicting the consequences of T-tubule remodelling and the relationship with heart failure and Ca²⁺-dependent arrhythmogenesis. Myocyte T-tubule remodelling leads to alterations at multiple levels, including ultrastructural, electrical, and signal transduction changes, collectively contributing to the progression of cardiac failure and the genesis of fatal arrhythmias.