Remodeling of T-Tubules and Reduced Synchrony of Ca ²⁺ Release in Myocytes From Chronically Ischemic Myocardium

Abstract

Abstract-In ventricular cardiac myocytes, T-tubule density is an important determinant of the synchrony of sarcoplasmic reticulum (SR) Ca 2ϩ release and could be involved in the reduced SR Ca 2ϩ release in ischemic cardiomyopathy. We therefore investigated T-tubule density and properties of SR Ca 2ϩ release in pigs, 6 weeks after inducing severe stenosis of the circumflex coronary artery (91Ϯ3%, Nϭ13) with myocardial infarction (8.8Ϯ2.0% of total left ventricular mass). Severe dysfunction in the infarct and adjacent myocardium was documented by magnetic resonance and Doppler myocardial velocity imaging. Myocytes isolated from the adjacent myocardium were compared with myocytes from the same region in weight-matched control pigs. T-tubule density quantified from the di-8-ANEPPS (di-8-butyl-aminonaphthyl-ethylene-pyridinium-propyl-sulfonate) sarcolemmal staining was decreased by 27Ϯ7% (PϽ0.05). Synchrony of SR Ca 2ϩ release (confocal line scan images during whole-cell voltage clamp) was reduced in myocardium myocytes. Delayed release (ie, ] i occurring later than 20 ms) occurred at 35.5Ϯ6.4% of the scan line in myocardial infarction versus 22.7Ϯ2.5% in control pigs (PϽ0.05), prolonging the time to peak of the line-averaged [Ca 2ϩ ] i transient (121Ϯ9 versus 102Ϯ5 ms in control pigs, PϽ0.05). Delayed release colocalized with regions of T-tubule rarefaction and could not be suppressed by activation of protein kinase A. The whole-cell averaged [Ca 2ϩ ] i transient amplitude was reduced, whereas L-type Ca 2ϩ current density was unchanged and SR content was increased, indicating a reduction in the gain of Ca 2ϩ -induced Ca 2ϩ release. In conclusion, reduced T-tubule density during ischemic remodeling is associated with reduced synchrony of Ca 2ϩ release and reduced efficiency of coupling Ca 2ϩ influx to Ca Key Words: myocardial infarction Ⅲ contractility Ⅲ myocytes Ⅲ calcium A lthough new therapeutic approaches have decreased the mortality associated with myocardial infarction (MI) over the past decades, 1 many patients nevertheless sustain a regional loss of myocardial contractile tissue following an ischemic event. The resulting increased hemodynamic burden on the left ventricle leads to structural and functional changes in the remaining viable myocardium, which further reduces ventricular performance, a process referred to as myocardial remodeling. 2 Sustained regional chronic and/or intermittent ischemia further contributes to this process, and the resulting ischemic cardiomyopathy is currently among the major causes of heart failure. 3 Contractile dysfunction of the ventricle is partly related to the abnormal loading in vivo 4 and partly to the intrinsic properties of the cardiomyocytes. Myocytes isolated from patients with ischemic cardiomyopathy at the time of heart transplantation have a reduced contractile function resulting from abnormal Ca 2ϩ handling. [5][6][7] Animal models have examined the mechanisms of cellular dysfunction in ischemic cardiomyopathy in more detail. Myocytes from the infarct border...

Extreme sarcoplasmic reticulum volume loss and compensatory T-tubule remodeling after Serca2 knockout

“…The increased frequency of LTTs in KO mimics the disposition during early differentiation, when tubules are essentially longitudinal (9). Although KO animals exhibit heart failure symptoms (3,4), there are significant differences between the increased presence of LTTs observed here and T-tubule remodeling normally reported during heart failure development (10)(11)(12)(13)(14)(15). First, whereas the transverse component of the network and its association with dyads are disarranged in classic heart failure models (16), KO cardiomyocytes exhibit a maintained transverse and unaltered dyadic architecture.…”

Human cardiomyocyte calcium handling and transverse tubules in mid‐stage of post‐myocardial‐infarction heart failure

“…Disrupted T‐tubule density has previously been demonstrated in explanted end‐stage HF human hearts from different aetiologies, also including ischaemic heart disease 2, 45, 46, 47, 48, 49. Data from both larger animal models like pig and dogs49, 50 and smaller animal models like mice and rats report disrupted T‐tubule density also in earlier stages of the disease 51.…”

“…HF is characterized by several abnormalities in the excitation–contraction coupling, such as reduced and slower systolic Ca 2+ release from the sarcoplasmic reticulum (SR), elevated diastolic cytoplasmic Ca 2+ , and reduced diastolic Ca 2+ removal, leading to reduced contractile function. Several mechanisms are responsible for this: disrupted cleft spacing between the L‐type Ca 2+ channel and ryanodine receptors 2 (RyR2) by reduced density of transverse (T) tubules;2 increased RyR2 Ca 2+ sensitivity leading to increased spontaneous Ca 2+ release events from SR causing after‐depolarization and trigger arrhythmias;3 reduced SR Ca 2+ adenosine triphosphatase 2a (SERCA2a) and increased Na + /Ca 2+ exchanger activities 4. All these changes at the cellular level may explain the resulting breakdown of normal force–frequency relationships in HF, causing inadequate cardiac output responsiveness during physical effort 5.…”

Size Matters: Ryanodine Receptor Cluster Size Affects Arrhythmogenic Sarcoplasmic Reticulum Calcium Release

“…However, pathological conditions such as heart failure with altered RyR sensitization1 and structure cluster and T‐tubule–SR organization35, 36, 37, 38, 39, 40 could undermine these intrinsically beneficial effects and contribute to cardiac dysfunction and arrhythmogenesis.…”