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Impaired calcium handling mechanisms in atrial trabeculae of diabetic patients.

ABSTRACT: The aim of this study was to investigate cardiomyocyte Ca²⁺ handling and contractile function in freshly excised human atrial tissue from diabetic and non-diabetic patients undergoing routine surgery. Multicellular trabeculae (283 ± 20 μm in diameter) were dissected from the endocardial surface of freshly obtained right atrial appendage samples from consenting surgical patients. Trabeculae were mounted in a force transducer at optimal length, electrically stimulated to contract, and loaded with fura-2/AM for intracellular Ca²⁺ measurements. The response to stimulation frequencies encompassing the physiological range was recorded at 37°C. Myofilament Ca²⁺ sensitivity was assessed from phase plots and high potassium contractures of force against [Ca²⁺ ]_i . Trabeculae from diabetic patients (n = 12) had increased diastolic (resting) [Ca²⁺ ]_i (p = 0.03) and reduced Ca²⁺ transient amplitude (p = 0.04) when compared to non-diabetic patients (n = 11), with no difference in the Ca²⁺ transient time course. Diastolic stress was increased (p = 0.008) in trabeculae from diabetic patients, and peak developed stress decreased (p ≤ 0.001), which were not accounted for by reduction in the cardiomyocyte, or contractile protein, content of trabeculae. Trabeculae from diabetic patients also displayed diminished myofilament Ca²⁺ sensitivity (p = 0.018) compared to non-diabetic patients. Our data provides evidence of impaired calcium handling during excitation-contraction coupling with resulting contractile dysfunction in atrial tissue from patients with type 2 diabetes in comparison to the non-diabetic. This highlights the importance of targeting cardiomyocyte Ca²⁺ homeostasis in developing more effective treatment options for diabetic heart disease in the future.

SUBMITTER: Jones TLM

PROVIDER: S-EPMC9904963 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Impaired calcium handling mechanisms in atrial trabeculae of diabetic patients.

Jones Timothy L M TLM Kaur Sarbjot S Kang Nicholas N Ruygrok Peter N PN Ward Marie-Louise ML

Physiological reports 20230201 3

The aim of this study was to investigate cardiomyocyte Ca<sup>2+</sup> handling and contractile function in freshly excised human atrial tissue from diabetic and non-diabetic patients undergoing routine surgery. Multicellular trabeculae (283 ± 20 μm in diameter) were dissected from the endocardial surface of freshly obtained right atrial appendage samples from consenting surgical patients. Trabeculae were mounted in a force transducer at optimal length, electrically stimulated to contract, and l ...[more]

PMID: 36750180

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Project description:AimsAtrial fibrillation (AF) is a commonly occurring arrhythmia after cardiac surgery (postoperative AF, poAF) and is associated with poorer outcomes. Considering that reduced atrial contractile function is a predictor of poAF and that Ca2+ plays an important role in both excitation-contraction coupling and atrial arrhythmogenesis, this study aims to test whether alterations of intracellular Ca2+ handling contribute to impaired atrial contractility and to the arrhythmogenic substrate predisposing patients to poAF.Methods and resultsRight atrial appendages were obtained from patients in sinus rhythm undergoing open-heart surgery. Cardiomyocytes were investigated by simultaneous measurement of [Ca2+]i and action potentials (APs, patch-clamp). Patients were followed-up for 6 days to identify those with and without poAF. Speckle-tracking analysis of preoperative echocardiography revealed reduced left atrial contraction strain in poAF patients. At the time of surgery, cellular Ca2+ transients (CaTs) and the sarcoplasmic reticulum (SR) Ca2+ content were smaller in the poAF group. CaT decay was slower in poAF, but the decay of caffeine-induced Ca2+ transients was unaltered, suggesting preserved sodium-calcium exchanger function. In agreement, western blots revealed reduced SERCA2a expression in poAF patients but unaltered phospholamban expression/phosphorylation. Computational modelling indicated that reduced SERCA activity promotes occurrence of CaT and AP alternans. Indeed, alternans of CaT and AP occurred more often and at lower stimulation frequencies in atrial myocytes from poAF patients. Resting membrane potential and AP duration were comparable between both groups at various pacing frequencies (0.25-8 Hz).ConclusionsBiochemical, functional, and modelling data implicate reduced SERCA-mediated Ca2+ reuptake into the SR as a major contributor to impaired preoperative atrial contractile function and to the pre-existing arrhythmogenic substrate in patients developing poAF.

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Impaired calcium handling mechanisms in atrial trabeculae of diabetic patients.

Publications

Impaired calcium handling mechanisms in atrial trabeculae of diabetic patients.

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