Cardiac T-Tubule cBIN1-Microdomain, a Diagnostic Marker and Therapeutic Target of Heart Failure

Abstract

Since its first identification as a cardiac transverse tubule (t-tubule) protein, followed by the cloning of the cardiac isoform responsible for t-tubule membrane microdomain formation, cardiac bridging integrator 1 (cBIN1) and its organized microdomains have emerged as a key mechanism in maintaining normal beat-to-beat heart contraction and relaxation. The abnormal remodeling of cBIN1-microdomains occurs in stressed and diseased cardiomyocytes, contributing to the pathophysiology of heart failure. Due to the homeostatic turnover of t-tubule cBIN1-microdomains via microvesicle release into the peripheral circulation, plasma cBIN1 can be assayed as a liquid biopsy of cardiomyocyte health. A new blood test cBIN1 score (CS) has been developed as a dimensionless inverse index derived from plasma cBIN1 concentration with a diagnostic and prognostic power for clinical outcomes in stable ambulatory patients with heart failure with reduced or preserved ejection fraction (HFrEF or HFpEF). Recent evidence further indicates that exogenous cBIN1 introduced by adeno-associated virus 9-based gene therapy can rescue cardiac contraction and relaxation in failing hearts. The therapeutic potential of cBIN1 gene therapy is enormous given its ability to rescue cardiac inotropy and provide lusitropic protection in the meantime. These unprecedented capabilities of cBIN1 gene therapy are shifting the current paradigm of therapy development for heart failure, particularly HFpEF.

SNTA1-deficient human cardiomyocytes are associated with increased structural components, calcium handling disorder, and shorter field potential duration

“…Therefore, rescuing diminished cardiac BIN1 expression could both rescue CACNA1C tra cking and restore normal T-tubule membrane morphology [34]. BIN1 could become a therapeutic target for heart failure [35][36]. When the cytoplasmic free calcium is elevating, calcium binds to troponin C and triggers contraction, and cause the concentrations of intracellular free calcium to elevate from 0∼100 nM to ∼1 µM compared with the diastole period [37].…”

Biomarkers of Volume Overload and Edema in Heart Failure With Reduced Ejection Fraction

“…A recent study exposed that cBIN1, a key mechanism in maintaining normal heart contraction, relaxation, and cardiomyocyte health, expresses various alterations in HF. Moreover, gene therapy with exogenous cBIN1 rescued cardiac lusitropic and inotropic properties, proving not only its great therapeutic potential in failing hearts (86), but also serving as a biomarker of cardiomyocyte remodeling (87).…”

Diagnostic and prognostic value of cardiospecific integrator protein in patients after myocardial infarction

“…Белок cBIN1 имеет решаю щее значение для нормальной биологии кардиомиоцитов и физиологии сердца, а также участвует в ремоделировании пораженных кардиомиоцитов и патофизиологии СН [6][7][8]. Так, показано, что при развитии ХСН снижается экспрессия cBIN1 и количественное определение cBIN1 в крови может точно измерить гомеостатический уровень Т-канальца cBIN1 в сердце у пациентов с нормальным или больным сердцем как показатель «жидкостной биопсии» сердечной ткани [9]. Был разработан новый показатель cBIN1 в анализе крови -CS как безразмерный обратный показатель, производный от концентрации cBIN1 в плазме, обладаю щий диагностической и прогностической силой для определения клинических исходов у пациентов с СН.…”

“…Показатель cBIN1(CS) измеряет клеточное ремоделирование миокарда [8,10,11]. В отличие от жидкостной биопсии Т-канальцев cBIN1-микродоменов кардиомиоцитов, CS точно определяет биохимическое состояние кардиомиоцитов, тем самым помогает установить функциональный резерв и потенциал восстановления поврежденного миокарда [12]. CS является обратным показателем сBIN-1 в плазме -низкий уровень белка при СН соответствует повышению CS [10].…”