Unlike some lower vertebrates which can completely regenerate their heart, the human heart is a terminally differentiated organ. Cardiomyocytes lost during cardiac injury and heart failure cannot be replaced due to their limited proliferative capacity. Therefore, cardiac injury generally leads to progressive failure. Here, we summarize the latest progress in research on methods to induce cardiomyocyte cell cycle entry and heart repair through the alteration of cardiomyocyte plasticity, which is emerging as an effective strategy to compensate for the loss of functional cardiomyocytes and improve the impaired heart functions.

Cardiomyocytes (CMs) lost during ischemic cardiac injury cannot be replaced due to their limited proliferative capacity. Calcium is an important signal transducer that regulates key cellular processes, but its role in regulating CM proliferation is incompletely understood. Here we show a robust pathway for new calcium signaling-based cardiac regenerative strategies. A drug screen targeting proteins involved in CM calcium cycling in human embryonic stem cell-derived cardiac organoids (hCOs) revealed that only the inhibition of L-Type Calcium Channel (LTCC) induced the CM cell cycle. Furthermore, overexpression of Ras-related associated with Diabetes (RRAD), an endogenous inhibitor of LTCC, induced CM cell cycle activity in vitro, in human cardiac slices, and in vivo. Mechanistically, LTCC inhibition by RRAD or nifedipine induced CM cell cycle by modulating calcineurin activity. Moreover, ectopic expression of RRAD/CDK4/CCND in combination induced CM proliferation in vitro and in vivo, improved cardiac function and reduced scar size post-myocardial infarction.

Atrial fibrillation (AF) is a common arrhythmia with increasing incidence and prevalence, associated with increased morbidity and mortality. The list of predisposing factors is extensive and includes coronary artery disease (CAD) as a significant trigger. Coronary spasm, an uncommon form of CAD, can very rarely present with AF. We report an adult male with no significant risk factors or family history, except for smoking, who presented with recurrent palpitations diagnosed and managed as paroxysmal AF. Within one year, the patient experienced recurrent attacks of acute chest pain associated with paroxysms of AF. Coronary angiography showed normal coronary anatomy, and coronary spasm was confirmed by a provocation test, which was associated with the development of arrhythmia. The calcium channel blocker (CCB) nifedipine and isosorbide mononitrate prevented the recurrence of these attacks. CAD should be managed as part of the holistic management of paroxysmal AF, and coronary artery spasms should be considered and treated with coronary dilators, especially CCBs.

Aims: Adult cardiomyocytes (CMs) have minimal proliferative capacity, limiting the heart's ability to regenerate after injury. While neonatal CMs can proliferate, the signalling pathways governing this process are poorly understood. This study aims to identify and reintroduce the neonatal-specific CM proliferation sensitizing signal to restore cell cycle in adult CMs. Methods and results: We identified CD36 as a marker for the neonatal spontaneously proliferating CMs. Bulk and single cell RNA-seq, and spatial transcriptomics analyses of the P1 WT, CD36KO and CD36CKO hearts revealed that a CD36/FABP5/PPARδ signalling axis was uniquely expressed in spontaneously proliferating CMs. Using unbiased metabolomics and spatial metabolomics, we discovered that CD36KO and CD36cKO hearts had a 50% reduction in retinoic acid (RA) levels, implicating CD36 in regulating RA intracellular levels. Moreover, the pro-proliferative effect of RA treatment was lost in CD36KO or FABP5 knockdown CMs. To confirm the causality of this proposed mechanism, in vivo, crossing CD36KO with CM-specific PPARδ overexpression (PPARδCTG) only in CMs rescued the proliferation deficiency phenotype in CD36KO in the P1 hearts. Finally, reintroduction of FABP5, the rate limiting step of this signalling pathway, in adult hearts, using an inducible CM-specific FABP5 knock-in mouse (FABP5KI) was sufficient to drive CM cell-cycle entry and led to significantly improved cardiac function following myocardial infarction in adult mice. Conclusion: RA/CD36/FABP5/PPARδ signalling pathway is essential for spontaneous neonatal CM proliferation. Re-activating this pathway in adult hearts through FABP5 overexpression is sufficient to induce functional recovery after ischaemic injury, identifying FABP5 as a potential therapeutic target for cardiac regeneration.

Cardiomyocytes (CMs) lost during ischemic cardiac injury cannot be replaced due to their limited proliferative capacity, which leads to progressive heart failure. Calcium (Ca2+) is an important signal transducer that regulates key cellular processes, but its role in regulating CM proliferation is incompletely understood. A drug screen targeting proteins involved in CM calcium cycling in human embryonic stem cell-derived cardiac organoids (hCOs) revealed that only the inhibition of L-Type Calcium Channel (LTCC), but not other Ca2+ regulatory proteins (SERCA or RYR), induced the CM cell cycle. Furthermore, overexpression of Ras-related associated with Diabetes (RRAD), an endogenous inhibitor of LTCC, induced CM cell cycle activity in vitro, in human cardiac slices, and in vivo. Mechanistically, LTCC inhibition by RRAD induces the cell cycle in CMs by modulating calcineurin activity and translocating Hoxb13 to the CM nucleus. Together, this represents a robust pathway for regenerative strategies.