The nucleus of a cardiomyocyte has been increasingly recognized as a morphologically distinct and partially independent calcium (Ca²⁺) signaling microdomain, with its own Ca²⁺-regulatory mechanisms and important effects on cardiac gene expression. In this review, we (1) provide a comprehensive overview of the current state of research on the dynamics and regulation of nuclear Ca²⁺ signaling in cardiomyocytes, (2) address the role of nuclear Ca²⁺ in the development and progression of cardiac pathologies, such as heart failure and atrial fibrillation, and (3) discuss novel aspects of experimental methods to investigate nuclear Ca²⁺ handling and its downstream effects in the heart. Finally, we highlight current challenges and limitations and recommend future directions for addressing key open questions.

Excessive β-adrenergic stimulation and tachycardia are potent triggers of cardiac remodeling; however, their exact cellular effects remain elusive. Here, we sought to determine the potency of β-adrenergic stimulation and tachycardia to modulate gene expression profiles of cardiomyocytes. Using neonatal rat ventricular cardiomyocytes, we showed that tachycardia caused a significant upregulation of sodium–calcium exchanger (NCX) and the activation of calcium/calmodulin-dependent kinase II (CaMKII) in the nuclear region. Acute isoprenaline treatment ameliorated NCX-upregulation and potentiated CaMKII activity, specifically on the sarcoplasmic reticulum and the nuclear envelope, while preincubation with the β-blocker propranolol abolished both isoprenaline-mediated effects. On a transcriptional level, screening for hypertrophy-related genes revealed tachycardia-induced upregulation of interleukin-6 receptor (IL6R). While isoprenaline prevented this effect, pharmacological intervention with propranolol or NCX inhibitor ORM-10962 demonstrated that simultaneous CaMKII activation on the subcellular Ca²⁺ stores and prevention of NCX upregulation are needed for keeping IL6R activation low. Finally, using hypertensive Dahl salt-sensitive rats, we showed that blunted β-adrenergic signaling is associated with NCX upregulation and enhanced IL6R signaling. We therefore propose a previously unrecognized protective role of β-adrenergic signaling, which is compromised in cardiac pathologies, in preventing IL6R overactivation under increased workload. A better understanding of these processes may contribute to refinement of therapeutic options for patients receiving β-blockers.

Excess salt is a major contributor to hypertension and hypertensive kidney injury, yet the early molecular events linking salt exposure to kidney damage remain incompletely understood. The Dahl salt-sensitive rat is a well-established model of salt-induced hypertension, but early metabolic and transcriptional remodeling in the kidney has not been fully characterized. We investigated early kidney alterations in 35 Dahl salt-sensitive rats fed a high-sodium (HSD) or low-sodium diet (LSD). A subgroup of HSD-fed rats received the ACE inhibitor imidapril at a subdepressor dose (1 mg/kg/day) to examine blood pressure-independent effects. Kidney tissue from 12-week-old animals was analyzed using histology, electron microscopy, transcriptomics, metabolomics, and angiotensin peptide profiling. HSD-fed rats developed hypertension by week 9 and showed kidney remodeling by week 12, including metabolic and transcriptional alterations suggestive of disrupted tricarboxylic acid cycle activity and impaired oxidative phosphorylation in the absence of overt fibrosis. Intra-kidney angiotensin I, II, and angiotensin 1–7 levels were reduced under HSD. Subdepressor ACE inhibition did not significantly alter blood pressure, kidney injury, angiotensin peptide levels, or the transcriptional and metabolic alterations observed in HSD-fed animals. These findings indicate that high salt intake induces early metabolic and extracellular matrix remodeling that is not modified by subdepressor ACE inhibition.

Mitochondria are central to cardiomyocyte function, and their spatial organization regulates nuclear signaling and gene transcription, holding potential for novel cardioprotective interventions. We developed a transmission electron microscopy platform optimized for resolving mitochondrial subpopulations and nuclear architecture in adult cardiomyocytes. This approach reliably captures longitudinal sections containing the center of the nucleus and perinuclear regions, enabling consistent imaging of subcellular nanostructures, assessment of pharmacological effects within the same organism, and visualization of extracellular vesicles carrying dysfunctional mitochondria. Integrated with an analysis workflow employing machine learning-based segmentation for annotation, the method allows automated quantification of mitochondrial and nuclear architecture and positioning. Using Drp1-deficient mice with impaired mitochondrial fission, we demonstrate this tool's ability to uncover nanoscale remodeling of mitochondria and nuclei under stress. Our platform overcomes challenges in electron microscopy analysis, providing a powerful resource to interrogate mitochondrial-nuclear dynamics in cardiac (patho)physiology. These insights will inform therapeutic targeting of bioenergetic failure.