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The \"athlete's heart\" phenotype, featuring resting bradycardia, has traditionally been viewed as a benign adaptation. However, emerging evidence associates prolonged, high-intensity endurance training with an increased risk of clinical sinoatrial node dysfunction. This systematic review synthesizes evidence on exercise-induced intrinsic Sinoatrial Node (SAN) electrophysiological remodelling and evaluates its dual nature along the adaptation-pathology continuum. Following PRISMA guidelines, a systematic search of PubMed, Web of Science, and Google Scholar (2000-2025) identified 17 eligible studies. Analysis revealed that in humans, rodents, and rabbits, exercise induces intrinsic SAN electrophysiological remodelling-a \"membrane clock\" reset characterized by coordinated downregulation of pacemaker currents, notably Hyperpolarization-activated cyclic nucleotide-gated cation channel (I ), via the Nkx2.5-miR-423-5p transcription factor pathway. Evidence for \"calcium clock\" involvement remains inconsistent. In contrast, large animal models (e.g., dogs, horses) show only parasympathetic-mediated bradycardia without intrinsic remodelling. Training loads may induce structural changes (e.g., fibrosis), providing an anatomical substrate for pathology. Moderating factors such as training type and ageing contribute to a phenotype of \"acquired SAN reserve reduction. Exercise-induced intrinsic SAN remodelling is a physiological adaptation mechanism that, under certain conditions, can cross a threshold to become a pathological cause of clinical dysfunction. Recognizing this continuum is essential for risk stratification and future therapeutic innovation.

The sinoatrial node (SAN), the leading pacemaker region, generates electrical impulses that propagate throughout the heart. SAN dysfunction with bradyarrhythmia is well documented in heart failure (HF). However, the underlying mechanisms are not completely understood. Mitochondria are critical to cellular processes that determine the life or death of the cell. The release of Ca2+ from the ryanodine receptors 2 (RyR2) on the sarcoplasmic reticulum (SR) at mitochondria—SR microdomains serves as the critical communication to match energy production to meet metabolic demands. Therefore, we tested the hypothesis that alterations in the mitochondria—SR connectomics contribute to SAN dysfunction in HF. We took advantage of a mouse model of chronic pressure overload—induced HF by transverse aortic constriction (TAC) and a SAN-specific CRISPR-Cas9—mediated knockdown of mitofusin-2 (Mfn2), the mitochondria—SR tethering GTPase protein. TAC mice exhibited impaired cardiac function with HF, cardiac fibrosis, and profound SAN dysfunction. Ultrastructural imaging using electron microscope (EM) tomography revealed abnormal mitochondrial structure with increased mitochondria—SR distance. The expression of Mfn2 was significantly down-regulated and showed reduced colocalization with RyR2 in HF SAN cells. Indeed, SAN-specific Mfn2 knockdown led to alterations in the mitochondria—SR microdomains and SAN dysfunction. Finally, disruptions in the mitochondria—SR microdomains resulted in abnormal mitochondrial Ca2+ handling, alterations in localized protein kinase A (PKA) activity, and impaired mitochondrial function in HF SAN cells. The current study provides insights into the role of mitochondria—SR microdomains in SAN automaticity and possible therapeutic targets for SAN dysfunction in HF patients.

Transient receptor potential (TRP) channels are nonselective cationic channels that are generally Ca2+ permeable and have a heterogeneous expression in the heart. In the myocardium, TRP channels participate in several physiological functions, such as modulation of action potential waveform, pacemaking, conduction, inotropy, lusitropy, Ca2+ and Mg2+ handling, store-operated Ca2+ entry, embryonic development, mitochondrial function and adaptive remodelling. Moreover, TRP channels are also involved in various pathological mechanisms, such as arrhythmias, ischaemia–reperfusion injuries, Ca2+-handling defects, fibrosis, maladaptive remodelling, inherited cardiopathies and cell death. In this Review, we present the current knowledge of the roles of TRP channels in different cardiac regions (sinus node, atria, ventricles and Purkinje fibres) and cells types (cardiomyocytes and fibroblasts) and discuss their contribution to pathophysiological mechanisms, which will help to identify the best candidates for new therapeutic targets among the cardiac TRP family.Transient receptor potential (TRP) channels are a family of 28 nonselective cationic channels that are heterogeneously expressed in different regions and cell types of the heart. In this Review, the authors summarize the various physiological and pathological cardiac processes in which TRP channels are involved.

It is highly debated how cyclic adenosine monophosphate-dependent regulation (CDR) of the major pacemaker channel HCN4 in the sinoatrial node (SAN) is involved in heart rate regulation by the autonomic nervous system. We addressed this question using a knockin mouse line expressing cyclic adenosine monophosphate-insensitive HCN4 channels. This mouse line displayed a complex cardiac phenotype characterized by sinus dysrhythmia, severe sinus bradycardia, sinus pauses and chronotropic incompetence. Furthermore, the absence of CDR leads to inappropriately enhanced heart rate responses of the SAN to vagal nerve activity in vivo. The mechanism underlying these symptoms can be explained by the presence of nonfiring pacemaker cells. We provide evidence that a tonic and mutual interaction process (tonic entrainment) between firing and nonfiring cells slows down the overall rhythm of the SAN. Most importantly, we show that the proportion of firing cells can be increased by CDR of HCN4 to efficiently oppose enhanced responses to vagal activity. In conclusion, we provide evidence for a novel role of CDR of HCN4 for the central pacemaker process in the sinoatrial node. The involvement of cAMP-dependent regulation of HCN4 in the chronotropic heart rate response is a matter of debate. Here the authors use a knockin mouse model expressing cAMP-insensitive HCN4 channels to discover an inhibitory nonfiring cell pool in the sinoatrial node and a tonic and mutual interaction between firing and nonfiring pacemaker cells that is controlled by cAMP-dependent regulation of HCN4, with implications in chronotropic heart rate responses.

Sinoatrial node (SAN) dysfunction often accompanies supraventricular tachyarrhythmias such as atrial fibrillation (AF), which is referred to as tachycardia-bradycardia syndrome (TBS). Although there have been many studies on electrical remodeling in TBS, the regulatory mechanisms that cause electrical remodeling in the SAN and atrial muscles by chronic bradycardia or tachycardia have not yet been fully investigated. Here we hypothesized Pitx2c, a transcription factor that played a central role in the late aspects of left-right asymmetric morphogenesis, regulated an interrelationship between the SAN and the atrial muscles and was involved in TBS-like pathology. To test this hypothesis, we generated transgenic mice overexpressing Pitx2c specifically in the atria (OE mice). Although Pitx2c is normally expressed only in the left atria (LA), the expression levels of Pitx2c protein in the right atria (RA) were significantly increased to similar levels of those in the LA of non-transgenic control mice (WT). We found the heart rate of OE mice was significantly variable although the average heart rate was similar between WT and OE mice. Electrophysiological examination showed OE mice exhibited prolonged SAN recovery time and higher AF inducibility. Histological analysis revealed SAN-specific ion channel HCN4-positive cells were hardly detected in the SAN of OE mice, along with ectopic expression in the RA. Furthermore, transcription factors associated with SAN formation were down-regulated in the RA of OE mice. We conclude that SAN dysfunction by Pitx2 dysregulation predisposed OE mice to a TBS-like phenotype, and Pitx2c is a key regulator that defines SAN function in the atria.

Physiologically relevant increases in transcription factor dosage and their role in development and disease remain largely unexplored. Genomic deletions upstream of the Paired-like homeodomain transcription factor gene ( PITX2 ), identified in patients with sinus node dysfunction and atrial fibrillation and modeled in mice ( delB ), rewire the local epigenetic landscape, increasing PITX2 expression. Here, we demonstrate that pacemaker cardiomyocytes in the embryonic delB sinus node ectopically express PITX2 at physiological dosages in a heterogeneous pattern. The prenatal delB sinus node forms discrete subdomains showing PITX2 dosage-dependent mild or severe loss of pacemaker cardiomyocyte identity. Respective subdomain sizes and severity of sinus node dysfunction and atrial arrhythmia susceptibility align with PITX2 dosage. Ectopic PITX2c expression in human induced pluripotent stem cell-derived pacemaker cardiomyocytes causes PITX2 dosage-dependent transcriptional and electrophysiological changes paralleling those in delB mice. Our findings provide a mechanistic link between genetic variation–driven ectopic PITX2 expression, sinus node dysfunction and atrial arrhythmogenesis, illustrating how spatiotemporally defined increases in transcription factor dosage can translate into developmental defects and disease predisposition. Genomic deletions upstream of PITX2 are strongly associated with atrial fibrillation, the most common cardiac arrhythmia. Here, the authors report that ectopic PITX2 expression dosage-dependently disrupts pacemaker cell state and function, and atrial rhythm, linking chromatin conformation of the PITX2 locus to both sinus node dysfunction and atrial fibrillation.

Diabetes increases oxidant stress and doubles the risk of dying after myocardial infarction, but the mechanisms underlying increased mortality are unknown. Mice with streptozotocin-induced diabetes developed profound heart rate slowing and doubled mortality compared with controls after myocardial infarction. Oxidized Ca(2+)/calmodulin-dependent protein kinase II (ox-CaMKII) was significantly increased in pacemaker tissues from diabetic patients compared with that in nondiabetic patients after myocardial infarction. Streptozotocin-treated mice had increased pacemaker cell ox-CaMKII and apoptosis, which were further enhanced by myocardial infarction. We developed a knockin mouse model of oxidation-resistant CaMKIIδ (MM-VV), the isoform associated with cardiovascular disease. Streptozotocin-treated MM-VV mice and WT mice infused with MitoTEMPO, a mitochondrial targeted antioxidant, expressed significantly less ox-CaMKII, exhibited increased pacemaker cell survival, maintained normal heart rates, and were resistant to diabetes-attributable mortality after myocardial infarction. Our findings suggest that activation of a mitochondrial/ox-CaMKII pathway contributes to increased sudden death in diabetic patients after myocardial infarction.

Sinus node dysfunction, a prevalent arrhythmia in aging populations, is characterized by fibrosis and loss of pacemaker activity, necessitating pacemaker implantation. Current therapies fail to reverse the underlying pathology. Small extracellular vesicles derived from human induced pluripotent stem cells possess regenerative potential but lack targeted delivery. Here, we engineer platelet membrane-fused vesicles that synergistically combine collagen targeting for ischemic injury homing with immune evasion. In a rat model of sinus node dysfunction, these modified vesicles exhibit 3.1-fold higher accumulation in the sinoatrial node compared to unmodified vesicles, resulting in a 63% reduction in fibrosis and significant restoration of heart rate and intrinsic pacemaker function. The vesicles mitigate fibroblast activation and protect cardiomyocytes from oxidative stress. This study establishes a targeted, cell-free nanotherapeutic platform for resolving fibrosis and electrophysiological dysfunction in sinus node disease. Sinus node dysfunction (SND) is a prevalent arrhythmia syndrome characterized by sinoatrial node pacemaker failure. This study engineers stem cell-derived vesicles with platelet membranes for targeted delivery to the ischemic sinoatrial node as a cell-free nanotherapeutic strategy for treatment of SND.

Mechanisms for human sinoatrial node (SAN) dysfunction are poorly understood and whether human SAN excitability requires voltage-gated sodium channels (Nav) remains controversial. Here, we report that neuronal (n)Nav blockade and selective nNav1.6 blockade during high-resolution optical mapping in explanted human hearts depress intranodal SAN conduction, which worsens during autonomic stimulation and overdrive suppression to conduction failure. Partial cardiac (c)Nav blockade further impairs automaticity and intranodal conduction, leading to beat-to-beat variability and reentry. Multiple nNav transcripts are higher in SAN vs atria; heterogeneous alterations of several isoforms, specifically nNav1.6, are associated with heart failure and chronic alcohol consumption. In silico simulations of Nav distributions suggest that I Na is essential for SAN conduction, especially in fibrotic failing hearts. Our results reveal that not only cNav but nNav are also integral for preventing disease-induced failure in human SAN intranodal conduction. Disease-impaired nNav may underlie patient-specific SAN dysfunctions and should be considered to treat arrhythmias. The role of of voltage-gated sodium channels (Nav) in pacemaking and conduction of the human sinoatrial node is unclear. Here, the authors investigate existence and function of neuronal and cardiac Nav in human sinoatrial nodes, and demonstrate their alterations in explanted human diseased hearts.

Background Sinus node dysfunction because of abnormal impulse generation or sinoatrial conduction block causes bradycardia that can be difficult to differentiate from high parasympathetic/low sympathetic modulation (HP/LSM). Hypothesis Beat‐to‐beat relationships of sinus node dysfunction are quantifiably distinguishable by Poincaré plots, machine learning, and 3‐dimensional density grid analysis. Moreover, computer modeling establishes sinoatrial conduction block as a mechanism. Animals Three groups of dogs were studied with a diagnosis of: (1) balanced autonomic modulation (n = 26), (2) HP/LSM (n = 26), and (3) sinus node dysfunction (n = 21). Methods Heart rate parameters and Poincaré plot data were determined [median (25%‐75%)]. Recordings were randomly assigned to training or testing. Supervised machine learning of the training data was evaluated with the testing data. The computer model included impulse rate, exit block probability, and HP/LSM. Results Confusion matrices illustrated the effectiveness in diagnosing by both machine learning and Poincaré density grid. Sinus pauses >2 s differentiated (P < .0001) HP/LSM (2340; 583‐3947 s) from sinus node dysfunction (8503; 7078‐10 050 s), but average heart rate did not. The shortest linear intervals were longer with sinus node dysfunction (315; 278‐323 ms) vs HP/LSM (260; 251‐292 ms; P = .008), but the longest linear intervals were shorter with sinus node dysfunction (620; 565‐698 ms) vs HP/LSM (843; 799‐888 ms; P < .0001). Conclusions Number and duration of pauses, not heart rate, differentiated sinus node dysfunction from HP/LSM. Machine learning and Poincaré density grid can accurately identify sinus node dysfunction. Computer modeling supports sinoatrial conduction block as a mechanism of sinus node dysfunction.