Search Results (24)

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia globally, linked to significant cardiovascular morbidity and mortality. Catheter ablation has emerged as a primary therapeutic approach, yet substantial recurrence rates limit its long-term efficacy. This review critically examines the molecular mechanisms underlying AF recurrence post-ablation, synthesizing recent findings from current literature. Key molecular pathways identified include structural remodeling mediated by fibrosis involving transforming growth factor-beta 1 (TGF-β1) and matrix metalloproteinases (MMPs), ion-channel dysregulation, inflammatory pathways, autonomic nervous system imbalance, and genetic and epigenetic alterations. Despite considerable advances, critical gaps persist due to small, heterogeneous studies and insufficient long-term follow-up. Comprehensive mechanistic research integrating genomics, proteomics, and advanced imaging is urgently needed to better characterize these pathways. Future studies must validate biomarkers such as TGF-β1, MMPs, connexins, and novel markers like GDF-15 and relaxin. Clinical translation of these molecular insights through precision diagnostics and personalized interventions holds great promise to enhance patient selection, optimize ablation strategies, reduce recurrence, and ultimately improve clinical outcomes in AF management. Full article

Background: Crisponi/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by severe neonatal manifestations including paroxysmal muscle contractions, tendency for hyperthermia, and feeding and swallowing difficulties with high neonatal mortality. Pathogenic variants in the Cytokine Receptor-Like Factor 1 (CRLF1) gene have been associated with CS/CISS. These variants result in a loss of function of the encoded protein, which disrupts the formation of a functional heterodimer with Cardiotrophin-Like Cytokine Factor 1 (CLCF1). This complex is essential for the development of autonomic and sensory nervous systems, as well as for bone remodeling. We report two patients affected by CS harboring pathogenic variants in the CRLF1 gene. Methods—case reports: The first patient was diagnosed postnatally, presenting with non-epileptic paroxysmal events characterized by opisthotonus and orofacial contractions. He survived beyond infancy, later developing scoliosis and persistent episodes of hyperthermia. In the second patient, a prenatal ultrasound at 20 weeks of gestation revealed bilateral camptodactyly, also referred to as the ‘horn’s sign’, raising early suspicion of CS. The diagnosis was subsequently confirmed both clinically and genetically. After birth, the infant developed severe dysphagia, apnea, and paroxysmal events not associated with epileptiform activity on EEG. Sanger sequencing identified a homozygous c.708_709delinsT frameshift variant in the CRLF1 gene. The patient died at 30 days of age due to respiratory failure. Results and conclusions: With this manuscript, we aim to further delineate the phenotypic spectrum of this rare condition and propose the ‘horn’s sign’ as a targeted prenatal marker for early diagnosis in populations with known founder mutations or familial risk factors. Full article

Asthma is a multifactorial respiratory disease that naturally occurs in horses, humans, and cats, presenting common clinical signs and species-specific mechanisms. This review addresses the impact of asthma on the cardiovascular and neurological systems, with a primary focus on horses. It highlights the need for new biomarkers beyond the respiratory system due to diagnostic difficulties in animals. A comprehensive literature search was conducted using PubMed and Google Scholar, focusing on cardiovascular and neurological manifestations of asthma in humans, horses, cats, and experimental animal models. Studies were qualitatively compared, noting species-specific differences and mechanisms. Humans with asthma show an increased risk of cardiovascular disease and elevated cardiac biomarkers during exacerbations, while horses develop pulmonary hypertension and vascular remodeling. Cats exhibit significant pulmonary vascular changes. Heart rate variability analysis reveals altered autonomic function in humans and horses. Increased peripheral airway innervation and cough reflex sensitivity are noted across species. The renin–angiotensin–aldosterone system (RAAS) plays a crucial role in asthma pathophysiology in murine models. Asthma impacts the cardiovascular and nervous systems differently across species, emphasizing the importance of comparative medicine. Future research should integrate cardiovascular, autonomic, and inflammatory pathways to develop effective therapeutic approaches in human and veterinary medicine, leveraging insights from naturally occurring asthma models. Full article

Microglia, as the immune guardians of the central nervous system (CNS), have the ability to maintain neural homeostasis, respond to environmental changes, and remodel the synaptic landscape. However, persistent microglial activation can lead to chronic neuroinflammation, which can alter neuronal signaling pathways, resulting in accelerated cognitive decline. Phosphoinositol 3-kinase (PI3K) has emerged as a critical driver, connecting inflammation to neurodegeneration, serving as the nexus of numerous intracellular processes that govern microglial activation. This review focuses on the relationship between PI3K signaling and microglial activation, which might lead to cognitive impairment, inflammation, or even neurodegeneration. The review delves into the components of the PI3K signaling cascade, isoforms, and receptors of PI3K, as well as the downstream effects of PI3K signaling, including its effectors such as protein kinase B (Akt) and mammalian target of rapamycin (mTOR) and the negative regulator phosphatase and tensin homolog (PTEN). Experiments have shown that the overproduction of certain cytokines, coupled with abnormal oxidative stress, is a consequence of poor PI3K regulation, resulting in excessive synapse pruning and, consequently, impacting learning and memory functions. The review also highlights the implications of autonomously activated microglia exhibiting M1/M2 polarization driven by PI3K on hippocampal, cortical, and subcortical circuits. Conclusions from behavioral studies, electrophysiology, and neuroimaging linking cognitive performance and PI3K activity were evaluated, along with new approaches to therapy using selective inhibitors or gene editing. The review concludes by highlighting important knowledge gaps, including the specific effects of different isoforms, the risks associated with long-term pathway modulation, and the limitations of translational potential, underscoring the crucial role of PI3K in mitigating cognitive impairment driven by neuroinflammation. Full article

The imbalance in the interaction between the autonomic nervous system and the immune system serves as a central mechanism in the onset and progression of cardiovascular diseases. The excessive activation of the sympathetic nervous system and suppression of vagal function contribute to chronic inflammation and cardiac remodeling. Precision medicine, by integrating multidimensional data such as genomics and metabolomics, offers a novel perspective for the personalized design of exercise interventions. This systematic review explores the bidirectional regulatory mechanisms of exercise interventions on the autonomic nervous system–immune axis and examines the potential applications of precision medicine in optimizing exercise prescriptions and clinical translation. Exercise significantly improves cardiovascular function through immunometabolic reprogramming, which includes suppressing sympathetic overactivity, enhancing vagal tone, and modulating the IL-6/IL-10 balance, as well as activating the short-chain fatty acid (SCFA)–Treg axis. Moreover, precision-medicine-driven ACE I/D gene typing provides a basis for selecting tailored exercise prescriptions, thereby significantly enhancing the efficacy of exercise interventions. By leveraging a multi-tiered “neuro–immune–metabolic” regulatory framework, exercise interventions contribute to improved cardiovascular health. The application of precision medicine technology overcomes individual variability constraints, advancing exercise prescription design from generalized recommendations toward personalized and dynamically adaptive strategies. Full article

Cardiac adaptations induced by aerobic exercise have been shown to reduce the risk of cardiovascular disease, and the autonomic nervous system is closely associated with the development of cardiovascular disease. Aerobic exercise intervention has been shown to enhance cardiac function and mitigate myocardial fibrosis and hypertrophy in heart failure mice. Further insights reveal that cardiomyocytes experiencing chronic heart failure undergo modifications in their lipidomic profile, including remodeling of multiple myocardial membrane phospholipids. Notably, there is a decrease in the total content of cardiolipin, as well as in the levels of total lysolipid CL and the CL (22:6). These alterations disrupt mitochondrial quality control processes, leading to abnormal expressions of proteins such as Drp1, MFN2, OPA1, and BNIP3, thereby resulting in a disrupted mitochondrial dynamic network. Whereas aerobic exercise ameliorated mitochondrial damage to a large extent by activating parasympathetic nerves, this beneficial effect was accomplished by modulating myocardial membrane phospholipid remodeling and restoring the mitochondrial dynamic network. In conclusion, aerobic exercise activated the parasympathetic state in mice and attenuated lipid peroxidation and oxidative stress injury, thereby maintaining mitochondrial dynamic homeostasis and improving cardiac function. Full article

Pulmonary vein isolation (PVI) is an established treatment for atrial fibrillation (AF). While it is known to affect the autonomic nervous system, the relationship between left atrial (LA) remodeling and PVI-mediated neuromodulation remains unclear. We aimed to assess the neuromodulatory effects of PVI using skin sympathetic nerve activity (SKNA). SKNA was recorded one day before and 2–3 days after PVI in 28 paroxysmal AF (PAF) and 33 persistent AF (PerAF) groups. Baseline low frequency to high frequency (LF/HF) ratio was higher in the PAF group (1.23 [interquartile range {IQR}: 0.79–1.76] vs. 0.74 [IQR: 0.49–1.38], p = 0.017). After PVI, the PAF group demonstrated significant reductions in burst amplitude (1.46 [IQR: 1.04–2.84] vs. 1.09 [IQR: 0.78–2.17] μV, p = 0.015) and LF/HF ratio (0.91 [IQR: 0.73–1.52] vs. 0.71 [IQR: 0.48–1.21], p = 0.012), whereas the PerAF group exhibited no such changes. A weak positive correlation was observed between the percentage change in LF/HF ratio and LA volume index in the PAF group (r = 0.572, p = 0.002). PVI significantly decreased SKNA in PAF patients but not in PerAF. LA remodeling may hinder the effectiveness of PVI-mediated neuromodulation. Full article

Pulmonary hypertension (PH) is a severe and chronic disease characterized by increased pulmonary vascular resistance and remodeling, often precipitating right-sided heart dysfunction and death. Although the condition is progressive and incurable, current therapies for the disease focus on multiple different drugs and general supportive therapies to manage symptoms and prolong survival, ranging from medications more specific to pulmonary arterial hypertension (PAH) to exercise training. Moreover, there are multiple studies exploring novel experimental drugs and therapies including unique neurostimulation, to help better manage the disease. Here, we provide a narrative review focusing on current PH treatments that target multiple underlying biochemical mechanisms, including imbalances in vasoconstrictor–vasodilator and autonomic nervous system function, inflammation, and bone morphogenic protein (BMP) signaling. We also focus on the potential of novel therapies for managing PH, focusing on multiple types of neurostimulation including acupuncture. Lastly, we also touch upon the disease’s different subgroups, clinical presentations and prognosis, diagnostics, demographics, and cost. Full article

Sleep is a complex biobehavioural process essential for overall health, with various dimensions including duration, continuity, timing, and satisfaction. This study investigated the intricate relationships between common sleep disorders such as insomnia and obstructive sleep apnoea (OSA) and their impact on atrial fibrillation (AF), a prevalent arrhythmia with significant health implications. Using a comprehensive review of the current literature, this study examined the pathophysiological mechanisms linking sleep disorders to cardiovascular risks, focusing on autonomic nervous system disturbances, inflammation, and oxidative stress associated with OSA. These findings indicate that sleep disorders significantly elevate the risk of AF through mechanisms such as increased sympathetic activity and structural cardiac remodelling. Additionally, this study highlights the potential benefits of treating sleep disorders, particularly with continuous positive airway pressure (CPAP) therapy, in reducing AF recurrence and improving cardiovascular outcomes. This conclusion emphasises the importance of integrated therapeutic approaches that address both sleep disorders and AF to enhance patient outcomes and quality of life. Future research should explore these connections to develop more effective and holistic treatment strategies. Full article

Experimental evidence suggests that chronic intermittent hypoxia (CIH), a major hallmark of obstructive sleep apnea (OSA), boosts carotid body (CB) responsiveness, thereby causing increased sympathetic activity, arterial and pulmonary hypertension, and cardiovascular disease. An enhanced circulatory chemoreflex, oxidative stress, and NO signaling appear to play important roles in these responses to CIH in rodents. Since the guinea pig has a hypofunctional CB (i.e., it is a natural CB knockout), in this study we used it as a model to investigate the CB dependence of the effects of CIH on pulmonary vascular responses, including those mediated by NO, by comparing them with those previously described in the rat. We have analyzed pulmonary artery pressure (PAP), the hypoxic pulmonary vasoconstriction (HPV) response, endothelial function both in vivo and in vitro, and vascular remodeling (intima–media thickness, collagen fiber content, and vessel lumen area). We demonstrate that 30 days of the exposure of guinea pigs to CIH (FiO₂, 5% for 40 s, 30 cycles/h) induces pulmonary artery remodeling but does not alter endothelial function or the contractile response to phenylephrine (PE) in these arteries. In contrast, CIH exposure increased the systemic arterial pressure and enhanced the contractile response to PE while decreasing endothelium-dependent vasorelaxation to carbachol in the aorta without causing its remodeling. We conclude that since all of these effects are independent of CB sensitization, there must be other oxygen sensors, beyond the CB, with the capacity to alter the autonomic control of the heart and vascular function and structure in CIH. Full article

Myocardial remodeling is developed by increased stress in acute or chronic pathophysiologies. Stressed heart morphology (SHM) is a new description representing basal septal hypertrophy (BSH) caused by emotional stress and chronic stress due to increased afterload in hypertension. Acute stress cardiomyopathy (ASC) and hypertension could be together in clinical practice. Therefore, there are some geometric and functional aspects regarding this specific location, septal base under acute and chronic stress stimuli. The findings by our and the other research groups support that hypertension-mediated myocardial involvement could be pre-existed in ASC cases. Beyond a frequently seen predominant base, hyperkinetic tissue response is detected in both hypertension and ASC. Furthermore, hypertension is the responsible factor in recurrent ASC. The most supportive prospective finding is BSH in which a hypercontractile base takes a longer time to exist morphologically than an acutely developed syndrome under both physiologic exercise and pressure overload by transaortic binding in small animals using microimaging. However, cardiac decompensation with apical ballooning could mask the possible underlying hypertensive disease. In fact, enough time for the assessment of previous hypertension history or segmental analysis could not be provided in an emergency unit, since ASC is accepted as an acute coronary syndrome during an acute episode. Additional supportive findings for SHM are increased stress scores in hypertensive BSH and the existence of similar tissue aspects in excessive sympathetic overdrive like pheochromocytoma which could result in both hypertensive disease and ASC. Exercise hypertension as the typical form of blood pressure variability is the sum of physiologic exercise and pathologic increased blood pressure and results in increased mortality. Hypertension is not rare in patients with a high stress score and leads to repetitive attacks in ASC supporting the important role of an emotional component as well as the potential danger due to multiple stressors at the same time. In the current review, the impact of multiple stressors on segmental or global myocardial remodeling and the hazardous potential of multiple stressors at the same time are discussed. As a result, incidentally determined segmental remodeling could be recalled in patients with multiple stressors and contribute to the early and combined management of both hypertension and chronic stress in the prevention of global remodeling and heart failure. Full article

Anterior cruciate ligament (ACL) injuries mainly arise from non-contact mechanisms during sport performance, with most injuries occurring among youth or adolescent-age athletes, particularly females. The growing popularity of elite-level sport training has increased the total volume, intensity and frequency of exercise and competition loading to levels that may exceed natural healing capacity. Growing evidence suggests that the prevailing mechanism that leads to non-contact ACL injury from sudden mechanical fatigue failure may be accumulated microtrauma. Given the consequences of primary ACL injury on the future health and quality of life of youth and adolescent athletes, the objective of this review is to identify key “recovery science” factors that can help prevent these injuries. Recovery science is any aspect of sports training (type, volume, intensity, frequency), nutrition, and sleep/rest or other therapeutic modalities that may prevent the accumulated microtrauma that precedes non-contact ACL injury from sudden mechanical fatigue failure. This review discusses ACL injury epidemiology, current surgical efficacy, the native ACL vascular network, regional ACL histological complexities such as the entheses and crimp patterns, extracellular matrix remodeling, the concept of causal histogenesis, exercise dosage and ligament metabolism, central nervous system reorganization post-ACL rupture, homeostasis regulation, nutrition, sleep and the autonomic nervous system. Based on this information, now may be a good time to re-think primary ACL injury prevention strategies with greater use of modified sport training, improved active recovery that includes well-planned nutrition, and healthy sleep patterns. The scientific rationale behind the efficacy of regenerative orthobiologics and concomitant therapies for primary ACL injury prevention in youth and adolescent athletes are also discussed. Full article

The autonomic nervous system is crucial in initiating and maintaining atrial fibrillation (AF). Catestatin is a multipurpose peptide that regulates cardiovascular systems and reduces harmful, excessive activity of the sympathetic nervous system by blocking the release of catecholamines. We aimed to determine whether serum catestatin concentrations are associated with AF severity, duration indices, and various clinical and laboratory indicators in these individuals to better define the clinical value of catestatin in patients with AF. The present single center study enrolled 73 participants with AF and 72 healthy age-matched controls. Serum catestatin concentrations were markedly higher in AF patients than controls (14.11 (10.21–26.02) ng/mL vs. 10.93 (5.70–20.01) ng/mL, p = 0.013). Furthermore, patients with a more severe form of AF had significantly higher serum catestatin (17.56 (12.80–40.35) vs. 10.98 (8.38–20.91) ng/mL, p = 0.001). Patients with higher CHA₂DS₂-VASc scores (17.58 (11.89–37.87) vs. 13.02 (8.47–22.75) ng/mL, p = 0.034) and higher NT-proBNP levels (17.58 (IQR 13.91–34.62) vs. 13.23 (IQR 9.04–22.61), p = 0.036) had significantly higher serum catestatin concentrations. Finally, AF duration correlated negatively with serum catestatin levels (r = −0.348, p = 0.003). The results of the present study implicate the promising role of catestatin in the intricate pathophysiology of AF, which should be explored in future research. Full article

Chronic thromboembolic pulmonary hypertension (CTEPH) develops in 1.5–2.0% of patients experiencing pulmonary embolism (PE) and is characterized by stable pulmonary artery obstruction, heart failure, and poor prognosis. Little is known about involvement of autonomic nervous system (ANS) in the mechanisms of CTEPH. This study was aimed at evaluation of the effect of vagal and sympathetic denervation, as well as stimulation of the parasympathetic nervous system, on the outcomes of CTEPH in rats. CTEPH was induced by multiple intravenous injections of alginate microspheres. Sympathetic and vagal denervation was performed using unilateral surgical ablation of the stellate ganglion and vagotomy, respectively. Stimulation of the parasympathetic nervous system was carried out by administering pyridostigmine. The effect of neuromodulatory effects was assessed in terms of hemodynamics, histology, and gene expression. The results demonstrated the key role of ANS in the development of CTEPH. Sympathetic denervation as well as parasympathetic stimulation resulted in attenuated pulmonary vascular remodeling. These salutary changes were associated with altered MMP2 and TIMP1 expression in the lung and decreased FGFb level in the blood. Unilateral vagotomy had no effect on physiological and morphological outcomes of the study. The data obtained contribute to the identification of new therapeutic targets for CTEPH treatment. Full article

In the heart, cardiac function is regulated by the autonomic nervous system (ANS) that extends through the myocardium and establishes junctions at the sinus node and ventricular levels. Thus, an increase or decrease in neuronal activity acutely affects myocardial function and chronically affects its structure through remodeling processes. The neuro–cardiac junction (NCJ), which is the major structure of this system, is poorly understood and only a few cell models allow us to study it. Here, we present an innovant neuro–cardiac organ-on-chip model to study this structure to better understand the mechanisms involved in the establishment of NCJ. To create such a system, we used microfluidic devices composed of two separate cell culture compartments interconnected by asymmetric microchannels. Rat PC12 cells were differentiated to recapitulate the characteristics of sympathetic neurons, and cultivated with cardiomyocytes derived from human induced pluripotent stem cells (hiPSC). We confirmed the presence of a specialized structure between the two cell types that allows neuromodulation and observed that the neuronal stimulation impacts the excitation–contraction coupling properties including the intracellular calcium handling. Finally, we also co-cultivated human neurons (hiPSC-NRs) with human cardiomyocytes (hiPSC-CMs), both obtained from the same hiPSC line. Hence, we have developed a neuro–cardiac compartmentalized in vitro model system that allows us to recapitulate the structural and functional properties of the neuro–cardiac junction and that can also be used to better understand the interaction between the heart and brain in humans, as well as to evaluate the impact of drugs on a reconstructed human neuro–cardiac system. Full article