Neurological disorders including depression, anxiety, post-traumatic stress disorder (PTSD), schizophrenia, autism and epilepsy are associated with an increased incidence of cardiovascular disorders and susceptibility to heart failure. The underlying molecular mechanisms that link neurological disorders and adverse cardiac function are poorly understood. Further, a lack of progress is likely due to a paucity of studies that investigate the relationship between neurological disorders and cardiac electrical activity in health and disease. Therefore, there is an important need to understand the spatiotemporal behavior of neurocardiac mechanisms. This can be advanced through the identification and validation of neurological and cardiac signaling pathways that may be adversely regulated. In this review we highlight how dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis, autonomic nervous system (ANS) activity and inflammation, predispose to psychiatric disorders and cardiac dysfunction. Moreover, antipsychotic and antidepressant medications increase the risk for adverse cardiac events, mostly through the block of the human ether-a-go-go-related gene (hERG), which plays a critical role in cardiac repolarization. Therefore, understanding how neurological disorders lead to adverse cardiac ion channel remodeling is likely to have significant implications for the development of effective therapeutic interventions and helps improve the rational development of targeted therapeutics with significant clinical implications.

Aims  NOS1AP single-nucleotide polymorphisms (SNPs) correlate with QT prolongation and cardiac sudden death in patients affected by long QT syndrome type 1 (LQT1). NOS1AP targets NOS1 to intracellular effectors. We hypothesize that NOS1AP SNPs cause NOS1 dysfunction and this may converge with prolonged action-potential duration (APD) to facilitate arrhythmias. Here we test (i) the effects of NOS1 inhibition and their interaction with prolonged APD in a guinea pig cardiomyocyte (GP-CMs) LQT1 model; (ii) whether pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from LQT1 patients differing for NOS1AP variants and mutation penetrance display a phenotype compatible with NOS1 deficiency. Methods and results  In GP-CMs, NOS1 was inhibited by S-Methyl-L-thiocitrulline acetate (SMTC) or Vinyl-L-NIO hydrochloride (L-VNIO); LQT1 was mimicked by IKs blockade (JNJ303) and β-adrenergic stimulation (isoproterenol). hiPSC-CMs were obtained from symptomatic (S) and asymptomatic (AS) KCNQ1-A341V carriers, harbouring the minor and major alleles of NOS1AP SNPs (rs16847548 and rs4657139), respectively. In GP-CMs, NOS1 inhibition prolonged APD, enhanced ICaL and INaL, slowed Ca2+ decay, and induced delayed afterdepolarizations. Under action-potential clamp, switching to shorter APD suppressed ‘transient inward current’ events induced by NOS1 inhibition and reduced cytosolic Ca2+. In S (vs. AS) hiPSC-CMs, APD was longer and ICaL larger; NOS1AP and NOS1 expression and co-localization were decreased. Conclusion  The minor NOS1AP alleles are associated with NOS1 loss of function. The latter likely contributes to APD prolongation in LQT1 and converges with it to perturb Ca2+ handling. This establishes a mechanistic link between NOS1AP SNPs and aggravation of the arrhythmia phenotype in prolonged repolarization syndromes.

Blockade of the late Na current (I ) protects from ischemia/reperfusion damage; nevertheless, information on changes in I during acute ischemia and their effect on intracellular milieu is missing. I , cytosolic Na and Ca activities (Na, Ca) were measured in isolated rat ventricular myocytes during 7 min of simulated ischemia (ISC); in all the conditions tested, effects consistently exerted by ranolazine (RAN) and tetrodotoxin (TTX) were interpreted as due to I blockade. The results indicate that I was enhanced during ISC in spite of changes in action potential (AP) contour; I significantly contributed to Na rise, but only marginally to Ca rise. The impact of I on Ca was markedly enhanced by blockade of the sarcolemmal(s) Na/Ca exchanger (NCX) and was due to the presence of (Na-sensitive) Ca efflux through mitochondrial NCX (mNCX). sNCX blockade increased Ca and decreased Na, thus indicating that, throughout ISC, sNCX operated in the forward mode, in spite of the substantial Na increment. Thus, a robust Ca source, other than sNCX and including mitochondria, contributed to Ca during ISC. Most, but not all, of RAN effects were shared by TTX. (1) The paradigm that attributes Ca accumulation during acute ischemia to decrease/reversal of sNCX transport may not be of general applicability; (2) I is enhanced during ISC, when the effect of Na on mitochondrial Ca transport may substantially contribute to I impact on Ca; (3) RAN may act mostly, but not exclusively, through I blockade during ISC.

Circadian rhythms are involved in many physiological and pathological processes in different tissues, including the heart. Circadian rhythms play a critical role in adverse cardiac function with implications for heart failure and sudden cardiac death, highlighting a significant contribution of circadian mechanisms to normal sinus rhythm in health and disease. Cardiac arrhythmias are a leading cause of morbidity and mortality in patients with heart failure and likely cause ∼250,000 deaths annually in the United States alone; however, the molecular mechanisms are poorly understood. This suggests the need to improve our current understanding of the underlying molecular mechanisms that increase vulnerability to arrhythmias. Obesity and its associated pathologies, including diabetes, have emerged as dangerous disease conditions that predispose to adverse cardiac electrical remodeling leading to fatal arrhythmias. The increasing epidemic of obesity and diabetes suggests vulnerability to arrhythmias will remain high in patients. An important objective would be to identify novel and unappreciated cellular mechanisms or signaling pathways that modulate obesity and/or diabetes. In this review we discuss circadian rhythms control of metabolic and environmental cues, cardiac ion channels, and mechanisms that predispose to supraventricular and ventricular arrhythmias including hormonal signaling and the autonomic nervous system, and how understanding their functional interplay may help to inform the development and optimization of effective clinical and therapeutic interventions with implications for chronotherapy.

Functional humanized in vitro nerve models are coveted as an alternative to animal models due to their ease of access, lower cost, clinical relevance and no need for recurrent animal sacrifice. To this end, we developed a sensory nerve model using induced pluripotent stem cells-derived nociceptors that are electrically active and exhibit a functional response to noxious stimuli. The differentiated neurons were co-cultured with primary Schwann cells on an aligned microfibrous scaffold to produce biomimetic peripheral nerve tissue. Compared to glass coverslips, our scaffold enhances tissue development and stabilization. Using this model, we demonstrate that myelin damage can be induced from hyperglycemia exposure (glucose at 45 mM) and mitigated by epalrestat (1 µM) supplementation. Through fibrin embedding of the platform, we were able to create 3D anisotropic myelinated tissue, reaching over 6.5 mm in length. Finally, as a proof-of-concept, we incorporated pancreatic pseudoislets and endometrial organoids into our nerve platform, to demonstrate the potential in generating nociceptor innervation models. In summary, we propose here an improved tool for neurobiology research with potential applications in pathology modeling, drug screening and target tissue innervation.