Cardiac Sympathetic Innervation Research Articles

Reprogramming of the developing heart by Hif1a-deficient sympathetic system and maternal diabetes exposure.

Maternal diabetes is a recognized risk factor for both short-term and long-term complications in offspring. Beyond the direct teratogenicity of maternal diabetes, the intrauterine environment can influence the offspring's cardiovascular health. Abnormalities in the cardiac sympathetic system are implicated in conditions such as sudden infant death syndrome, cardiac arrhythmic death, heart failure, and certain congenital heart defects in children from diabetic pregnancies. However, the mechanisms by which maternal diabetes affects the development of the cardiac sympathetic system and, consequently, heightens health risks and predisposes to cardiovascular disease remain poorly understood. In the mouse model, we performed a comprehensive analysis of the combined impact of a Hif1a-deficient sympathetic system and the maternal diabetes environment on both heart development and the formation of the cardiac sympathetic system. The synergic negative effect of exposure to maternal diabetes and Hif1a deficiency resulted in the most pronounced deficit in cardiac sympathetic innervation and the development of the adrenal medulla. Abnormalities in the cardiac sympathetic system were accompanied by a smaller heart, reduced ventricular wall thickness, and dilated subepicardial veins and coronary arteries in the myocardium, along with anomalies in the branching and connections of the main coronary arteries. Transcriptional profiling by RNA sequencing (RNA-seq) revealed significant transcriptome changes in Hif1a-deficient sympathetic neurons, primarily associated with cell cycle regulation, proliferation, and mitosis, explaining the shrinkage of the sympathetic neuron population. Our data demonstrate that a failure to adequately activate the HIF-1α regulatory pathway, particularly in the context of maternal diabetes, may contribute to abnormalities in the cardiac sympathetic system. In conclusion, our findings indicate that the interplay between deficiencies in the cardiac sympathetic system and subtle structural alternations in the vasculature, microvasculature, and myocardium during heart development not only increases the risk of cardiovascular disease but also diminishes the adaptability to the stress associated with the transition to extrauterine life, thus increasing the risk of neonatal death.

Sleep-induced limb vasodilation in individuals confined to bed for 24 h

The sleep/wake rhythm in limbs has been scarcely studied, especially due to the difficulty associated with continuous monitoring of arterial flow to the forearm and leg for a 24-h period. Addressing this constraint, we employed indium-gallium-in-silicone strain-gauge venous-occlusion plethysmography, an automated method facilitating the measurement of 24-h limb arterial flow in bed-confined subjects without disturbing their natural sleep. This article presents the state of the art in this field. Our examination of 60 healthy normotensive individuals revealed a distinctive sleep/wake rhythm in limb arterial flow, characterized by elevated values during sleep (32.7% in the forearm, P < 0.0001; 39.1% in the leg, P < 0.0001). Correspondingly, limb resistance mirrored the trend of flow (-32.7%, P < 0.0001; -33.5%, P < 0.0001), with these variations attributed to sleep-induced limb vasodilation. Sleep-associated vasodilation was also evident in 21 hypertensive individuals (leg resistance: -33.1%, P < 0.0001) and 13 heart transplant recipients lacking vagal and sympathetic cardiac innervation (resistance: -33.6%, P < 0.0001). On the contrary, among 11 subjects with an interrupted spinal cord, we observed forearm vasodilation (resistance: -36.6%, P < 0.0001) but observed no leg vasodilation if the spinal lesion was under T2 (innervating the leg). Furthermore, a loss of sleep-induced vasodilation occurred in both the forearm and leg if the injury was above C7 (innervating both forearm and leg). Our conclusion posits the existence of sleep-induced limb vasodilation, a phenomenon attributed to signals traveling along the spinal cord, with the heart playing no discernible role in this rhythmic process, and arterial hypertension deemed irrelevant. Comprehensive further studies are imperative to elucidate the precise triggers of limb vasodilation during sleep.

Estimating motor progression trajectory pursuant to temporal dynamic status of cardiac denervation in Parkinson's disease.

Parkinson's disease (PD) is a multifaceted disease that encompasses diverse clinical phenotypes. The diversity of PD could be subtyped based on the temporal dynamic status of cardiac sympathetic innervation; (1) initially, denervated myocardium (peripheral nervous system-predominant; PNS-predominant), (2) preserved myocardium (central nervous system-predominant; CNS-predominant), and (3) preserved myocardium who developed cardiac sympathetic denervation (CSD) on the subsequent imaging (Converter; delayed cardiac denervation). This study assessed how the cardiac denervation could reflect the pathobiology. We investigated whether this phenotyping could help predict the motor progression trajectory of PD. Cardiac sympathetic innervation was evaluated using initial and sequential 123I-meta-iodobenzylguanidine myocardial scintigraphy and patients were stratified into three groups as above. Motor severity and progression were evaluated in each patient. The association between subtypes and dopaminergic nigrostriatal degeneration was analyzed. The influence of cardiac denervation on motor progression was also investigated. Among the enrolled 195 patients, 144 PD subjects were defined as PNS-predominant, 16 as Converter, and 35 as CNS-predominant. The most severe nigrostriatal degeneration was observed in the PNS-predominant group and the dopaminergic degeneration was the most asymmetric in the CNS-predominant group. Positive linear trends of nigrostriatal degeneration and its asymmetric degeneration of striatum and globus pallidus were found across the patterns of cardiac sympathetic innervation (PNS-predominant vs. Converter vs. CNS-predominant). It indicated an increasing degree of asymmetric degeneration among the groups. A longitudinal estimation of motor progression revealed distinct cardiac denervation trajectories for each subtype. These results implicated that the subtypes of CSD might indicate a predominant origin and spreading pattern of pathobiology.

Kiosk 6R-FB-03 - Impaired Cardiac Sympathetic Innervation Activity Is Associated with Myocardial Extracellular Remodeling and Discriminates Between HF Phenotypes

Kiosk 6R-FB-03 - Impaired Cardiac Sympathetic Innervation Activity Is Associated with Myocardial Extracellular Remodeling and Discriminates Between HF Phenotypes

Chronic intermittent hypoxia remodels catecholaminergic nerve innervation in mouse atria.

Chronic intermittent hypoxia (CIH, a model for sleep apnoea) is a major risk factor for several cardiovascular diseases. Autonomic imbalance (sympathetic overactivity and parasympathetic withdrawal) has emerged as a causal contributor of CIH-induced cardiovascular disease. Previously, we showed that CIH remodels the parasympathetic pathway. However, whether CIH induces remodelling of the cardiac sympathetic innervation remains unknown. Mice (male, C57BL/6J, 2-3months) were exposed to either room air (RA, 21% O2 ) or CIH (alternating 21% and 5.7% O2 , every 6min, 10 hday-1 ) for 8-10weeks. Flat-mounts of their left and right atria were immunohistochemically labelled for tyrosine hydroxylase (TH, a sympathetic marker). Using a confocal microscope (or fluorescence microscope) and Neurlocudia 360digitization and tracing system, we scanned both the left and right atria and quantitatively analysed the sympathetic axon density in both groups. The segmentation data was mapped onto a 3D mouse heart scaffold. Our findings indicated that CIH significantly remodelled the TH immunoreactive (-IR) innervation of the atria by increasing its density at the sinoatrial node, the auricles and the major veins attached to the atria (P < 0.05, n=7). Additionally, CIH increased the branching points of TH-IR axons and decreased the distance between varicosities. Abnormal patterns of TH-IR axons around intrinsic cardiac ganglia were also found following CIH. We postulate that the increased sympathetic innervation may further amplify the effects of enhanced CIH-induced central sympathetic drive to the heart. Our work provides an anatomical foundation for the understanding of CIH-induced autonomic imbalance. KEY POINTS: Chronic intermittent hypoxia (CIH, a model for sleep apnoea) causes sympathetic overactivity, cardiovascular remodelling and hypertension. We determined the effect of CIH on sympathetic innervation of the mouse atria. In vivo CIH for 8-10weeks resulted in an aberrant axonal pattern around the principal neurons within intrinsic cardiac ganglia and an increase in the density, branching point, tortuosity of catecholaminergic axons and atrial wall thickness. Utilizing mapping tool available from NIH (SPARC) Program, the topographical distribution of the catecholaminergic innervation of the atria were integrated into a novel 3D heart scaffold for precise anatomical distribution and holistic quantitative comparison between normal and CIH mice. This work provides a unique neuroanatomical understanding of the pathophysiology of CIH-induced autonomic remodelling.

Value of nuclide scintigraphy in the diagnosis and prognosis of cardiac amyloidosis.

Amyloidosis is a local or systemic disease caused by the deposition of misfolded proteins outside the cell, with rapid progression, and dire prognosis. Common types of cardiac amyloidosis are monoclonal immunoglobulin light chain amyloidosis (AL-CA) and transthyretin cardiac amyloidosis (ATTR-CA). Nuclear medicine examinations can be accurate, rapid, and non-invasive to help diagnose diseases and can effectively predict the prognosis of patients with CA. Technetium (99Tcm)-labeled bisphosphonate imaging has been included in the consensus of experts and has become the first-line imaging method for the diagnosis of ATTR-CA. 123I-metaiodoenzylguanidine (MIBG) as a norepinephrine analogue can effectively assess cardiac sympathetic innervation in patients with CA. Aβ- amyloid imaging agents such as 11C-pittsburgh compound B and 18F-flubetaben are expected to be new techniques for diagnosing AL-CA and incorporating them into cardiac staging systems for AL-CA patients in the future. New imaging agents such as 18F-NaF has been widely used in the diagnosis, treatment response monitoring, and prognosis assessment of CA. Summarizing the research value of nuclide imaging in CA may provide new ideas for clinical realization of early detection of CA and accurate assessment of disease prognosis.

Heterogeneous cardiac sympathetic innervation gradients promote arrhythmogenesis in murine dilated cardiomyopathy.

Ventricular arrhythmias (VAs) in heart failure are enhanced by sympathoexcitation. However, radiotracer studies of catecholamine uptake in failing human hearts demonstrate a proclivity for VAs in patients with reduced cardiac sympathetic innervation. We hypothesized that this counterintuitive finding is explained by heterogeneous loss of sympathetic nerves in the failing heart. In a murine model of dilated cardiomyopathy (DCM), delayed PET imaging of sympathetic nerve density using the catecholamine analog [11C]meta-Hydroxyephedrine demonstrated global hypoinnervation in ventricular myocardium. Although reduced, sympathetic innervation in 2 distinct DCM models invariably exhibited transmural (epicardial to endocardial) gradients, with the endocardium being devoid of sympathetic nerve fibers versus controls. Further, the severity of transmural innervation gradients was correlated with VAs. Transmural innervation gradients were also identified in human left ventricular free wall samples from DCM versus controls. We investigated mechanisms underlying this relationship by in silico studies in 1D, 2D, and 3D models of failing and normal human hearts, finding that arrhythmogenesis increased as heterogeneity in sympathetic innervation worsened. Specifically, both DCM-induced myocyte electrical remodeling and spatially inhomogeneous innervation gradients synergistically worsened arrhythmogenesis. Thus, heterogeneous innervation gradients in DCM promoted arrhythmogenesis. Restoration of homogeneous sympathetic innervation in the failing heart may reduce VAs.

Decreased cholinesterase level combined with renal dysfunction and sympathetic denervation associated with increased cardiac mortality in systolic heart failure.

Cardiac mortality in patients with heart failure (HF) is likely to be aggravated by malnutrition, assessed by serum cholinesterase (ChE) level, as well as by kidney dysfunction or impairment of cardiac sympathetic denervation. Their prognostic interactions, however, have not been determined. A total of 991 systolic HF patients were enrolled in our HF database following clinical evaluation including evaluation of the nutrition state and assessment of standardized heart-to-mediastinum ratio (sHMR) of iodine-123-labeled meta-iodobenzylguanidine activity. Patients were followed up for an average of 43 months with the primary endpoint of fatal cardiac events (CEs). The CE patient group had a lower level of ChE, lower estimated glomerular filtration rate (eGFR) and lower late sHMR than those in the non-CE patient group. A five-parameter model with the addition of serum ChE selected in the multivariate logistic analysis (model 2) significantly increased the AUC predicting risk of cardiac events compared with a four-parameter model without serum ChE (model 1), and net reclassification analysis also suggested that the model with the addition of serum cholinesterase significantly improved cardiac event prediction. Moreover, in overall multivariate Cox hazard analysis, serum ChE, eGFR and late sHMR were identified to be significant prognostic determinants. HF patients with two or all of the prognostic variables of serum ChE < 230 U/L, eGFR < 48.8 ml/min/1.73 m2 and late sHMR < 1.90 had significantly and incrementally increased CE rates compared to those in HF patients with none or only one of the prognostic variables. Decreases in cholinesterase level and kidney function further increase cardiac mortality risk in HF patients with impairment of cardiac sympathetic innervation.

[18F]-mFBG imaging for COVID-19-induced cardiac sympathetic innervation impairment.

[18F]-mFBG imaging for COVID-19-induced cardiac sympathetic innervation impairment.

Myocardial Functional Imaging in Pediatric Nuclear Cardiology.

The role of nuclear medicine in pediatric cardiology has grown rapidly over the years, providing useful functional and prognostic information and playing a complementary role to morphological imaging in the evaluation of myocardial perfusion, cardiovascular inflammation and infections, and cardiac sympathetic innervation. The aim of this narrative review is to summarize and highlight the most important evidence on pediatric nuclear cardiology, describing clinical applications and the possibilities, advantages, and limitations of nuclear medicine techniques. Moreover, a special focus will be given to the minimization of radiation exposure in pediatric nuclear cardiology imaging, a critical topic in children.

Abstract P3114: Sex Differences In Ventricular Function And Mortality In Sema3a Deficient Mice With Dilated Cardiomyopathy

Introduction: Clinical studies consistently report sex differences in heart failure (HF) outcomes. Disrupted cardiac sympathetic innervation patterns have not been investigated as a potential mechanism. Hypothesis: We aimed to explore whether cardiac sympathetic innervation patterns disrupted by deletion of the neurorepellent, Semaphorin3a (Sema3a), in murine dilated cardiomyopathy (DCM), has a deleterious effect in male compared to female mice. Methods: Utilizing the established Tg9 model of nonischemic HF (DCM+), we compared serial left ventricular ejection fraction (LVEF), ventricular arrhythmogenesis, mortality, and innervation patterns using immunohistochemistry in male vs. female DCM+Sema3a KO mice (with disrupted innervation) to male and female DCM+Sema3a WT animals. Results: Immunohistochemistry revealed greater disruption in sympathetic innervation amongst Sema3a deficient (DCM+Sema3a KO ) mice (n=11) compared to DCM+Sema3a WT (n=10) and WT mice (n=7) ( ****p&lt;0.0001). There was no significant difference in arrhythmogenesis between DCM+Sema3a WT versus DCM+Sema3a KO mice. Mortality was significantly greater in DCM+Sema3a KO mice compared to DCM+Sema3a WT and WT mice (*p=0.04). This was attributable to pump failure, as LVEF was lower in DCM+Sema3a KO mice that died compared to DCM+Sema3a KO mice who did not (*p=0.03). When outcomes were compared for male versus female mice, we observed sex differences in mortality, with female DCM+Sema3a KO mice exhibiting higher mortality and greater LV dysfunction than males (*p=0.03). This difference was not seen in male vs female DCM+Sema3a WT mice, suggesting that the sex differences are related to Sema3a gene deletion, and thus, disrupted innervation patterns, not DCM alone. Conclusion: Our data suggests that there are sex-based differences in DCM outcomes that may involve Sema3a signaling. Further studies validating this finding and identifying underlying mechanisms are warranted.

The high ventricular function in the shortfin mako shark (Isurus oxyrinchus)

The shortfin mako sharks ( Isurus oxyrinchus) belongs to the family Lamnidae, which is a group of high performance regional endothermic elasmobranch fishes that has metabolic rates (47.4±8 ml/kg/min) higher than ectothermic elasmobranchs, and also rivals that of mammals. As in all elasmobranchs, the mako sharks do not possess direct cardiac sympathetic innervation to elevate cardiac performance, but it still retains an ancient design of a capacious semi-rigid pericardium (5.4±0.6 ml/kg) likely to accommodate its large atrial diastolic volume. This study test the hypothesis that the increase in cardiac output in the mako is influenced by a strong positive lusitrophic effect that serves to increase stroke volume, which in turn invokes the Frank-Starling’s effects. The objectives is to show differences in the physiology and biochemical properties between mako (Is) and an ectothermic blue shark ( Prioance glauca, Pg), both are oceanic species and share similar life history. Echocardiography showed a higher early to late filling velocity ratio (p=0.036) in the Is (0.92±0.16, [n=15]) than in Pg (0.45±0.04, [9]). The early time velocity integral is also greater in Is (8.8±2.4 cm, [15]) vs Pg (6.8±0.8 cm [9]) indicating a stronger conduit filling imparted by the energy from previous systole in Is. However, basal cAMP (Is: 31±12 [7] vs Pg: 31±1 [3] fmol/min/μg) and stimulated cAMP with isoproterenol+GTPγS (Is: 65±21 [7] vs Pg: 59±7 [3] fmol/min/μg) activity are similar in both groups. This suggests that the differences in ventricular contractility are not through the classic adrenergic signaling pathway involving adenylyl cyclases, but likely through the mechanical stretching of the myofibrils from diastole. Caveolin distribution of the ventricular tissues following sucrose density gradient shows a higher degree of Caveolin-1/3 in the buoyant fraction and little in the in the heavy fraction in both shark species indicating an absence of t-tubules. However, Is shows a remarkably high amount of buoyant Cav-1/3 fraction compared to Pg. We posit that the high fraction abundance of Cav-1/3 provides a gateway for corticotropin-releasing factor, such as urotensin I or possibly an ancestral precursor of urocortin, which has been shown to elevate heart function in mammals. The study is supported by NSF IBN93-16621. No disclosure. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Dysregulation of hypoxia-inducible factor 1α in the sympathetic nervous system accelerates diabetic cardiomyopathy

BackgroundAn altered sympathetic nervous system is implicated in many cardiac pathologies, ranging from sudden infant death syndrome to common diseases of adulthood such as hypertension, myocardial ischemia, cardiac arrhythmias, myocardial infarction, and heart failure. Although the mechanisms responsible for disruption of this well-organized system are the subject of intensive investigations, the exact processes controlling the cardiac sympathetic nervous system are still not fully understood. A conditional knockout of the Hif1a gene was reported to affect the development of sympathetic ganglia and sympathetic innervation of the heart. This study characterized how the combination of HIF-1α deficiency and streptozotocin (STZ)-induced diabetes affects the cardiac sympathetic nervous system and heart function of adult animals.MethodsMolecular characteristics of Hif1a deficient sympathetic neurons were identified by RNA sequencing. Diabetes was induced in Hif1a knockout and control mice by low doses of STZ treatment. Heart function was assessed by echocardiography. Mechanisms involved in adverse structural remodeling of the myocardium, i.e. advanced glycation end products, fibrosis, cell death, and inflammation, was assessed by immunohistological analyses.ResultsWe demonstrated that the deletion of Hif1a alters the transcriptome of sympathetic neurons, and that diabetic mice with the Hif1a-deficient sympathetic system have significant systolic dysfunction, worsened cardiac sympathetic innervation, and structural remodeling of the myocardium.ConclusionsWe provide evidence that the combination of diabetes and the Hif1a deficient sympathetic nervous system results in compromised cardiac performance and accelerated adverse myocardial remodeling, associated with the progression of diabetic cardiomyopathy.

Cardiac sympathetic innervation and mortality risk scores in patients with heart failure.

In the risk stratification and selection of patients with Heart Failure (HF) eligible for Implantable Cardioverter Defibrillator (ICD) therapy, 123 I-meta-IodineBenzylGuanidine (123 I-mIBG) scintigraphy has emerged as an effective non-invasive method to assess cardiac adrenergic innervation. Similarly, clinical risk scores have been proposed to identify patients with HF at risk of all-cause mortality, for whom the net clinical benefit of device implantation would presumably be lower. Nevertheless, the association between the two classes of tools, one suggestive of arrhythmic risk, the other of all-causes mortality, needs further investigation. To test the relationship between the risk scores for predicting mortality and cardiac sympathetic innervation, assessed through myocardial 123 I-mIBG imaging, in a population of patients with HF. in HF patients undergoing 123 I-mIBG scintigraphy, eight risk stratification models were assessed: AAACC, FADES, MADIT, MADIT-ICD non-arrhythmic mortality score, PACE, Parkash, SHOCKED and Sjoblom. Cardiac adrenergic impairment was assessed by late Heart to Mediastinum ratio (H/M) <1.6. Among 269 patients suffering from HF, late H/M showed significant negative correlation with all the predicting models, although generally weak, ranging from -0.15 (p=0.013) for PACE to -0.32 (p < 0.001) for FADES. The scores showed poor discrimination for cardiac innervation, with areas under the curve (AUC) ranging from 0.546 for Parkash to 0.621 for FADES. A weak association emerged among mortality risk scores and cardiac innervation, suggesting to integrate in clinical practice tools indicative of both arrhythmic and general mortality risks, when evaluating patients affected by HF eligible for device implantation.

Catecholaminergic axon innervation and morphology in flat-mounts of atria and ventricles of mice.

Sympathetic efferent axons regulate cardiac functions. However, the topographical distribution and morphology of cardiac sympathetic efferent axons remain insufficiently characterized due to the technical challenges involved in immunohistochemical labeling of the thick walls of the whole heart. In this study, flat-mounts of the left and right atria and ventricles of FVB mice were immunolabeled for tyrosine hydroxylase (TH), a marker of sympathetic nerves. Atrial and ventricular flat-mounts were scanned using a confocal microscope to construct montages. We found (1) In the atria: A few large TH-immunoreactive (IR) axon bundles entered both atria, branched into small bundles and then single axons that eventually formed very dense terminal networks in the epicardium, myocardium and inlet regions of great vessels to the atria. Varicose TH-IR axons formed close contact with cardiomyocytes, vessels, and adipocytes. Multiple intrinsic cardiac ganglia (ICG) were identified in the epicardium of both atria, and a subpopulation of the neurons in the ICG were TH-IR. Most TH-IR axons in bundles traveled through ICG before forming dense varicose terminal networks in cardiomyocytes. We did not observe varicose TH-IR terminalsencircling ICG neurons. (2) In the left and right ventricles and interventricular septum: TH-IR axons formed dense terminal networks in the epicardium, myocardium, andvasculature. Collectively, TH labeling is achievable in flat-mounts of thick cardiac walls, enabling detailed mapping of catecholaminergic axons and terminal structures in the whole heart at single-cell/axon/varicosity scale. This approach provides a foundation for future quantification of the topographical organization of the cardiac sympathetic innervation in different pathological conditions.

Cardiac sympathetic innervation is an unrecognized disease target in autosomal dominant optic atrophy

The Optic Atrophy-1 protein (Opa1) controls mitochondrial (mt) fusion and cristae morphology, ATP production, maintenance of mtDNA, and apoptosis. Mutations in Opa1 gene cause Autosomal Dominant Optic Atrophy (ADOA), a neurodegenerative disease characterized by “retinal ganglion cell” death and visual loss. Recently, ADOA has been described as a “multi-systemic disease” also featuring myopathy, peripheral neuropathy, Parkinsonism and cardiac rhythm alterations. Sympathetic neurons (SNs) are the main extrinsic regulators of heart activity in basal and stress conditions, and their homeostasis strikingly depend on the correct mitochondrial dynamics. We here determined the effect of ADOA genetics on cardiac sympathetic innervation. The majority of Opa1 gene mutations result in truncated forms of the protein, leading to reduction in its cellular content. To study the impact of Opa1 haploinsufficiency on cardiac innervation, we generated transgenic mice with SN-specific Opa1 deletion (TH-Opa1+/− mice), which, in heterozygosity, causes 50% reduction of protein expression. Heart function of TH-Opa1+/− mice was assessed by ECHO and ECG telemetry. Cardiac innervation was evaluated by confocal IF, and whole-mount IF in tissue clarified heart blocks. In vitro assays achieved insights on the effects of Opa1 haploinsufficiency on SNs. SNs were also evaluated in skin biopsies from ADOA patients, and age- and sex-matched controls. We here found that SN density is significantly reduced in the skin of ADOA patients, indicating thatSNs are additional, previously neglected, targets of ADOA. To isolate the effects of Opa1 haploinsufficiency in SNs, we analyzed hearts of adult and aged TH-Opa1+/− mice, which showed intact morphology and contractile function. Looking at cardiac innervation, confocal IF and 3-D reconstruction of the SN network revealed a significant reduction in innervation density, which appeared evident already in adult mice, and worsened during ageing. Consistently, TH-Opa1+/− mice showed decreased Heart Rate Variability and increased incidence of arrhythmic beats. In vitro assays demonstrated the causal role of Opa1 haploinsufficiency in affecting SNs, by compromising TrkA/NGF signaling, which is key to sustain neuronal viability. Our data demonstrates that Opa1 haploinsufficiency also affects peripheral autonomic innervation, thus explaining extra-retinal symptoms experienced by ADOA patients.

Novel view of arrhythmogenic cardiomyopathy as a “multicellular disease” affecting cardiac sympathetic innervation

Arrhythmogenic Cardiomyopathy (AC) is an incurable familial cardiac disease, mainly due to mutations in desmosomal genes, accounting for most cases of stress-related arrhythmic sudden death, in the young and athletes. AC hearts display cardiomyocyte (CM) death and diffuse fibro-fatty lesions, which compromise cardiac contractile performance and generate the substrate for arrhythmias. Correlation between physical/emotional stresses and arrhythmias incriminates sympathetic neurons (SNs), which may be the sought-after killers in disguise.

Abstract 10134: Role of Cardiac Sympathetic Nerves in Mediating the Central Nervous System Cardioprotective Effects of Leptin After Ischemia/Reperfusion Injury

We previously demonstrated that central nervous system (CNS) administration of leptin improves left ventricular (LV) function after myocardial infarction through mechanisms that are poorly understood. Increased cardiac sympathetic activity is an important compensatory mechanism to maintain cardiac output after ischemic injury, and previous studies showed that centrally-administered leptin increases sympathetic outflow to various tissues. In the present study, we tested the hypothesis that leptin’s CNS-mediated cardioprotective effects are mediated via cardiac sympathetic nerves. Male and female Wistar rats (~8 weeks of age) were submitted to cervical ganglia denervation (CGx) and instrumented with an intracerebroventricular (ICV) cannula in the brain lateral ventricle. After recovery and baseline assessment of cardiac function by echocardiography (ECHO) and an exercise performance test (Vmax), myocardial ischemia/reperfusion (I/R) was induced by temporary (60 min) ligation of the left anterior descending coronary artery. Vehicle (saline, 0.5 μL/hr) or leptin (0.62 μg/hr) was infused chronically for 28 days starting 20 min after reperfusion using osmotic pumps implanted subcutaneously in the scapular region and connected to the ICV cannula. Cardiac function was assessed weekly by ECHO. At the end of week 4, a final Vmax was performed and +dP/dt max was accessed by LV catheterization using a Millar catheter. Despite ~70% reduction in cardiac tyrosine hydroxylase positive fibers compared to sham, CGx did not prevent leptin’s CNS-mediated cardioprotective effects as indicated by improved ejection fraction (55±1 vs. 29±3 %), global longitudinal strain (-19±2 vs. -3±2 %), +dP/dt max (10214±614 vs. 7174±716 mmHg/s) and exercise performance (1.3±14 vs. -46.3±14 Δ% compared to baseline before I/R) when compared with CGx vehicle-treated animals. CGx also did not prevent the effect of ICV leptin to reduce septal collagen deposition and heart weight/tibia length post-I/R. These results suggests that leptin, via its CNS actions, improves cardiac function and remodeling after I/R injury independent of cardiac sympathetic innervation.

Abstract 13505: COVID-19 and Cardiovascular Disease Patient Hearts Harbor Sympathetic Remodeling and Altered Angiotensin Converting Enzyme 2 Localization

Cardiac complications of COVID-19 have been well described and are associated with significant morbidity and mortality. Concomitantly, various pre-existing cardiovascular diseases (CVDs) are established risk factors for developing severe COVID-19 illness and death. The mechanisms of cardiac injury after COVID-19 remain incompletely understood. Further, whether and how SARS-CoV-2 directly infects the heart is unclear. In this study, we investigated cardiac sympathetic innervation and the cellular localization of angiotensin converting enzyme 2 (ACE2) to test the hypothesis that pre-existing or acute changes in these parameters could contribute to cardiac complications of COVID-19. We performed immunohistochemical (IHC) analysis on sections of left ventricular (LV) wall from twenty autopsied human hearts consisting of a control group, a CVD group, and COVID-19 ARDS and COVID-19 non-ARDS groups. Using tyrosine hydroxylase as a noradrenergic marker, we observed substantial sympathetic nerve loss in CVD LVs compared to the control group, which is consistent with previous work suggesting loss of sympathetic activity in severe heart failure. Additionally, we observed mild and heterogeneous nerve loss in both COVID-19 groups. Using an ACE2 antibody, we observed robust transmural staining localized to pericytes in the control group. The CVD hearts displayed significant loss of ACE2 in pericytes and increased ACE2 in cardiomyocytes. Both COVID-19 groups displayed a modest increase in cardiomyocyte ACE2 compared to controls, and pericyte ACE2 staining was generally maintained. We also performed IHC for PDGF receptor β, an established marker for pericytes, and confirmed ACE2 localization to pericytes. The observed sympathetic nerve remodeling could play a key role in arrhythmogenesis in acute or post-acute COVID-19 patients. Further, if SARS-CoV-2 does infect the heart, then our data demonstrate the primary target would be through microvasculature associated pericytes, not cardiomyocytes. Finally, the upregulation of cardiomyocyte ACE2 in both CVD and COVID-19 groups could play a contributing role in COVID-19 associated cardiac injury or a compensatory role in cardiac pathogenesis by attenuating the local effects of angiotensin II.

Central Nervous System Actions of Leptin Improve Cardiac Function After Ischemia-Reperfusion: Roles of Sympathetic Innervation and Sex Differences.

Background Therapeutic strategies for preventing paradoxical reperfusion injury after myocardial ischemia are limited. We tested whether central nervous system actions of leptin induce important protective effects on cardiac function and metabolism after myocardial ischemia/reperfusion (I/R) injury, the role of cardiac sympathetic innervation in mediating these effects, and whether there are major sex differences in the cardioprotective effects of chronic central nervous system leptin infusion. Methods and Results Myocardial I/R was induced by temporary ligation of the left descending coronary artery in male and female Wistar rats instrumented with intracerebroventricular cannula in the lateral ventricle. Vehicle or leptin (0.62 μg/h) infusion was started immediately after reperfusion and continued for 28 days using osmotic minipumps connected to the intracerebroventricular cannula. Cardiac function was assessed by echocardiography, ventricular pressures, and exercise performance. Intracerebroventricular leptin treatment markedly attenuated cardiac dysfunction post-I/R as evidenced by improved ejection fraction (56.7±1.9 versus 22.6%±1.1%), maximal rate of left ventricle rise (11 680±2122 versus 5022±441 mm Hg) and exercise performance (-4.2±7.9 versus -68.2±3.8 Δ%) compared with vehicle-treated rats. Intracerebroventricular leptin infusion reduced infarct size in females, but not males, when compared with ad-lib fed or pair-fed saline-treated rats. Intracerebroventricular leptin treatment also increased cardiac NAD+/NADH content (≈10-fold) and improved mitochondrial function when compared with vehicle treatment. Cervical ganglia denervation did not attenuate the cardiac protective effects of leptin after I/R injury. Conclusions These data indicate that leptin, via its central nervous system actions, markedly improves overall heart function and mitochondrial metabolism after I/R injury regardless of sex, effects that are largely independent of cardiac sympathetic innervation.