The quest to improve sudden cardiac death prediction using sympathetic innervation scintigraphy: Chasing a mirage?
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ABSTRACT:
SUBMITTER: Al Badarin FJ
PROVIDER: S-EPMC6864257 | biostudies-literature | 2020 Jun
REPOSITORIES: biostudies-literature
Publications
The quest to improve sudden cardiac death prediction using sympathetic innervation scintigraphy: Chasing a mirage?
Al Badarin Firas J FJ Peri-Okonny Poghni P
Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology 20190520 3
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Project description:Afferent and efferent cardiac neurotransmission via the cardiac nerves intricately modulates nearly all physiological functions of the heart (chronotropy, dromotropy, lusitropy, and inotropy). Afferent information from the heart is transmitted to higher levels of the nervous system for processing (intrinsic cardiac nervous system, extracardiac-intrathoracic ganglia, spinal cord, brain stem, and higher centers), which ultimately results in efferent cardiomotor neural impulses (via the sympathetic and parasympathetic nerves). This system forms interacting feedback loops that provide physiological stability for maintaining normal rhythm and life-sustaining circulation. This system also ensures that there is fine-tuned regulation of sympathetic-parasympathetic balance in the heart under normal and stressed states in the short (beat to beat), intermediate (minutes to hours), and long term (days to years). This important neurovisceral/autonomic nervous system also plays a major role in the pathophysiology and progression of heart disease, including heart failure and arrhythmias leading to sudden cardiac death. Transdifferentiation of neurons in heart failure, functional denervation, cardiac and extracardiac neural remodeling has also been identified and characterized during the progression of disease. Recent advances in understanding the cellular and molecular processes governing innervation and the functional control of the myocardium in health and disease provide a rational mechanistic basis for the development of neuraxial therapies for preventing sudden cardiac death and other arrhythmias. Advances in cellular, molecular, and bioengineering realms have underscored the emergence of this area as an important avenue of scientific inquiry and therapeutic intervention.
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Project description:Neural remodeling in the autonomic nervous system contributes to sudden cardiac death. The fabric of cardiac excitability and propagation is controlled by autonomic innervation. Heart disease predisposes to malignant ventricular arrhythmias by causing neural remodeling at the level of the myocardium, the intrinsic cardiac ganglia, extracardiac intrathoracic sympathetic ganglia, extrathoracic ganglia, spinal cord, and the brainstem, as well as the higher centers and the cortex. Therapeutic strategies at each of these levels aim to restore the balance between the sympathetic and parasympathetic branches. Understanding this complex neural network will provide important therapeutic insights into the treatment of sudden cardiac death.
| S-EPMC5777242 | biostudies-other
Project description:Although cardio-vascular incidents and sudden cardiac death (SCD) are among the leading causes of premature death in the general population, the origins remain unidentified in many cases. Genome-wide association studies have identified Meis1 as a risk factor for SCD. We report that Meis1 inactivation in the mouse neural crest leads to an altered sympatho-vagal regulation of cardiac rhythmicity in adults characterized by a chronotropic incompetence and cardiac conduction defects, thus increasing the susceptibility to SCD. We demonstrated that Meis1 is a major regulator of sympathetic target-field innervation and that Meis1 deficient sympathetic neurons die by apoptosis from early embryonic stages to perinatal stages. In addition, we showed that Meis1 regulates the transcription of key molecules necessary for the endosomal machinery. Accordingly, the traffic of Rab5(+) endosomes is severely altered in Meis1-inactivated sympathetic neurons. These results suggest that Meis1 interacts with various trophic factors signaling pathways during postmitotic neurons differentiation.
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Project description: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.
| S-EPMC9673649 | biostudies-literature
Project description:Arrhythmic sudden cardiac death (SCD) may be caused by ventricular tachycardia/fibrillation or pulseless electric activity/asystole. Effective risk stratification to identify patients at risk of arrhythmic SCD is essential for targeting our healthcare and research resources to tackle this important public health issue. Although our understanding of SCD because of pulseless electric activity/asystole is growing, the overwhelming majority of research in risk stratification has focused on SCD-ventricular tachycardia/ventricular fibrillation. This review focuses on existing and novel risk stratification tools for SCD-ventricular tachycardia/ventricular fibrillation. For patients with left ventricular dysfunction or myocardial infarction, advances in imaging, measures of cardiac autonomic function, and measures of repolarization have shown considerable promise in refining risk. Yet the majority of SCD-ventricular tachycardia/ventricular fibrillation occurs in patients without known cardiac disease. Biomarkers and novel imaging techniques may provide further risk stratification in the general population beyond traditional risk stratification for coronary artery disease alone. Despite these advances, significant challenges in risk stratification remain that must be overcome before a meaningful impact on SCD can be realized.
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Project description:Nerve Growth Factor (NGF) is a target tissue derived neurotrophin required for normal sympathetic neuron survival and target tissue innervation. NGF signaling regulates gene expression in sympathetic neurons, which in turn mediates critical aspects of neuron survival, axon extension and terminal axon branching during sympathetic nervous system (SNS) development. Egr3 is a transcription factor regulated by NGF signaling in sympathetic neurons that is essential for normal SNS development. Germline Egr3-deficient mice have physiologic dysautonomia characterized by apoptotic sympathetic neuron death and abnormal innervation to many target tissues. The extent to which sympathetic innervation abnormalities in the absence of Egr3 is caused by altered innervation or by neuron death during development is unknown. Using Bax-deficient mice to abrogate apoptotic sympathetic neuron death in vivo, we show that Egr3 has an essential role in target tissue innervation in the absence of neuron death. Sympathetic target tissue innervation is abnormal in many target tissues in the absence of neuron death, and like NGF, Egr3 also appears to effect target tissue innervation heterogeneously. In some tissues, such as heart, spleen, bowel, kidney, pineal gland and the eye, Egr3 is essential for normal innervation, whereas in other tissues such as lung, stomach, pancreas and liver, Egr3 appears to have little role in innervation. Moreover, in salivary glands and heart, two tissues where Egr3 has an essential role in sympathetic innervation, NGF and NT-3 are expressed normally in the absence of Egr3 indicating that abnormal target tissue innervation is not due to deregulation of these neurotrophins in target tissues. Taken together, these results clearly demonstrate a role for Egr3 in mediating sympathetic target tissue innervation that is independent of neuron survival or neurotrophin deregulation.
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Project description:Hemodialysis patients carry a large burden of cardiovascular disease; most onerous is the high risk for sudden cardiac death. Defining sudden cardiac death among hemodialysis patients and understanding its pathogenesis are challenging, but inferences from the existing literature reveal differences between sudden cardiac death among hemodialysis patients and the general population. Vascular calcifications and left ventricular hypertrophy may play a role in the pathophysiology of sudden cardiac death, whereas traditional cardiovascular risk factors seem to have a more muted effect. Arrhythmic triggers also differ in this group as compared to the general population, with some arising uniquely from the hemodialysis procedure. Combined, these factors may alter the types of terminal arrhythmias that lead to sudden cardiac death among hemodialysis patients, having important implications for prevention strategies. This review highlights current knowledge on the epidemiology, pathophysiology, and risk factors for sudden cardiac death among hemodialysis patients. We then examine strategies for prevention, including the use of specific cardiac medications and device-based therapies such as implantable defibrillators. We also discuss dialysis-specific prevention strategies, including minimizing exposure to low potassium and calcium dialysate concentrations, extending dialysis treatment times or adding sessions to avoid rapid ultrafiltration, and lowering dialysate temperature.
| S-EPMC5457912 | biostudies-literature
Project description:Purpose of reviewTo survey recent developments in the field of genetics encompassing discovery of new candidate genes, new diagnostic strategies, and new therapies for sudden cardiac death (SCD) syndromes.Recent findingsIn addition to new mutations in known SCD genes, several novel genes not previously implicated in SCD causation have been found, particularly in long QT syndrome (e.g., KCNJ5, AKAP9, SNTA1), idiopathic ventricular fibrillation (e.g., DPP6, KCNJ8), dilated cardiomyopathy (e.g., NEBL), and hypertrophic cardiomyopathy (HCM; e.g., NEXN). Genetic SCD animal models have provided novel insights into the cellular mechanism and pathogenesis of nearly all the major SCD syndromes, which has led to several new drug therapies for patients with genetic arrhythmia syndromes (e.g., flecainide in catecholaminergic polymorphic ventricular tachycardia). Furthermore, genetic contributions to acquired heart diseases are increasingly being recognized. For example, a 21q21 locus is strongly associated with ventricular fibrillation after myocardial infarction. Near this locus is CXADR, a gene encoding a viral receptor implicated in myocarditis and dilated cardiomyopathy. Finally, common variants in cardiac ion channels and proteins likely contribute to common cardiac phenotypes.SummaryMajor strides have been made in uncovering new genes, mechanisms, and syndromes that have significantly advanced the diagnosis and treatment of genetic SCD disorders.
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Project description:The prevention and treatment of sudden cardiac death (SCD) remains a significant public health challenge. For patients with a history of sudden death attributable to ventricular arrhythmia, implantable cardioverter-defibrillator (ICD) therapy is a mainstay of treatment, although these patients remain at high risk for recurrent ventricular arrhythmia and defibrillator therapies. In this review, we summarize landmark clinical trials evaluating the efficacy of ICD therapy in secondary prevention patients, review clinical outcomes including mode of death in survivors of SCD, and highlight the role for systematic diagnostic evaluation. We additionally discuss the invasive electrophysiological management of these patients, including ICD selection and programming as well as the role and timing of antiarrhythmic drug therapy and catheter ablation. Finally, we frame future challenges and needs to advance the care for secondary prevention patients.
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