Sudden cardiac death due to ventricular arrhythmia in diabetes mellitus: A bench to bedside review.

Diabetes mellitus (DM) confers an increased risk of sudden cardiac death (SCD) independent of its associated cardiovascular comorbidities. DM induces adverse structural, electrophysiologic, and autonomic cardiac remodeling that can increase one's risk of ventricular arrhythmias and SCD. Although glycemic control and prevention of microvascular and macrovascular complications are cornerstones in the management of DM, they are not adequate for the prevention of SCD. In this narrative review, we describe the contribution of DM to the pathophysiologic mechanism of SCD beyond its role in atherosclerotic cardiovascular disease and heart failure. On the basis of this pathophysiologic framework, we outline potential preventive and therapeutic strategies to mitigate the risk of SCD in this population of high-risk patients.

Exercise-Induced QRS Prolongation in Brugada Syndrome: Implications for Improving Disease Phenotyping and Diagnosis.

BACKGROUND: Abnormal ventricular activation at rest is reported in Brugada syndrome (BrS). OBJECTIVES: The aim of this study was to evaluate the usefulness of dynamic changes in ventricular activation during exercise to improve disease phenotyping and diagnosis of BrS. METHODS: Digital 12-lead electrocardiograms during stress testing were analyzed retrospectively at baseline, peak exercise, and recovery in 53 patients with BrS and 52 controls. Biventricular activation was assessed from QRS duration (QRSd), whereas right ventricular activation was assessed from S wave duration in the lateral leads (I and V6) and terminal R wave duration in aVR. Exercise-induced changes in QRS parameters to predict a positive procainamide response were assessed in separate test and validation cohorts with suspected BrS. RESULTS: Baseline electrocardiogram parameters were similar between BrS and controls. QRSd shortened with exercise in all controls but prolonged in all BrS (-6.1 ± 6.0 ms vs 7.1 ± 6.5 ms [P < 0.001] in V6). QRSd in recovery was longer in BrS compared with controls (90 ± 12 ms vs 82 ± 11 ms in V6; P = 0.002). Both groups demonstrated exercise-induced S duration prolongation in V6, with greater prolongation in BrS (8.2 ± 14.3 ms vs 1.2 ± 12.4 ms; P < 0.001). Any exercise-induced QRSd prolongation in V6 differentiated those with a positive vs negative procainamide response with 100% sensitivity and 95% specificity in the test cohort, and 87% sensitivity and 93% specificity in the validation cohort. CONCLUSIONS: Exercise-induced QRSd prolongation is ubiquitous in BrS primarily owing to delayed right ventricular activation. This electrocardiogram phenotype predicts a positive procainamide response and may provide a noninvasive screening tool to aid in the diagnosis of BrS before drug challenge.

Impaired Cardiac AMPK (5'-Adenosine Monophosphate-Activated Protein Kinase) and Ca2+-Handling, and Action Potential Duration Heterogeneity in Ibrutinib-Induced Ventricular Arrhythmia Vulnerability.

BACKGROUND: We recently demonstrated that acute administration of ibrutinib, a Bruton's tyrosine kinase inhibitor used in chemotherapy for blood malignancies, increases ventricular arrhythmia (VA) vulnerability. A pathway of ibrutinib-induced vulnerability to VA that can be modulated for cardioprotection remains unclear. METHODS AND RESULTS: The effects of ibrutinib on cardiac electrical activity and Ca2+ dynamics were investigated in Langendorff-perfused hearts using optical mapping. We also conducted Western blotting analysis to evaluate the impact of ibrutinib on various regulatory and Ca2+-handling proteins in rat cardiac tissues. Treatment with ibrutinib (10 mg/kg per day) for 4 weeks was associated with an increased VA inducibility (72.2%±6.3% versus 38.9±7.0% in controls, P<0.002) and shorter action potential durations during pacing at various frequencies (P<0.05). Ibrutinib also decreased heart rate thresholds for beat-to-beat duration alternans of the cardiac action potential (P<0.05). Significant changes in myocardial Ca2+ transients included lower amplitude alternans ratios (P<0.05), longer times-to-peak (P<0.05), and greater spontaneous intracellular Ca2+ elevations (P<0.01). We also found lower abundance and phosphorylation of myocardial AMPK (5'-adenosine monophosphate-activated protein kinase), indicating reduced AMPK activity in hearts after ibrutinib treatment. An acute treatment with the AMPK activator 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside ameliorated abnormalities in action potential and Ca2+ dynamics, and significantly reduced VA inducibility (37.1%±13.4% versus 72.2%±6.3% in the absence of 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside, P<0.05) in hearts from ibrutinib-treated rats. CONCLUSIONS: VA vulnerability inflicted by ibrutinib may be mediated in part by an impairment of myocardial AMPK activity. Pharmacological activation of AMPK may be a protective strategy against ibrutinib-induced cardiotoxicity.

Arrhythmogenic Ventricular Remodeling by Next-Generation Bruton's Tyrosine Kinase Inhibitor Acalabrutinib.

Cardiac arrhythmias remain a significant concern with Ibrutinib (IBR), a first-generation Bruton's tyrosine kinase inhibitor (BTKi). Acalabrutinib (ABR), a next-generation BTKi, is associated with reduced atrial arrhythmia events. However, the role of ABR in ventricular arrhythmia (VA) has not been adequately evaluated. Our study aimed to investigate VA vulnerability and ventricular electrophysiology following chronic ABR therapy in male Sprague-Dawley rats utilizing epicardial optical mapping for ventricular voltage and Ca2+ dynamics and VA induction by electrical stimulation in ex-vivo perfused hearts. Ventricular tissues were snap-frozen for protein analysis for sarcoplasmic Ca2+ and metabolic regulatory proteins. The results show that both ABR and IBR treatments increased VA vulnerability, with ABR showing higher VA regularity index (RI). IBR, but not ABR, is associated with the abbreviation of action potential duration (APD) and APD alternans. Both IBR and ABR increased diastolic Ca2+ leak and Ca2+ alternans, reduced conduction velocity (CV), and increased CV dispersion. Decreased SERCA2a expression and AMPK phosphorylation were observed with both treatments. Our results suggest that ABR treatment also increases the risk of VA by inducing proarrhythmic changes in Ca2+ signaling and membrane electrophysiology, as seen with IBR. However, the different impacts of these two BTKi on ventricular electrophysiology may contribute to differences in VA vulnerability and distinct VA characteristics.

Knockdown of SCN5A alters metabolic-associated genes and aggravates hypertrophy in the cardiomyoblast.

SCN5A mutations have been reported to cause various cardiomyopathies in humans. Most of the SCN5A mutations causes loss of function and thereby, alters the overall cellular function. Therefore, to understand the loss of SCN5A function in cardiomyocytes, we have knocked down the SCN5A gene (SCN5A-KD) in H9c2 cells and explored the cell phenotype and molecular behaviors in the presence and absence of isoproterenol (ISO), an adrenergic receptor agonist that induces cardiac hypertrophy. Expression of several genes related to hypertrophy, inflammation, fibrosis, and energy metabolism pathways were evaluated. It was found that the mRNA expression of hypertrophy-related gene, brain (B-type) natriuretic peptide (BNP) was significantly increased in SCN5A-KD cells as compared to 'control' H9c2 cells. There was a further increase in the mRNA expressions of BNP and ßMHC in SCN5A-KD cells after ISO treatment compared to their respective controls. Pro-inflammatory cytokine, tumor necrosis factor-alpha expression was significantly increased in 'SCN5A-KD' H9c2 cells. Further, metabolism-related genes like glucose transporter type 4, cluster of differentiation 36, peroxisome proliferator-activated receptor alpha, and peroxisome proliferator-activated receptor-gamma were significantly elevated in the SCN5A-KD cells as compared to the control cells. Upregulation of these metabolic genes is associated with increased ATP production. The study revealed that SCN5A knock-down causes alteration of gene expression related to cardiac hypertrophy, inflammation, and energy metabolism pathways, which may promote cardiac remodelling and cardiomyopathy.

Effect of Low-Level Tragus Stimulation on Cardiac Metabolism in Heart Failure with Preserved Ejection Fraction: A Transcriptomics-Based Analysis.

Abnormal cardiac metabolism precedes and contributes to structural changes in heart failure. Low-level tragus stimulation (LLTS) can attenuate structural remodeling in heart failure with preserved ejection fraction (HFpEF). The role of LLTS on cardiac metabolism is not known. Dahl salt-sensitive rats of 7 weeks of age were randomized into three groups: low salt (0.3% NaCl) diet (control group; n = 6), high salt diet (8% NaCl) with either LLTS (active group; n = 8), or sham stimulation (sham group; n = 5). Both active and sham groups received the high salt diet for 10 weeks with active LLTS or sham stimulation (20 Hz, 2 mA, 0.2 ms) for 30 min daily for the last 4 weeks. At the endpoint, left ventricular tissue was used for RNA sequencing and transcriptomic analysis. The Ingenuity Pathway Analysis tool (IPA) was used to identify canonical metabolic pathways and upstream regulators. Principal component analysis demonstrated overlapping expression of important metabolic genes between the LLTS, and control groups compared to the sham group. Canonical metabolic pathway analysis showed downregulation of the oxidative phosphorylation (Z-score: -4.707, control vs. sham) in HFpEF and LLTS improved the oxidative phosphorylation (Z-score = -2.309, active vs. sham). HFpEF was associated with the abnormalities of metabolic upstream regulators, including PPARGC1α, insulin receptor signaling, PPARα, PPARδ, PPARGC1ß, the fatty acid transporter SLC27A2, and lysine-specific demethylase 5A (KDM5A). LLTS attenuated abnormal insulin receptor and KDM5A signaling. HFpEF is associated with abnormal cardiac metabolism. LLTS, by modulating the functioning of crucial upstream regulators, improves cardiac metabolism and mitochondrial oxidative phosphorylation.

Noninvasive Vagus Nerve Stimulation in Postural Tachycardia Syndrome: A Randomized Clinical Trial.

BACKGROUND: Low-level transcutaneous stimulation of the auricular branch of the vagus nerve at the tragus is antiarrhythmic and anti-inflammatory in animals and humans. Preliminary studies show that transcutaneous vagus nerve stimulation (tVNS) is beneficial in animal models of postural tachycardia syndrome (POTS). OBJECTIVES: In this study the authors conducted a sham-controlled, double-blind, randomized clinical trial to examine the effect of tVNS on POTS over a 2-month period relative to sham stimulation. METHODS: tVNS (20 Hz, 1 mA below discomfort threshold) was delivered using an ear clip attached to either the tragus (active; n = 12) or the ear lobe (sham; n = 14) for 1 hour daily over a 2-month period. Postural tachycardia was assessed during the baseline and 2-month visit. Heart rate variability based on 5-minute electrocardiogram, serum cytokines, and antiautonomic autoantibodies were measured at the respective time points. RESULTS: Mean age was 34 ± 11 years (100% female; 81% Caucasian). Adherence to daily stimulation was 83% in the active arm and 86% in the sham arm (P > 0.05). Postural tachycardia was significantly less in the active arm compared with the sham arm at 2 months (mean postural increase in heart rate 17.6 ± 9.9 beats/min vs 31.7 ± 14.4 beats/min; P = 0.01). Antiadrenergic autoantibodies and inflammatory cytokines were lower in the active arm compared with the sham arm at 2 months (P < 0.05). Heart rate variability was better in the active arm. No device-related side effects were observed. CONCLUSIONS: Our results support the emerging paradigm of noninvasive neuromodulation to treat POTS. Mechanistically, this effect appears to be related to reduction of antiautonomic autoantibodies and inflammatory cytokines, and improvement in autonomic tone. Further studies are warranted. (Autoimmune Basis for Postural Tachycardia Syndrome; NCT05043051).

Potential consequences of cardioneuroablation for vasovagal syncope: A call for appropriately designed, sham-controlled clinical trials.

Cardioneuroablation (CNA) is being increasingly used to treat patients with vasovagal syncope (VVS). Bradycardia, in the cardioinhibitory subtype of VVS, results from transient parasympathetic overactivity leading to sinus bradycardia and/or atrioventricular block. By mitigating parasympathetic overactivity, CNA has been shown to improve VVS symptoms in clinical studies with relatively small sample sizes and short follow-up periods (<5 years) at selected centers. However, CNA may potentially tip the autonomic balance to a state of sympathovagal imbalance with attenuation of cardiac parasympathetic activity. A higher heart rate is associated with adverse cardiovascular events and increased mortality in healthy populations without cardiovascular diseases. Chronic sympathovagal imbalance may also affect the pathophysiology of spectra of cardiovascular disorders including atrial and ventricular arrhythmias. This review addresses potential long-term pathophysiological consequences of CNA for VVS.

Noninvasive low-level tragus stimulation attenuates inflammation and oxidative stress in acute heart failure.

PURPOSE: Acute decompensated heart failure (ADHF) is associated with inflammation, oxidative stress, and excess sympathetic drive. It is unknown whether neuromodulation would improve inflammation and oxidative stress in acute heart failure. We, therefore, performed this proof-of-concept study to evaluate the effects of neuromodulation using noninvasive low-level tragus stimulation on inflammation and oxidative stress in ADHF. METHODS: Nineteen patients with ejection fraction < 40% were randomized to neuromodulation 4 h twice daily (6-10 a.m. and 6-10 p.m.) (n = 8) or sham stimulation (n = 11) during hospital admission. All patients received standard-of-care treatment. Blood samples were collected at admission and discharge. Serum cytokines were assayed using standard immunosorbent techniques. Reactive oxygen species inducibility from cultured coronary endothelial cells exposed to patient sera was determined using a dihydrodichlorofluorescein probe test (expressed as fluorescein units). RESULTS: Compared to sham stimulation, neuromodulation was associated with a significant reduction of circulating serum interleukin-6 levels (-78% vs. -9%; p = 0.012). Similarly, neuromodulation led to a reduction of endothelial cell oxidative stress in the neuromodulation group (1363 units to 978 units, p = 0.003) compared to sham stimulation (1146 units to 1083 units, p = 0.094). No significant differences in heart rate, blood pressure, or renal function were noted between the two groups. CONCLUSION: In this proof-of-concept pilot study, in acute decompensated heart failure, neuromodulation was feasible and safe and was associated with a reduction in systemic inflammation and attenuation of coronary endothelial cellular oxidative stress. CLINICAL TRIAL REGISTRATION: NCT02898181.

Uncoupling cytosolic calcium from membrane voltage by transient receptor potential melastatin 4 channel (TRPM4) modulation: A novel strategy to treat ventricular arrhythmias.

The current antiarrhythmic paradigm is mainly centered around modulating membrane voltage. However, abnormal cytosolic calcium (Ca2+) signaling, which plays an important role in driving membrane voltage, has not been targeted for therapeutic purposes in arrhythmogenesis. There is clear evidence for bidirectional coupling between membrane voltage and intracellular Ca2+. Cytosolic Ca2+ regulates membrane voltage through Ca2+-sensitive membrane currents. As a component of Ca2+-sensitive currents, Ca2+-activated nonspecific cationic current through the TRPM4 (transient receptor potential melastatin 4) channel plays a significant role in Ca2+-driven changes in membrane electrophysiology. In myopathic and ischemic ventricles, upregulation and/or enhanced activity of this current is associated with the generation of afterdepolarization (both early and delayed), reduction of repolarization reserve, and increased propensity to ventricular arrhythmias. In this review, we describe a novel concept for the management of ventricular arrhythmias in the remodeled ventricle based on mechanistic concepts from experimental studies, by uncoupling the Ca2+-induced changes in membrane voltage by inhibition of this TRPM4-mediated current.

Noninvasive low-level tragus stimulation attenuates inflammation and oxidative stress in acute heart failure.

Purpose: Acute decompensated heart failure is associated with inflammation, oxidative stress, and excess sympathetic drive. It is unknown if neuromodulation would improve inflammation and oxidative stress in acute heart failure. We, therefore, performed this proof-of-concept study to evaluate the effects of neuromodulation using noninvasive low-level Tragus stimulation on inflammation and oxidative stress in ADHF. Methods: 19 patients with ejection fraction < 40% were randomized to neuromodulation- 4 hours twice daily (6 AM-10 AM and 6 PM-10 PM) (n = 8) or sham stimulation (n = 11) during hospital admission. All patients received standard-of-care treatment. Blood samples were collected at admission and discharge. Serum cytokines were assayed using standard immunosorbent techniques. Reactive oxygen species inducibility from cultured coronary endothelial cells exposed to patient sera was determined using dihydrodichlorofluorescein probe test (expressed as fluorescein units). Results: Compared to sham stimulation, neuromodulation was associated with a significant reduction of circulating serum Interleukin-6 levels (-78% vs -9%; p = 0.012). Similarly, neuromodulation led to reduction of endothelial cell oxidative stress, in the neuromodulation group (1363 units to 978 units, p = 0.003) compared to sham stimulation (1146 units to 1083 units, p = 0.094). No significant difference in heart rate, blood pressure or renal function were noted between the two groups. Conclusion: In this proof-of-concept pilot study, in acute systolic heart failure, neuromodulation was feasible and safe and was associated with a reduction in systemic inflammation and attenuation of cellular oxidative stress. Clinical trial: NCT02898181.

Protein kinase A: A potential marker of sympathovagal imbalance in heart failure.

Mitigation of cardiac autonomic dysregulation by neuromodulation technologies is emerging as a new therapeutic modality of heart failure (HF). This recent progress has necessitated the identification of a biomarker for the quantification of sympathovagal balance, the potential target of 'neuromodulation' strategies. The currently available autonomic nervous system assessment parameters do not truly reflect the sympathovagal balance of the ventricle. Protein kinase A (PKA) is an intracellular enzyme that plays a major role in the pathophysiology of functional and structural ventricular remodeling in HF. Interestingly, sympathetic and parasympathetic activations exert reciprocal influence on the activity of PKA. The current review attempts to evaluate the potential concept and feasibility of using in vitro assessment of PKA activity as a marker of sympathovagal balance in HF.

Restoration of calcium release synchrony: A novel target for heart failure and ventricular arrhythmia.

Myocardial calcium (Ca2+) signaling plays a crucial role in contractile function and membrane electrophysiology. An abnormal myocardial Ca2+ transient is linked to heart failure and ventricular arrhythmias. At the subcellular level, the synchronous release of Ca2+ sparks from sarcoplasmic Ca2+ release units determines the configuration and amplitude of the global Ca2+ transient. This narrative review evaluates the role of aberrant Ca2+ release synchrony in the pathophysiology of cardiomyopathies and ventricular arrhythmias. The potential therapeutic benefits of restoration of Ca2+ release synchrony in heart failure and ventricular arrhythmias are also discussed.

The neurometabolic axis: A novel therapeutic target in heart failure.

Abnormal cardiac metabolism or cardiac metabolic remodeling is reported before the onset of heart failure with reduced ejection fraction (HFrEF) and is known to trigger and maintain the mechanical dysfunction and electrical, and structural abnormalities of the ventricle. A dysregulated cardiac autonomic tone characterized by sympathetic overdrive with blunted parasympathetic activation is another pathophysiological hallmark of HF. Emerging evidence suggests a link between autonomic nervous system activity and cardiac metabolism. Chronic ß-adrenergic activation promotes maladaptive metabolic remodeling whereas cholinergic activation attenuates the metabolic aberrations through favorable modulation of key metabolic regulatory molecules. Restoration of sympathovagal balance by neuromodulation strategies is emerging as a novel nonpharmacological treatment strategy in HF. The current review attempts to evaluate the 'neuro-metabolic axis' in HFrEF and whether neuromodulation can mitigate the adverse metabolic remodeling in HFrEF.

Autonomic Nervous System and Cardiac Metabolism: Links Between Autonomic and Metabolic Remodeling in Atrial Fibrillation.

Simultaneous activation of the sympathetic and parasympathetic nervous systems is crucial for the initiation of paroxysmal atrial fibrillation (AF). However, unbalanced activation of the sympathetic system is characteristic of autonomic remodeling in long-standing persistent AF. Moreover, the adrenergic activation-induced metabolic derangements provide a milieu for acute AF and promote the transition from the paroxysmal to the persistent phase of AF. On the other hand, cholinergic activation ameliorates the maladaptive metabolic remodeling in the face of metabolic challenges. Selective inhibition of the sympathetic system and restoration of the balance of the cholinergic system by neuromodulation is emerging as a novel nonpharmacologic strategy for managing AF. This review explores the link between cardiac autonomic and metabolic remodeling and the potential roles of different autonomic modulation strategies on atrial metabolic aberrations in AF.

Non-invasive Vagus Nerve Simulation in Postural Orthostatic Tachycardia Syndrome.

Postural orthostatic tachycardia syndrome (POTS) is a chronic debilitating condition of orthostatic intolerance, predominantly affecting young females. Other than postural tachycardia, symptoms of POTS include a spectrum of non-cardiac, systemic and neuropsychiatric features. Despite the availability of widespread pharmacological and non-pharmacological therapeutic options, the management of POTS remains challenging. Exaggerated parasympathetic withdrawal and sympathetic overdrive during postural stress are principal mechanisms of postural tachycardia in POTS. Non-invasive, transcutaneous, vagus nerve stimulation (tVNS) is known to restore sympathovagal balance and is emerging as a novel therapeutic strategy in cardiovascular conditions including arrhythmias and heart failure. Furthermore, tVNS also exerts immunomodulatory and anti-inflammatory effects. This review explores the effects of tVNS on the pathophysiology of POTS and its potential as an alternative non-pharmacological option in this condition.

An Unusual Genetic Observation in a Case of Short-Coupled PVC-Triggered Ventricular Fibrillation.

Ventricular fibrillation induced by short-coupled premature ventricular complex is an uncommon cause of cardiac arrest in young individuals with no structural heart disease. The genetic substrate of this condition is heterogeneous and remains incompletely defined. We describe a case of short-coupled premature ventricular complex-triggered ventricular fibrillation with a likely pathogenic variant in the titin (TTN) gene. (Level of Difficulty: Advanced.).