Celastrol exerts antiarrhythmic effects in chronic heart failure via NLRP3/Caspase-1/IL-1ß signaling pathway.

OBJECTIVES: Celastrol has widespread therapeutic applications in various pathological conditions, including chronic inflammation. Previous studies have demonstrated the potent cardioprotective effects of celastrol. Nevertheless, limited attention has been given to its potential in reducing ventricular arrhythmias (VAs) following myocardial infarction (MI). Hence, this study aimed to elucidate the potential mechanisms underlying the regulatory effects of celastrol on VAs and cardiac electrophysiological parameters in rats after MI. METHODS: Sprague-Dawley rats were divided at random: the sham, MI, and MI + celastrol groups. The left coronary artery was occluded in the MI and MI + Cel groups. Electrocardiogram, heart rate variability (HRV), ventricular electrophysiological parameters analysis, histology staining of ventricles, Enzyme-linked immunosorbent assay (ELISA), western blotting and Quantitative real-time polymerase chain reaction (qRT-PCR) were performed to elucidate the underlying mechanism of celastrol. Besides, H9c2 cells were subjected to hypoxic conditions to create an in vitro model of MI and then treated with celastrol for 24 hours. Nigericin was used to activate the NLRP3 inflammasome. RESULTS: Compared with that MI group, cardiac electrophysiology instability was significantly alleviated in the MI + celastrol group. Additionally, celastrol improved HRV, upregulated the levels of Cx43, Kv.4.2, Kv4.3 and Cav1.2, mitigated myocardial fibrosis, and inhibited the NLRP3 inflammasome pathway. In vitro conditions also supported the regulatory effects of celastrol on the NLRP3 inflammasome pathway. CONCLUSIONS: Celastrol could alleviate the adverse effects of VAs after MI partially by promoting autonomic nerve remodeling, ventricular electrical reconstruction and ion channel remodeling, and alleviating ventricular fibrosis and inflammatory responses partly by through inhibiting the NLRP3/Caspase-1/IL-1ß pathway.

Arrhythmic Mitral Valve Prolapse Syndrome and Ventricular Arrhythmias: A Comprehensive Review and the Role of Catheter Ablation.

Mitral valve prolapse (MVP) affects 2-3% of the general population, and despite its benign prognosis overall, it is associated with sudden death in a small subset of patients. The term "arrhythmic MVP syndrome" (AMVPS) refers to the presence of frequent or complex ventricular arrhythmias, commonly reported in female patients with a stereotypical phenotype including bileaflet myxomatous disease, ECG repolarisation abnormalities in inferior leads, mitral annular disjunction, and significant fibrosis in the inferolateral LV and papillary muscles. Modern imaging technologies have led to the identification of new risk factors that have been implemented in recent risk stratification guidelines; however, screening for patients with MVP who are at risk of sudden cardiac death (SCD) remains challenging. In addition, there is a limited amount of data on the outcomes of different treatment approaches in AMVP and no specific indication for targeted or disease-modifying therapies within current guidelines. Potential arrhythmic substrates in patients with AMVP syndrome have been the subject of interest in previous studies, with areas consisting of fibrosis at the papillary muscle level and the Purkinje system. Premature ventricular contractions (PVCs) originating from these areas have been shown to play an important role as triggers for ventricular fibrillation and SCD in patients with AMVP. Catheter ablation has emerged as a potential treatment modality in patients with MVP and ventricular arrhythmias (VAs), targeting arrhythmic substrates and triggering PVC foci. The aim of this review is to explore the role of catheter ablation in treating patients with AMVP.

Ventricular unloading causes prolongation of the QT interval and induces ventricular arrhythmias in rat hearts.

Introduction: Ventricular unloading during prolonged bed rest, mechanical circulatory support or microgravity has repeatedly been linked to potentially life-threatening arrhythmias. It is unresolved, whether this arrhythmic phenotype is caused by the reduction in cardiac workload or rather by underlying diseases or external stimuli. We hypothesized that the reduction in cardiac workload alone is sufficient to impair ventricular repolarization and to induce arrhythmias in hearts. Methods: Rat hearts were unloaded using the heterotopic heart transplantation. The ECG of unloaded and of control hearts were telemetrically recorded over 56 days resulting in >5 × 106 cardiac cycles in each heart. Long-term electrical remodeling was analyzed using a novel semi-automatic arrhythmia detection algorithm. Results: 56 days of unloading reduced left ventricular weight by approximately 50%. While unloading did not affect average HRs, it markedly prolonged the QT interval by approximately 66% and induced a median tenfold increase in the incidence of ventricular arrhythmias in comparison to control hearts. Conclusion: The current study provides direct evidence that the previously reported hypertrophic phenotype of repolarization during cardiac unloading translates into an impaired ventricular repolarization and ventricular arrhythmias in vivo. This supports the concept that the reduction in cardiac workload is a causal driver of the development of arrhythmias during ventricular unloading.

Cardiac magnetic resonance reveals concealed structural heart disease in patients with frequent premature ventricular contractions and normal echocardiography: A systematic review.

Premature ventricular contractions (PVCs) are a common form of arrhythmic events, often representing an idiopathic and benign condition without further therapeutic interventions. However, in certain circumstances PVCs may represent the epiphenomenon of a concealed structural heart disease (SHD). Surface 12­leads EKG and 24-h dynamic EKG are necessary to assess their main characteristics such as site of origin, frequency and complexity. Echocardiography represents the first-line imaging tool recommended to evaluate cardiac structures and function. Cardiac Magnetic Resonance (CMR) is recognized as a superior modality for detecting structural cardiac alterations, that might evade detection by conventional echocardiography. Moreover, in specific populations such as athletes, CMR may have a crucial role to exclude a concealed SHD and the risk of serious arrhythmic events during sport activity. Some clinical characteristics such as male sex, older age or family history of sudden cardiac death (SCD) or cardiomyopathy, and some electrocardiographic features of PVCs, in particular a right branch bundle block (RBBB) with superior/intermediate axis morphology, the reproducibility of VAs during exercise test (ET) or the evidence of complex ventricular arrhythmias, may warrant a CMR evaluation, due to the high probability of SHD. In this systematic review our objective was to provide an exhaustive overview on the role of CMR in detecting a concealed SHD in patients with high daily burden of PVCs and a normal echocardiographic evaluation, paving the way for a more extensive utilization of CMR in presence of certain high-risk clinical and/or EKG features identified during the diagnostic workup.

Inpatient mortality and outcomes of COVID-19 among patients with non-ischemic cardiomyopathy: A propensity matched analysis.

BACKGROUND: Patients with chronic medical conditions, particularly cardiovascular diseases, are at a greater risk of adverse outcomes due to COVID-19. The effect of COVID-19 on patients with non-ischemic cardiomyopathy (NICM) is not known well. OBJECTIVES: To study the impact of COVID-19 infection on NICM hospital mortality and other outcomes. METHODS: This study included a cohort of patients from the 2020 and 2021 National Inpatient Sample databases. Patients hospitalized for COVID-19 with and without NICM were matched using a 1:1 propensity score-matching ratio. Outcomes analyzed were in-hospital mortality, rates of acute kidney injury (AKI), acute myocardial infarction (AMI), cardiogenic shock, cardiac arrest, mechanical ventilation, tracheal intubation, pulmonary embolism (PE), ventricular tachycardia (VT), ventricular fibrillation (VF), length of stay (LOS), and total hospitalization charges. RESULTS: A total of 2,532,652 patients met the inclusion criteria (1,199,008 females [47.3 %], predominantly white 1,456,203 (57.5 %); mean [SD] age 63 [5.4] years), including 64,155 (2.5 %) patients with a history of NICM. Following propensity matching, 10,258 COVID-19 patients with and without NICM were matched. Patients with NICM had higher rates of AMI (11.1 vs. 7.1 %, p < 0.001), cardiogenic shock (2 vs. 0.6 %, p < 0.001), cardiac arrest (4.4 vs. 3.2 %, p < 0.01), mechanical ventilation (13.7 vs 12 %, p < 0.01), VT (8.5 vs. 2.2 %, p < 0.001), and VF (1.0 vs 0.25 %, p < 0.001). The odds ratios for in-hospital mortality, AKI, and PE did not differ significantly. CONCLUSION: A History of NICM does not affect COVID-19 mortality but increases the risk of cardiovascular complications.

Diagnostic and Prognostic Value of Right Ventricular Fat Quantification from Computed Tomography in Arrhythmogenic Right Ventricular Cardiomyopathy.

Background: In arrhythmogenic right ventricular cardiomyopathy (ARVC) non-invasive scar evaluation is not included among the diagnostic criteria or the predictors of ventricular arrhythmias (VA) and sudden death (SD). Computed tomography (CT) has excellent spatial resolution and allows a clear distinction between myocardium and fat; thus, it has great potential for the evaluation of myocardial scar in ARVC. Objective: The objective of this study is to evaluate the feasibility, and the diagnostic and prognostic value of semi-automated quantification of right ventricular (RV) fat replacement from CT images. Methods: An observational case-control study was carried out including 23 patients with a definite (19) or borderline (4) ARVC diagnosis and 23 age- and sex-matched controls without structural heart disease. All patients underwent contrast-enhanced cardiac CT. RV images were semi-automatically reconstructed with the ADAS-3D software (ADAS3D Medical, Barcelona, Spain). A fibrofatty scar was defined as values of Hounsfield Units (HU) <-10. Within the scar, a border zone (between -10 HU and -50 HU) and dense scar (<-50 HU) were distinguished. Results: All ARVC patients had an RV scar and all scar-related measurements were significantly higher in ARVC cases than in controls (p < 0.001). The total scar area and dense scar area showed no overlapping values between cases and controls, achieving perfect diagnostic performance (sensitivity and specificity of 100%). Among ARVC patients, 16 (70%) had experienced sustained VA or aborted SD. Among all clinical, ECG and imaging parameters, the dense scar area was the only one with a statistically significant association with VA and SD (p = 0.003). Conclusions: In ARVC, RV myocardial fat quantification from CT is feasible and may have considerable diagnostic and prognostic value.

Defective recovery of QT dispersion due to no-reflow following acute interventional therapy in patients with ST-segment elevation myocardial infarction.

Background: Previous studies have suggested that adequate myocardial reperfusion after percutaneous coronary intervention (PCI) can improve the inhomogeneity of myocardial repolarization. However, it remains unclear whether no-reflow (NR) following emergency PCI involves disadvantages related to ventricular repolarization indices. The present study aimed to determine the effect of NR on QT dispersion (QTd) in patients with ST-segment elevation myocardial infarction (STEMI) and to evaluate the prognostic value of the relative reduction of QTd on ventricular arrhythmia events (VAEs). Methods: A prospective case-control study was conducted. According to the inclusion criteria, 275 patients with STEMI who underwent primary PCI treatment at the First People's Hospital of Anqing affiliated to Anhui Medical University from January 2020 to May 2023 were enrolled. According to whether NR occurred during PCI, these patients were divided into two groups: an NR group and a non-NR group. Subsequently, the QT intervals were measured before and at 12 hours after PCI. Afterward, the QTd, corrected QTd (QTcd), and the relative reduction of QTd and QTcd 12 hours pre- and postprocedure (ΔQTd-R and ΔQTcd-R, respectively) were calculated. Finally, multivariable logistic regression analysis was performed to predict the risk of VAE occurrence. Results: In the non-NR group, there was a significant decrease from baseline in postprocedure QTd (48±17 vs. 73±22 ms; P=0.009) and QTcd (54±19 vs. 80±23 ms; P=0.01); in contrast, the NR group showed no significant difference in QTd (64±20 vs. 75±23 ms; P=0.58) or QTd (70±22 vs. 82±26 ms; P=0.45). Furthermore, the ΔQTd-R and ΔQTcd-R were both lower in the NR group than in the non-NR group (P<0.05); however, the rate of VAEs was higher in the NR group than in the non-NR group (15.2% vs. 6.2%; P=0.02). The multivariable logistic regression analysis results revealed that each increase of 12% in ΔQTcd-R was an independent predictor of VAEs (odds ratio: 0.547; 95% confidence interval: 0.228-0.976). Conclusions: The NR phenomenon following primary PCI in patients with STEMI leads to the defective recovery of QTd and QTcd. Furthermore, ΔQTcd-R can be viewed as an effective indicator for evaluating the myocardial repolarization inhomogeneity, and short-term clinical outcomes.

When annuloplasty is not enough: a case report of ventricular arrhythmias stepwise abolition after mitral valve re-repair.

Background: Some patients affected by mitral valve (MV) prolapse (MVP) are at higher risk of ventricular arrhythmias (VAs), but the underlying pathogenesis, as well as the effects of surgery on VA, remain not fully understood. Mitral valve repair, however, represents a privileged point of view to deepen the understanding of arrhythmogenesis in this context. Hence, we report an interesting case of MV re-repair. Case summary: A 52-year-old man was referred to our institution for severe mitral regurgitation (MR) due to P2 prolapse in the context of myxomatous MV degeneration. Pre-operative imaging showed systolic mitral annular disjunction, left ventricular (LV) wall curling, Pickelhaube's sign, and a prolapsing tricuspid valve (TV) with only mild regurgitation. Twenty-four-hour electrocardiogram (ECG) Holter revealed a significant burden of premature ventricular contractions (PVCs), most of them originating from anterior papillary muscle (APM), posterior papillary muscle (PPM), and mitral annulus (MA). Quadrangular resection of P2 and mitral annuloplasty were performed. One year later, relapse of severe MR due to a residual P2M1 prolapse occurred. Twenty-four-hour ECG Holter showed no PVCs from PPM and MA, while those from APM persisted. A central edge-to-edge repair was effectively used to fix the residual prolapse. After 1 year from REDO surgery, a third ECG Holter confirmed the absence of any remaining LV PVCs, but still few ectopic beats originating from TV were recorded. Discussion: Here, we report a case of VA resolution after specific, anatomical triggers addressing surgical gestures. Our experience confirms that MV surgery may have a role in MVP patients' arrhythmias correction.

Can Hyperthermia Unveil Brugada Pattern?

Brugada syndrome (BrS) is characterized by ST segment elevations in the right precordial leads, V1 - V3, with additional findings of ventricular arrhythmias and family history (FH) of sudden cardiac death (SCD) at a young age. Here, we describe a case of hyperthermia, unveiling the Brugada electrocardiography (EKG) pattern and the resolution of EKG findings with appropriate hyperthermia management. It is important to distinguish the Brugada EKG pattern from other causes of ST elevations and treat appropriately to prevent patients from developing ventricular fibrillation and SCD. It is key to identify environmental triggers in patients presenting with Brugada EKG pattern and closely monitor for ventricular fibrillation. Educating patients on prompt fever treatment with antipyretics and avoiding medications like sodium channel blockers during the febrile event is paramount to counter patients going into ventricular fibrillation. It is also crucial for close follow-up of these patients, offering them genetic testing for BrS and screening families of patients with BrS.

Unlocking the enigma: decoding premature ventricular complexes for effective clinical assessment and risk management.

The identification of ventricular premature complexes during a cardiological evaluation necessitates the implementation of diagnostic processes aimed at discerning the clinical context that may predispose individuals to a high risk of sudden cardiac death. Epidemiological studies reveal that ventricular premature beats occur in approximately 75% of healthy (or seemingly healthy) individuals, as long as there is no evidence of underlying structural heart disease, such as benign idiopathic ventricular extrasystole originating from the right and left ventricular outflow tracts. In the real world, however, ventricular ectopic beats with morphologies very similar to seemingly benign occurrences are not uncommon. They are notable in subjects exhibiting rapid and complex repetitive forms during exercise testing and Holter electrocardiogram. Additionally, these subjects may display more or less extensive scarring signs on cardiac magnetic resonance and may have a family history of cardiomyopathy and/or sudden cardiac death. Therefore, the purpose of this review is to critically analyse the process of evaluating premature ventricular complexes, which is crucial for accurate risk stratification. The latter cannot overlook some inevitable elements, including morphology, origin, complexity, and the associated clinical setting (absence or presence of structural heart disease).

Comparative Efficacy and Safety of Pulsed Field Ablation Versus Radiofrequency Ablation of Idiopathic LV Arrhythmias.

BACKGROUND: Comparative efficacy and safety data on radiofrequency ablation (RFA) versus pulsed field ablation (PFA) for common idiopathic left ventricular arrhythmia (LV-VAs) locations are lacking. OBJECTIVES: This study sough to compare RFA with PFA of common idiopathic LV-VAs locations. METHODS: Ten swine were randomized to PFA or RFA of LV interventricular septum, papillary muscle, LV summit via distal coronary sinus, and LV epicardium via subxiphoid approach. Ablations were delivered using an investigational dual-energy (RFA/PFA) contact force (CF) and local impedance-sensing catheter. After 1-week survival, animals were euthanized for lesion assessment. RESULTS: A total of 55 PFA (4 applications/site of 2.0 KV, target CF ≥10 g) and 36 RFA (CF ≥10 g, 25-50 W targeting ≥50 Ω local impedance drop, 60-second duration) were performed. LV interventricular septum: average PFA depth 7.8 mm vs RFA 7.9 mm (P = 0.78) and no adverse events. Papillary muscle: average PFA depth 8.1 mm vs RFA 4.5 mm (P < 0.01). Left ventricular summit: average PFA depth 5.6 mm vs RFA 2.7 mm (P < 0.01). Steam-pop and/or ventricular fibrillation in 4 of 12 RFA vs 0 of 12 PFA (P < 0.01), no ST-segment changes observed. Epicardium: average PFA depth 6.4 mm vs RFA 3.3 mm (P < 0.01). Transient ST-segment elevations/depressions occurred in 4 of 5 swine in the PFA arm vs 0 of 5 in the RFA arm (P < 0.01). Angiography acutely and at 7 days showed normal coronaries in all cases. CONCLUSIONS: In this swine study, compared with RFA, PFA of common idiopathic LV-VAs locations produced deeper lesions with fewer steam pops. However, PFA was associated with higher rates of transient ST-segment elevations and depressions with direct epicardium ablation.

Mode and Characteristics of Arrhythmia Initiation in Idiopathic Ventricular Fibrillation: A THESIS Substudy.

BACKGROUND: There is limited information on the mode of arrhythmia initiation in idiopathic ventricular fibrillation (IVF). A non-pause-dependent mechanism has been suggested to be the rule. OBJECTIVES: The aim of this study was to assess the mode and characteristics of initiation of polymorphic ventricular tachycardia (PVT) in patients with short or long-coupled PVT/IVF included in THESIS (THerapy Efficacy in Short or long-coupled idiopathic ventricular fibrillation: an International Survey), a multicenter study involving 287 IVF patients treated with drugs or radiofrequency ablation. METHODS: We reviewed the initiation of 410 episodes of ≥1 PVT triplet in 180 patients (58.3% females; age 39.6 ± 13.6 years) with IVF. The incidence of pause-dependency arrhythmia initiation (prolongation by >20 ms of the preceding cycle length) was assessed. RESULTS: Most arrhythmias (n = 295; 72%) occurred during baseline supraventricular rhythm without ambient premature ventricular complexes (PVCs), whereas 106 (25.9%) occurred during baseline rhythm including PVCs. Nine (2.2%) arrhythmias occurred during atrial/ventricular pacing and were excluded from further analysis. Mode of PVT initiation was pause-dependent in 45 (15.6%) and 64 (60.4%) of instances in the first and second settings, respectively, for a total of 109 of 401 (27.2%). More than one type of pause-dependent and/or non-pause-dependent initiation (mean: 2.6) occurred in 94.4% of patients with ≥4 events. Coupling intervals of initiating PVCs were <350 ms, 350-500 ms, and >500 ms in 76.6%, 20.72%, and 2.7% of arrhythmia initiations, respectively. CONCLUSIONS: Pause-dependent initiation occurred in more than a quarter of arrhythmic episodes in IVF patients. PVCs having long (between 350 and 500 ms) and very long (>500 ms) coupling intervals were observed at the initiation of nearly a quarter of PVT episodes.

Roles of ß-adrenoceptor Subtypes and Therapeutics in Human Cardiovascular Disease: Heart Failure, Tachyarrhythmias and Other Cardiovascular Disorders.

ß-Adrenoceptors (ß-ARs) provide an important therapeutic target for the treatment of cardiovascular disease. Three ß-ARs, ß1-AR, ß2-AR, ß3-AR are localized to the human heart. Activation of ß1-AR and ß2-ARs increases heart rate, force of contraction (inotropy) and consequently cardiac output to meet physiological demand. However, in disease, chronic over-activation of ß1-AR is responsible for the progression of disease (e.g. heart failure) mediated by pathological hypertrophy, adverse remodelling and premature cell death. Furthermore, activation of ß1-AR is critical in the pathogenesis of cardiac arrhythmias while activation of ß2-AR directly influences blood pressure haemostasis. There is an increasing awareness of the contribution of ß2-AR in cardiovascular disease, particularly arrhythmia generation. All ß-blockers used therapeutically to treat cardiovascular disease block ß1-AR with variable blockade of ß2-AR depending on relative affinity for ß1-AR vs ß2-AR. Since the introduction of ß-blockers into clinical practice in 1965, ß-blockers with different properties have been trialled, used and evaluated, leading to better understanding of their therapeutic effects and tolerability in various cardiovascular conditions. ß-Blockers with the property of intrinsic sympathomimetic activity (ISA), i.e. ß-blockers that also activate the receptor, were used in the past for post-treatment of myocardial infarction and had limited use in heart failure. The ß-blocker carvedilol continues to intrigue due to numerous properties that differentiate it from other ß-blockers and is used successfully in the treatment of heart failure. The discovery of ß3-AR in human heart created interest in the role of ß3-AR in heart failure but has not resulted in therapeutics at this stage.

Role of cardiac magnetic resonance in stratifying arrhythmogenic risk in mitral valve prolapse patients: a systematic review and meta-analysis.

OBJECTIVES: To perform a systematic review and meta-analysis of studies investigating the diagnostic value of cardiac magnetic resonance (CMR) features for arrhythmic risk stratification in mitral valve prolapse (MVP) patients. MATERIALS AND METHODS: EMBASE, PubMed/MEDLINE, and CENTRAL were searched for studies reporting MVP patients who underwent CMR with assessment of: left ventricular (LV) size and function, mitral regurgitation (MR), prolapse distance, mitral annular disjunction (MAD), curling, late gadolinium enhancement (LGE), and T1 mapping, and reported the association with arrhythmia. The primary endpoint was complex ventricular arrhythmias (co-VAs) as defined by any non-sustained ventricular tachycardia, sustained ventricular tachycardia, ventricular fibrillation, or aborted sudden cardiac death. Meta-analysis was performed when at least three studies investigated a CMR feature. PROSPERO registration number: CRD42023374185. RESULTS: The meta-analysis included 11 studies with 1278 patients. MR severity, leaflet length/thickness, curling, MAD distance, and mapping techniques were not meta-analyzed as reported in < 3 studies. LV end-diastolic volume index, LV ejection fraction, and prolapse distance showed small non-significant effect sizes. LGE showed a strong and significant association with co-VA with a LogORs of 2.12 (95% confidence interval (CI): [1.00, 3.23]), for MAD the log odds-ratio was 0.95 (95% CI: [0.30, 1.60]). The predictive accuracy of LGE was substantial, with a hierarchical summary ROC AUC of 0.83 (95% CI: [0.69, 0.91]) and sensitivity and specificity rates of 0.70 (95% CI: [0.41, 0.89]) and 0.80 (95% CI: [0.67, 0.89]), respectively. CONCLUSIONS: Our study highlights the role of LGE as the key CMR feature for arrhythmia risk stratification in MVP patients. MAD might complement arrhythmic risk stratification. CLINICAL RELEVANCE STATEMENT: LGE is a key factor for arrhythmogenic risk in MVP patients, with additional contribution from MAD. Combining MRI findings with clinical characteristics is critical for evaluating and accurately stratifying arrhythmogenic risk in MVP patients. KEY POINTS: MVP affects 2-3% of the population, with some facing increased risk for arrhythmia. LGE can assess arrhythmia risk, and MAD may further stratify patients. CMR is critical for MVP arrhythmia risk stratification, making it essential in a comprehensive evaluation.

Associations Between Biomarkers of Myocardial Injury and Systemic Inflammation and Risk of Incident Ventricular Arrhythmia.

BACKGROUND: Cardiac troponins (cTns) and biomarkers of inflammation are elevated in heart failure (HF) and predict cardiovascular risk. Whether these biomarkers associate with risk of ventricular arrhythmias (VAs) is unclear. OBJECTIVES: This study sought to assess whether cTnT, growth differentiation factor 15 (GDF-15), interleukin-6 (IL-6), and C-reactive protein (CRP) concentrations are associated with incident VA. METHODS: In a prospective, observational study of patients treated with implantable cardioverter-defibrillator, cTnT, GDF-15, IL-6, and CRP were measured at baseline and after 1.4 ± 0.5 years and were associated with implantable cardioverter-defibrillator-detected incident VA, HF hospitalizations, and mortality. RESULTS: This study included 489 patients aged 66 ± 12 years and 83% were men. Median concentrations of cTnT were 15 (Q1-Q3: 9-25) ng/L at inclusion, and higher concentrations were associated with higher age, male sex, diabetes mellitus, coronary artery disease, and HF. During 3.1 ± 0.7 years of follow-up, 137 patients (28%) had ≥1 VA. cTnT concentrations were associated with an increased VA risk (per log-unit, HR: 1.63; 95% CI: 1.31-2.01; P < 0.001), also after adjustment for age, sex, body mass index, coronary artery disease, HF, renal function, and left ventricular ejection fraction (P < 0.001). GDF-15, IL-6, and CRP concentrations were not associated with incident VA, but all (including cTnT) were associated with HF hospitalization and mortality. Changes in cTnT, GDF-15, IL-6, and CRP from baseline to 1.4 years were not associated with subsequent VA. CONCLUSIONS: Higher concentrations of cTnT, GDF-15, IL-6, and CRP associate with HF hospitalization and death, but only cTnT predict incident VA. These findings suggest that myocardial injury rather than inflammation may play a pathophysiological role in VA and sudden cardiac death.

Prevalence and electrocardiographic and electrophysiological characteristics of idiopathic ventricular arrhythmias originating from the septal left ventricular summit.

INTRODUCTION: The left ventricular summit (LVS) is the highest point on the epicardial surface of the left ventricle. A part of the LVS that is located between the left coronary arteries (lateral-LVS) is one of the major sites of idiopathic ventricular arrhythmia (VA) origins. Some idiopathic epicardial VAs can be ablated at endocardial sites adjacent to the epicardial area septal to the lateral-LVS (septal-LVS). This study examined the prevalence and electrocardiographic and electrophysiological characteristics of septal-LVS VAs. METHODS: We studied consecutive patients with idiopathic VAs originating from the LVS (67 patients) and aortic root (93 patients). RESULTS: Based on the ablation results, among 67 LVS VAs, 54 were classified as lateral and 13 as septal-LVS VAs. As compared with the lateral-LVS VAs, the septal-LVS VAs were characterized by a greater prevalence of left bundle branch block with left inferior-axis QRS pattern, later precordial transition, lower R-wave amplitude ratio in leads III to II, lower Q-wave amplitude ratio in leads aVL to aVR, and later local ventricular activation time relative to the QRS onset during VAs (V-QRS) in the great cardiac vein. The electrocardiographic and electrophysiological characteristics of the septal-LVS VAs were similar to those of the aortic root VAs. However, the V-QRS at the successful ablation site was significantly later during the septal-LVS VAs than aortic root VAs (p < .0001). The precordial transition was significantly later during the septal-LVS VAs than aortic root VAs (p < .05). CONCLUSIONS: Septal-LVS VAs are considered a distinct subgroup of idiopathic VAs originating from the left ventricular outflow tract.

Molecular Pathways and Animal Models of Arrhythmias.

Arrhythmias account for over 300,000 annual deaths in the United States, and approximately half of all deaths are associated with heart disease. Mechanisms underlying arrhythmia risk are complex; however, work in humans and animal models over the past 25 years has identified a host of molecular pathways linked with both arrhythmia substrates and triggers. This chapter will focus on select arrhythmia pathways solved by linking human clinical and genetic data with animal models.

NaV1.8 as Proarrhythmic Target in a Ventricular Cardiac Stem Cell Model.

The sodium channel NaV1.8, encoded by the SCN10A gene, has recently emerged as a potential regulator of cardiac electrophysiology. We have previously shown that NaV1.8 contributes to arrhythmogenesis by inducing a persistent Na+ current (late Na+ current, INaL) in human atrial and ventricular cardiomyocytes (CM). We now aim to further investigate the contribution of NaV1.8 to human ventricular arrhythmogenesis at the CM-specific level using pharmacological inhibition as well as a genetic knockout (KO) of SCN10A in induced pluripotent stem cell CM (iPSC-CM). In functional voltage-clamp experiments, we demonstrate that INaL was significantly reduced in ventricular SCN10A-KO iPSC-CM and in control CM after a specific pharmacological inhibition of NaV1.8. In contrast, we did not find any effects on ventricular APD90. The frequency of spontaneous sarcoplasmic reticulum Ca2+ sparks and waves were reduced in SCN10A-KO iPSC-CM and control cells following the pharmacological inhibition of NaV1.8. We further analyzed potential triggers of arrhythmias and found reduced delayed afterdepolarizations (DAD) in SCN10A-KO iPSC-CM and after the specific inhibition of NaV1.8 in control cells. In conclusion, we show that NaV1.8-induced INaL primarily impacts arrhythmogenesis at a subcellular level, with minimal effects on systolic cellular Ca2+ release. The inhibition or knockout of NaV1.8 diminishes proarrhythmic triggers in ventricular CM. In conjunction with our previously published results, this work confirms NaV1.8 as a proarrhythmic target that may be useful in an anti-arrhythmic therapeutic strategy.

Empagliflozin's role in reducing ventricular repolarization heterogeneity: insights into cardiovascular mortality decline from the EMPATHY-HEART trial.

BACKGROUND: The incidence of myocardial infarction (MI) and sudden cardiac death (SCD) is significantly higher in individuals with Type 2 Diabetes Mellitus (T2DM) than in the general population. Strategies for the prevention of fatal arrhythmias are often insufficient, highlighting the need for additional non-invasive diagnostic tools. The T-wave heterogeneity (TWH) index measures variations in ventricular repolarization and has emerged as a promising predictor for severe ventricular arrhythmias. Although the EMPA-REG trial reported reduced cardiovascular mortality with empagliflozin, the underlying mechanisms remain unclear. This study investigates the potential of empagliflozin in mitigating cardiac electrical instability in patients with T2DM and coronary heart disease (CHD) by examining changes in TWH. METHODS: Participants were adult outpatients with T2DM and CHD who exhibited TWH > 80 µV at baseline. They received a 25 mg daily dose of empagliflozin and were evaluated clinically including electrocardiogram (ECG) measurements at baseline and after 4 weeks. TWH was computed from leads V4, V5, and V6 using a validated technique. The primary study outcome was a significant (p < 0.05) change in TWH following empagliflozin administration. RESULTS: An initial review of 6,000 medical records pinpointed 800 patients for TWH evaluation. Of these, 412 exhibited TWH above 80 µV, with 97 completing clinical assessments and 90 meeting the criteria for high cardiovascular risk enrollment. Empagliflozin adherence exceeded 80%, resulting in notable reductions in blood pressure without affecting heart rate. Side effects were generally mild, with 13.3% experiencing Level 1 hypoglycemia, alongside infrequent urinary and genital infections. The treatment consistently reduced mean TWH from 116 to 103 µV (p = 0.01). CONCLUSIONS: The EMPATHY-HEART trial preliminarily suggests that empagliflozin decreases heterogeneity in ventricular repolarization among patients with T2DM and CHD. This reduction in TWH may provide insight into the mechanism behind the decreased cardiovascular mortality observed in previous trials, potentially offering a therapeutic pathway to mitigate the risk of severe arrhythmias in this population. TRIAL REGISTRATION: NCT: 04117763.