Arrhythmic risk profile in mitral valve prolapse: A systematic review and metanalysis of 1715 patients.

INTRODUCTION: Mitral valve prolapse (MVP) is a common clinical condition in the general population. A subgroup of patients with MVP may experience ventricular arrhythmias and sudden cardiac death ("arrhythmic mitral valve prolapse" [AMVP]) but how to stratify arrhythmic risk is still unclear. Our meta-analysis aims to identify predictive factors for arrhythmic risk in patients with MVP. METHODS: We systematically searched Medline, Cochrane, Journals@Ovid, Scopus electronic databases for studies published up to December 28, 2022 and comparing AMVP and nonarrhythmic mitral valve prolapse (NAMVP) for what concerns history, electrocardiographic, echocardiographic and cardiac magnetic resonance features. The effect size was estimated using a random-effect model as odds ratio (OR) and mean difference (MD). RESULTS: A total of 10 studies enrolling 1715 patients were included. Late gadolinium enhancement (LGE) (OR: 16.67; p = .005), T-wave inversion (TWI) (OR: 2.63; p < .0001), bileaflet MVP (OR: 1.92; p < .0001) and mitral anulus disjunction (MAD) (OR: 2.60; p < .0001) were more represented among patients with AMVP than in NAMVP. Patients with AMVP were shown to have longer anterior mitral leaflet (AML) (MD: 2.63 mm; p < .0001), posterior mitral leaflet (MD: 2.96 mm; p < .0001), thicker AML (MD: 0.49 mm; p < .0001), longer MAD length (MD: 1.24 mm; p < .0001) and higher amount of LGE (MD: 1.41%; p < .0001) than NAMVP. AMVP showed increased mechanical dispersion (MD: 8.04 ms; 95% confidence interval: 5.13-10.96; p < .0001) compared with NAMVP. CONCLUSIONS: Our meta-analysis proved that LGE, TWI, bileaflet MVP, and MAD are predictive factors for arrhythmic risk in MVP patients.

Arrhythmogenic Cardiomyopathy: Definition, Classification and Arrhythmic Risk Stratification.

Arrhythmogenic cardiomyopathy (ACM) is a heart disease characterized by a fibrotic replacement of myocardial tissue and a consequent predisposition to ventricular arrhythmic events, especially in the young. Post-mortem studies and the subsequent diffusion of cardiac MRI have shown that left ventricular involvement in arrhythmogenic cardiomyopathy is common and often develops early. Regarding the arrhythmic risk stratification, the current scores underestimate the arrhythmic risk of patients with arrhythmogenic cardiomyopathy with left involvement. Indeed, the data on arrhythmic risk stratification in this group of patients are contradictory and not exhaustive, with the consequence of not correctly identifying patients at a high arrhythmic risk who deserve protection from arrhythmic death. We propose a literature review on arrhythmic risk stratification in patients with ACM and left involvement to identify the main features associated with an increased arrhythmic risk in this group of patients.

Elevated Interleukin-6 Levels Are Associated With an Increased Risk of QTc Interval Prolongation in a Large Cohort of US Veterans.

BACKGROUND: Although accumulating data indicate that IL-6 (interleukin-6) can promote heart rate-corrected QT interval (QTc) prolongation via direct and indirect effects on cardiac electrophysiology, current evidence comes from basic investigations and small clinical studies only. Therefore, IL-6 is still largely ignored in the clinical management of long-QT syndrome and related arrhythmias. The aim of this study was to estimate the risk of QTc prolongation associated with elevated IL-6 levels in a large population of unselected subjects. METHODS AND RESULTS: An observational study using the Veterans Affairs Informatics and Computing Infrastructure was performed. Participants were US veterans who had an ECG and were tested for IL-6. Descriptive statistics and univariate and multivariate regression analyses were performed to study the relationship between IL-6 and QTc prolongation risk. Study population comprised 1085 individuals, 306 showing normal (<5 pg/mL), 376 moderately high (5-25 pg/mL), and 403 high (>25 pg/mL) IL-6 levels. Subjects with elevated IL-6 showed a concentration-dependent increase in the prevalence of QTc prolongation, and those presenting with QTc prolongation exhibited higher circulating IL-6 levels. Stepwise multivariate regression analyses demonstrated that increased IL-6 level was significantly associated with a risk of QTc prolongation up to 2 times the odds of the reference category of QTc (e.g. QTc >470 ms men/480 ms women ms: odds ratio, 2.28 [95% CI, 1.12-4.50] for IL-6 >25 pg/mL) regardless of the underlying cause. Specifically, the mean QTc increase observed in the presence of elevated IL-6 was quantitatively comparable (IL-6 >25 pg/mL:+6.7 ms) to that of major recognized QT-prolonging risk factors, such as hypokalemia and history of myocardial infarction. CONCLUSIONS: Our data provide evidence that a high circulating IL-6 level is a robust risk factor for QTc prolongation in a large cohort of US veterans, supporting a potentially important arrhythmogenic role for this cytokine in the general population.

Mechanisms of ischaemia-induced arrhythmias in hypertrophic cardiomyopathy: a large-scale computational study.

AIMS: Lethal arrhythmias in hypertrophic cardiomyopathy (HCM) are widely attributed to myocardial ischaemia and fibrosis. How these factors modulate arrhythmic risk remains largely unknown, especially as invasive mapping protocols are not routinely used in these patients. By leveraging multiscale digital twin technologies, we aim to investigate ischaemic mechanisms of increased arrhythmic risk in HCM. METHODS AND RESULTS: Computational models of human HCM cardiomyocytes, tissue, and ventricles were used to simulate outcomes of Phase 1A acute myocardial ischaemia. Cellular response predictions were validated with patch-clamp studies of human HCM cardiomyocytes (n = 12 cells, N = 5 patients). Ventricular simulations were informed by typical distributions of subendocardial/transmural ischaemia as analysed in perfusion scans (N = 28 patients). S1-S2 pacing protocols were used to quantify arrhythmic risk for scenarios in which regions of septal obstructive hypertrophy were affected by (i) ischaemia, (ii) ischaemia and impaired repolarization, and (iii) ischaemia, impaired repolarization, and diffuse fibrosis. HCM cardiomyocytes exhibited enhanced action potential and abnormal effective refractory period shortening to ischaemic insults. Analysis of ∼75 000 re-entry induction cases revealed that the abnormal HCM cellular response enabled establishment of arrhythmia at milder ischaemia than otherwise possible in healthy myocardium, due to larger refractoriness gradients that promoted conduction block. Arrhythmias were more easily sustained in transmural than subendocardial ischaemia. Mechanisms of ischaemia-fibrosis interaction were strongly electrophysiology dependent. Fibrosis enabled asymmetric re-entry patterns and break-up into sustained ventricular tachycardia. CONCLUSION: HCM ventricles exhibited an increased risk to non-sustained and sustained re-entry, largely dominated by an impaired cellular response and deleterious interactions with the diffuse fibrotic substrate.

Effects of ranolazine on the arrhythmic substrate in hypertrophic cardiomyopathy.

Introduction: Hypertrophic cardiomyopathy (HCM) is a leading cause of lethal arrhythmias in the young. Although the arrhythmic substrate has been hypothesised to be amenable to late Na+ block with ranolazine, the specific mechanisms are not fully understood. Therefore, this study aimed to investigate the substrate mechanisms of safety and antiarrhythmic efficacy of ranolazine in HCM. Methods: Computational models of human tissue and ventricles were used to simulate the electrophysiological behaviour of diseased HCM myocardium for variable degrees of repolarisation impairment, validated against in vitro and clinical recordings. S1-S2 pacing protocols were used to quantify arrhythmic risk in scenarios of (i) untreated HCM-remodelled myocardium and (ii) myocardium treated with 3µM, 6µM and 10µM ranolazine, for variable repolarisation heterogeneity sizes and pacing rates. ECGs were derived from biventricular simulations to identify ECG biomarkers linked to antiarrhythmic effects. Results: 10µM ranolazine given to models manifesting ventricular tachycardia (VT) at baseline led to a 40% reduction in number of VT episodes on pooled analysis of >40,000 re-entry inducibility simulations. Antiarrhythmic efficacy and safety were dependent on the degree of repolarisation impairment, with optimal benefit in models with maximum JTc interval <370 ms. Ranolazine increased risk of VT only in models with severe-extreme repolarisation impairment. Conclusion: Ranolazine efficacy and safety may be critically dependent upon the degree of repolarisation impairment in HCM. For moderate repolarisation impairment, reductions in refractoriness heterogeneity by ranolazine may prevent conduction blocks and re-entry. With severe-extreme disease substrates, reductions of the refractory period can increase re-entry sustainability.

Clinical characterization of type 1 long QT syndrome caused by C-terminus Kv7.1 variants.

BACKGROUND: Variants in the KCNQ1 gene, encoding the α-subunit of the slow component of delayed rectifier K+ channel Kv7.1, cause long QT syndrome (LQTS) type 1. The location of variants may be one of the factors in determining prognosis. However, detailed genotype-phenotype relationships associated with C-terminus variants remain unelucidated. OBJECTIVE: We investigated the clinical characteristics and variant-specific arrhythmic risks in patients with LQTS carrying Kv7.1 C-terminus variants. METHODS: The study comprises 202 consecutive patients with LQTS (98 probands and 104 family members) who carry a rare heterozygous variant in the Kv7.1 C-terminus. Their clinical characteristics and arrhythmic events were investigated. RESULTS: We identified 36 unique C-terminus variants (25 missense and 11 non-missense). The p.R366W variant was identified in 8 families, and p.T587M was identified in 21 families in large numbers from northwestern Japan. As for the location of the variant, we found that the variants in highly conserved regions and nonhelical domains were associated with longer QTc intervals compared with the variants in other regions. Both p.R366W and p.T587M variants are located in the highly conserved and functionally pivotal regions close to helices A and D, which are associated with calmodulin binding and channel assembly (tetramerization), respectively. The probands carrying p.T587M and p.R366W variants had worse arrhythmia outcomes compared with those with other C-terminus variants. The haplotype analysis of p.T587M families was suggestive of a founder effect. CONCLUSION: The arrhythmic risk of C-terminus variants in Kv7.1 in LQTS is not homogeneous, and locations of variants can be a determining factor for prognosis.

Missense and Non-Missense Lamin A/C Gene Mutations Are Similarly Associated with Major Arrhythmic Cardiac Events: A 20-Year Single-Centre Experience.

Arrhythmic risk stratification in patients with Lamin A/C gene (LMNA)-related cardiomyopathy influences clinical decisions. An implantable cardioverter defibrillator (ICD) should be considered in patients with an estimated 5-year risk of malignant ventricular arrhythmia (MVA) of ≥10%. The risk prediction score for MVA includes non-missense LMNA mutations, despite their role as an established risk factor for sudden cardiac death (SCD) has been questioned in several studies. The purpose of this study is to investigate cardiac features and find gene-phenotype correlations that would contribute to the evidence on the prognostic implications of non-missense vs. missense mutations in a cohort of LMNA mutant patients. An observational, prospective study was conducted in which 54 patients positive for a Lamin A/C mutation were enrolled, and 20 probands (37%) were included. The median age at first clinical manifestation was 41 (IQR 19) years. The median follow-up was 8 years (IQR 8). The type of LMNA gene mutation was distributed as follows: missense in 26 patients (48%), non-frameshift insertions in 16 (30%), frameshift deletions in 5 (9%), and nonsense in 7 (13%). Among the missense mutation carriers, two (8%) died and four (15%) were admitted onto the heart transplant list or underwent transplantation, with a major adverse cardiovascular event (MACE) rate of 35%. No statistically significant differences in MACE prevalence were identified according to the missense and non-missense mutation groups (p value = 0.847). Our data shift the spotlight on this considerable topic and could suggest that some missense mutations may deserve attention regarding SCD risk stratification in real-world clinical settings.

Autonomic Dysfunction and Cardiovascular Risk in Patients with Rheumatoid Arthritis: Can Heart Rate Variability Analysis Contribute to a Better Evaluation of the Cardiovascular Profile of a Patient?

(1) Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease of autoimmune etiology. Increased scientific evidence suggests that immune-mediated inflammatory dis-eases are associated with autonomic nervous system (ANS) dysfunction. Studies proved that autonomic imbalance is correlated with RA evolution and may explain augmented cardiovascular pathology and mortality not attributable to classical risk factors. (2) Methods: 75 patients (25 males, 50 females) with RA were submitted to standard ECG recording and 24 h Holter monitoring. Twenty-five healthy patients were used as controls. Both time (SDNN, SDANN, SDANN Index, RRmed, rMSSD, and pNN50) and frequency domain (TP, VLF, HF, LF and LF/HF) heart rate variability (HRV) parameters were obtained. Parameters were compared to controls, and correlations with the QTc-interval and inflammatory status expressed through the C-reactive protein (CRP) were evaluated. (3) Results: In patients with a CRP > 5 mg/L, HRV parameters were lower compared to controls and to patients with a CRP ≤ 5 mg/L. All HRV parameters generated by Holter monitoring are negatively correlated with CRP levels and QTc values. The number of premature ventricular contractions (PVC) recorded is correlated with SDNN, SDANN, and LF/HF values. (4) Conclusions: Our study supports recent data suggesting that in RA there is an autonomic system dysfunction strongly connected with the inflammatory status of the patient. The autonomic dysfunction can contribute to the increased risk of cardiovascular death observed in patients with RA.

Interatrial block as a first clinical presentation of atrial cardiomyopathy related to a novel LMNA variant: a case report.

Background: Interatrial block (IAB) is a conduction delay in Bachmann's bundle with a well-described association with structural heart disease, supraventricular arrhythmias, and cardiovascular events. Case summary: We report the case of an asymptomatic 35-year-old man in whom the presence of IAB at electrocardiogram led to a comprehensive evaluation including speckle-tracking echocardiography, 24 h Holter monitoring, and genetic testing. Speckle-tracking echocardiography demonstrated a decrease in the longitudinal strain of interventricular septum, a typical feature of LMNA-related cardiomyopathy, and decreased indices of left atrial deformation. A diagnosis of cardiac laminopathy related to the frame shift variant c.1367 (p.Asn456Thrfs*24) of the LMNA gene was made. A dual-chamber implantable cardioverter defibrillator implantation was performed for the high risk of life-threatening ventricular tachyarrhythmias. Discussion: This case demonstrates that IAB could be a rare presentation of a life-threatening laminopathy. Strain echocardiography is an essential tool to evaluate the deposition of fibrosis tissue in subclinical cardiomyopathies. Our report describes a novel variant of LMNA gene associated with a high risk of sudden cardiac death.