Life-threatening Ventricular Arrhythmias Research Articles

Targeting arrhythmogenic macrophages: lessons learned from arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac condition characterized by cardiac remodeling and life-threatening ventricular arrhythmias. In this issue of the JCI, Chelko, Penna, and colleagues mechanistically addressed the intricate contribution of immune-mediated injury in ACM pathogenesis. Inhibition of nuclear factor κ-B (NF-κB) and infiltration of monocyte-derived macrophages expressing C-C motif chemokine receptor-2 (CCR2) alleviated the phenotypic ACM features (i.e., fibrofatty replacement, contractile dysfunction, and ventricular arrhythmias) in desmoglein 2-mutant (Dsg2mut/mut) mice. These findings pave the way for efficacious and targetable immune therapy for patients with ACM.

Mitral valve prolapse: arrhythmic risk during pregnancy and postpartum.

Arrhythmic mitral valve prolapse (AMVP) is linked to life-threatening ventricular arrhythmias (VAs), and young women are considered at high risk. Cases of AMVP in women with malignant VA during pregnancy have emerged, but the arrhythmic risk during pregnancy is unknown. The authors aimed to describe features of women with high-risk AMVP who developed malignant VA during the perinatal period and to assess if pregnancy and the postpartum period were associated with a higher risk of malignant VA. This retrospective international multi-centre case series included high-risk women with AMVP who experienced malignant VA and at least one pregnancy. Malignant VA included ventricular fibrillation, sustained ventricular tachycardia, or appropriate shock from an implantable cardioverter defibrillator. The authors compared the incidence of malignant VA in non-pregnant periods and perinatal period; the latter defined as occurring during pregnancy and within 6 months after delivery. The authors included 18 women with AMVP from 11 centres. During 7.5 (interquartile range 5.8-16.6) years of follow-up, 37 malignant VAs occurred, of which 18 were pregnancy related occurring in 13 (72%) unique patients. Pregnancy and 6 months after delivery showed increased incidence rate of malignant VA compared to the non-pregnancy period (univariate incidence rate ratio 2.66, 95% confidence interval 1.23-5.76). The perinatal period could impose increased risk of malignant VA in women with high-risk AMVP. The data may provide general guidance for pre-conception counselling and for nuanced shared decision-making between patients and clinicians.

Mitral annular disjunction and mitral valve prolapse extrapolating adult data to an adolescent cohort?

The aim of this study is to provide an update on mitral valve prolapse (MVP) and mitral annular disjunction (MAD) and who may be at risk for ventricular arrhythmias and sudden cardiac death. MVP is generally considered a benign condition. However, a small subset of patients may be at risk for life-threatening ventricular arrhythmias. Among the risk factors identified in adults include patients with bileaflet mitral valves, myxomatous changes, myocardial fibrosis, and the presence of MAD. Advances in multimodal imaging have allowed for improved identification of fibrosis, anatomical valve derangements, and the amount of MAD. Recent guidelines have suggested that patients with MVP with or without MAD may be at risk for life-threatening arrhythmias if they have had prior ventricular arrhythmias, ventricular dysfunction, or unexplained syncope. Yet, extrapolation of adult data to a pediatric cohort with similar MVP and MAD at this juncture is challenging. There is, however, early evidence that some pediatric patients with significant myocardial fibrosis or abnormal tissue Doppler may be at risk for ventricular tachycardia. Mitral valve prolapse and mitral annular disjunction at times coexist and at other times can be seen as isolated entities. While the incidence of arrhythmic MVP is quite rare, there is increasing evidence that certain select adults with MVP may be at risk for ventricular tachycardia and sudden cardiac death. Future multicenter studies are needed to better understand the natural history of arrhythmic mitral valve disease and how early disease manifestation in children may impact findings now being reported in young adults.

Prevalence of Pathogenic Variants inCardiomyopathy-Associated Genes inAcute Myocarditis: A Systematic Review and Meta-Analysis.

Acute myocarditis is an inflammatory condition that may precede the development of dilated or arrhythmogenic cardiomyopathy. The aim of this study was to investigate the reported prevalence of pathogenic or likely pathogenic (P/LP) variants in cardiomyopathy-associated genes in patients with acute myocarditis. For this systematic review and meta-analysis, the PubMed and Embase databases were searched on March 4, 2023. Observational studies evaluating the prevalence of P/LP variants in cardiomyopathy-associated genes in patients with acute myocarditis were included. Studies were stratified into adult and pediatric age groups and for the following scenarios: 1) complicated myocarditis (ie, presenting with acute heart failure, reduced left ventricular ejection fraction, or life-threatening ventricular arrhythmias); and 2) uncomplicated myocarditis. The study was registered with the International Prospective Register of Systematic Reviews (CRD42023408668) and followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Of 732 studies identified, 8 met the inclusion criteria, providing data for 586 patients with acute myocarditis. A total of 89 P/LP variants in cardiomyopathy-associated genes were reported in 85 patients. For uncomplicated myocarditis, the pooled prevalence was 4.2% (95%CI: 1.8%-7.4%; I2=1.4%), whereas for complicated myocarditis, the pooled prevalence was 21.9% (95%CI: 14.3%-30.5%; I2=38.8%) and 44.5% (95%CI: 22.7%-67.4%; I2=52.8%) in adults and children, respectively. P/LP variants in desmosomal genes were predominant in uncomplicated myocarditis (64%), whereas sarcomeric gene variants were more prevalent in complicated myocarditis (58% in adults and 71% in children). Genetic variants are present in a large proportion of patients with acute myocarditis. The prevalence of genetic variants and the genes involved vary according to age and clinical presentation.

Clinical and cardiac MRI characteristics: prognosis in patients with alcoholic cardiomyopathy

Alcoholic cardiomyopathy (ACM) is recognized as a type of non-ischemic dilated cardiomyopathy (DCM). To date, the clinical prognosis of ACM remains a topic of debate in previous studies and there are limited studies on its cardiac MRI characteristics. The aim of this study was to summarize the clinical and MRI features of ACM patients and to identify the predictors of adverse prognosis based on clinical characteristics and MRI imaging findings. Adult patients who were clinically diagnosed with ACM and underwent enhanced CMR between September 2015 and August 2022 were retrospectively enrolled. The primary endpoints were major adverse cardiovascular events, including cardiac-related death, heart transplantation, hospitalization for heart failure and life-threatening ventricular arrhythmias (sustained ventricular tachycardia, ventricular fibrillation, or ICD shock). The risk factors associated with these primary end points were identified using multivariable Cox analysis. A total of 62 ACM patients (50±9 years, 62 men) were included. The majority of patients presented with symptoms of heart failure. Over a median follow-up period of 30.3 months (IQR 12.2-57.7 months), 24 patients reached the primary endpoints. For clinical variables, multivariable analysis showed that drinking duration (HR=1.05; 95%CI:1.01, 1.11; p=0.03) and persistent drinking (HR=3.71; 95%CI:1.46, 9.44; p=0.01) were associated with MACE. For CMR variables, late gadolinium enhancement (LGE) percent (HR = 1.09; 95% CI: 1.03, 1.14; p<0.001) stood out as an independent predictor for MACE. In ACM patients, persistent drinking and cardiac MRI-defined myocardial scar were associated with adverse outcomes such as cardiac death, heart transplantation, hospitalization for heart failure or life-threatening ventricular arrhythmias.

Novel Gain-of-Function Mutation in the Kv11.1 Channel Found in the Patient with Brugada Syndrome and Mild QTc Shortening.

Brugada syndrome (BrS) is an inherited disease characterized by right precordial ST-segment elevation in the right precordial leads on electrocardiograms (ECG), and high risk of life-threatening ventricular arrhythmia and sudden cardiac death (SCD). Mutations in the responsible genes have not been fully characterized in the BrS patients, except for the SCN5A gene. We identified a new genetic variant, c.1189C>T (p.R397C), in the KCNH2 gene in the asymptomatic male proband diagnosed with BrS and mild QTc shortening. We hypothesize that this variant could alter IKr-current and may be causative for the rare non-SCN5A-related form of BrS. To assess its pathogenicity, we performed patch-clamp analysis on IKr reconstituted with this KCNH2 mutation in the Chinese hamster ovary cells and compared the phenotype with the wild type. It appeared that the R397C mutation does not affect the IKr density, but facilitates activation, hampers inactivation of the hERG channels, and increases magnitude of the window current suggesting that the p.R397C is a gain-of-function mutation. In silico modeling demonstrated that this missense mutation potentially leads to the shortening of action potential in the heart.

Ventricular Arrhythmias and Hemodynamic Collapse During Acute Coronary Syndrome- Increased Risk for Sudden Cardiac Death?

In acute phase of acute coronary syndrome (ACS), ventricular tachycardia (VT) and/or ventricular fibrillation (VF) leading to resuscitation are not considered to be associated with increased long-term sudden cardiac death (SCD) because the cause - acute ischemia - is believed to be reversible.Aim of this study was to investigate whether ventricular arrhythmias leading to sudden cardiac arrest during ACS associate with the risk of incident SCD in patients with normal or mildly impaired left ventricular ejection fraction (LVEF). This study is based on a retrospective analysis of all 8,062 consecutive ACS patients undergoing coronary angiography with baseline LVEF ≥40% between 2007-2018 (follow-up until December 31st, 2021). The primary outcome was SCD equivalent life-threatening ventricular arrhythmias (LTVA) composing of true SCDs, aborted SCDs by successful resuscitation or appropriate ICD therapy. The risk of sudden LTVA was estimated with multivariate subdistribution hazard model using other deaths as competing events. Two-hundred and thirteen (n=211, 2.6%) patients suffered acute phase VF/VT leading to resuscitation and survived to discharge and most happened before angiography (80.6%, N=170) and were VF (92.9%, N=196). During a median follow-up of 7.6 years, 3.9% (N=316) of all the patients had LTVA (10.0% in VF/VT group vs 3.8% in other patients). VF/VTs during ACS associated with an increased risk for future SCD (HR 3.07; 95% CI 1.94-4.85, p<0.001). Most LTVAs occurred in patients without ICDs. VF/VT in ACS associates with remarkably high long-term risk for SCD in patients with LVEF ≥40%.

Ser194Leu DSG2 mutation, associated with arrhythmogenic left ventricular cardiomyopathy and ventricular tachycardia.

Arrhythmogenic cardiomyopathy (AC) is an inherited cardiomyopathy characterized by fibro-fatty replacement of cardiomyocytes, leading to life-threatening ventricular arrhythmia and heart failure. Pathogenic variants of desmoglein2 gene (DSG2) have been reported as genetic etiologies of AC. In contrast, many reported DSG2 variants are benign or variants of uncertain significance. Correct genetic variant classification is crucial for determining the best medical therapy for the patient and family members. Pathogenicity of the DSG2 Ser194Leu variant that was identified by whole exome sequencing in a patient, who presented with ventricular tachycardia and was diagnosed with AC, was investigated by electron microscopy and immunohistochemical staining of endomyocardial biopsy sample. Electron microscopy demonstrated a widened gap in the adhering junction and a less well-organized intercalated disk region in the mutated cardiomyocytes compared to the control. Immunohistochemical staining in the proband diagnosed with AC showed reduced expression of desmoglein 2 and connexin 43 and intercalated disc distortion. Reduced expression of DSG2 and Connexin 43 were observed in cellular cytoplasm and gap junctions. Additionally, we detected perinuclear accumulation of DSG2 and Connexin 43 in the proband sample. Ser194Leu is a missense pathogenic mutation of DSG2 gene associated with arrhythmogenic left ventricular cardiomyopathy.

Sex- and age-dependent susceptibility to ventricular arrhythmias in the rat heart ex vivo

The incidence of life-threatening ventricular arrhythmias, the most common cause of sudden cardiac death (SCD), depends largely on the arrhythmic substrate that develops in the myocardium during the aging process. There is a large deficit of comparative studies on the development of this substrate in both sexes, with a particular paucity of studies in females. To identify the substrates of arrhythmia, fibrosis, cardiomyocyte hypertrophy, mitochondrial density, oxidative stress, antioxidant defense and intracellular Ca2+ signaling in isolated cardiomyocytes were measured in the hearts of 3- and 24-month-old female and male rats. Arrhythmia susceptibility was assessed in ex vivo perfused hearts after exposure to isoproterenol (ISO) and hydrogen peroxide (H2O2). The number of ventricular premature beats (PVBs), ventricular tachycardia (VT) and ventricular fibrillation (VF) episodes, as well as intrinsic heart rate, QRS and QT duration, were measured in ECG signals recorded from the surfaces of the beating hearts. After ISO administration, VT/VFs were formed only in the hearts of males, mainly older ones. In contrast, H2O2 led to VT/VF formation in the hearts of rats of both sexes but much more frequently in older males. We identified several components of the arrhythmia substrate that develop in the myocardium during the aging process, including high spontaneous ryanodine receptor activity in cardiomyocytes, fibrosis of varying severity in different layers of the myocardium (nonheterogenic fibrosis), and high levels of oxidative stress as measured by nitrated tyrosine levels. All of these elements appeared at a much greater intensity in male individuals during the aging process. On the other hand, in aging females, antioxidant defense at the level of H2O2 detoxification, measured as glutathione peroxidase expression, was weaker than that in males of the same age. We showed that sex has a significant effect on the development of an arrhythmic substrate during aging. This substrate determines the incidence of life-threatening ventricular arrhythmias in the presence of additional stimuli with proarrhythmic potential, such as catecholamine stimulation or oxidative stress, which are constant elements in the pathomechanism of most cardiovascular diseases.

Prognostic value of morphological, biochemical, molecular markers of fibrosis in patients with hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) at the cellular level is characterized by hypertrophy, cardiomyocyte disorganization and myocardial fibrosis areas. The leading death cause in HCM remains sudden cardiac death (SCD). Despite the existing risk scores for SCD in HCM, there are still patients with uncertain SCD risk. In addition, SCD cases are also recorded among low-risk patients. From the above, search for novel markers for a more accurate risk assessment should be continued. Fibrosis is currently suspected to be a substrate of potentially life-threatening ventricular arrhythmias. Despite the increasingly widespread use of cardiac magnetic resonance imaging in the diagnosis of myocardial fibrosis and stratification of patients at high SCD risk, the determination of myocardial fibrosis biomarkers remains a relevant and promising area. The article presents the results of studies proving the diagnostic significance and relationship with the risk of life-threatening cardiac arrhythmias of the following markers: C-propeptide of type I procollagen, matrix metalloproteinase proteins, tissue inhibitor of metalloproteinases 1, microRNA family, soluble suppression of tumorigenicity 2, galectin-3, apelin. Evaluation of these biomarkers can be used to improve risk stratification of patients with HCM.

Management of life-threatening ventricular arrhythmias: What is going on with autonomic neuromodulation

Management of life-threatening ventricular arrhythmias: What is going on with autonomic neuromodulation

ECG-based risk stratification of sudden cardiac death and life-threatening ventricular arrhythmias

Risk stratification of sudden cardiac death and life-threatening ventricular arrhythmias remains an unsolved problem of modern cardiology. Technological progress in the field of electrocardiography and cardiac monitoring enables discovering and researching potential ECG risk predictors based on novel methods of ECG data analysis.

Artificial Intelligence in the Differential Diagnosis of Cardiomyopathy Phenotypes.

Artificial intelligence (AI) is rapidly being applied to the medical field, especially in the cardiovascular domain. AI approaches have demonstrated their applicability in the detection, diagnosis, and management of several cardiovascular diseases, enhancing disease stratification and typing. Cardiomyopathies are a leading cause of heart failure and life-threatening ventricular arrhythmias. Identifying the etiologies is fundamental for the management and diagnostic pathway of these heart muscle diseases, requiring the integration of various data, including personal and family history, clinical examination, electrocardiography, and laboratory investigations, as well as multimodality imaging, making the clinical diagnosis challenging. In this scenario, AI has demonstrated its capability to capture subtle connections from a multitude of multiparametric datasets, enabling the discovery of hidden relationships in data and handling more complex tasks than traditional methods. This review aims to present a comprehensive overview of the main concepts related to AI and its subset. Additionally, we review the existing literature on AI-based models in the differential diagnosis of cardiomyopathy phenotypes, and we finally examine the advantages and limitations of these AI approaches.

Arrhythmias in patients with acute ST-elevation myocardial infarction induced by various risk factors during the first day after myocardial reperfusion by primary percutaneous coronary intervention

Introduction. Acute coronary syndrome, in particular acute ST-elevation myocardial infarction (STEMI), is often accompanied by complex hemodynamically significant arrhythmias and conduction disorders. Such patients have a worse prognosis compared to patients with sinus rhythm. Arrhythmias in patients with STEMI are facilitated by the presence of comorbidities such as arterial hypertension, diabetes mellitus, obesity, and post-COVID-19 syndrome. The aim of the study. To elucidate the nature of arrhythmias in patients with acute STEMI induced by various risk factors during the first day after myocardial reperfusion by primary percutaneous coronary intervention. Materials and methods. The study involved 50 patients aged 45 to 83 years (average age – 63,4 ± 9,6 years; men – 70,97 %, women – 29,03 %), who were treated during 2021-2023 at the cardiology and reperfusion therapy department of Cardio-vascular center of ʺSaint Panteleimon Hospital in Lvivʺ and the infarction department of ʺLviv Regional Clinical Cardiological Centerʺ. The patients under investigation were subjected to daily electrocardiogram (ECG) monitoring for 24 hours after stenting of the infarct-related coronary artery, using a 7-channel ECG recorder Solvaig 06000.7 with computer processing of the recording using the DiaCard2 software. The obtained material was further subjected to software packages Microsoft Excel 2022, Statistica 10. Results. It was established that among supraventricular rhythm disturbances the most common were premature contractions, the average number of which per patient was significantly higher in the presence of obesity. Similarly high it was in post COVID-19 patients, as well as in those with hypertension. In post-coronavirus infection and in hypertension cases, extrasystoles were often in the form of pairs, triplets, bigemia, and trigemia; paroxysms of supraventricular tachycardia were also recorded in these patients. Among the ventricular arrhythmias also the most frequent were premature cardiac contractions, significantly more oftenly recorded in patients with hypertension and those experienced COVID-19; only in these patients were documented extrasystoles in the form of pairs, triplets, bigeminy, trigeminy, runs of ʺR to Tʺ, which are currently considered as harbingers of life-threatening ventricular arrhythmias. In the presence of hypertension and post-COVID-19, episodes of unstable ventricular tachycardia were also observed. Conclusions. In patients with STEMI, both supraventricular and ventricular premature contractions and episodes of supraventricular and unstable ventricular tachycardia are quite common during the first day after primary percutaneous coronary intervention with infarct-related coronary artery stenting, which is evidence of myocardial electrical instability. The nature of rhythm disturbances in the presence of hypertension and post-COVID-19 is prognostically unfavorable and indicates a higher risk of lifethreatening arrhythmias in these patients. Myocardial revascularization should be supplemented with optimal medical treatment in order to prevent the adverse cardiovascular events in post-STEMI patients. Further research should be directed toward elucidation of predictive value of detected arrhythmias with respect to the occurrence of unfavorable cardiovascular events in the early and long-term post-infarction period.

Myocardial Mechanics and Associated Valvular and Vascular Abnormalities in Left Ventricular Noncompaction Cardiomyopathy.

Left ventricular (LV) non-compaction (LVNC) is a rare genetic cardiomyopathy due to abnormal intra-uterine arrest of compaction of the myocardial fibers during endomyocardial embryogenesis. Due to the partial or complete absence of LV compaction, the structure of the LV wall shows characteristic abnormalities, including a thin compacted epicardium and a thick non-compacted endocardium with prominent trabeculations and deep intertrabecular recesses. LVNC is frequently associated with chronic heart failure, life-threatening ventricular arrhythmias, and systemic embolic events. According to recent findings, in the presence of LVNC, dysfunctional LV proved to be associated with left atrial volumetric and functional abnormalities and consequential dilated and functionally impaired mitral annulus, partly explaining the higher prevalence of regurgitation. Although the non-compaction process morphologically affects only the LV, signs of remodeling of the right heart were also detected. Moreover, dilation and stiffening of the aorta were present. The aim of the present detailed review was to summarize findings regarding changes in cardiac mechanics, valvular abnormalities, and vascular remodeling detected in patients with LVNC.

Arrhythmogenic Right Ventricular Dysplasia Presenting with Sustained Ventricular Tachycardia: A Case Report

Arrhythmogenic right ventricular dysplasia (ARVD) is a cardiomyopathy characterized pathologically by fibrofatty tissue replacement of the myocyte of the right ventricle (RV) and clinically by life-threatening ventricular arrhythmias in young people. It is a major cause of sudden death. We present the case of a 60-year-old man with cardiovascular risk factors, was admitted for unstable ventricular tachycardia (VT) treated immediately with synchronized cardioversion. After the stabilization of the patient, Electrocardiogram demonstrated an epsilon wave in precordial leads and diffuse T-wave inversions. Transthoracic echocardiography revealed a dilated, hypokinetic right ventricle with moderately reduced function and a focal area of dyskinesia. The diagnosis of arrhythmogenic right ventricular dysplasia (ARVD) was made and an implantable cardioverter defibrillator (ICD) was indicated for secondary prevention. This case report will present the clinical presentation, diagnosis and management of this rare disease.

A novel DSP zebrafish model reveals training- and drug-induced modulation of arrhythmogenic cardiomyopathy phenotypes

Arrhythmogenic cardiomyopathy (AC) is an inherited disorder characterized by progressive loss of the ventricular myocardium causing life-threatening ventricular arrhythmias, syncope and sudden cardiac death in young and athletes. About 40% of AC cases carry one or more mutations in genes encoding for desmosomal proteins, including Desmoplakin (Dsp). We present here the first stable Dsp knock-out (KO) zebrafish line able to model cardiac alterations and cell signalling dysregulation, characteristic of the AC disease, on which environmental factors and candidate drugs can be tested. Our stable Dsp knock-out (KO) zebrafish line was characterized by cardiac alterations, oedema and bradycardia at larval stages. Histological analysis of mutated adult hearts showed reduced contractile structures and abnormal shape of the ventricle, with thinning of the myocardial layer, vessels dilation and presence of adipocytes within the myocardium. Moreover, TEM analysis revealed “pale”, disorganized and delocalized desmosomes. Intensive physical training protocol caused a global worsening of the cardiac phenotype, accelerating the progression of the disease. Of note, we detected a decrease of Wnt/β-catenin signalling, recently associated with AC pathogenesis, as well as Hippo/YAP-TAZ and TGF-β pathway dysregulation. Pharmacological treatment of mutated larvae with SB216763, a Wnt/β-catenin agonist, rescued pathway expression and cardiac abnormalities, stabilizing the heart rhythm. Overall, our Dsp KO zebrafish line recapitulates many AC features observed in human patients, pointing at zebrafish as a suitable system for in vivo analysis of environmental modulators, such as the physical exercise, and the screening of pathway-targeted drugs, especially related to the Wnt/β-catenin signalling cascade.

Amiodarone: Is it Safe in Stress Cardiomyopathy?

Amiodarone is a broad-spectrum antiarrhythmic agent used in day-to-day practice to treat ventricular tachycardia (VT) and supraventricular tachycardias like atrial flutter/atrial fibrillation. 1 It can cause QT prolongation and rarely precipitate life-threatening ventricular arrhythmias like Torsade de Pointes (TdP). 1 Torsades is characterized by prolonged ventricular repolarization with QT intervals generally exceeding 500 milliseconds. 1 , 2 Risk factors for drug-induced QT prolongation are female sex, congestive heart failure, and so on. 2 This case report describes a woman with stress cardiomyopathy 3 and atrial fibrillation who was treated with Amiodarone which precipitated Torsades. Therefore knowledge of side effects, monitoring for drug effects, and timely withdrawal of the offending drug is important. 2

Neurohormonal status is associated with long-term appropriate implantable cardioverter defibrillator therapy for life-threatening ventricular arrhythmia

Abstract Background Neurohormonal status is associated with the risk of life-threatening ventricular arrhythmia. Purpose We aimed to assess whether neurohormonal status in patients with an implantable cardioverter defibrillator (ICD) is correlated with the risk of long-term appropriate shock or overdrive delivered by the ICD for life-threatening arrhythmia. Methods A total of 331 clinically stable patients with ICD without any past history of shock or overdrive for life-threatening ventricular arrhythmia were enrolled in a two-center prospective cohort and followed up for a median time of 7.9 years. At enrolment, patients’ medical history, treatment, clinical and imaging data were recorded and, blood and, blood samples were drawn for the assessment of standard biological parameters as well as 3 neurohormones (aldosterone, A type NT-pro-Atrial natriuretic peptide (ANP) and MR-pro-Adrenomedullin (ADM). The primary endpoint of the study was the occurrence of appropriate shock or overdrive delivered by the ICD (ICD therapy). A multivariable cox model adjusted on age, gender, primary or secondary prevention ICD as well as all baseline variables unequally distributed between groups with or without ICD therapy was used for the assessment of the relationship between the 3 neurohormones and the primary endpoint. Results The population consisted of patients with a mean age of 60±15 years, among which 59(18%) women and 160(48%) with a secondary prevention indication for ICD. At baseline all data were similar between patients with or without ICD therapy with the exception of weight, systolic blood pressure, left ventricular ejection fraction (LVEF) and serum potassium and creatinine levels. No other variable, including MADIT and SHOCKED score were significantly associated with the risk of ICD therapy. Death was recorded in 114(34%) patients and a total of 78(24%), 76(23%) and 106(33%) patients had appropriate shock, overdrive and ICD therapy respectively during the follow-up. On multivariable analysis, highest levels of ANP and lowest levels of ADM but not aldosterone were independently associated with life-threatening ventricular arrhythmia requiring ICD therapy (table). Other correlates of ICD therapy were lower LVEF and, higher weight, serum potassium and creatinine concentrations. ANP and ADM had a stepwise additive impact on the risk of ICD therapy. (Figure 1) Conclusions In a stable all comer population with ICD and no history of ICD therapy, blood levels of neurohormones ANP and ADM are associated with the risk of life-threatening ventricular arrhythmia requiring ICD-delivered shock or overdrive independent of other correlates. ANP and ADM concentrations may be useful in identifying patients at high risk of such arrhythmia and who may most benefit from ICD implantation.

Single-nucleus RNA sequencing of TMEM43 induced arrhythmogenic cardiomyopathy reveals altered cell compositions and transcriptional states in mice

Abstract Introduction and purpose TMEM43 induced Arrhythmogenic cardiomyopathy, also referred to as arrhythmogenic cardiomyopathy type 5 or ACM5, is caused by a point mutation in TMEM43 (p.S358L). The disease is characterised by chamber dilation and a progressive dystrophy of the ventricular myocardium causing life-threatening ventricular arrhythmias and sudden cardiac death. Loss of cardiomyocytes and fibrofatty replacement of the myocardium is clearly observed in our transgenic mouse model of ACM5 overexpressing TMEM43-S358L in postnatal cardiomyocytes. However, the mechanisms underlying cardiomyocyte death and fibroblast activation remain elusive, precluding the development of effective therapeutic options. Here we applied the state-of-the-art analysis on single-nucleus RNA sequencing (snRNA-seq) to characterise the cellular compositions and molecular states in ACM5 mouse hearts. Methods Left ventricular heart tissues of severely affected ACM5 mice and their corresponding transgenic controls overexpressing wild-type TMEM43 were used for snRNA-seq analysis. We identified 10 major cell types, which aggregated into 23 distinct clusters on the basis of transcriptional similarity. Results ACM5 nuclei showed significant depletion of cardiomyocytes and expanded populations of fibroblasts and myeloid cells. Fibroblasts from mutant mice acquired an activated phenotype related to remodelling of the extracellular matrix with a large number of genes like LOX, POSTN, NOX4 or COL1A1 significantly upregulated. In addition, the mutant cardiomyocytes showed altered transcriptional states characterized by cardiac stress and heart failure markers such as NPPB or MYH7. Interestingly, we were able to identify a cluster of mutant cardiomyocytes with a highly apoptotic profile. This cluster is also enriched in genes related to the unfolding protein response (UPR) stress sensors and the DNA damage response (DDR), elucidating a new potential mechanism of myocyte death in ACM5. Furthermore, heterogeneity of the myeloid populations is also observed. The number of tissue resident macrophages is increased in mutant samples and myeloid cells show additional disease-associated transcriptional states that are almost entirely absent in control samples. Conclusion Together these data illuminated shared and distinct cell and molecular architectures of ACM5 in mouse hearts. Further confirmation on diverse gene expression profiles like the UPR and DDR pathways related to cardiomyocyte death will establish a valuable resource to explore novel therapeutic targets and personalized therapies for ACM5.