Patient characteristics, predictors and outcome of pacemaker patients upgraded to an implantable cardioverter defibrillator.

AIMS: Pacemaker (PM) patients may require a subsequent upgrade to an implantable cardioverter defibrillator (ICD). Limited data exists on this patient population. We sought to characterize this population, to assess predictors for ICD upgrade, and to report the outcome. METHODS: From our prospective PM and ICD implantation registry, all patients who underwent PM and/or ICD implantations at our center were analyzed. Patient characteristics and outcomes of PM patients with subsequent ICD upgrade were compared to age- and sex-matched patients with de novo ICD implantation, and to PM patients without subsequent upgrade. RESULTS: Of 1'301 ICD implantations, 60 (5%) were upgraded from PMs. Median time from PM implantation to ICD upgrade was 2.6 years (IQR 1.3-5.4). Of 2'195 PM patients, 28 patients underwent subsequent ICD upgrades, corresponding to an estimated annual incidence of an ICD upgrade of at least 0.33%. Lower LVEF (p = .05) and male sex (p = .038) were independent predictors for ICD upgrade. Survival without death, transplant and LVAD implantation were worse both for upgraded ICD patients compared to matched patients with de novo ICD implantation (p = .05), as well as for PM patients with subsequent upgrade compared to matched PM patients not requiring an upgrade (p = .036). CONCLUSIONS: One of 20 ICD implantations are upgrade of patients with a PM. At least one of 30 PM patients will require an ICD upgrade in the following 10 years. Predictors for ICD upgrade are male sex and lower LVEF at PM implantation. Upgraded patients have worse outcomes.

Frequency, Penetrance, and Variable Expressivity of Dilated Cardiomyopathy-Associated Putative Pathogenic Gene Variants in UK Biobank Participants.

BACKGROUND: There is a paucity of data regarding the phenotype of dilated cardiomyopathy (DCM) gene variants in the general population. We aimed to determine the frequency and penetrance of DCM-associated putative pathogenic gene variants in a general adult population, with a focus on the expression of clinical and subclinical phenotype, including structural, functional, and arrhythmic disease features. METHODS: UK Biobank participants who had undergone whole exome sequencing, ECG, and cardiovascular magnetic resonance imaging were selected for study. Three variant-calling strategies (1 primary and 2 secondary) were used to identify participants with putative pathogenic variants in 44 DCM genes. The observed phenotype was graded DCM (clinical or cardiovascular magnetic resonance diagnosis); early DCM features, including arrhythmia or conduction disease, isolated ventricular dilation, and hypokinetic nondilated cardiomyopathy; or phenotype-negative. RESULTS: Among 18 665 individuals included in the study, 1463 (7.8%) possessed ≥1 putative pathogenic variant in 44 DCM genes by the main variant calling strategy. A clinical diagnosis of DCM was present in 0.34% and early DCM features in 5.7% of individuals with putative pathogenic variants. ECG and cardiovascular magnetic resonance analysis revealed evidence of subclinical DCM in an additional 1.6% and early DCM features in an additional 15.9% of individuals with putative pathogenic variants. Arrhythmias or conduction disease (15.2%) were the most common early DCM features, followed by hypokinetic nondilated cardiomyopathy (4%). The combined clinical/subclinical penetrance was ≤30% with all 3 variant filtering strategies. Clinical DCM was slightly more prevalent among participants with putative pathogenic variants in definitive/strong evidence genes as compared with those with variants in moderate/limited evidence genes. CONCLUSIONS: In the UK Biobank, ≈1 of 6 of adults with putative pathogenic variants in DCM genes exhibited early DCM features potentially associated with DCM genotype, most commonly manifesting with arrhythmias in the absence of substantial ventricular dilation or dysfunction.

Identification of Cx43 variants predisposing to ventricular fibrillation in the acute phase of ST-elevation myocardial infarction.

AIMS: Ventricular fibrillation (VF) occurring in the acute phase of ST-elevation myocardial infarction (STEMI) is the leading cause of sudden cardiac death worldwide. Several studies showed that reduced connexin 43 (Cx43) expression and reduced conduction velocity increase the risk of VF in acute myocardial infarction (MI). Furthermore, genetic background might predispose individuals to primary VF (PVF). The primary objective was to evaluate the presence of GJA1 variants in STEMI patients. The secondary objective was to evaluate the arrhythmogenic impact of GJA1 variants in STEMI patients with VF. METHODS AND RESULTS: The MAP-IDM prospective cohort study included 966 STEMI patients and was designed to identify genetic predisposition to VF. A total of 483 (50.0%) STEMI patients with PVF were included. The presence of GJA1 variants increased the risk of VF in STEMI patients [from 49.1 to 70.8%, P = 0.0423; odds ratio (OR): 0.40; 95% confidence interval: 0.16-0.97; P = 0.04]. The risk of PVF decreased with beta-blocker intake (from 53.5 to 44.8%, P = 0.0085), atrial fibrillation (from 50.7 to 26.4%, P = 0.0022), and with left ventricular ejection fraction >50% (from 60.2 to 41.4%, P < 0.0001). Among 16 GJA1 variants, three novel heterozygous missense variants were identified in three patients: V236I, H248R, and I327M. In vitro studies of these variants showed altered Cx43 localization and decreased cellular communication, mainly during acidosis. CONCLUSION: Connexin 43 variants are associated with increased VF susceptibility in STEMI patients. Restoring Cx43 function may be a potential therapeutic target to prevent PVF in patients with acute MI. CLINICAL TRIAL REGISTRATION: Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT00859300.

Acute and long-term outcomes of quadripolar IS-4 versus bipolar IS-1 left ventricular leads in cardiac resynchronization therapy: A retrospective registry study.

BACKGROUND: The implantation procedure of left ventricular (LV) leads and the management of cardiac resynchronization therapy (CRT) patients can be challenging. The IS-4 standard for CRT offers additional pacing vectors compared to bipolar leads (IS-1). IS-4 leads improve procedural outcome and may also result in lower adverse events during follow-up (FU) and improve clinical outcome in CRT patients. Further long-term FU data comparing the two lead designs are necessary. METHODS: In this retrospective, single-center study we included adult patients implanted with a CRT-Defibrillator (CRT-D) or CRT-Pacemaker (CRT-P) with a quadripolar (IS-4 group) or bipolar (IS-1 group) LV lead and with available ≥3 years clinical FU. The combined primary endpoint was a combination of predefined, lead-related adverse events. Secondary endpoints were all single components of the primary endpoint. RESULTS: Overall, 133 patients (IS-4 n = 66; IS-1 n = 67) with a mean FU of 4.03 ± 1.93 years were included. Lead-related adverse events were less frequent in patients with an IS-4 lead than with an IS-1 lead (n = 8, 12.1% vs. n = 23, 34.3%; p = .002). The secondary outcomes showed a lower rate of LV lead deactivation/explantation and LV lead dislodgement/dysfunction (4.5% vs. 22.4%; p = .003; 4.5% vs. 17.9%; p = .015, respectively) in the IS-4 patient group. Less patients suffered from unresolved phrenic nerve stimulation with an IS-4 lead (3.0% vs. 13.4%; p = .029). LV lead-related re-interventions were fewer in case of an IS-4 lead (6.1% vs. 17.9%; p = .036). CONCLUSION: In this retrospective analysis, the IS-4 LV lead is associated with lower lead-related complication rates than the IS-1 lead at long-term FU.

Validation of a clinical model for predicting left versus right ventricular outflow tract origin of idiopathic ventricular arrhythmias.

BACKGROUND: Prediction of the chamber of origin in patients with outflow tract ventricular arrhythmias (OTVA) remains challenging. A clinical risk score based on age, sex and presence of hypertension was associated with a left ventricular outflow tract (LVOT) origin. We aimed to validate this clinical score to predict an LVOT origin in patients with OTVA. METHODS: In a two-center observational cohort study, unselected patients undergoing catheter ablation (CA) for OTVA were enrolled. All procedures were performed using an electroanatomical mapping system. Successful ablation was defined as a ≥80% reduction of the initial overall PVC burden after 3 months of follow-up. Patients with unsuccessful ablation were excluded from this analysis. RESULTS: We included 187 consecutive patients with successful CA of idiopathic OTVA. Mean age was 52 ± 15 years, 102 patients (55%) were female, and 74 (40%) suffered from hypertension. A LVOT origin was found in 64 patients (34%). A score incorporating age, sex and presence of hypertension reached 73% sensitivity and 67% specificity for a low (0-1) and high (2-3) score, to predict an LVOT origin. The combination of one ECG algorithm (V2 S/V3 R-index) with the clinical score resulted in a sensitivity and specificity of 81% and 70% for PVCs with R/S transition at V3 . CONCLUSION: The published clinical score yielded a lower sensitivity and specificity in our cohort. However, for PVCs with R/S transition at V3, the combination with an existing ECG algorithm can improve the predictability of LVOT origin.

Inflammation and Immune Response in Arrhythmogenic Cardiomyopathy: State-of-the-Art Review.

Arrhythmogenic cardiomyopathy (ACM) is a primary disease of the myocardium, predominantly caused by genetic defects in proteins of the cardiac intercalated disc, particularly, desmosomes. Transmission is mostly autosomal dominant with incomplete penetrance. ACM also has wide phenotype variability, ranging from premature ventricular contractions to sudden cardiac death and heart failure. Among other drivers and modulators of phenotype, inflammation in response to viral infection and immune triggers have been postulated to be an aggravator of cardiac myocyte damage and necrosis. This theory is supported by multiple pieces of evidence, including the presence of inflammatory infiltrates in more than two-thirds of ACM hearts, detection of different cardiotropic viruses in sporadic cases of ACM, the fact that patients with ACM often fulfill the histological criteria of active myocarditis, and the abundance of anti-desmoglein-2, antiheart, and anti-intercalated disk autoantibodies in patients with arrhythmogenic right ventricular cardiomyopathy. In keeping with the frequent familial occurrence of ACM, it has been proposed that, in addition to genetic predisposition to progressive myocardial damage, a heritable susceptibility to viral infections and immune reactions may explain familial clustering of ACM. Moreover, considerable in vitro and in vivo evidence implicates activated inflammatory signaling in ACM. Although the role of inflammation/immune response in ACM is not entirely clear, inflammation as a driver of phenotype and a potential target for mechanism-based therapy warrants further research. This review discusses the present evidence supporting the role of inflammatory and immune responses in ACM pathogenesis and proposes opportunities for translational and clinical investigation.

Sex-Related Differences in Cardiac Channelopathies: Implications for Clinical Practice.

Sex-related differences in prevalence, clinical presentation, and outcome of cardiac channelopathies are increasingly recognized, despite their autosomal transmission and hence equal genetic predisposition among sexes. In congenital long-QT syndrome, adult women carry a greater risk for Torsades de pointes and sudden cardiac death than do men. In contrast, Brugada syndrome is observed predominantly in adult men, with a considerably higher risk of arrhythmic sudden cardiac death in adult men than in women. In both conditions, the risk for arrhythmias varies with age. Sex-associated differences appear less evident in other cardiac channelopathies, likely a reflection of their rare(r) occurrence and our limited knowledge. In several cardiac channelopathies, sex-specific predictors of outcome have been identified. Together with genetic and environmental factors, sex hormones contribute to the sex-related disparities in cardiac channelopathies through modulation of the expression and function of cardiac ion channels. Despite these insights, essential knowledge gaps exist in the mechanistic understanding of these differences, warranting further investigation. Precise application of the available knowledge may improve the individualized care of patients with cardiac channelopathies. Promoting the reporting of sex-related phenotype and outcome parameters in clinical and experimental studies and advancing research on cardiac channelopathy animal models should translate into improved patient outcomes. This review provides a critical digest of the current evidence for sex-related differences in cardiac channelopathies and emphasizes their clinical implications and remaining gaps requiring further research.

Evidence-Based Assessment of Genes in Dilated Cardiomyopathy.

BACKGROUND: Each of the cardiomyopathies, classically categorized as hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy, has a signature genetic theme. Hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning >10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted. METHODS: An international panel with clinical and scientific expertise in DCM genetics evaluated evidence supporting monogenic relationships of genes with idiopathic DCM. The panel used the Clinical Genome Resource semiquantitative gene-disease clinical validity classification framework with modifications for DCM genetics to classify genes into categories on the basis of the strength of currently available evidence. Representation of DCM genes on clinically available genetic testing panels was evaluated. RESULTS: Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from 8 gene ontologies were classified as having definitive (BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN) or strong (DSP) evidence. Seven genes (14%; ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, VCL) including 2 additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of these 19 genes, 6 were similarly classified for hypertrophic cardiomyopathy and 3 for arrhythmogenic right ventricular cardiomyopathy. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of the 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence. CONCLUSIONS: In the curation of 51 genes, 19 had high evidence (12 definitive/strong, 7 moderate). It is notable that these 19 genes explain only a minority of cases, leaving the remainder of DCM genetic architecture incompletely addressed. Clinical genetic testing panels include most high-evidence genes; however, genes lacking robust evidence are also commonly included. We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes.

Validation of a multipolar pulsed-field ablation catheter for endpoint assessment in pulmonary vein isolation procedures.

AIMS: To validate the performance of a multipolar pulsed-field ablation (PFA) catheter compared to a standard pentaspline 3D-mapping catheter for endpoint assessment of pulmonary vein isolation (PVI). PFA for PVI using single-shot devices combines the benefits of high procedural efficacy and safety. A newly available multipolar PFA catheter allows real-time recording of pulmonary vein (PV) signals during PVI. METHODS AND RESULTS: Patients undergoing first PVI using PFA with the standard ablation protocol (eight applications per PV) were studied. Entrance and exit block (10 V/2 ms) were assessed using the PFA catheter. Subsequently, a high-density 3D electroanatomical bipolar voltage map (3D-EAM) was constructed using a standard pentaspline 3D-mapping catheter. Additional PFA applications were delivered only after confirmation of residual PV connection by 3D-EAM. In 56 patients, 213 PVs were targeted for ablation. Acute PVI was achieved in 100% of PVs: in 199/213 (93%) PVs with the standard ablation protocol alone and in the remaining 14 PVs after additional PFA applications. The accuracy of PV assessment with the PFA catheter after the standard ablation protocol was 91% (194/213 veins). In 5/213 (2.3%) PVs, the PFA catheter incorrectly indicated PV-isolation. In 14/213 (6.6%), the PFA catheter incorrectly indicated residual PV-conduction due to high-output pace-capture. Lowering the output to 5 V/1 ms reduced this observation to 0.9% (2/213) and increased the overall accuracy to 97% (206/213). CONCLUSION: A novel multipolar PFA catheter allows reliable endpoint assessment for PVI. Due to its design, far-field sensing and high-output pace-capture can occur. Lowering the pacing output increases the accuracy from 91 to 97%.

Efficacy and safety of ethanol infusion into the vein of Marshall for mitral isthmus ablation.

INTRODUCTION: Chemical ablation by retrograde infusion of ethanol into the vein of Marshall (VOM-EI) can facilitate the achievement of mitral isthmus block. This study sought to describe the efficacy and safety of this technique. METHODS AND RESULTS: Twenty-two consecutive patients (14 males, median age 71 years) with attempted VOM-EI for mitral isthmus ablation were included in the study. VOM-EI was successfully performed with a median of 4 ml of 96% ethanol in 19 patients (86%) and the mitral isthmus was successfully blocked in all (100%). Touch up endocardial and/or epicardial ablation after VOM-EI was necessary for 12 patients (63%). Perimitral flutter was present in 12 patients (63%) during VOM-EI and terminated or slowed by VOM-EI in 4 and 3 patients, respectively. The low-voltage area of the mitral isthmus region increased from 3.1 cm2 (interquartile range [IQR] 0-7.9) before to 13.2 cm2 (IQR: 8.2-15.0) after VOM-EI and correlated significantly with the volume of ethanol injected (p = .03). Median high-sensitive cardiac troponin-T increased significantly from 330 ng/L (IQR: 221-516) the evening of the procedure to 598 ng/L (IQR: 382-769; p = .02) the following morning. A small pericardial effusion occurred in three patients (16%), mild pericarditis in one (5%), and uneventful VOM dissection in two (11%). After a median follow-up of 3.5 months (IQR: 3.0-11.0), 10 of 18 patients (56%) with VOM-EI and available follow-up had arrhythmia recurrence. Repeat ablation was performed in five patients (50%) and peri-mitral flutter diagnosed in three (60%). CONCLUSION: VOM-EI is feasible, safe, and effective to achieve acute mitral isthmus block.

Impact of contact force sensing technology on outcome of catheter ablation of idiopathic pre-mature ventricular contractions originating from the outflow tracts.

AIMS: Catheter ablation of frequent idiopathic pre-mature ventricular contractions (PVC) is increasingly performed. While potential benefits of contact force (CF)-sensing technology for atrial fibrillation ablation have been assessed in several studies, the impact of CF-sensing on ventricular arrhythmia ablation remains unknown. This study aimed to compare outcomes of idiopathic outflow tract PVC ablation when using standard ablation catheters as opposed to CF-sensing catheters. METHODS AND RESULTS: In a retrospective multi-centre study, unselected patients undergoing catheter ablation of idiopathic outflow tract PVCs between 2013 and 2016 were enrolled. All procedures were performed using irrigated-tip ablation catheters and a 3D electro-anatomical mapping system. Sustained ablation success was defined as a ≥80% reduction of pre-procedural PVC burden determined by 24 h Holter ECG during follow-up. Overall, 218 patients were enrolled (median age 52 years, 51% males). Baseline and procedural data were similar in the standard ablation (24%) and the CF-sensing group (76%). Overall, the median PVC burden decreased from 21% (IQR 10-30%) before ablation to 0.2% (IQR 0-3.0%) after a median follow-up of 2.3 months (IQR 1.4-3.9 months). The rates of both acute (91% vs. 91%, P = 0.94) and sustained success (79% vs. 74%, P = 0.44) were similar in the standard ablation and the CF-sensing groups. No differences were observed in subgroups according to arrhythmia origin from the RVOT (65%) or LVOT (35%). Complications were rare (1.8%) and evenly distributed between the two groups. CONCLUSION: The use of CF-sensing technology is not associated with increased success rate nor decreased complication rate in idiopathic outflow tract PVC ablation.

Pre-procedural arrhythmia burden and the outcome of catheter ablation of idiopathic premature ventricular complexes.

BACKGROUND: Radiofrequency catheter ablation of idiopathic premature ventricular complexes (PVCs) is an effective method for eliminating symptoms and preventing/reversing arrhythmia-induced cardiomyopathy. One reason for procedural failure is low PVC frequency during the procedure. We aimed to investigate the relation between pre-procedural PVC burden and outcome of idiopathic PVC catheter ablation. METHODS: Patients who underwent idiopathic PVC ablation between 2013 and 2019 at two tertiary referral centers were retrospectively included. All procedures were performed using irrigated-tip ablation catheters and a 3D electro-anatomical mapping system. Sustained ablation success was defined as a ≥80% reduction of pre-procedural PVC burden determined by 24h-Holter at follow-up. RESULTS: Overall, 254 patients (median age 54 years [IQR 42-64]; 47% male) were enrolled. The median pre-ablation PVC-burden was 22% (IQR 11-31%), which was reduced to a post-ablation PVC burden of 0.3% (IQR 0-4%) after a median of 90 days. Sustained ablation success was achieved in 182 patients (72%). Pre-procedural PVC burden did not differ between patients with sustained ablation success and recurrence during follow-up (median 21% vs. 22%, p = .76). When assessed in pre-ablation PVC-burden groups of ≤5%, 6-15%, 16-30%, and ≥31%, sustained ablation success was achieved in 67%, 75%, 71%, and 72%, respectively, with no significant difference (p = .89). Sustained ablation outcome for PVC-burden ≤5% versus >5% showed no difference either (67% vs. 72%, p = .52). CONCLUSIONS: Pre-procedural Holter-determined PVC burden does not predict the outcome of idiopathic PVC ablation. Thus, catheter ablation may be a reasonable first choice also for patients with symptomatic yet rare PVCs.

Man vs machine: Performance of manual vs automated electrocardiogram analysis for predicting the chamber of origin of idiopathic ventricular arrhythmia.

BACKGROUND: Radiofrequency catheter ablation of idiopathic ventricular arrhythmias (VAs) is performed to eliminate symptoms and to prevent or reverse arrhythmia-induced cardiomyopathy. Preprocedural prediction of the chamber of VA origin is critical for patient counseling, procedure planning, and guidance of invasive mapping. OBJECTIVE: We aimed to assess the performance of manual expert versus automated 12-lead electrocardiogram (ECG) analysis in the prediction of VA origin. METHODS: Patients with ablation of idiopathic VA and sustained success were included. The VA origin was defined as the site where ablation caused arrhythmia suppression. Standard baseline 12-lead ECGs with documentation of the VA were analyzed manually in a blinded fashion by three electrophysiologists and three electrophysiology (EP) fellows. In addition, the same standard 12-lead ECG was analyzed by an automated computer algorithm using a vectorcardiographic approach. RESULTS: Thirty-eight patients (median age, 47 [interquartile range, 37-58]; 68% female) were enrolled. The VA originated from the right ventricle in 24 (63%) and the left ventricle in 14 (37%) patients. The electrophysiologists and EP fellows identified the VA chamber of origin with a similar accuracy of 73% and 72% (P = .72). The automated algorithm showed a higher accuracy of 89% (P = .03 compared with electrophysiologists and EP fellows). This resulted in a sensitivity of 95% and specificity of 86%. CONCLUSION: While the manual ECG analysis of the standard 12-lead ECG by both electrophysiologists and EP fellows correctly identified the chamber of VA origin in around 75% of cases, an automated vectorcardiographic computer algorithm achieved an accuracy of 89% with clinically acceptable diagnostic parameters.

State of the Art Review on Genetics and Precision Medicine in Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy characterised by ventricular arrhythmia and an increased risk of sudden cardiac death (SCD). Numerous genetic determinants and phenotypic manifestations have been discovered in ACM, posing a significant clinical challenge. Further to this, wider evaluation of family members has revealed incomplete penetrance and variable expressivity in ACM, suggesting a complex genotype-phenotype relationship. This review details the genetic basis of ACM with specific genotype-phenotype associations, providing the reader with a nuanced perspective of this condition; whilst also proposing a future roadmap to delivering precision medicine-based management in ACM.

Molecular and genetic insights into progressive cardiac conduction disease.

Progressive cardiac conduction disease (PCCD) is often a primarily genetic disorder, with clinical and genetic overlaps with other inherited cardiac and metabolic diseases. A number of genes have been implicated in PCCD pathogenesis with or without structural heart disease or systemic manifestations. Precise genetic diagnosis contributes to risk stratification, better selection of specific therapy and allows familiar cascade screening. Cardiologists should be aware of the different phenotypes emerging from different gene-mutations and the potential risk of sudden cardiac death. Genetic forms of PCCD often overlap or coexist with other inherited heart diseases or manifest in the context of multisystem syndromes. Despite the significant advances in the knowledge of the genetic architecture of PCCD and overlapping diseases, in a measurable fraction of PCCD cases, including in familial clustering of disease, investigations of known cardiac disease-associated genes fail to reveal the underlying substrate, suggesting that new causal genes are yet to be discovered. Here, we provide insight into genetics and molecular mechanisms of PCCD and related diseases. We also highlight the phenotypic overlaps of PCCD with other inherited cardiac and metabolic diseases, present unmet challenges in clinical practice, and summarize the available therapeutic options for affected patients.

Late-onset severe long QT syndrome.

We report a case of torsades de pointes arrhythmia as the first manifestation of congenital Long QT syndrome in a 77-year-old man with family history of sudden unexplained death. This case illustrates the importance of vigilant clinical assessment and genetic counseling in families with sudden death in order to identify properly asymptomatic relatives at risk for cardiac events. It also demonstrates that Long QT syndrome can still manifest with potentially fatal arrhythmias late in life in previously asymptomatic elderly patients.

Unraveling Complexities in Genetically Elusive Long QT Syndrome.

Genetic testing has become standard of care for patients with long QT syndrome (LQTS), providing diagnostic, prognostic, and therapeutic information for both probands and their family members. However, up to a quarter of patients with LQTS do not have identifiable Mendelian pathogenic variants in the currently known LQTS-associated genes. This absence of genetic confirmation, intriguingly, does not lessen the severity of LQTS, with the prognosis in these gene-elusive patients with unequivocal LQTS mirroring genotype-positive patients in the limited data available. Such a conundrum instigates an exploration into the causes of corrected QT interval (QTc) prolongation in these cases, unveiling a broad spectrum of potential scenarios and mechanisms. These include multiple environmental influences on QTc prolongation, exercise-induced repolarization abnormalities, and the profound implications of the constantly evolving nature of genetic testing and variant interpretation. In addition, the rapid advances in genetics have the potential to uncover new causal genes, and polygenic risk factors may aid in the diagnosis of high-risk patients. Navigating this multifaceted landscape requires a systematic approach and expert knowledge, integrating the dynamic nature of genetics and patient-specific influences for accurate diagnosis, management, and counseling of patients. The role of a subspecialized expert cardiogenetic clinic is paramount in evaluation to navigate this complexity. Amid these intricate aspects, this review outlines potential causes of gene-elusive LQTS. It also provides an outline for the evaluation of patients with negative and inconclusive genetic test results and underscores the need for ongoing adaptation and reassessment in our understanding of LQTS, as the complexities of gene-elusive LQTS are increasingly deciphered.