Electrocardiogram in Friedreich's ataxia: A short-term surrogate endpoint for treatment efficacy.

Friedreich's ataxia is a rare degenerative neuromuscular disorder, caused by a homozygous GAA triplet repeat expansion in the frataxin (FXN) gene, with a broad clinical phenotype characterized by progressive gait and limb ataxia, dysarthria, and loss of lower limb reflexes; cardiac involvement is represented by hypertrophic cardiomyopathy, ventricular arrhythmias, and sudden cardiac deaths. Currently, no definite therapy is available, while many drugs are under investigation; for this reasons, we need markers of short- and long-term treatment efficacy acting on different tissue for trial evaluation. We describe the case of a 21-year-old patient affected by Friedreich's ataxia on wheel-chair, with initial cardiac involvement and electrocardiographic features characterized by thiamine treatment-related negative T wave and QTc variations. We discuss plausible physiopathology and potential ECG role implications as an intermediate marker of treatment response in future clinical trials considering patients affected by Friedreich's ataxia.

Clinical and economic impact of multipoint left ventricular pacing: A comparative analysis from the Italian registry on multipoint pacing in cardiac resynchronization therapy (IRON-MPP).

INTRODUCTION: Early evidence suggests that multipoint left ventricular pacing (MPP) may improve response to cardiac resynchronization therapy (CRT). It is unknown whether this benefit is sustained and cost-effective. We used real-world data to evaluate long-term impact of MPP-ON clinical status, heart failure hospitalizations (HFH) and costs. METHODS: The Italian registry on multipoint left ventricular pacing is a prospective, multicenter registry of patients implanted with MPP-enabled CRT devices. For this analysis, clinical and echocardiographic data were collected through 24 months and compared between patients with (MPP-ON) or without (MPP-OFF) early MPP activation at implant. The total cost of each HFH was estimated with national Italian reimbursement rates. RESULTS: The study included 190 MPP-OFF and 128 MPP-ON patients with similar baseline characteristics. At 1 and 2 years, the MPP-ON group had lower rates of HFH vs MPP-OFF (1-year hazard ratio [HR]: 0.14, P = .0014; 2-year HR: 0.38, P = .009). The finding persisted in a subgroup of patients with consistent MPP activation through follow-up (1-year HR: 0.19; P = .0061; 2-year HR: 0.39, P = .022). Total HFH per-patient costs were lower in the MPP-ON vs the MPP-OFF group at 1 year (€101 ± 50 vs €698 ± 195, P < .001) and 2 years (€366 ± 149 vs €801 ± 203, P = .038). More MPP-ON patients had ≥5% improvement in ejection fraction (76.8% vs 65.4%, P = .025) and clinical composite score (66.7% vs 47.5%, P = .01). CONCLUSIONS: In this multicenter clinical study, early MPP activation was associated with a significant reduction in cumulative HFH and related costs after 1 and 2 years of follow-up.

Double missense mutations in cardiac myosin-binding protein C and myopalladin genes: A case report with diffuse coronary disease, complete atrioventricular block, and progression to dilated cardiomyopathy.

Cardiomyopathies caused by double gene mutations are rare but conferred a remarkably increased risk of end-stage progression, arrhythmias, and poor outcome. Compound genetic mutations leading to complex phenotype in the setting of cardiomyopathies represent an important challenge in clinical practice, and genetic tests allow risk stratification and personalized clinical management of patients. We report a case of a 50-year-old woman with congestive heart failure characterized by dilated cardiomyopathy, diffuse coronary disease, complete atrioventricular block, and missense mutations in cardiac myosin-binding protein C (MYBPC3) and myopalladin (MYPN). We discuss the plausible role of genetic profile in phenotype determination.

Impact of multipoint pacing on projected battery longevity in cardiac resynchronization therapy. An IRON-MPP study sub-analysis.

BACKGROUND: Multipoint pacing (MPP) may improve clinical outcomes in patients with cardiac resynchronization therapy defibrillators (CRT-D), but its impact on battery longevity in a real-world population has not been investigated in large trials. OBJECTIVE: Compare projected battery longevity in CRT-D patients with and without MPP during long-term follow-up. METHODS: The Italian registry on multipoint left ventricular pacing (IRON-MPP) is a prospective, multicenter registry of patients implanted with MPP-capable CRT-D devices. Projected battery longevity during follow-up was compared for patients with MPP (MPP ON) vs single-site (MPP OFF) left ventricular pacing at CRT-D implantation. A sub-analysis excluded crossover patients with MPP activation or deactivation occurring after implantation. A second sub-analysis excluded patients with a right or left ventricular pacing amplitude >2.5 V. RESULTS: Out of 237 CRT-D patients (71 ± 9 years, 81% male) followed for 1.9 ± 0.8 years, 102 (43%) had MPP ON at implantation. Programmed atrial and ventricular outputs and percentage of pacing were similar between groups. MPP was associated with a 0.44 years reduction in projected battery longevity (P = .03) during long-term follow-up. Results were similar for the first and second sub-analyses, with a 0.57 years (P < .001) and 0.71 years (P < .001) reduction in projected longevity, respectively. CONCLUSION: In this long-term real-world registry, early MPP activation is associated with less than a 1-year reduction in projected battery life compared to single-site biventricular pacing.

Real-life outcome of implantable cardioverter-defibrillator and cardiac resynchronization defibrillator replacement/upgrade in a contemporary population: observations from the multicentre DECODE registry.

AIMS: The benefit of prolonged implantable cardioverter-defibrillator (ICD)/cardiac resynchronization therapy defibrillator (CRT-D) therapy following device replacement is hindered by clinical and procedure-related adverse events (AEs). Adverse events rate is highest in more complex devices and at upgrades, as per the REPLACE registry experience, but is changing owing to the improvement in device technology and medical care. We aimed at understanding the extent and type of AEs in a contemporary Italian population. METHODS AND RESULTS: Detect long-term complications after ICD replacement (DECODE) was a prospective, single-arm, multicentre cohort study aimed at estimating medium- to long-term AEs in a large population of patients undergoing ICD/cardiac resynchronization defibrillator replacement/upgrade from 2013 to 2015. We prospectively analysed all clinical and device-related AEs at 12-month follow-up (FU) of 983 consecutive patients (median age 71 years, 76% male, 55% ischaemic, 47% CRT-D) followed for 353 ± 49 days. Seven percent of the patients died (60.6% for cardiovascular reasons), whereas 104 AEs occurred; 43 (4.4%) patients needed at least one surgical action to treat the AE. Adverse events rates were 3.3/100 years lead-related, 3.4/100 years bleedings, and 1.6/100 years infective. The primary endpoint was predicted by hospitalization in the month prior to the procedure [hazard ratio (HR) = 2.23, 1.16-4.29; 0.0169] and by upgrade (HR = 1.75, 1.02-2.99, 0.0441). One hundred and twelve (11.4%) patients met the combined endpoint of death from any cause, cardiac implantable electronic device (CIED)-related infection, and surgical action/hospitalization required to treat the AE. Hospitalization within 30 days prior to the procedure (HR = 2.07, 1.13-3.81; 0.0199), anticoagulation (HR = 1.97, 1.26-3.07; 0.003), and ischaemic cardiomyopathy (HR = 1.67, 95% confidence interval 1.06-2.63; P = 0.0276) were associated with the combined endpoint during FU. CONCLUSIONS: Adverse events following CIED replacement/upgrade are lower than previously reported, possibly owing to improved patients care. Hospitalization in the month prior to the procedure, upgrade, and clinical profile (anticoagulation, ischaemic cardiomyopathy) hint to increased risk, suggesting an individualized planning of the procedure to minimize overall AEs. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov/ Identifier: NCT02076789.

Inappropriate shock and percutaneous cardiac intervention: A lesson to learn in the cath lab.

Coronary disease is a common condition in patients affected by heart failure with severely reduced ejection fraction (HFrEF). This condition represents an indication for implantable cardioverter defibrillator (ICD) in order to reduce the risk of sudden death related to arrhythmias. Nevertheless, inappropriate shocks are associated with worse quality of life, hospitalization, and death. We present the case of an inappropriate shock related to percutaneous coronary intervention during the insertion and advancement of the guidewire into the left anterior descending artery (LAD) in a patient with an ICD. Physicians' awareness about the clinical implication of noise arising during a coronary procedure is very important in patients with an ICD or pacemaker, to avoid inappropriate shock or pacing inhibition and to raise the possibility of lead implantation in or helix protrusion into the coronary lumen.

Sudden death in mild hypertrophic cardiomyopathy with compound DSG2/DSC2/MYH6 mutations: Revisiting phenotype after genetic assessment in a master runner athlete.

Cardiomyopathies represent a well-known cause of heart failure and sudden death. Although cardiomyopathies are generally categorized in distinct nosographic entities, characterized by single gene-to-disease causal relationships, recently, oligogenic mutations have also been associated to relevant cardiac clinical features. We report the case of a master athlete carrying trigenic mutations in desmoglein-2 (DSG2), desmocollin-2 (DSC2) and heavy chain myosin 6 (MYH6), which determine a mild hypertrophic phenotype associated both to ventricular tachyarrhythmias and atrio-ventricular block. We discuss the differential diagnosis and prognostic approach in patient affected by complex cardiomyopathy phenotype, along with the importance of sport restriction and sudden death prevention.

Appropriate implantable cardioverter-defibrillator interventions in cardiac resynchronization therapy-defibrillator (CRT-D) patients undergoing device replacement: time to downgrade from CRT-D to CRT-pacemaker? Insights from real-world clinical practice in the DECODE CRT-D analysis.

Aim: Ventricular tachycardia (VT)/ventricular fibrillation (VF) occurrence after cardiac resynchronization therapy-defibrillator (CRT-D) replacement is unknown; hence, there is no practical guideline to recommend either CRT-D or CRT-pacemaker at the time of device replacement. We observed the 1-year VT/VF occurrence after CRT-D replacement in a subanalysis of the Detect Long-term Complications after ICD Replacement (DECODE) registry. Methods and results: A total of 332 consecutive patients who had undergone CRT-D replacement from 2013 to 2015 were enrolled in 36 Italian centres. The primary endpoint was the number of patients with any appropriate implantable cardioverter-defibrillator (ICD) interventions during 12-month follow-up. The secondary endpoint comprised death from any cause and appropriate ICD interventions. At replacement, 214 (64.5%) patients had a left ventricular ejection fraction ≤ 35% and 138 (41.6%) patients had a secondary prevention indication for ICD. Seventy (21.1%) patients had no longer indication to ICD therapy. During a median follow-up period of 406.5 (362-533) days, VT/VF requiring therapy delivery occurred in 57 (17%) patients, specifically in 7% of those who no longer had an ICD indication. On multivariate analysis, number of criteria for ICD replacement independently predicted appropriate ICD intervention during follow-up [hazard ratio (HR) = 1.62, 95% confidence interval (CI) 1.07-2.46; log-rank P = 0.02]. The combined endpoint of death from any cause or appropriate ICD therapy occurred in 76 (23%) patients. Only NYHA class remained associated with this combined endpoint (HR = 1.97, 95% CI 1.23-3.14; P = 0.005). Conclusions: The DECODE registry showed the 'real-world' experience of CRT-D recipients approaching device replacement, in which 7% of patients who no longer had an indication for ICD therapy experienced appropriate ICD interventions.

Sudden cardiac death in J wave syndrome with short QT associated to a novel mutation in Nav 1.8 coding gene SCN10A: First case report for a possible pharmacogenomic role.

INTRODUCTION: Sudden cardiac death is an important cause of mortality in the general population. It represents an important challenge for clinicians, often being the only symptom of a broad spectrum of cardiac pathologies and inherited heart conditions. Early repolarization syndrome and Brugada syndrome are part of the wider "J-wave" syndrome, which may also include the short QT syndrome as a third factor of an ionic channel imbalance in the arrhythmogenic landscape. CASE PRESENTATION: We describe the case of a woman struck down by sudden cardiac death, with short QT and early repolarization, in which we found an extremely rare and putatively pathogenic heterozygous variant in the SCN10A gene. Variants involving SCN10A, which encodes a voltage-gated sodium channel, were already associated with alterations of cardiac conduction parameters and the cardiac rhythm disorder, thereby influencing the cardiac physiology and predisposing to arrhythmia. CONCLUSION: We underline the role of genetic predisposition to sudden cardiac death and, for the first time, suggest a possible environmental effect, such as a pharmacological therapy in the setting of sudden death, with the purpose to increase awareness in clinical practice.

Sofosbuvir and ribavirin for genotype 2 HCV infected patients with cirrhosis: A real life experience.

BACKGROUND & AIMS: Sofosbuvir (SOF) and weight-based ribarivin (RBV) represented until recently the standard of care in hepatitis C virus (HCV) genotype (GT)2 patients. In registration studies 12-16weeks duration were associated with a 90% sustained virological response at 12weeks (SVR12). Real life cohorts showed lower SVR12 rates. METHODS: SVR12 rates attained in an Italian real life cohort and possible benefits of a duration extended up to 20weeks was investigated in HCV GT2 patients with cirrhosis. The role of 2k/1b chimeras as potential predictor of treatment failure was also analysed. RESULTS: Overall, 291 HCV GT2 infected patients with bridging fibrosis or cirrhosis were evaluated. Median age was 68years (18-87); 163 were treatment naïve. Of 168 cirrhotic patients, 149 had Child-Pugh score A and 19 B, 50 platelets count <100,000/mm3 and 62 albumin <3.5g/dl. SVR12 were 95.53% overall, with 99.15% in non-cirrhotic patients and 93.06% in cirrhotic patients. In patients who completed treatment, SVR rates for cirrhotic patients resulted in 94.51%, and 94.94% after 16 or 20weeks respectively. Predictors of SVR were low platelet count and esophageal varices (OR 7.2; 95% CI 1.67-31.25; p=0.0022 and OR 0.1; 95% CI 0.01-0.72; p=0.0079, respectively). Anemia was mild in 12.4%, moderate in 3.4%, and severe in 2.4% of cases. Anemia was slightly more frequent among longer duration but not associated with treatment discontinuations. No 2k/1b strains or genotypes different from those at baseline were identified at relapse. CONCLUSIONS: In GT2 cirrhotic patients, SOF/RBV for 16 or 20weeks is associated with real life SVR12 rates of 95%. LAY SUMMARY: A duration of treatment of 16-20weeks was recommended for treatment of HCV GT2 patients using the combination of sofosbuvir and ribavirin. Real life experiences, where patients received 12weeks of treatment regardless of the severity of liver disease, suggested that response rates are lower than expected, in particular in patients with liver cirrhosis. A misleading genotyping of a 2k/1b strain as GT2 was also hypothesized as a further explanation for less effectiveness. We demonstrated that using the recommended extended duration in patients with more severe disease 95% of patients with severe liver disease including cirrhosis can be cured and that 2k/1b strain plays only a secondary role in specific countries like Germany. Although this combination has been recently replaced by sofosbuvir and velpatasvir fixed dose combination as the standard of care for treating HCV GT2 patients, our findings may inform physicians from countries where the new regimen is not yet available.

Multipoint pacing via a quadripolar left-ventricular lead: preliminary results from the Italian registry on multipoint left-ventricular pacing in cardiac resynchronization therapy (IRON-MPP).

AIMS: This registry was created to describe the experience of 76 Italian centres with a large cohort of recipients of multipoint pacing (MPP) capable cardiac resynchronization therapy (CRT) devices. METHODS AND RESULTS: A total of 507 patients in whom these devices had been successfully implanted were enrolled between August 2013 and May 2015. We analysed: (i) current clinical practices for the management of such patients, and (ii) the impact of MPP on heart failure clinical composite response and on the absolute change in ejection fraction (EF) at 6 months. Multipoint pacing was programmed to 'ON' in 46% of patients before discharge. Methods of optimizing MPP programming were most commonly based on either the greatest narrowing of the QRS complex (38%) or the electrical delays between the electrodes (34%). Clinical and echocardiographic follow-up data were evaluated in 232 patients. These patients were divided into two groups according to whether MPP was programmed to 'ON' (n = 94) or 'OFF' (n = 138) at the time of discharge. At 6 months, EF was significantly higher in the MPP group than in the biventricular-pacing group (39.1 ± 9.6 vs. 34.7 ± 7.6%; P < 0.001). Even after adjustments, early MPP activation remained an independent predictor of absolute increase in LVEF of ≥5% (odds ratio 2.5; P = 0.001). At 6 months, an improvement in clinical composite score was recorded in a greater proportion of patients with MPP-ON than in controls (56 vs. 38%; P = 0.009). On comparing optimal MPP and conventional vectors, QRS was also seen to have decreased significantly (P < 0.001). CONCLUSION: This study provides information that is essential in order to deal with the expected increase in the number of patients receiving MPP devices in the coming years. The results revealed different practices among centres, and establishing the optimal programming that can maximize the benefit of MPP remains a challenging issue. Compared with conventional CRT, MPP improved clinical status and resulted in an additional increase in EF. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrial.gov/. Unique identifier: NCT02606071.

Device Longevity in a Contemporary Cohort of ICD/CRT-D Patients Undergoing Device Replacement.

INTRODUCTION: The longevity of defibrillators (ICD) is extremely important from both a clinical and economic perspective. We studied the reasons for device replacement, the longevity of removed ICD, and the existence of possible factors associated with shorter service life. METHODS AND RESULTS: Consecutive patients who underwent ICD replacement from March 2013 to May 2015 in 36 Italian centers were included in this analysis. Data on replaced devices were collected. A total of 953 patients were included in this analysis. In 813 (85%) patients the reason for replacement was battery depletion, while 88 (9%) devices were removed for clinical reasons and the remaining 52 because of system failure (i.e., lead or ICD generator failure or a safety advisory indication). The median service life was 5.9 years (25th-75th percentile, 4.9-6.9) for single- and dual-chamber ICD and 4.9 years (25th-75th percentile, 4.0-5.7) for CRT-D. On multivariate analysis, the factors CRT-D device, SC/DC ICD generator from Biotronik, percentage of ventricular pacing, and the occurrence of a system failure were positively associated with a replacement procedure. By contrast, the device from Boston Scientific was an independent protective factor against replacement. Considerable differences were seen in battery duration in both ICD and CRT-D. Specifically, Biotronik devices showed the shortest longevity among ICD and Boston Scientific showed the longest longevity among CRT-D (log-rank test, P < 0.001 for pairwise comparisons). CONCLUSION: Several factors were associated with shorter service life of ICD devices: CRT-D, occurrence of system failure and percentage of ventricular pacing. Our results confirmed significant differences among manufacturers.

The Role of TOMM40 in Cardiovascular Mortality and Conduction Disorders: An Observational Study.

Aims: TOMM40 single nucleotide polymorphism (SNP) rs2075650 consists of allelic variation c.275-31A > G and it has been linked to Alzheimer disease, apolipoprotein and cholesterol levels and other risk factors. However, data on its role in cardiovascular disorders are lacking. The first aim of the study is to evaluate mortality according to TOMM40 genotype in a cohort of selected patients affected by advanced atherosclerosis. Second aim was to investigate the relationship between Xg and AA alleles and the presence of conduction disorders and implantation of defibrillator (ICD) or pacemaker (PM) in our cohort. Materials and Methods: We enrolled 276 patients (mean age 70.16 ± 7.96 years) affected by hemodynamic significant carotid stenosis and/or ischemia of the lower limbs of II or III stadium Fontaine. We divided the population into two groups according to the genotype (Xg and AA carriers). We evaluated several electrocardiographic and echocardiographic parameters, including heart rate, rhythm, presence of right and left bundle branch block (LBBB and RBBB), PR interval, QRS duration and morphology, QTc interval, and left ventricular ejection fraction (LVEF). We clinically followed these patients for 82.53 ± 30.02 months and we evaluated the incidence of cardiovascular events, number of deaths and PM/ICD implantations. Results: We did not find a difference in total mortality between Xg and AA carriers (16.3 % vs. 19.4%; p = 0.62). However, we found a higher mortality for fatal cardiovascular events in Xg carriers (8.2% vs. 4.4%; HR = 4.53, 95% CI 1.179-17.367; p = 0.04) with respect to AA carriers. We noted a higher percentage of LBBB in Xg carriers (10.2% vs. 3.1%, p = 0.027), which was statistically significant. Presence of right bundle branch block (RBBB) was also higher in Xg (10.2% vs. 4.4%, p = 0.10), but without reaching statistically significant difference compared to AA patients. We did not observe significant differences in heart rate, presence of sinus rhythm, number of device implantations, PR and QTc intervals, QRS duration and LVEF between the two groups. At the time of enrolment, we observed a tendency for device implant in Xg carriers at a younger age compared to AA carriers (58.50 ± 0.71 y vs. 72.14 ± 11.11 y, p = 0.10). During the follow-up, we noted no statistical difference for new device implantations in Xg respect to AA carriers (8.2% vs. 3.5%; HR = 2.384, 95% CI 0.718-7.922; p = 0.156). The tendency to implant Xg at a younger age compared to AA patients was confirmed during follow-up, but without reaching a significant difference(69.50 ± 2.89 y vs. 75.63 ± 8.35 y, p = 0.074). Finally, we pointed out that Xg carriers underwent device implantation 7.27 ± 4.43 years before AA (65.83 ± 6.11 years vs. 73.10 ± 10.39 years) and that difference reached a statistically significant difference (p = 0.049) when we considered all patients, from enrollment to follow-up. Conclusions: In our study we observed that TOMM40 Xg patients affected by advanced atherosclerosis have a higher incidence of developing fatal cardiovascular events, higher incidence of LBBB and an earlier age of PM or ICD implantations, as compared to AA carriers. Further studies will be needed to evaluate the genomic contribution of TOMM40 SNPs to cardiovascular deaths and cardiac conduction diseases.

Involvement of APOE in Incidence of Revascularization in Patients Affected by Peripheral Arterial Disease: A Prospective Study from Southern Italy.

INTRODUCTION: Atherosclerosis is a complex multifactorial disease and apolipoprotein E (APOE) polymorphism has been associated with cardiovascular events. The APOE gene, located on chromosome 19q13.2, has an important role in lipid metabolism, in particular on circulating cholesterol levels, implying further pleiotropic effects; from its polymorphism are derived three alleles (ε2, ε3 and ε4), which induce different phenotypes, while its impact on carotid and femoral atherosclerosis is still controversial. OBJECTIVES: The aim of the study is to investigate the relationship between APOE genotypes and peripheral revascularization in a cohort of patients affected by advanced peripheral arterial disease (PAD) at a prolonged follow-up. MATERIALS AND METHODS: Some 332 patients (259 males and 73 females; mean age 70.86 ± 7.95 years) with severe PAD were enrolled in a longitudinal study, with a 90.75 ± 32.25 month follow-up, assessing major adverse cardiovascular events (MACE). RESULTS: As compared with ε3/ε3, in ε4 patients we observed a significant higher incidence of carotid (13.2% vs. 5.6%; HR = 2.485, 95% CI 1.062-5.814; p = 0.036) and lower limb (11.8% vs. 4.3%; HR = 2.765, 95% CI 1.091-7.008; p = 0.032) revascularizations and, accordingly, a higher incidence of total peripheral revascularizations (13.5% vs. 9.5%; HR = 2.705, 95% CI 1.420-5.151; p = 0.002). HR remained statistically significant even when adjusted for classic cardiovascular risk factors. CONCLUSIONS: In our observational study, we confirm that the ε4 allele is associated with higher total peripheral revascularization in patients with advanced atherosclerotic vascular disease at prolonged follow-up.

Pulmonary-vein isolation for atrial fibrillation in patients with heart failure.

BACKGROUND: Pulmonary-vein isolation is increasingly being used to treat atrial fibrillation in patients with heart failure. METHODS: In this prospective, multicenter clinical trial, we randomly assigned patients with symptomatic, drug-resistant atrial fibrillation, an ejection fraction of 40% or less, and New York Heart Association class II or III heart failure to undergo either pulmonary-vein isolation or atrioventricular-node ablation with biventricular pacing. All patients completed the Minnesota Living with Heart Failure questionnaire (scores range from 0 to 105, with a higher score indicating a worse quality of life) and underwent echocardiography and a 6-minute walk test (the composite primary end point). Over a 6-month period, patients were monitored for both symptomatic and asymptomatic episodes of atrial fibrillation. RESULTS: In all, 41 patients underwent pulmonary-vein isolation, and 40 underwent atrioventricular-node ablation with biventricular pacing; none were lost to follow-up at 6 months. The composite primary end point favored the group that underwent pulmonary-vein isolation, with an improved questionnaire score at 6 months (60, vs. 82 in the group that underwent atrioventricular-node ablation with biventricular pacing; P<0.001), a longer 6-minute-walk distance (340 m vs. 297 m, P<0.001), and a higher ejection fraction (35% vs. 28%, P<0.001). In the group that underwent pulmonary-vein isolation, 88% of patients receiving antiarrhythmic drugs and 71% of those not receiving such drugs were free of atrial fibrillation at 6 months. In the group that underwent pulmonary-vein isolation, pulmonary-vein stenosis developed in two patients, pericardial effusion in one, and pulmonary edema in another; in the group that underwent atrioventricular-node ablation with biventricular pacing, lead dislodgment was found in one patient and pneumothorax in another. CONCLUSIONS: Pulmonary-vein isolation was superior to atrioventricular-node ablation with biventricular pacing in patients with heart failure who had drug-refractory atrial fibrillation. (ClinicalTrials.gov number, NCT00599976.)

Phenotypic Variability of a Pathogenic PKP2 Mutation in an Italian Family Affected by Arrhythmogenic Cardiomyopathy and Juvenile Sudden Death: Considerations From Molecular Autopsy to Sport Restriction.

Background: Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder with an estimated prevalence between 1:2,000 and 1:5,000 and is characterized by the fibrofatty replacement of cardiomyocytes that predisposes to malignant arrhythmias, heart failure, and sudden cardiac death. The diagnosis is based on the 2010 Task Force Criteria including family history, electrocardiographic traits and arrhythmogenic pattern, specific gene mutations, and structural and/or histological abnormalities. Most ACMs display an autosomal dominant mode of inheritance often with incomplete penetrance and variable expressivity. Genetic screening of patients with ACM identifies pathogenic or likely pathogenic variants, prevalently in genes encoding the cardiac desmosome (PKP2, DSP, DSC2, DSG2, and JUP) or less frequently in non-desmosomal genes (CTNNA3, PLN, TMEM43, RYR2, SCN5A, CDH2, and DES). Methods: In the present study, we performed molecular autopsy in a boy who died suddenly during physical exertion. In addition to post-mortem examination, a DNA sample was analyzed with next-generation sequencing (NGS). Results: The genetic analysis revealed the presence of pathogenic heterozygous c.314del (p.Pro105Leufs*7) frameshift variant in the PKP2 gene. Cascade screening of family members allowed us to identify 12 mutation carriers and to intervene on subjects at risk, many of whom were athletes. Conclusions: Molecular autopsy can establish cardiogenetic diagnosis and allow appropriate preventative measures in high-risk relatives.

A high number of 'natural' mitochondrial DNA polymorphisms in a symptomatic Brugada syndrome type 1 patient.

Brugada syndrome (BrS) is a rare genetic arrhythmic disorder with a complex model of transmission. At least 20 different genes have been identified as BrS-causal or susceptibility genes. Of these, SCN5A is the most frequently mutated. Coregulation of different mutations or genetic variants, including mitochondrial DNA (mtDNA), may contribute to the clinical phenotype of the disease. In thepresent study, we analysed the mitochondrial genome of a symptomatic BrS type 1 patient to investigate a possible mitochondrial involvement recently found in the arrhytmogenic diseases. No pathogenic mutation was identified; however, a high number of singlenucleotide polymorphisms were found (n=21) and some of them were already been reported in molecular autopsy case for sudden death.The results reported here further support our hypothesis on the potential role of mtDNA polymorphisms in mitochondrial dysfunction, which may represent a risk factor for arrhythmogenic disease.

Role of Subclinical Iatrogenic Hyperthyroidism in the Setting of Heart Disease and Arrhythmic Burden.

BACKGROUND: Subclinical hyperthyroidism is defined by a subnormal serum thyroidstimulating hormone (TSH) level with normal free thyroxine (FT4) and free triiodothyronine (FT3) levels. Its prevalence varies from 0.6% to 16% in the elderly and can increase to 20% in patients receiving thyroid hormone replacement therapy. Thyroid disease and/or replacement therapy are frequently associated with cardiovascular involvement. CASES PRESENTATION: We report three clinical cases of patients with initial subclinical hyperthyroidism and cardiological manifestations, including supraventricular and ventricular extrasystoles, prolapse of the mitral valve with severe regurgitation, higher mean heart rate and deterioration of the arrhythmias on arrhythmogenic dysplasia substrate. CONCLUSION: We discuss the role of appropriate and early correction of thyroid dysfunction in improving cardiological manifestations.

Electrical Remodeling of Ventricular Repolarization Abnormality after Treatment in Pheochromocytoma: U Wave Finding in a Retrospective Analysis.

Background: Pheochromocytoma is a rare neuroendocrine tumor, clinically characterized by high blood pressure, palpitations, and headache. It is often associated with abnormalities of the ventricular repolarization phase; the dispersion of ventricular repolarization is the basis for ventricular arrhythmias (torsion de point, ventricular tachycardia or ventricular fibrillation). Objectives: Analysis of abnormal ventricular repolarization focused on the presence and amount of U wave in patients affected by pheochromocytoma and its modification after surgery. Materials and Methods: We reviewed pathology records of 722 patients admitted for adrenal nodule or suspected chromaffin-cell tumor and identified 39 patients affected by pheochromocytoma. Metanephrine, normetanephrine, and 3-methoxytyramine have been assessed by determining concentrations in 24-hour urine collection. Standard 12-lead electrocardiogram records have been reviewed with analysis of heart rate, P wave, PR interval, QRS duration, QTc, and U wave. Then we selected and compared 22 patients of 39 affected by pheochromocytoma, with both clinical and electrocardiographic data before and after surgery. Results: In our cohort of 39 patients affected by pheochromocytoma, we found U wave in ECG, before treatment, in 82.8 percent of patients, while only 37.0 percent after treatment (p<0.001) and we observed a statistically significant correlation between this wave and the urinary metanephrine. After surgery, in the selected 22 patients, we observed a clear significant reduction in systemic blood pressure, fasting glucose, metanephrine, normetanephrine, and 3-methoxytyramine. We found a significant reduction of U wave presence and leads involved in these patients after surgery (90.9% versus 9%). We observed a linear correlation between the amount of U waves in 12-lead electrocardiogram and metanephrine (r2=0.333, p=0.015), 3-methoxytyramine levels (r2=0.458, p=0.006), and tumor size (r2=0.429, p=0.003). Conclusions: In our retrospective analysis, patients affected by pheochromocytoma presented U wave in electrocardiogram. The presence and amount of U wave were associated with the metanephrine levels and the tumor size with significant reduction after surgical removal.