Genotype-phenotype correlation in arrhythmogenic right ventricular cardiomyopathy-risk of arrhythmias and heart failure.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is predominantly caused by desmosomal genetic variants, and clinical hallmarks include arrhythmias and systolic dysfunction. We aimed at studying the impact of the implicated gene(s) on the disease course. METHODS: The Nordic ARVC Registry holds data on a multinational cohort of ARVC families. The effects of genotype on electrocardiographic features, imaging findings and clinical events were analysed. RESULTS: We evaluated 419 patients (55% men), with a mean follow-up of 11.2±7.4 years. A pathogenic desmosomal variant was identified in 62% of the 230 families: PKP2 in 41%, DSG2 in 13%, DSP in 7% and DSC2 in 3%. Reduced left ventricular ejection fraction (LVEF) ≤45% on cardiac MRI was more frequent among patients with DSC2/DSG2/DSP than PKP2 ARVC (27% vs 4%, p<0.01). In contrast, in Cox regression modelling of patients with definite ARVC, we found a higher risk of arrhythmias among PKP2 than DSC2/DSG2/DSP carriers: HR 0.25 (0.10-0.68, p<0.01) for atrial fibrillation/flutter, HR 0.67 (0.44-1.0, p=0.06) for ventricular arrhythmias and HR 0.63 (0.42-0.95, p<0.05) for any arrhythmia. Gene-negative patients had an intermediate risk (16%) of LVEF ≤45% and a risk of the combined arrhythmic endpoint comparable with DSC2/DSG2/DSP carriers. Male sex was a risk factor for both arrhythmias and reduced LVEF across all genotype groups (p<0.01). CONCLUSION: In this large cohort of ARVC families with long-term follow-up, we found PKP2 genotype to be more arrhythmic than DSC2/DSG2/DSP or gene-negative carrier status, whereas reduced LVEF was mostly seen among DSC2/DSG2/DSP carriers. Male sex was associated with a more severe phenotype.

Effect of Rehabilitation on Sleep Quality After Ablation for Atrial Fibrillation: Data From a Randomized Trial.

BACKGROUND: Low sleep quality is common in patients with atrial fibrillation (AF). Positive effects of cardiac rehabilitation on patients treated for AF with ablation have been found, but whether cardiac rehabilitation affects sleep quality is unknown. The objectives of this study were to investigate (1) differences in sleep quality between cardiac rehabilitation and usual care groups and (2) whether other factors could affect sleep quality. METHODS: From the randomized CopenHeartRFA trial, 210 patients treated for AF with ablation were included. A rehabilitation program consisting of physical exercise and psychoeducational consultations was tested. Sleep quality was measured with the Pittsburg Sleep Quality Index (PSQI) questionnaire before intervention and at the end of intervention. Anxiety, depression, and European Heart Rhythm Association scores were assessed. RESULTS: No difference between groups in sleep quality was found (PSQI global mean [SD] score, 6.60 [3.61] points for the cardiac rehabilitation group [n = 83] and 6.08 [3.60] points for the usual care group [n = 90]; P = .34), although improvements in sleep quality were noted in both groups. Sleep latency, duration, and efficiency were significant by type of AF at 1 month. Anxiety, depression, and higher European Heart Rhythm Association scores at 4 months were associated with a higher PSQI global mean score at the end of intervention. CONCLUSION: The rehabilitation program showed no effect on sleep quality. A large proportion of patients reported poor sleep quality, and patients reporting anxiety, depression, or AF symptoms described worse sleep quality compared with patients who did not experience anxiety, depression, or AF symptoms. More research in the field is warranted.

Rationale, design, and baseline characteristics of the DANish randomized, controlled, multicenter study to assess the efficacy of Implantable cardioverter defibrillators in patients with non-ischemic Systolic Heart failure on mortality (DANISH).

BACKGROUND: The effect of an implantable cardioverter defibrillator (ICD) in patients with symptomatic systolic heart failure (HF) caused by coronary artery disease is well documented. However, the effect of primary prophylactic ICDs in patients with systolic HF not due to coronary artery disease is much weaker. In addition, HF management has improved, since the landmark ICD trials and a large proportion of patients now receive cardiac resynchronization therapy (CRT) where the effect of ICD treatment is unknown. METHODS: In the DANISH study, 1,116 patients with symptomatic systolic HF not caused by coronary artery disease have been randomized to receive an ICD or not, in addition to contemporary standard therapy. The primary outcome of the trial is time to all-cause death. Follow-up will continue until June 2016 with a median follow-up period of 5 years. Baseline characteristics show that enrolled patients are treated according to current guidelines. At baseline, 97% of patients received an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, 92% received a ß-blocker, 58% a mineralocorticoid receptor antagonist, and 58% were scheduled to receive CRT. Median age was 63 years (range, 21-84 years) at baseline, and 28% were women. CONCLUSION: DANISH will provide pertinent information about the effect on all-cause mortality of a primary prophylactic ICD in patients with symptomatic systolic HF not caused by coronary artery disease on contemporary standard therapy including CRT.

Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval.

AIMS: We studied whether variants previously associated with congenital long QT syndrome (cLQTS) have an effect on the QTc interval in a Danish population sample. Furthermore, we assessed whether carriers of variants in cLQTS-associated genes are more prone to experience syncope compared with non-carriers and whether carriers have an increased mortality compared with non-carriers. METHODS AND RESULTS: All genetic variants previously associated with cLQTS were surveyed using the Human Gene Mutation Database. We screened a Danish population-based sample with available whole-exome sequencing data (n = 870) and genotype array data (n = 6161) for putative cLQTS genetic variants. In total, 33 of 1358 variants previously reported to associate with cLQTS were identified. Of these, 10 variants were found in 8 or more individuals. Electrocardiogram results showed normal mean QTc intervals in carriers compared with non-carriers. Syncope data analysis between variant and non-variant carriers showed that 4 of 227 (1.8%) and 95 of 5861 (1.6%) individuals, respectively, had experienced syncope during follow-up (P = 0.80). There was no significant difference in overall mortality rates between carriers [7/217 (3.2%)] and non-carriers [301/6453 (4.7%)] (P = 0.24). CONCLUSION: We present QTc data and register data, indicating that 26 cLQTS-associated variants neither had any effect on the QTc intervals nor on syncope propensity or overall mortality. Based on the frequency of individual gene variants, we suggest that the 10 variants frequently identified, assumed to relate to cLQTS, are less likely to associate with a dominant monogenic form of the disease.

The acquisition and retention of ECG interpretation skills after a standardized web-based ECG tutorial-a randomised study.

BACKGROUND: Electrocardiogram (ECG) interpretation is of great importance for patient management. However, medical students frequently lack proficiency in ECG interpretation and rate their ECG training as inadequate. Our aim was to examine the effect of a standalone web-based ECG tutorial and to assess the retention of skills using multiple follow-up intervals. METHODS: 203 medical students were included in the study. All participants completed a pre-test, an ECG tutorial, and a post-test. The participants were also randomised to complete a retention-test after short (2-4 weeks), medium (10-12 weeks), or long (18-20 weeks) follow-up. Intragroup comparisons of test scores were done using paired-samples t-test. Intergroup comparisons of test scores were performed using independent-samples t-test and ANOVA, whereas demographic data were compared using ANOVA and Chi-squared test. RESULTS: The overall mean test score improved significantly from 52.7 (SD 16.8) in the pre-test to 68.4 (SD 12.3) in the post-test (p < 0.001). Junior and senior students demonstrated significantly different baseline scores (45.5 vs. 57.8 points; p < 0.001), but showed comparable score gains (16.5 and 15.1 points, respectively; p = 0.48). All three follow-up groups experienced a decrease in test score between post-test and retention-test: from 67.4 (SD 12.3) to 60.2 (SD 8.3) in the short follow-up group, from 71.4 (SD 12.0) to 60.8 (SD 8.9) in the medium follow-up group, and from 66.1 (SD 12.1) to 58.6 (SD 8.6) in the long follow-up group (p < 0.001 for all). However, there were no significant differences in mean retention-test score between the groups (p = 0.33). Both junior and senior students showed a decline in test score at follow-up (from 62.0 (SD 10.6) to 56.2 (SD 9.8) and from 72.9 (SD 11.4) to 62.5 (SD 6.6), respectively). When comparing the pre-test to retention-test delta scores, junior students had learned significantly more than senior students (junior students improved 10.7 points and senior students improved 4.7 points, p = 0.003). CONCLUSION: A standalone web-based ECG tutorial can be an effective means of teaching ECG interpretation skills to medical students. The newly acquired skills are, however, rapidly lost when the intervention is not repeated.

Are medical students being taught anatomy in a way that best prepares them to be a physician?

Reasoning in a clinical context is an attribute of medical expertise. Clinical reasoning in medical school can be encouraged by teaching basic science with a clinical emphasis. The aim of this study was to investigate whether anatomy is being taught in a way that facilitates the development of clinical reasoning. Two multiple-choice tests on thoracic anatomy were developed using a modified Delphi approach with groups of four clinical consultants and four teachers, respectively, expressing their opinions about knowledge relevant to thoracic anatomy. Validity was assessed by administering the tests to clinical consultants, anatomy teachers, and pre-course medical students. Post-course medical students took both tests to explore the focus of the course, i.e., whether it facilitated clinical reasoning. The pre-course students scored significantly lower than the teachers and post-course students on both tests and lower than the consultants on the consultants' test (P < 0.001 for all comparisons). The teachers significantly outperformed the consultants (P = 0.03 on the consultants' test, P < 0.001 on the teachers' test) and the medical students (P < 0.001 on both tests). The post-course students scored significantly lower on the consultants' test (P = 0.001) and significantly higher on the teachers' test (P = 0.02) than the consultants. This study demonstrates poor performances by medical students on a test containing clinically relevant anatomy, implying that the teaching they have received has not encouraged clinical reasoning.

Anxiety predicts mortality in ICD patients: results from the cross-sectional national CopenHeartICD survey with register follow-up.

BACKGROUND: Although highly effective in preventing arrhythmic death, patients receiving an implantable cardioverter defibrillator (ICD) may still experience psychological difficulties such as anxiety, depression, and reduced quality of life. The objectives of this study were to describe patient-reported outcomes among ICD patients: (1) compared to a matched healthy population, (2) compared by ICD indication, (3) factors predicting patient-reported outcomes, and (4) if patient-reported outcomes predicted mortality. METHODS: The study was a mailed survey to an unselected group of patients 18+ years old receiving ICD between January 1, 2011 and June 30, 2011 (n = 499). The following instruments were used: SF-36, Hospital Anxiety and Depression Scale, HeartQoL, EQ-5D, and the Multidimensional Fatigue Inventory. RESULTS: The response rate was 72%. Mean age was 65.5 years and 82% patients were males. Fifty-three percent of patients had primary prevention indication ICD. Compared to an age- and gender-matched population without disease, the ICD population had worse mental health (55.0 vs 51.7 points) and physical health (52.6 vs 41.9 points). Patients with primary prevention indication had lower levels of perceived health, quality of life, and fatigue; for example, physical health 39.8 versus 44.3 points, compared to secondary prevention indication. Anxiety, poor perceived health, fatigue, and low quality of life were all predictors of mortality, anxiety being the strongest with an adjusted odds ratio of 4.17 (1.49; 11.66). CONCLUSIONS: Patients with primary prevention ICD had lower levels of perceived health, quality of life, and more fatigue. Anxiety, poor perceived health, fatigue, and low quality of life were all predictors of mortality.

Novel oral anticoagulants for stroke prevention in atrial fibrillation: results of the European Heart Rhythm Association survey.

The purpose of this European Heart Rhythm Association (EHRA) survey was to assess clinical practice in relation to stroke prevention in atrial fibrillation (AF), particularly into the use of novel oral anticoagulants (NOACs) for stroke prevention, among members of the EHRA electrophysiology (EP) research network. In this EP Wire survey, we have provided some insights into current practice in Europe for the use of NOACs for stroke prevention in AF. There were clear practice differences evident, and also the need for greater adherence to the guidelines, especially since guideline adherent management results in better outcomes in AF.

Renal 123I-MIBG Uptake before and after Live-Donor Kidney Transplantation.

Increased sympathetic activity is suggested to be part of the pathogenesis in several diseases. Methods to evaluate sympathetic activity and renal nervous denervation procedural success are lacking. Scintigraphy using the norepinephrine analog Iodine-123 Metaiodobenzylguanidine (123I-MIBG) might provide information on renal sympathetic nervous activity. Renal transplantation induces complete denervation of the kidney and as such represents an ideal model to evaluate the renal 123I-MIBG scintigraphy method. The aim of this study was to evaluate whether renal 123I-MIBG scintigraphy can detect changes in renal sympathetic nervous activity following renal transplantation. Renal 123I-MIBG scintigraphy was performed in eleven renal transplant recipients at 1, 3, and 6 months following transplantation and in their respective living donors prior to their kidney donation. Relative uptake as well as washout was obtained. In transplanted patients, the relative 4 h uptake of 123I-MIBG, as measured by the kidney/background ratio, was 2.7 (0.4) (mean (SD)), 2.7 (0.5), and 2.5 (0.4) at 1, 3, and 6 months post-transplantation, respectively, as compared with the 4.0 (0.4) value in the donor kidney before donor nephrectomy (p < 0.01). There was no significant change in washout-rate between pre-transplantation and any of the follow-up time points. Living donor kidney transplantation was at 6 months post transplantation, associated with an almost 40% reduction in the relative 4 h 123I-MIBG uptake of the kidney. Further studies will help to fully establish its implications as a marker of renal innervation or denervation.

Impact of device programming on the success of the first anti-tachycardia pacing therapy: An anonymized large-scale study.

BACKGROUND: Antitachycardia pacing (ATP) is an effective treatment for ventricular tachycardia (VT). We evaluated the efficacy of different ATP programs based on a large remote monitoring data set from patients with implantable cardioverter-defibrillators (ICDs). METHODS: A dataset from 18,679 ICD patients was used to evaluate the first delivered ATP treatment. We considered all device programs that were used for at least 50 patients, leaving us with 7 different programs and a total of 32,045 episodes. We used the two-proportions z-test (α = 0.01) to compare the probability of success and the probability for acceleration in each group with the corresponding values of the default setting. RESULTS: Overall, the first ATP treatment terminated in 78.4%-97.5% of episodes with slow VT and 81.5%-91.1% of episodes with fast VT. The default setting of the ATP programs with the number of sequences S = 3 was applied to treat 30.1% of the slow and 36.6% of the fast episodes. Reducing the maximum number of sequences to S = 2 decreased the success rate for slow VT (P < 0.0001, h = 0.38), while the setting S = 4 resulted in the highest success rate of 97.5% (P < 0.0001, h = 0.27). CONCLUSION: While the default programs performed well, we found that increasing the number of sequences from 3 to 4 was a promising option to improve the overall ATP performance.

Duration of Heart Failure and Effect of Defibrillator Implantation in Patients With Nonischemic Systolic Heart Failure.

BACKGROUND: Patients with nonischemic systolic heart failure (HF) have increased risk of sudden cardiac death (SCD) and death from progressive pump failure. Whether the risk of SCD changes over time is unknown. We seek here to investigate the relation between duration of HF, mode of death, and effect of implantable cardioverter-defibrillator implantation. METHODS AND RESULTS: We examined the risk of all-cause death and SCD according to the duration of HF among patients with nonischemic systolic HF enrolled in the DANISH (Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality). In all, 1116 patients were included. Patients were divided according to quartiles of HF duration (≤8, 9≤18, 19≤65, and ≥66 months). Patients with the longest duration of HF were older, more often men, had more comorbidity, and more often received a cardiac resynchronization therapy device. Doubling of HF duration was an independent predictor of both all-cause mortality (hazard ratio [HR], 1.27; 95% CI, 1.17-1.38; P<0.0001), and SCD (HR, 1.29; 95% CI, 1.11-1.50; P=0.0007). The proportion of deaths caused by SCD was not different between HF quartiles (P=0.91), and the effect of implantable cardioverter-defibrillator implantation on all-cause mortality was not modified by the duration of HF (P=0.59). CONCLUSIONS: Duration of HF predicted both all-cause mortality and risk of SCD independently of other risk indicators. However, the proportion of death caused by SCD did not change with longer duration of HF, and the effect of implantable cardioverter-defibrillator was not modified by the duration of HF. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00542945.

Role of PR-Interval In Predicting the Occurrence of Atrial Fibrillation.

The identification of individuals at high risk of developing atrial fibrillation (AF) is important to prevent potentially lethal and invalidating complications of this arrhythmia. Recently, several studies have investigated the association between PR-interval and the risk of AF and have tested the value of PR-interval in personalized risk scores for AF. However, the results of these studies are generally conflicting. When looking for an association between a prolonged PR-interval (first-degree atrioventricular [AV] block vs. normal PR-interval) and an increased risk of AF, not all studies were able to find a consistent and statistically significant association. In two recent studies, however, the investigators were able to show an increased risk of AF for individuals with PR-intervals in the short range compared with individuals in the middle range. The existence of a true U-shaped relationship could potentially explain part of the conflicting results from investigators only looking for an increased risk for longer PR-intervals. However, regardless of these speculations, the association seems relatively weak. The significance of PR-interval in risk prediction of AF has been tested in three independent risk scores where model selection primarily was based on improvement in c-statistics. In one risk score, PR-interval improved the predictive value of the risk model, whereas it did not in the other two risk scores. Further studies are warranted before any final conclusion can be drawn, although based on the current evidence, it is reasonable to conclude that the predictive value of PR-interval in AF risk prediction is limited.

The CopenHeartSF trial--comprehensive sexual rehabilitation programme for male patients with implantable cardioverter defibrillator or ischaemic heart disease and impaired sexual function: protocol of a randomised clinical trial.

INTRODUCTION: Sexuality is an important part of people's physical and mental health. Patients with heart disease often suffer from sexual dysfunction. Sexual dysfunction has a negative impact on quality of life and well-being in persons with heart disease, and sexual dysfunction is associated with anxiety and depression. Treatment and care possibilities seem to be lacking. Studies indicate that non-pharmacological interventions such as exercise training and psychoeducation possess the potential of reducing sexual dysfunction in patients with heart disease. The CopenHeartSF trial will investigate the effect of a comprehensive sexual rehabilitation programme versus usual care. METHODS AND ANALYSIS: CopenHeartSF is an investigator-initiated randomised clinical superiority trial with blinded outcome assessment, with 1:1 central randomisation to sexual rehabilitation plus usual care versus usual care alone. Based on sample size calculations, 154 male patients with impaired sexual function due to implantable cardioverter defibrillator or ischaemic heart disease will be included from two university hospitals in Denmark. All patients receive usual care and patients allocated to the experimental intervention group follow a 12-week sexual rehabilitation programme consisting of an individualised exercise programme and psychoeducative consultation with a specially trained nurse. The primary outcome is sexual function measured by the International Index of Erectile Function. The secondary outcome measure is psychosocial adjustment to illness by the Psychosocial Adjustment to Illness Scale, sexual domain. A number of explorative analyses will also be conducted. ETHICS AND DISSEMINATION: CopenHeartSF is approved by the regional ethics committee (no H-4-2012-168) and the Danish Data Protection Agency (no 2007-58-0015) and is performed in accordance with good clinical practice and the Declaration of Helsinki in its latest form. REGISTRATION: Clinicaltrials.gov identifier: NCT01796353.

Advanced quantitative echocardiography in arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular (RV) cardiomyopathy (ARVC) is a regional disease of the RV myocardium with variable degrees of left ventricular involvement. Three-dimensional echocardiography and Doppler tissue imaging (DTI) are new echocardiographic modalities for the evaluation of global and regional function, but the diagnostic potential remains to be assessed. METHODS: Twenty patients with previously established ARVC were evaluated by 3-dimensional echocardiography and DTI, and compared with 32 age- and sex-matched control subjects. RESULTS: Using 3-dimensional echocardiography, patients with ARVC had a decreased RV ejection fraction (0.47 +/- 0.08 vs 0.53 +/- 0.05, P < .01), and a decreased peak lateral systolic annular velocity by pulsed wave imaging of both the RV (11.9 +/- 2.6 vs 15.1 +/- 3.7 cm/s, P < .01) and the left ventricle (7.0 +/- 2.6 vs 9.5 +/- 1.9 cm/s, P < .01). DTI showed decreased regional systolic strain, but with wide variation in the measurements. CONCLUSION: Three-dimensional echocardiography identifies decreased RV ejection fraction in ARVC. Assessment of regional contractility by DTI is limited by wide variation. Echocardiographic evaluation of the longitudinal motility appears to be a sensitive marker of preclinical left ventricular involvement.

Mechanisms for enlarging lesion size during irrigated tip radiofrequency ablation: is there a virtual electrode effect?

INTRODUCTION: Irrigated tip radiofrequency ablation of cardiac arrhythmias was developed to increase the size of the radiofrequency-induced lesion, since cooling of the electrode tip allows use of higher power settings. The purpose of this study was to determine if the increased lesion size during irrigated tip ablation is caused by the cooling effect solely or if increased electrical conductivity around the tip also contributes by increasing the "current-delivering size" of the tip: the so-called "virtual electrode effect." METHODS AND RESULTS: In vitro strips of left ventricular porcine myocardium and in vivo canine left ventricles were ablated. In vitro closed loop tip and showerhead irrigated tip catheters were compared. In vitro and in vivo showerhead tip catheters irrigated with solutions having different ionic content were compared. We found no difference in lesion size for closed loop and showerhead-type catheters (998 +/- 345 vs. 811 +/- 313 mm(3) during power-controlled ablation and 227 +/- 76 vs 318 +/- 127 mm(3) during temperature-controlled ablation). For irrigation with liquids having increasing ionic strength we found a decrease in lesion volume in vitro (361 +/- 249 vs. 812 +/- 229 mm(3) (P < 0.001) for power-controlled and 156 +/- 78 vs. 318 +/- 127 mm(3) (P < 0.05) for temperature-controlled ablation and nonsignificant differences in vivo. CONCLUSIONS: The mechanism for enlarging lesion size during radiofrequency irrigated-tip ablation is that higher power levels can be used. There is no virtual electrode effect caused by the highly conductive surroundings of the tip during irrigation. In vitro this effect is shown to be opposite: it decreases lesion size.