Utility of Left and Right Ventricular Strain in Arrhythmogenic Right Ventricular Cardiomyopathy: A Prospective Multicenter Registry.

BACKGROUND: Imaging evaluation of arrhythmogenic right ventricular cardiomyopathy (ARVC) remains challenging. Myocardial strain assessment by echocardiography is an increasingly utilized technique for detecting subclinical left ventricular (LV) and right ventricular (RV) dysfunction. We aimed to evaluate the diagnostic and prognostic utility of LV and RV strain in ARVC. METHODS: Patients with suspected ARVC (n = 109) from a multicenter registry were clinically phenotyped using the 2010 ARVC Revised Task Force Criteria and underwent baseline strain echocardiography. Diagnostic performance of LV and RV strain was evaluated using the area under the receiver operating characteristic curve analysis against the 2010 ARVC Revised Task Force Criteria, and the prognostic value was assessed using the Kaplan-Meier analysis. RESULTS: Mean age was 45.3±14.7 years, and 48% of patients were female. Estimation of RV strain was feasible in 99/109 (91%), and LV strain was feasible in 85/109 (78%) patients. ARVC prevalence by 2010 ARVC Revised Task Force Criteria is 91/109 (83%) and 83/99 (84%) in those with RV strain measurements. RV global longitudinal strain and RV free wall strain had diagnostic area under the receiver operating characteristic curve of 0.76 and 0.77, respectively (both P<0.001; difference NS). Abnormal RV global longitudinal strain phenotype (RV global longitudinal strain > -17.9%) and RV free wall strain phenotype (RV free wall strain > -21.2%) were identified in 41/69 (59%) and 56/69 (81%) of subjects, respectively, who were not identified by conventional echocardiographic criteria but still met the overall 2010 ARVC Revised Task Force Criteria for ARVC. LV global longitudinal strain did not add diagnostic value but was prognostic for composite end points of death, heart transplantation, or ventricular arrhythmia (log-rank P=0.04). CONCLUSIONS: In a prospective, multicenter registry of ARVC, RV strain assessment added diagnostic value to current echocardiographic criteria by identifying patients who are missed by current echocardiographic criteria yet still fulfill the diagnosis of ARVC. LV strain, by contrast, did not add incremental diagnostic value but was prognostic for identification of high-risk patients.

Genetic variant annotation scores in congenital long QT syndrome.

BACKGROUND: Congenital Long QT Syndrome (LQTS) is a hereditary arrhythmic disorder. We aimed to assess the performance of current genetic variant annotation scores among LQTS patients and their predictive impact. METHODS: We evaluated 2025 patients with unique mutations for LQT1-LQT3. A patient-specific score was calculated for each of four established genetic variant annotation algorithms: CADD, SIFT, REVEL, and PolyPhen-2. The scores were tested for the identification of LQTS and their predictive performance for cardiac events (CE) and life-threatening events (LTE) and then compared with the predictive performance of LQTS categorization based on mutation location/function. Score performance was tested using Harrell's C-index. RESULTS: A total of 917 subjects were classified as LQT1, 838 as LQT2, and 270 as LQT3. The identification of a pathogenic variant occurred in 99% with CADD, 92% with SIFT, 100% with REVEL, and 86% with PolyPhen-2. However, none of the genetic scores correlated with the risk of CE (Harrell's C-index: CADD = 0.50, SIFT = 0.51, REVEL = 0.50, and PolyPhen-2 = 0.52) or LTE (Harrell's C-index: CADD = 0.50, SIFT = 0.53, REVEL = 0.54, and PolyPhen-2 = 0.52). In contrast, high-risk mutation categorization based on location/function was a powerful independent predictor of CE (HR = 1.88; p < .001) and LTE (HR = 1.89, p < .001). CONCLUSION: In congenital LQTS patients, well-established algorithms (CADD, SIFT, REVEL, and PolyPhen-2) were able to identify the majority of the causal variants as pathogenic. However, the scores did not predict clinical outcomes. These results indicate that mutation location/functional assays are essential for accurate interpretation of the risk associated with LQTS mutations.

Design and characteristics of the prophylactic intra-operative ventricular arrhythmia ablation in high-risk LVAD candidates (PIVATAL) trial.

BACKGROUND: The use of a Left Ventricular Assist Device (LVAD) in patients with advanced heart failure refractory to optimal medical management has progressed steadily over the past two decades. Data have demonstrated reduced LVAD efficacy, worse clinical outcome, and higher mortality for patients who experience significant ventricular tachyarrhythmia (VTA). We hypothesize that a novel prophylactic intra-operative VTA ablation protocol at the time of LVAD implantation may reduce the recurrent VTA and adverse events postimplant. METHODS: We designed a prospective, multicenter, open-label, randomized-controlled clinical trial enrolling 100 patients who are LVAD candidates with a history of VTA in the previous 5 years. Enrolled patients will be randomized in a 1:1 fashion to intra-operative VTA ablation (n = 50) versus conventional medical management (n = 50) with LVAD implant. Arrhythmia outcomes data will be captured by an implantable cardioverter defibrillator (ICD) to monitor VTA events, with a uniform ICD programming protocol. Patients will be followed prospectively over a mean of 18 months (with a minimum of 9 months) after LVAD implantation to evaluate recurrent VTA, adverse events, and procedural outcomes. Secondary endpoints include right heart function/hemodynamics, healthcare utilization, and quality of life. CONCLUSION: The primary aim of this first-ever randomized trial is to assess the efficacy of intra-operative ablation during LVAD surgery in reducing VTA recurrence and improving clinical outcomes for patients with a history of VTA.

A QTc risk score in patients with obstructive sleep apnea.

INTRODUCTION: Patients with obstructive sleep apnea (OSA) are at risk for QTc prolongation, a known risk factor for increased mortality. The pro-QTc score can help identify individuals at increased risk for mortality associated with increased QTc however, it has not been evaluated in patients with OSA. The goal of this study was to evaluate the pro-QTc score in patients with OSA. METHODS: Medical records of patients undergoing a sleep study at our sleep center from February 2012 to August 2020 were analyzed. Presence or absence of OSA was determined by polysomnography. The pro-QTc score was calculated with 1 point assigned for each of the following: female sex, QT-prolonging diagnoses and conditions, QT-prolonging electrolyte abnormalities, and medications with known risk for QT-prolongation. Mortality was determined from the electronic medical record of an integrated healthcare system. RESULTS: There were 2246 patients (age 58 ± 15 years, 54% male, 82 dead) with OSA and 421 patients (age 54 ± 18 years, 43% male, 18 dead) without OSA. Of those with OSA, 1628 (72.5%) had at least one risk factor for QTc prolongation. A higher pro-QTc score was associated with greater mortality in patients with OSA (HR 1.48 per pro-QTc score, p < 0.001, 95% CI 1.3-1.7) but not in patients without OSA (HR 1.25 per pro-QTc score, p = 0.30, 95% CI 0.82-1.9), after adjusting for age, body mass index (BMI), and smoking status. CONCLUSION: In patients with OSA, a higher pro-QTc score was associated with greater mortality.

Newly developed cardiovascular risk factors in rheumatoid arthritis patients initiating biologic treatment.

Introduction: Rheumatoid arthritis (RA) is a risk factor (RF) for cardiovascular (CV) disease, a leading cause of mortality in RA patients. Material and methods: Consecutive records of RA patients with high disease activity screened upon biologic therapy initiation were reviewed between January 2001 and 2018. Patients with at least 6-month follow-up and baseline disease activity scores were enrolled (n = 353) and stratified into manifest CV disorder ("overt CVD"), any traditional CV risk factor ("atCVrisk") and no CV risk factor ("vlCVrisk") groups. Results: Overall, mean (SD) patient age was 51.4 (±12.2) years, and 291 (82.4%) subjects were female. Median follow-up was 41.9 (IQR 18.6, 80) months. Overall, 89 (25.2%) individuals developed at least one new CV RF, of which 65 (18.4%) acquired one and 24 (6.8%) two or more. Incident lipid disorders (42, 11.9%), followed by hypertension (14, 4%), atrial fibrillation (17, 4.8%) and venous thromboembolism (VTE) (16, 4.5%), were common. Incident major adverse cardiac events (MACE) were not reported in the vlCVrisk group, in contrast to atCVrisk (n = 8, 4.2%) or overt CVD (n = 4, 18.2%). Age was a significant predictor of incident CV risk factor (HR 1.04, 95% CI: 1.02-1.07; p < 0.01). In age-adjusted analyses, only baseline body mass index (BMI) (HR 1.11, 95% CI: 1.04-1.18; p < 0.01), but not ever smoking (p = 0.93), male sex (p = 0.26), positive RF (p = 0.24), positive ACPA (p = 0.90), or baseline disease activity (p = 0.19), were independent predictor of incident CV risk factors. Conclusions: Patients with RA initiating biologics should be screened for cardiometabolic risk factors, especially at an older age. The presence of at least one risk factor may be linked to a worse long-term prognosis.

Drug Retention and Safety of Secukinumab in a Real-World Cohort of Ankylosing Spondylitis and Psoriatic Arthritis Patients.

Real-life data that support effectiveness of secukinumab (SEC), an interleukin 17A inhibitor, in Poland are few. We aimed to evaluate SEC effectiveness based on drug retention and safety measures reported in electronic medical records (EMRs) of patients with psoriatic arthritis (PsA) and ankylosing spondylitis (AS) from two tertiary-care centers in the region of Lesser Poland. A total one-hundred eighty seven (127 PsA and 60 AS) first (n = 112), second (n = 59) and third-line SEC users were enrolled. The mean (SD) age of the sample was 45.7 (12.9), and 48% were male. All patients were classified with active and severe disease prior to initiation. Administrative delays for SEC users last a median 2 weeks. Median delay from symptom onset to diagnosis was 4 years (IQR 8), and differed by predominant disease subtype. The inefficacy rate was 10.7% and 18.6% for first and second-line users with median (IQR) drug maintenance estimated at 1.22 years (1.46) and 1.51 (1.38), respectively. First-year drug loss defined as drug switch due to inefficacy or adverse event was rare, with median estimates of 0.91 (95% CI; 0.85, 0.97) and 0.86 (95% CI; 0.77, 0.95) for first and second-line, respectively.

Predictors of proarrhythmic effect in heart failure patients after 9-week hybrid comprehensive telerehabilitation and their influence on cardiovascular mortality in long-term follow-up: Subanalysis of the TELEREH-HF randomized clinical trial.

BACKGROUND: Regular exercise training is beneficial in heart failure (HF) patients. However, its potential proarrhythmic effect is possible but has not been sufficiently investigated. OBJECTIVE: To identify patients at risk for proarrhythmic effect after the 9-week of hybrid comprehensive telerehabilitation (HCTR) program vs the 9-week of usual care (UC) and to investigate its predictors and impact on cardiovascular mortality based on data from the TELEREH-HF RCT. METHODS: Proarrhythmic effect, strictly defined on the basis of available standards was evaluated by comparing 24-h Holter ECG before and after 9-week of HCTR or UC of 773 HF patients (The New York Heart Association class I-III, left ventricular ejection fraction ≤40%). RESULTS: The proarrhytmic effect was found in 78 (20.4%) and in 61 (15.6%) patients in the HCTR and UC group respectively, and the difference between groups was not statistically significant (p = 0.081). However, univariate analysis identified several statistically significant predictors of proarrhythmia in HCTR only vs the UC group. After a multivariate analysis ischaemic aetiology of HF (OR = 2.27, p = 0.008), peak oxygen consumption at baseline <14 ml/kg/min (OR = 2.03, p = 0.012) and level of N-terminal-pro B-type natriuretic peptide (NT-proBNP) in the first and the second tercile (OR = 1.85, p = 0.043) were identified to be independent predictors of proarrhytmic effect of exercise training among the HF patients in HCTR group only. CONSLUSIONS: Patients who underwent a 9-week HCTR were not at a higher risk of proarrhythmic effect after its completion compared to UC. However, predictors of proarrhythmia such as ischemic aetiology of HF, poor physical capacity, lower NT-proBNP level were discovered in the HCTR group only, yet it does not cause a significant risk of cardiovascular mortality including sudden cardiac death in long-term follow-up.

Sex hormones and repolarization dynamics during the menstrual cycle in women with congenital long QT syndrome.

BACKGROUND: Women with congenital long QT syndrome (LQTS) experience increased cardiac event risk after the onset of adolescence, perhaps stemming from the known modulating effects of sex hormones on the cardiac potassium channels. OBJECTIVE: We hypothesized that the effect of sex hormones on cardiac ion channel function may modify electrocardiographic (ECG) parameters associated with the propensity for ventricular tachyarrhythmias during the menstrual cycle in women with LQTS. METHODS: We prospectively enrolled 65 women with congenital LQTS (type 1 LQTS [LQT1], n = 24 [36.9%]; type 2 LQTS [LQT2], n = 20 [30.8%]) and unaffected female relatives (n = 21 [32.3%]). Patients underwent three 7-day ECG recordings during their menstrual cycles. Simultaneous saliva testing of sex hormone levels was conducted on the first day of each 7-day ECG recording cycle. RESULTS: The mean age was 35 ± 8 years, without a significant difference among the groups. In women with LQT2, linear mixed effects models showed significant inverse correlations of the corrected QT interval with progesterone levels (P < .001) and with the progesterone to estradiol ratio (P < .001). Inverse relationships of the R-R interval with estradiol levels (P = .003) and of the T-wave duration with testosterone levels (P = .014) were also observed in women with LQT2. In contrast, no significant associations were observed between ECG parameters and sex hormone levels in women with LQT1 or unaffected relatives. CONCLUSION: This is the first study to prospectively assess correlations between repolarization dynamics and sex hormone levels during the menstrual cycle in women with congenital LQTS. Our findings show genotype-specific unique corrected QT dynamics during the menstrual cycle that may affect the propensity for ventricular tachyarrhythmia in women with LQTS, particularly women with LQT2.

Use of oral contraceptives in women with congenital long QT syndrome.

BACKGROUND: Use of oral contraceptives (OCs) may modulate the clinical course of women with congenital long QT syndrome (LQTS). The safety of OC use by sex hormone content has not been assessed in women with LQTS. OBJECTIVE: We aimed to evaluate the association of OCs with the risk of cardiac events (CEs) in women with LQTS. METHODS: Beginning in 2010, information on menarche onset, OC use, pregnancy, and menopause were obtained from women enrolled in the Rochester LQTS Registry. Type of OC was categorized as progestin-only, estrogen-only, or combined (estrogen/progestin). Andersen-Gill multivariate modeling was used to evaluate the association of time-dependent OC use with the burden of CE (total number of syncope, aborted cardiac arrest, and LQTS-related sudden cardiac death) from menarche onset through 40 years. Findings were adjusted for genotype, corrected QT duration, and time-dependent ß-blocker therapy. RESULTS: A total of 1659 women with LQTS followed through March 2021, of whom 370 (22%) were treated with an OC. During a cumulative follow-up of 35,797 years, there were a total of 2027 CE. Multivariate analysis showed that progestin-only OC was associated with a pronounced 2.8-fold (P = .01) increased risk of CEs in women who did not receive ß-blocker therapy, while ß-blockers were highly protective during progestin-only OC treatment (hazard ratio 0.22; P = .01; P = .006 for ß-blocker-by-OC interaction). The risk associated with OC use without concomitant ß-blocker treatment was pronounced in women with LQTS type 2. CONCLUSION: Our findings suggest that progestin-only OC should not be administered in women with LQTS without concomitant ß-blocker therapy. OCs should be used with caution in women with LQTS type 2.

Genetic Variant Score and Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Plakophilin-2 Mutation Carriers.

INTRODUCTION: Whether detailed genetic information contributes to risk stratification of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) remains uncertain. Pathogenic genetic variants in some genes seem to carry a higher risk for arrhythmia and earlier disease onset than others, but comparisons between variants in the same gene have not been done. Combined Annotation Dependent Depletion (CADD) score is a bioinformatics tool that measures the pathogenicity of each genetic variant. We hypothesized that a higher CADD score is associated with arrhythmic events and earlier age at ARVC manifestations in individuals carrying pathogenic or likely pathogenic genetic variants in plakophilin-2 (PKP2). METHODS: CADD scores were calculated using the data from pooled Scandinavian and North American ARVC cohorts, and their association with cardiac events defined as ventricular tachycardia/ventricular fibrillation (VT/VF) or syncope and age at definite ARVC diagnosis were assessed. RESULTS: In total, 33 unique genetic variants were reported in 179 patients (90 males, 71 probands, 96 with definite ARVC diagnosis at a median age of 35 years). Cardiac events were reported in 76 individuals (43%), of whom 53 had sustained VT/VF (35%). The CADD score was neither associated with age at cardiac events (HR 1.002, 95% CI: 0.953-1.054, p = 0.933) nor with age at definite ARVC diagnosis (HR 0.992, 95% CI: 0.947-1.039, p = 0.731). CONCLUSION: No correlation was found between CADD scores and clinical manifestations of ARVC, indicating that the score has no additional risk stratification value among carriers of pathogenic or likely pathogenic PKP2 genetic variants.

Motor Control Evaluation as a Significant Component in Upper Limb Function Assessment in Female Breast Cancer Patients after Mastectomy.

Breast cancer is the most prevalent malignancy among women. Conservative and operative treatment methods are associated with a risk of side effects pertaining to the shoulder complex. The surgery complications including chronic pain, upper limb and chest lymphedema, range of motion limitations, and motor control deficiencies may lead to upper limb function impairment and affect the quality of life negatively. Twenty-three women were examined in the tested group and twenty-two women in the control group. The motor control was assessed with dissociation tests as defined by Comerford and Mottram. In order to assess patient-perceived upper limb disability, the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire was used. The test of glenohumeral (GH) abduction control in frontal plane and in scapular plane and medial rotation control outcomes were found to be statistically significant. It pertains to both: Comparison between groups and analysis within the tested group-body sides comparison. The DASH questionnaire results analysis indicates that there was a higher degree of subjectively perceived disability of upper limb in the tested group. Surgical interventions in the breast cancer treatment and other medical procedures affect the level of motor control and perceived disability of upper limb negatively in this group of patients. Movement faults are statistically more prevalent in the tested group. Movement faults are more prevalent on the operated side in the tested group.

A counterpoint paper: Comments on the electrocardiographic part of the 2018 Fourth Universal Definition of Myocardial Infarction.

The Fourth Universal Definition of Myocardial Infarction (FUDMI) [published simultaneously in 2018 in numerous journals including Circulation, Journal of the American College of Cardiology and European Heart Journal] focuses mainly on the distinction between non-ischemic myocardial injury and myocardial infarction (MI), along with the role of cardiovascular magnetic resonance, in order to define the etiology of myocardial injury. As a consequence, there is less emphasis on updating the parts of the definition concerning the electrocardiographic (ECG) changes related to MI. Evidence of myocardial ischemia is a prerequisite for the diagnosis of MI and the ECG is the main available tool for i) detecting acute ischemia, ii) triage and iii) risk stratification upon presentation. This review focuses on multiple aspects of ECG interpretation that we firmly believe should be considered for incorporation in any future update to the Universal Definition of MI. Our counterpoint view is that: a) the use of the ECG following coronary artery bypass surgery should be better explored and defined; b) the emphasis in the FUDMI on convex versus concave ST-elevation, which is questionable, should be balanced by the fact that many patients with true ST-elevation MI (STEMI) present with a concave form of ST elevation; c) reciprocal ST-depression in STEMI caused by right coronary artery or left circumflex artery occlusion, should be set against the fact that not all anterior STEMIs present with reciprocal ST-depression which can also be seen in cardiomyopathy and left ventricular hypertrophy; d) the "posterior" leads V7-V9 should be placed on a horizontal line from V4, rather than follow the 5th intercostal space; e) ST-depression in V1-V3 is not a manifestation of ischemia of the basal inferior segment, placed horizontally; f) Interpreting ST-T changes in patients with conduction abnormalities and pacemakers should be further defined.

2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy: Executive summary.

Arrhythmogenic cardiomyopathy (ACM) is an arrhythmogenic disorder of the myocardium not secondary to ischemic, hypertensive, or valvular heart disease. ACM incorporates a broad spectrum of genetic, systemic, infectious, and inflammatory disorders. This designation includes, but is not limited to, arrhythmogenic right/left ventricular cardiomyopathy, cardiac amyloidosis, sarcoidosis, Chagas disease, and left ventricular noncompaction. The ACM phenotype overlaps with other cardiomyopathies, particularly dilated cardiomyopathy with arrhythmia presentation that may be associated with ventricular dilatation and/or impaired systolic function. This expert consensus statement provides the clinician with guidance on evaluation and management of ACM and includes clinically relevant information on genetics and disease mechanisms. PICO questions were utilized to evaluate contemporary evidence and provide clinical guidance related to exercise in arrhythmogenic right ventricular cardiomyopathy. Recommendations were developed and approved by an expert writing group, after a systematic literature search with evidence tables, and discussion of their own clinical experience, to present the current knowledge in the field. Each recommendation is presented using the Class of Recommendation and Level of Evidence system formulated by the American College of Cardiology and the American Heart Association and is accompanied by references and explanatory text to provide essential context. The ongoing recognition of the genetic basis of ACM provides the opportunity to examine the diverse triggers and potential common pathway for the development of disease and arrhythmia.

Association of Cardiac Resynchronization Therapy With Change in Left Ventricular Ejection Fraction in Patients With Chemotherapy-Induced Cardiomyopathy.

Importance: The incidence of chemotherapy-induced cardiomyopathy is increasing and is associated with poor clinical outcomes. Objective: To assess the association of cardiac resynchronization therapy (CRT) with improvement in cardiac function, as well as clinical improvement in patients with chemotherapy-induced cardiomyopathy. Design, Setting, and Participants: The Multicenter Automatic Defibrillator Implantation Trial-Chemotherapy-Induced Cardiomyopathy was an uncontrolled, prospective, cohort study conducted between November 21, 2014, and June 21, 2018, at 12 tertiary centers with cardio-oncology programs in the United States. Thirty patients were implanted with CRT owing to reduced left ventricular ejection fraction (LVEF≤35%), New York Heart Association class II-IV heart failure symptoms, and wide QRS complex, with established chemotherapy-induced cardiomyopathy and were followed up for 6 months after CRT implantation. The date of final follow-up was February 6, 2019. Exposures: CRT implantation according to standard of care. Main Outcomes and Measures: The primary end point was change in LVEF from baseline to 6 months after initiating CRT. Secondary outcomes included all-cause mortality and change in left ventricular end-systolic volume and end-diastolic volume. Results: Among 30 patients who were enrolled (mean [SD] age, 64 [11] years; 26 women [87%]; 73% had a history of breast cancer; 20% had a history of lymphoma or leukemia), primary end point data were available for 26 patients and secondary end point data were available for 23 patients. Patients had nonischemic cardiomyopathy with left bundle branch block, median LVEF of 29%, and a mean QRS duration of 152 ms. Patients with CRT experienced a statistically significant improvement in mean LVEF at 6 months from 28% to 39% (difference, 10.6% [95% CI, 8.0%-13.3%]; P < .001). This was accompanied by a reduction in LV end-systolic volume from 122.7 to 89.0 mL (difference, 37.0 mL [95% CI, 28.2-45.8]) and reduction in LV end-diastolic volume from 171.0 to 143.2 mL (difference, 31.9 mL [95% CI, 22.1-41.6]) (both P < .001). Adverse events included a procedure-related pneumothorax (1 patient), a device pocket infection (1 patient), and heart failure requiring hospitalization during follow-up (1 patient). Conclusions and Relevance: In this preliminary study of patients with chemotherapy-induced cardiomyopathy, CRT was associated with improvement in LVEF after 6 months. The findings are limited by the small sample size, short follow-up, and absence of a control group. Trial Registration: ClinicalTrials.gov Identifier: NCT02164721.

2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is an arrhythmogenic disorder of the myocardium not secondary to ischemic, hypertensive, or valvular heart disease. ACM incorporates a broad spectrum of genetic, systemic, infectious, and inflammatory disorders. This designation includes, but is not limited to, arrhythmogenic right/left ventricular cardiomyopathy, cardiac amyloidosis, sarcoidosis, Chagas disease, and left ventricular noncompaction. The ACM phenotype overlaps with other cardiomyopathies, particularly dilated cardiomyopathy with arrhythmia presentation that may be associated with ventricular dilatation and/or impaired systolic function. This expert consensus statement provides the clinician with guidance on evaluation and management of ACM and includes clinically relevant information on genetics and disease mechanisms. PICO questions were utilized to evaluate contemporary evidence and provide clinical guidance related to exercise in arrhythmogenic right ventricular cardiomyopathy. Recommendations were developed and approved by an expert writing group, after a systematic literature search with evidence tables, and discussion of their own clinical experience, to present the current knowledge in the field. Each recommendation is presented using the Class of Recommendation and Level of Evidence system formulated by the American College of Cardiology and the American Heart Association and is accompanied by references and explanatory text to provide essential context. The ongoing recognition of the genetic basis of ACM provides the opportunity to examine the diverse triggers and potential common pathway for the development of disease and arrhythmia.

Effectiveness of high rate and delayed detection ICD programming by race: A MADIT-RIT substudy.

INTRODUCTION: Data on inappropriate and appropriate ICD therapy, and efficacy of ICD programing strategies by race are limited. METHODS: In MADIT-RIT, we evaluated the risk of ICD therapy by race, and the efficacy of high rate cut-off ventricular tachycardia (VT) zone ≥200 beats per minute (bpm) (Arm B), or 60 seconds delay in VT zone 170-199 bpm (Arm C), compared to 2.5 seconds delay at 170 bpm (Arm A) among black and white patients. RESULTS: MADIT-RIT enrolled 272 (20%) black and 1119 (80%) white patients. The risk of inappropriate therapy was similar among blacks and whites, HR 1.25, 95% CI (0.82-1.93), P  =  0.30. High rate cut-off or delayed VT therapy was associated with significant reductions in inappropriate therapy among whites, Arm B versus Arm A, HR 0.15, 95% CI (0.08-0.29), P < 0.0001, Arm C versus Arm A, HR 0.19, 95% CI (0.11-0.33), P < 0.001, and black individuals Arm B versus Arm A, HR 0.24, 95% CI (0.01-0.56), P  =  0.0001, Arm C versus Arm A, HR 0.30, 95% CI (0.13-0.68), P  =  0.004, P interaction > 0.10). However, delayed VT therapy was associated with a trend toward greater reduction in appropriate therapy in black individuals, HR 0.08, 95% CI (0.03-0.27), P < 0.0001 relative to white individuals, HR 0.27, 95% CI (0.16-0.43), P < 0.0001, P interaction  =  0.077. CONCLUSION: In MADIT-RIT, high rate and delayed detection ICD programming provided similar benefit with reductions in both inappropriate therapy and unnecessary appropriate therapy among black and white individuals. CLINICALTRIALS. GOV IDENTIFIER: NCT00947310.

Multiple Comorbidities and Response to Cardiac Resynchronization Therapy: MADIT-CRT Long-Term Follow-Up.

BACKGROUND: Data regarding cardiac resynchronization therapy (CRT) in patients with multiple comorbidities are limited. OBJECTIVES: This study evaluated the association of multiple comorbidities with the benefits of CRT over implantable cardioverter-defibrillator (ICD) alone. METHODS: We examined 1,214 MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy) study patients with left bundle branch block (LBBB) and 0, 1, 2, or ≥3 comorbidities, including renal dysfunction, hypertension (HTN), diabetes, coronary artery disease, history of atrial arrhythmias, history of ventricular arrhythmias, current smoking, and cerebrovascular accident. In an adjusted analysis, we analyzed risk of heart failure (HF) events or death by comorbidity group in all patients and in patients with CRT with defibrillator (CRT-D) versus ICD. Then we examined percent change in left ventricular (LV) end-diastolic volume, LV end-systolic volume, LV ejection fraction, left atrial volume, and LV dyssynchrony at 1-year in CRT-D patients by comorbidity group. RESULTS: There was an inverse relationship between comorbidity burden and improvements in LV end-systolic volume, LV end-diastolic volume, left ventricular ejection fraction, left atrial volume, and LV dyssynchrony. In an adjusted model, there was an increasing risk of death or nonfatal HF events with increasing comorbidity burden regardless of treatment group (p < 0.001). During a mean follow-up of 4.65 years, there was no interaction with respect to comorbidity burden and the benefit of CRT-D versus ICD only for death or nonfatal HF events (interaction p = 0.943). In the groups with greatest comorbidity burden (2 and ≥3), the absolute risk reduction associated with CRT-D over ICD alone appeared greater than that seen for groups with less comorbidity burden (0 and 1). CONCLUSIONS: During long-term follow-up of MADIT-CRT study patients with LBBB randomized to CRT-D, there were differences in HF or death risk and in the degree of reverse remodeling among comorbidity groups. However, the burden of comorbidity does not appear to compromise the clinical benefits of CRT-D compared with ICD alone.

Effect of cardiac resynchronization therapy on the risk of ventricular tachyarrhythmias in patients with chronic kidney disease.

BACKGROUND: The effect of chronic kidney disease (CKD) on benefit from cardiac resynchronization therapy with defibrillator (CRT-D) in reducing ventricular tachyarrhythmia (VTA) risk among mild heart failure (HF) patients is not well understood. METHODS: We evaluated the impact of baseline renal function on VTAs in 1274 left bundle branch block (LBBB) patients enrolled in MADIT-CRT. Two prespecified subgroups were created based on estimated glomerular filtration rate (GFR): GFR <60 (n = 413) and GFR ≥60 ml/min/1.73 m2 (n = 861). Primary end point was ventricular tachycardia/ventricular fibrillation/death (VT/VF/death). Secondary end points were any VT/VF and ventricular tachycardia ≥ 200 bpm or VF (fast VT/VF). RESULTS: There were 413 (32%) LBBB patients presenting with CKD, primarily of moderate severity (GFR mean 48.1 ± 8.3). For patients with and without CKD, CRT-D was associated with lower risk of the primary end point (GFR<60: HR = 0.61, 95% CI: 0.41-0.89, p = .010; GFR≥60: HR = 0.58, 95% CI: 0.52-0.89, p = .005), relative to ICD-only treatment. For patients in both renal function categories, CRT-D in comparison to ICD alone was associated with lower risk of VT/VF (GFR<60: HR = 0.68, 95% CI: 0.42-1.10, p = .113; GFR≥60: HR = 0.65, 95% CI: 0.48-0.88, p = .005) and fast VT/VF (GFR<60: HR = 0.49, 95% CI: 0.25-0.96, p = .038; GFR≥60: HR = 0.55, 95% CI: 0.39-0.80, p = .001), when accounting for competing mortality risk. This effect was independent of CRT-induced reverse remodeling. CONCLUSION: Among mild HF patients with LBBB, those with and without CKD both derived benefit from CRT-D in risk reduction in VTAs, independent of cardiac reverse remodeling.