High Risk of Fatal and Nonfatal Venous Thromboembolism in Myotonic Dystrophy

International audienceMyotonic dystrophy (MD), the most common inherited myopathy, is associated with high cardiovascular mortality 1. A preliminary analysis of the DM1 Heart Registry (URL: ClinicalTrials.gov. Unique identifier: NCT01136330), a comprehensive database that captures information relative to the cardiac management of adults presenting to our center with MD 2 , revealed a high prevalence of venous thromboembolism (VTE). We designed this study to estimate the risk of VTE in MD and its survival consequences. We retrospectively analyzed the data relative to patients referred to our center between January 2000 and January 2015, including 1148 with MD and 1662 with other inherited myopathies (facioscapulohumeral, dystrophinopathy, mitochondrial, glycogen-and lipid-storage diseases, limb-girdle muscular dystrophies, nucleopathies, collagen VI-related disorders, myofibrillar, and congenital). This study was approved by our local Ethics Committee, and all patients granted their written informed consent to participate. We compared patient baseline characteristics using Wilcoxon rank-sum or Fisher exact tests as appropriate. VTE, defined as ≥1 episode of deep vein thrombosis or pulmonary embolism, was analyzed in a competing-risks framework, with death as a competing event. Cumulative incidences (probability of occurrence over follow-up), hazard ratios (HRs), and cumulative hazards of VTE were estimated. We searched for predictors of the hazard of VTE using Cox proportional hazards models for the cause-specific hazards on the time of study scale, with follow-up beginning on the date of inclusion in the study until the occurrence of VTE, death, or last follow-up, whichever occurred first. All patient characteristics described in the results were included in this analysis, including all variables from our database that represent known VTE risk factors. At first presentation, patients with MD, compared with others, were older (40 [29-51] years versus 39 [25-52] years; P=0.029); had a lower proportion of men (556 [48.4%] versus 990 [59.6%]; P<0.0001); had a more frequent personal history of VTE (40 [3.5%] versus 9 [0.5%]; P<0.0001), heart failure (12 [1.0%] versus 128 [7.7%]; P<0.0001), and conduction disease (461 [40.2%] versus 195 [11.7%]; P<0.0001); were treated with vitamin K antagonists (32 [3.0%] versus 25 [1.5%], P=0.009) and estrogen contraceptives (137 [11.9%] versus 140 [8.4%], P=0.002); and had a lower Walton score 3 (1 [0-3] versus 3 [1-6]; P<0.0001) and less frequent ambulation loss (80 [6.9%] versus 405 [24.4%], P<0.0001). A similar prevalence was observed for obesity (123 [10.9%] versus 183 [11.2%]; P=0.85), respiratory failure (133 [13.2%] versus 257 [15.8%]; P=0.071), and cancer (31 [2.8%] versus 33 [1.9%]; P=0.25). VT

High Risk of Fatal and Nonfatal Venous Thromboembolism in Myotonic Dystrophy

International audienceMyotonic dystrophy (MD), the most common inherited myopathy, is associated with high cardiovascular mortality 1. A preliminary analysis of the DM1 Heart Registry (URL: ClinicalTrials.gov. Unique identifier: NCT01136330), a comprehensive database that captures information relative to the cardiac management of adults presenting to our center with MD 2 , revealed a high prevalence of venous thromboembolism (VTE). We designed this study to estimate the risk of VTE in MD and its survival consequences. We retrospectively analyzed the data relative to patients referred to our center between January 2000 and January 2015, including 1148 with MD and 1662 with other inherited myopathies (facioscapulohumeral, dystrophinopathy, mitochondrial, glycogen-and lipid-storage diseases, limb-girdle muscular dystrophies, nucleopathies, collagen VI-related disorders, myofibrillar, and congenital). This study was approved by our local Ethics Committee, and all patients granted their written informed consent to participate. We compared patient baseline characteristics using Wilcoxon rank-sum or Fisher exact tests as appropriate. VTE, defined as ≥1 episode of deep vein thrombosis or pulmonary embolism, was analyzed in a competing-risks framework, with death as a competing event. Cumulative incidences (probability of occurrence over follow-up), hazard ratios (HRs), and cumulative hazards of VTE were estimated. We searched for predictors of the hazard of VTE using Cox proportional hazards models for the cause-specific hazards on the time of study scale, with follow-up beginning on the date of inclusion in the study until the occurrence of VTE, death, or last follow-up, whichever occurred first. All patient characteristics described in the results were included in this analysis, including all variables from our database that represent known VTE risk factors. At first presentation, patients with MD, compared with others, were older (40 [29-51] years versus 39 [25-52] years; P=0.029); had a lower proportion of men (556 [48.4%] versus 990 [59.6%]; P<0.0001); had a more frequent personal history of VTE (40 [3.5%] versus 9 [0.5%]; P<0.0001), heart failure (12 [1.0%] versus 128 [7.7%]; P<0.0001), and conduction disease (461 [40.2%] versus 195 [11.7%]; P<0.0001); were treated with vitamin K antagonists (32 [3.0%] versus 25 [1.5%], P=0.009) and estrogen contraceptives (137 [11.9%] versus 140 [8.4%], P=0.002); and had a lower Walton score 3 (1 [0-3] versus 3 [1-6]; P<0.0001) and less frequent ambulation loss (80 [6.9%] versus 405 [24.4%], P<0.0001). A similar prevalence was observed for obesity (123 [10.9%] versus 183 [11.2%]; P=0.85), respiratory failure (133 [13.2%] versus 257 [15.8%]; P=0.071), and cancer (31 [2.8%] versus 33 [1.9%]; P=0.25). VT

High Risk of Fatal and Non-Fatal Venous Thromboembolism in Myotonic Dystrophy

International audienceBackground: The risk of venous thromboembolism (VTE), defined as deep vein thrombosis, pulmonany embolism (PE), or both, in myotonic dystrophy (DM) is unknown. Our objective was to estimate the risk of VTE in DM and its impact on all-cause and cardiovascular mortality. Methods: In 1,148 retrospectively studied adults (592 women) suffering from DM, referred between January 2000 and January 2015, we estimated the cumulative incidence of VTE and proportion of all- cause and cardiovascular deaths, and compared the incidence of VTE with that in patients with other inherited myopathies followed at our center, and with a community-based French population. Results: Among all patients with DM (mean age=40.6#14.3; 592 women), 82 developed VTE over a 10.9-year follow-up (95% CI 2.4 to 14.7), representing a 10.3% cumulative incidence (95% CI 7.8 to 12.7%), and 253 died, 83 of a cardiovascular cause. In patients with DM, the incidence of VTE was higher than a) in 1,662 patients (mean age=39.7+16.2; 989 women) with other inherited myopathies (mean age=39.7+16.2), in whom the cumulative incidence was 2.2% (95% Cl 1.1 to 3.3) and hazard ratio (HR) 4.63 (95% CI 2.63 to 8.18; p<0.0001), and b) in a community-based population with a standardized rate ratio of 7.53 (95% CI 6.02 to 9.28; p<0.0001). VTE was independently predicted by age (HR=1.02; 95% CI 1.00 to 1.04; p=0.041), personal history of VTE (HR=4.71; 95% CI 2.20 to 10.1; p<0.0001), obesity (HR=2.31; 95% CI 1.30 to 4.08; p=0.004), loss of ambulation (HR=4.57;95% C| 2.12 to9.87; p=0.0001) and history of cancer (HR=3.89; 95% CI 1.62 to 9.32; p=0.002). The 26 deaths from PE in patients with DM represented 10.3% of all deaths and 31.3% of cardiovascular deaths. Conclusion: The risk of fatal and non-fatal VTE in patients with DM was high

Cardiac Outcomes in Adults With Mitochondrial Diseases

International audienceBackground: Patients with mitochondrial diseases are at risk of heart failure (HF) and arrhythmic major adverse cardiac events (MACE). Objectives: We developed prediction models to estimate the risk of HF and arrhythmic MACE in this population. Methods: We determined the incidence and searched for predictors of HF and arrhythmic MACE using Cox regression in 600 adult patients from a multicenter registry with genetically confirmed mitochondrial diseases. Results: Over a median follow-up time of 6.67 years, 29 patients (4.9%) reached the HF endpoint, including 19 hospitalizations for nonterminal HF, 2 cardiac transplantations, and 8 deaths from HF. Thirty others (5.1%) reached the arrhythmic MACE, including 21 with third-degree or type II second-degree atrioventricular blocks, 4 with sinus node dysfunction, and 5 sudden cardiac deaths. Predictors of HF were the m.3243A>G variant (HR: 4.3; 95% CI: 1.8-10.1), conduction defects (HR: 3.0; 95% CI: 1.3-6.9), left ventricular (LV) hypertrophy (HR: 2.6; 95% CI: 1.1-5.8), LV ejection fraction <50% (HR: 10.2; 95% CI: 4.6-22.3), and premature ventricular beats (HR: 4.1; 95% CI: 1.7-9.9). Independent predictors for arrhythmia were single, large-scale mtDNA deletions (HR: 4.3; 95% CI: 1.7-10.4), conduction defects (HR: 6.8; 95% CI: 3.0-15.4), and LV ejection fraction <50% (HR: 2.7; 95% CI: 1.1-7.1). C-indexes of the Cox regression models were 0.91 (95% CI: 0.88-0.95) and 0.80 (95% CI: 0.70-0.90) for the HF and arrhythmic MACE, respectively. Conclusions: We developed the first prediction models for HF and arrhythmic MACE in patients with mitochondrial diseases using genetic variant type and simple cardiac assessments

Association between prophylactic angiotensin-converting enzyme inhibitors and overall survival in Duchenne muscular dystrophy—analysis of registry data

International audienceAims: To estimate the effect of prophylactic angiotensin-converting enzyme inhibitors (ACEi) on survival in Duchenne muscular dystrophy (DMD).Methods and results: We analysed the data from the French multicentre DMD Heart Registry (ClinicalTrials.gov: NCT03443115). We estimated the association between the prophylactic prescription of ACEi and event-free survival in 668 patients aged 8 to 13 years, with normal left ventricular function, using (i) a Cox model with intervention as a time-dependent covariate, (ii) a propensity-based analysis comparing ACEi treatment vs. no treatment, and (iii) a set of sensitivity analyses. The study outcomes were overall survival and hospitalizations for heart failure (HF) or acute respiratory failure. Among the 668 patients included in the DMD Heart Registry, 576 (mean age 6.1 ± 2.8 years) were eligible for this study, of whom 390 were treated with ACEi prophylactically. Death occurred in 53 patients (13.5%) who were and 60 patients (32.3%) who were not treated prophylactically with ACEi, respectively. In a Cox model with intervention as a time-dependent variable, the hazard ratio (HR) associated with ACEi treatment was 0.49 [95% confidence interval (CI) 0.34-0.72] and 0.47 (95% CI 0.31-0.17) for overall mortality after adjustment for baseline variables. In the propensity-based analysis, 278 patients were included in the treatment group and 834 in the control group, with 18.5% and 30.4% 12-year estimated probability of death, respectively. ACEi were associated with a lower risk of death (HR 0.39; 95% CI 0.17-0.92) and hospitalization for HF (HR 0.16; 95% CI 0.04-0.62). All other sensitivity analyses yielded similar results.Conclusion: Prophylactic ACEi treatment in DMD was associated with a significantly higher overall survival and lower rates of hospitalization for HF