Alberto Palladino

Risk of arrhythmia in type I Myotonic Dystrophy: the role of clinical and genetic variables

Objective: To examine the association between the presence of arrhythmia in type 1 myotonic dystrophy (DM1) and clinical–genetic variables, evaluating their role as predictors of the risk of arrhythmia. Methods: 245 patients with genetically proven DM1 underwent clinical and non-invasive cardiological evaluation. Severity of muscular involvement was assessed according to the 5 point Muscular Disability Rating Score (MDRS). Data were analysed by univariate and multivariate models. Results: 245 patients were examined and cardiac arrhythmias were found in 63 subjects, 40 of whom required a device implant. Statistical analyses revealed that men had more than double the risk of developing arrhythmias compared with women (p = 0.018). Addition of each year of age caused an increased risk of arrhythmia equal to 3% (p = 0.030). Subjects with MDRS 5 had a risk of arrhythmia 12 times higher than patients with MDRS 1–2 (p<0.001). Although all of these variables were significantly associated with cardiac rhythm dysfunction, they had a low sensitivity for the prediction of arrhythmic risk Conclusion: Male sex, age and muscular disability were strongly associated with the development of arrhythmia in DM1. However, all of these variables were weak predictors of arrhythmic risk. These results suggest that other factors may be involved in the development of cardiac conduction abnormalities in DM1.

Risk of arrhythmias in myotonic dystrophy: trial design of the RAMYD study.

Objective Myotonic dystrophy type 1 (DM1) is the most frequent muscular dystrophy in adults. DM1 is a multisystem disorder also affecting the heart with an increased incidence of sudden death, which has been explained with the common impairment of the conduction system often requiring pacemaker implantation; however, the occurrence of sudden death despite pacemaker implantation and the observation of major ventricular arrhythmias generated the hypothesis that ventricular arrhythmias may play a causal role as well. The aim of the study was to assess the 2-year cumulative incidence and the value of noninvasive and invasive findings as predictive factors for sudden death, resuscitated cardiac arrest, ventricular fibrillation, sustained ventricular tachycardia and severe sinus dysfunction or high-degree atrioventricular block. Methods/design More than 500 DM1 patients will be evaluated at baseline with a clinical interview, 12-lead ECG, 24-h ECG and echocardiogram. Conventional and nonconventional indications to electrophysiological study, pacemaker, implantable cardioverter defibrillator or loop recorder implantation have been developed. In the case of an indication to electrophysiological study, pacemaker, implantable cardioverter defibrillator or loop recorder implant at baseline or at follow-up, the patient will be referred for the procedure. At the end of 2-year follow-up, all candidate prognostic factors will be tested for their association with the endpoints. Trial registration: ClinicalTrials.gov ID NCT00127582. Conclusion The available evidence supports the hypothesis that both bradyarrhythmias and tachyarrhythmias may cause sudden death in DM1, but the course of cardiac disease in DM1 is still unclear. We expect that this large, prospective, multicenter study will provide evidence to improve diagnostic and therapeutic strategies in DM1.

Low Intraocular Pressure Resulting from Ciliary Body Detachment in Patients with Myotonic Dystrophy

PURPOSE To investigate why myotonic dystrophy type 1 (DM1) patients have low intraocular pressure (IOP). DESIGN Prospective, comparative case series. PARTICIPANTS One hundred two eyes of 51 patients with DM1 (age range, 21-64 years) and 44 eyes of 22 healthy subjects of similar age (21-64 years). METHODS All participants underwent IOP measurement with Goldmann applanation tonometry and an in vivo examination of the ciliary body with a 35-MHz high-resolution B-scan. The findings were compared between the 2 groups. In both groups, only patients with no history of ocular trauma or surgery were included. The differences were evaluated using the unpaired Student t test. MAIN OUTCOME MEASUREMENTS Intraocular pressure, central corneal thickness (CCT), and echographic evidence of ciliary body detachment. RESULTS The mean ± standard deviation (SD) IOP in patients with DM1 was 10.9 ± 3.1 mmHg and that in the control patients was 15.4 ± 2.2 mmHg, a difference that reached significance (P<0.01). The mean ± SD CCT (measured at the pupillary center) was 574.4 ± 37.9 μm in the patients with DM1 and 557.8 ± 39.2 μm in the controls (P = 0.02). Detachment of the ciliary body was identified in all DM1 subjects. Size was variable and the detachment involved 1 or more quadrants. The number of quadrants affected by the detachment was not correlated with the IOP (R(2) = 0.088) or the size of the CTG expansion. No detachments were found in the healthy controls. CONCLUSIONS Detachment of the ciliary body may explain the low IOP values in patients with DM1. The finding of a ciliary body detachment in an individual who has not had recent eye surgery or trauma raises the possibility of a DM1 diagnosis.

P-Wave Duration and Dispersion in Patients With Emery-Dreifuss Muscular Dystrophy

Background Paroxysmal episodes of atrial fibrillation frequently occur in Emery-Dreifuss muscular dystrophy (EDMD). Although previous studies have documented a variety of electrocardiographic abnormalities in EDMD, little is still known about P-wave dispersion (PD), an independent risk factor for the development of atrial fibrillation. The aim of our study was to evaluate the P-wave duration and PD in patients with EDMD with conserved systolic and diastolic cardiac function. Methods The study involved 36 patients with EDMD (age, 20 [SD, 12] years; 26 men) and 36 healthy subjects used as controls, matched for age and sex. P-wave dispersion was carefully measured using 12-lead electrocardiogram. Compared with the healthy control group, patients with EDMD presented increased maximum P-wave duration (108.2 [SD, 22.2] vs 97.8 [SD, 11] milliseconds, P = 0.04) and PD (51.4 [SD, 12.8] vs 39.3 [SD, 9.7] milliseconds, P = 0.004) values. No statistically significant differences in left atrium diameter (37.1 [SD, 2.9] vs 34.1 [SD, 4.2] mm, P = 0.3) and maximum left atrium volume (15.2 [SD, 3.8] vs 14.1 [SD, 4.2] mL/m2, P = 0.4) were found between the 2 groups. We divided our study population into 2 subgroups, according to the different genetic diagnosis, patients with laminopathy EDMD (n = 17) or with emerinopathy EDMD (n = 19). No statistically significant differences were found in PD between the 2 subgroups (54.6 [SD, 15.6] vs 50.2 [SD, 11.5] milliseconds, P = 0.4). Conclusions Our study showed a significant increase of maximum P-wave duration and PD in patients with EDMD with conserved systolic and diastolic cardiac function.

Early onset of cardiomyopathy and primary prevention of sudden death in X-linked Emery–Dreifuss muscular dystrophy

We report the case of 14-year-old boy with X-linked Emery-Dreifuss muscular dystrophy who developed sick sinus syndrome and required placement of an implantable intracardiac cardioverter-defibrillator (ICD) to prevent sudden death. He demonstrated no significant risk factors for sudden death such as depressed left ventricular ejection fraction, or spontaneous or inducible ventricular tachycardia. One month after implantation, the patient experienced one appropriate ICD discharge.

T2-T3 sympathectomy versus sympathicotomy for essential palmar hyperhidrosis: comparison of effects on cardio-respiratory function.

OBJECTIVES The aim of this study was to determine cardio-respiratory changes after endothoracic sympathetic denervation and their correlation with the extent of denervation. METHODS A total of 45 patients with essential palmar hyperhidrosis were randomized into two groups: the conventional group (CG; 23 patients) and the simplified group (SG; 22 patients). In the CG, excision of T2 and T3 ganglia was performed, whereas in the SG only separation of the sympathetic chain was performed at the same level. Patients underwent respiratory and cardiovascular exercise tests before, at 2 weeks and again at 6 months after the procedure. The postoperative values were then compared with the preoperative values to assess the statistical difference. RESULTS Twenty-one patients in each group completed the study. In the SG, forced expiratory volume in 1 s (FEV 1; P < 0.01) and forced vital capacity (FVC; P < 0.01) were significantly reduced at 2 weeks, but returned to similar baseline values 6 months after the procedure. No significant cardiac changes were observed. In the CG, both FEV 1 and FVC were significantly reduced at 2 weeks (P < 0.01) and at 6 months after operation (P < 0.05). A significant reduction in forced expiratory flow between 25 and 75% of vital capacity (P < 0.01) and a relevant increase in airway resistance (P < 0.05) during the entire postoperative course were also observed. Heart rates at rest and at peak exercise were significantly reduced at 2 weeks (P < 0.01) and significantly decreased 6 months after the procedure (P < 0.05). No other changes were registered. The cardio-respiratory alterations remained at a sub-clinical level; all patients completed the exercise test without symptoms. CONCLUSION Sympathectomy may result in a disturbance of bronchomotor tone and cardiac function. Such changes remained at a sub-clinical level and seemed directly correlated with the extension of denervation.

ACE inhibition to slow progression of myocardial fibrosis in muscular dystrophies

Muscular dystrophy (MD) connotes a heterogeneous group of inherited disordersaffecting skeletal and cardiac muscle. Inseveral forms of MD, the cardiac disease may be the predominant manifestationof the underlying genetic myopathy. The cardiacinvolvement is due to progressive interstitial fibrosis and fatty replacement inboth the atria and ventricles, which may lead to cardiomyopathy, conductiondefects and tachyarrhythmias. Angiotensin-convertingenzyme inhibitors (ACE-Is) modulate the production of angiotensin II and limitthe amount of fibrosis in the myocardium, reducing mortality andhospitalization in cardiac patients. The aim of present review is to describethe antifibrotic proprieties of ACE inhibitor therapy and to summarize thecurrent body of scientific literature relating to the use of ACE-Is for theprevention and treatment of cardiomyopathy in patients with musculardystrophies.

P3.8 Cardiac involvement in patients with spinal muscular atrophies

The spinal muscular atrophies (SMAs) include a group of disorders characterized by progressive weakness of the lower motor neurons. Several types of SMAs have been described based on age onset of clinical features: Acute infantile (SMA type I), chronic infantile (SMA type II), chronic juvenile (SMA type III), and adult onset (SMA type IV) forms. The incidence is about 1:6,000 live births with a carrier frequency of 1:40 for the severe form and 1:80 for the juvenile form. The mortality and/or morbidity rates of SMAs are inversely correlated with the age at onset. SMAs are believed to only affect skeletal muscles; however, new data on SMA mice models suggest they may also impact the heart. Aim of the study was to retrospectively examine the cardiological records of 37 type molecularly confirmed II/III SMA patients, aged 6 to 65 years, in order to evaluate the onset and evolution of the cardiac involvement in these disorders. All patients had a standard ECG and a routine echocardiography. The parameters analysed were the following: Heart rate (HR), PQ interval, PQ segment, Cardiomyopathic Index (ratio QT/PQs), ventricular and supraventricular ectopic beats, pauses ≥ 2,5msec, ventricle diameters, wall and septum thickness, ejection fraction, fiber shortening. The results showed that HR and the other ECG parameters were within the normal limits except for the Cardiomyopathic Index that was higher than the normal values (2,6-4,2) in 2 patients. Left ventricular systolic function was within the normal limits in all patients. A dilation of the left ventricle without systolic dysfunction was observed in only 2 patients, aged respectively 65 and 63 years; however they were hypertensive and/or affected by coronary artery disease. Data here reported contribute to reassure patients and their clinicians that type II/III SMAs do not present heart dysfunction.

G.P.223

Limb-girdle muscular dystrophies (LGMDs) are a group of genetically determined autosomal disorders primary or predominantly involving girdle muscles. Twenty-five loci have been so far identified, 8 dominant (AD) and 17 recessive (AR). The dominant forms (LGMD1A-1H) are generally milder and relatively rare, accounting for 80% of cases in LGMD1B and 1D, often preceding skeletal muscle manifestation or remaining the only marker of the disease. Heart block was the first and most clinically significant cardiac disease in these forms, likely related to fibrosis of the conduction system and fatty infiltration. Implantation of a device was required in about 2/3 of cases to prevent cardiac sudden death. In the ARLGMDs, heart involvement was most frequently observed in sarcoglycanopathies LGMD2C, 2F, 2B and in LGMD2I with clinical pictures evolving toward a dilated cardiomyopathy. To be mentioned that cardiomyopathy was often associated with specific mutations: A525T in LGMD2C and L276I in LGMD2I. In the other forms of LGMD, heart involvement was rare, occurred later in life, likely related to the aging. We recommend that all patients with the above mentioned LGMDs, are carefully monitored for the development of cardiomyopathy, even in the absence of overt cardiac or muscle symptoms/signs and in the early stages of the disease, by not invasive procedures.