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1.  Clinical features of patients with dystrophinopathy sharing the 45-55 exon deletion of DMD gene 
Acta Myologica  2015;34(1):9-13.
Becker muscular dystrophy (BMD) was first described in 1953 by Emile Becker as a benign variant of Duchenne muscular Dystrophy (DMD). Compared with DMD, BMD is clinically more heterogeneous, with initial presentation in the teenage years and loss of ambulation beyond the age of 16 and a wide spectrum of clinical presentations, ranging from only myalgias and muscle cramps to exercise intolerance and myoglobinuria, asymptomatic elevation of serum creatin-kinase, or mild limb-girdle weakness and quadriceps myopathy. About 50% of patients become symptomatic by the age of 10 and the most part by the age of 20 years. However few patients can be free of symptoms till their fifties and cases of late-onset Becker Muscular Dystrophy have also been described.
In this report we describe the clinical features of patients with dystrophinopathy sharing a deletion of exons 45-55, occasionally or retrospectively diagnosed. These data are important for both the prognostic aspects of children presenting this dystrophin gene mutation, and for the genetic counseling in these families (reassuring them on the benign course of the disease), and last but not least to keep in mind a diagnosis of BMD in asymptomatic adults with mild hyperckemia.
PMCID: PMC4478772  PMID: 26155064
Becker muscular dystrophy; dystrophin; asymptomatic BMD
2.  Ventricular fibrillation induced by coagulating mode bipolar electrocautery during pacemaker implantation in Myotonic Dystrophy type 1 patient 
Acta Myologica  2014;33(3):149-151.
The occurrence of ventricular fibrillation, induced by bipolar electrocautery during elective dual chamber pacemaker implantation, is reported in a patient affected by Myotonic Distrophy type 1 with normal left ventricular ejection fraction
PMCID: PMC4369847  PMID: 25873784
ventricular fibrillation; bipolar electrocautery; pacemaker implantation; Myotonic Dystrophy type 1
3.  The effect of atrial preference pacing on atrial fibrillation electrophysiological substrate in Myotonic Dystrophy type 1 population 
Acta Myologica  2014;33(3):127-135.
P-wave dispersion is a non invasive indicator of intra-atrial conduction heterogeneity producing substrate for reentry, which is a pathophysiological mechanism of atrial fibrillation. The relationship between P-wave dispersion (PD) and atrial fibrillation (AF) in Myotonic dystrophy type 1 (DM1) patients is still unclear. Atrial Preference Pacing (APP) is an efficient algorithm to prevent paroxysmal AF in patients implanted with dual-chamber pacemaker. Aim of our study was to evaluate the possible correlation between atrial preference pacing algorithm, P-wave dispersion and AF burden in DM1 patients with normal cardiac function underwent permanent dual-chamber pacemaker implantation.
We enrolled 50 patients with DM1 (age 50.3 ± 7.3; 11 F) underwent dual-chamber pacemaker implantation for various degree of atrioventricula block. The study population was randomized following 1 months stabilization period to APP algorithm features programmed OFF or ON. Patients were assessed every 3 months for the first year, and every 6 months thereafter up to 3 years. At each follow-up visit, we counted: the number of premature atrial beats, the number and the mean duration of AF episodes, AF burden and the percentage of atrial and ventricular pacing.
APP ON Group showed lower number of AF episodes (117 ± 25 vs. 143 ± 37; p = 0.03) and AF burden (3059 ± 275 vs. 9010 ± 630 min; p < 0.04) than APP OFF Group. Atrial premature beats count (44903 ± 30689 vs. 13720 ± 7717 beats; p = 0.005) and Pwave dispersion values (42,1 ± 11 ms vs. 29,1 ± 4,2 ms, p = 0,003) were decreased in APP ON Group. We found a significant positive correlation between PD and AF burden (R = 0,8, p = 0.007).
Atrial preference pacing algorithm, decreasing the number of atrial premature beats and the P-wave dispersion, reduces the onset and perpetuator factors of AF episodes and decreases the AF burden in DM1 patients underwent dual chamber pacemaker implantation for various degree of atrioventricular blocks and documented atrial fibrillation.
PMCID: PMC4369849  PMID: 25873781
atrial fibrillation; Myotonic Dystrophy; atrial preference pacing
4.  Adenosine-induced sinus tachycardia in a patient with Myotonic Dystrophy type 1 
Acta Myologica  2014;33(2):104-106.
We report the case of a 32-year-old man with Myotonic Dystrophy type 1 showing adenosine-induced sinus tachycardia during transesophageal electrophysiological evaluation.
PMCID: PMC4299166  PMID: 25709381
sinus tachycardia; adenosine; proarrhythmic effect; myotonic dystrophy
5.  Far field R-wave sensing in Myotonic Dystrophy type 1: right atrial appendage versus Bachmann's bundle region lead placement 
Acta Myologica  2014;33(2):94-99.
Aim of the present study was to investigate far field R-wave sensing (FFRS) timing and characteristics in 34 Myotonic Dystrophy type 1 (DM1) patients undergoing dual chamber pacemaker implantation, comparing Bachmann's bundle (BB) stimulation (16 patients) site with the conventional right atrial appendage (RAA) pacing site (18 patients). All measurements were done during sinus rhythm and in supine position, with unipolar (UP) and bipolar (BP) sensing configuration. The presence, amplitude threshold (FFRS trsh) and FFRS timing were determined. There were no differences between both atrial sites in the Pmin and Pmean values of sensed P-wave amplitudes, as well as between UP and BP sensing configurations. The FFRS trsh was lower at the BB region in comparison to the RAA site. The mean BP FFRS trsh was significantly lower than UP configuration in both atrial locations. There were no significant differences in atrial pacing threshold, sensing threshold and atrial lead impedances at the implant time and at FFRS measurements. Bachmann's bundle area is an optimal atrial lead position for signal sensing as well as conventional RAA, but it offers the advantage of reducing the oversensing of R-wave on the atrial lead, thus improving functioning of standard dual chamber pacemakers in DM1 patients.
PMCID: PMC4299168  PMID: 25709379
far field; oversensing; far field R-wave sensing; myotonic dystrophy type 1; atrial lead; Bachmann's bundle
6.  Atrial fibrillation burden in Myotonic Dystrophy type 1 patients implanted with dual chamber pacemaker: the efficacy of the overdrive atrial algorithm at 2 year follow-up 
Acta Myologica  2013;32(3):142-147.
The role that atrial pacing therapy plays on the atrial fibrillation (AF) burden is still unclear. Aim of the study was to evaluate the effect of the atrial preference pacing algorithm on AF burden in patients affected by Myotonic Dystrophy type 1 (DM1) followed for a long follow up period. Sixty DM1 patients were -implanted with a dual chamber pacemaker (PM) for first degree or symptomatic type 1/type 2 second degree atrio-ventricular blocks- were followed for 2-years after implantation, by periodical examination. After 1 month of stabilization, they were randomized into two groups: 1) Patients implanted with conventional dual-chamber pacing mode (DDDR group) and 2) Patients implanted with DDDR plus Atrial Preference Pacing (APP) algorithm (APP ON group).
The results showed that atrial tachycardia (AT)/AF burden was significantly reduced at 1 year follow up in the APP ON group (2122 ± 428 minutes vs 4127 ± 388 minutes, P = 0.03), with a further reduction at the end of the 2 year follow up period (4652 ± 348 minutes vs 7564 ± 638 minutes, P = 0.005).
The data here reported show that the APP is an efficient algorithm to reduce AT/AF burden in DM1 patients implanted with dual chamber pacemaker.
PMCID: PMC4006281  PMID: 24803841
Atrial overdrive algorithm; atrial preference pacing; supraventricular tachyarrhythmias; Myotonic Dystrophy type 1
7.  Advances in basic and clinical research in laminopathies 
Acta Myologica  2013;32(1):18-22.
Lamins (LMNA) are the main proteins of the nuclear lamina considered to be the ancestors of all intermediate filament proteins. They form complex protein assemblies with integral proteins of the inner nuclear membrane, transcriptional regulators, histones and chromatin modifiers. During recent years, interest in lamins has greatly increased due to the identification of many distinct heritable human disorders associated with lamin mutations. These disorders, collectively termed laminopathies, range from muscular dystrophies to premature aging. They may affect muscle, fat, bone, nerve and skin tissues. The workshop was addressed to understand lamin organization and its roles in nuclear processes, mutations in lamins affecting cell and tissues functions, the biology of the nucleus and laminopathic disease mechanisms, all aspects important for designing future therapies.
PMCID: PMC3665372  PMID: 23853505
LMNA A/C gene; laminopathies; Emery-Dreifuss muscular dystrophy
8.  Use of a Lower Dosage Liver-Detargeted AAV Vector to Prevent Hamster Muscular Dystrophy 
Human Gene Therapy  2013;24(4):424-430.
The BIO14.6 hamster carries a mutation in the delta sarcoglycan gene causing muscular dystrophy and cardiomyopathy. The disease can be prevented by systemic delivery of delta sarcoglycan cDNA using adeno-associated viruses (AAVs). However, all AAVs also target the liver, raising concerns about their therapeutic efficacy in human applications. We compared the AAV2/8 with the chimeric AAV2/2i8, in which the 585-QQNTAP-590 motif of the AAV8 serotype was added to the heparan sulfate receptor footprint of the AAV2 strain. Both vectors carrying the human delta sarcoglycan cDNA were delivered into 24 14-day-old BIO14.6 hamsters. We followed transgene expression in muscle and liver for 7 months. We detected a sustained ectopic expression of delta sarcoglycan in the liver when using AAV2/8 but not AAV2/2i8. Genomic copies of AAV2/2i8 were not detectable in the liver, while at least 100-fold more copies of AAV2/8 were counted. In contrast, the hamster skeletal muscle expressed more delta sarcoglycan using AAV2/2i8 and were still healthy after 7 months at the lower dosage. We conclude that this chimeric vector is a robust option for safer and longer-term diseased muscle targeting.
Rotundo and colleagues generate a chimeric adeno-associated virus (AAV) 2/8 vector called AAV2/2i8, in which the 585-QQNTAP-590 motif of the AAV8 serotype is added to the heparan sulfate receptor footprint of the AAV2 strain. They show that muscle delivery of AAV2/2i8 works in the BIO14.6 hamster at lower dosages than AAV2/8 and that this occurs without any liver targeting, even within the context of intraperitoneal injections.
PMCID: PMC3631017  PMID: 23427808
9.  Increased dispersion of ventricular repolarization in emery dreifuss muscular dystrophy patients 
Sudden cardiac death (SCD) is common in patients with Emery-Dreifuss muscular dystrophy (EDMD) and is attributed to the development of life-threatening arrhythmias that occur in the presence of normal left ventricular systolic function. Heterogeneity of ventricular repolarization is considered to provide an electrophysiological substrate for malignant arrhythmias. QTc dispersion (QTc-D) and JTc dispersion (JTc-D) are electrocardiographic parameters indicative of heterogeneity of ventricular repolarization. The aim of our study was to evaluate the heterogeneity of ventricular repolarization in patients with Emery-Dreifuss muscular dystrophy with preserved systolic and diastolic cardiac function
The study involved 36 EDMD patients (age 20±12, 26 M) and 36 healthy subjects used as controls, matched for age and sex. Heart rate, QRS duration, maximum and minimum QT and JT interval, QTc-D and JTc-D measurements were performed.
Compared to the healthy control group, the EDMD group presented increased values of QTc-D (82.7±44.2 vs. 53.1±13.7; P=0,003) and JTc-D (73.6±32.3 vs. 60.4±11.1 ms; P=0.001). No correlation between QTc dispersion and ejection fraction (R=0.2, P=0.3) was found.
Our study showed a significant increase of QTc-D and JTc-D in Emery-Dreifuss muscular dystrophy patients with preserved systolic and diastolic cardiac function.
PMCID: PMC3560603  PMID: 23111739
Emery-Dreifuss muscular dystrophy (EDMD); sudden cardiac death (SCD); ventricular repolarization; QTc dispersion; JTc dispersion
10.  Right atrial preference pacing algorithm in the prevention of paroxysmal atrial fibrillation in myotonic dystrophy type 1 patients: a long term follow-up study 
Acta Myologica  2012;31(2):139-143.
Atrial Preference Pacing (APP) is a pacemaker (PM) algorithm that works by increasing the atrial pacing rate to achieve continuous suppression of a spontaneous atrial rhythm and prevent supraventricular tachyarrhythmias. We have previously shown that atrial preference pacing may significantly reduce the number and the duration of AF episodes in myotonic dystrophy type 1 (DM1) patients who are paced for standard indications.
However, the role that APP therapies play in the prevention of AF in a long-term period remains still unclear. Aim of the present prospective study was to evaluate whether this beneficial effect is maintained for 24-months follow-up period.
To this aim, 50 patients with Myotonic Dystrophy type 1 who underwent dual-chamber PM implantation for first- and second- degree atrioventricular block, were consecutively enrolled and followed for 2 years. One month later the stabilization period, after the implantation, they were randomized to APP algorithm programmed OFF or ON for 6 months each, using a cross-over design, and remained in the same program for the second year. The results showed that while the number of AF episodes during active treatment (APP ON phases) was lower than that registered during no treatment (APP OFF phases), no statistically significant difference was found in AF episodes duration between the two phases. Furthermore, during the APP OFF and APP ON phases, the percentage of atrial pacing was 0 and 99%, respectively, while the percentage of ventricular pacing did not show differences statistically significant (11 vs. 9%, P = 0.2). Atrial premature beats were significantly higher during APP OFF phases than during APP ON phases. Lead parameters remained stable over time and there were no lead-related complications. Based on these 24-months follow-up data, we can conclude that, in DM1 patients who underwent dual-chamber PM implantation, APP is an efficacy algorithm for preventing paroxysmal AF even in long term periods.
PMCID: PMC3476853  PMID: 23097606
myotonic dystrophy; atrial preference pacing; atrial fibrillation
11.  Improvement of survival in Duchenne Muscular Dystrophy: retrospective analysis of 835 patients 
Acta Myologica  2012;31(2):121-125.
Duchenne Muscular Dystrophy (DMD) is the most common muscle disease in children. Historically, DMD results in loss of ambulation between ages 7 and 13 years and death in the teens or 20s. In order to determine whether survival has improved over the decades and whether the impact of nocturnal ventilation combined with a better management of cardiac involvement has been able to modify the pattern of survival, we reviewed the notes of 835 DMD patients followed at the Naples Centre of Cardiomyology and Medical Genetics from 1961 to 2006. Patients were divided, by decade of birth, into 3 groups: 1) DMD born between 1961 and 1970; 2) DMD born between 1971 and 1980; 3) DMD born between 1981 and 1990; each group was in turn subdivided into 15 two-year classes, from 14 to 40 years of age. Age and causes of death, type of cardiac treatment and use of a mechanical ventilator were carefully analyzed.
The percentage of survivors in the different decades was statistically compared by chi-square test and Kaplan-Meier survival curves analyses. A significant decade on decade improvement in survival rate was observed at both the age of 20, where it passed from 23.3% of patients in group 1 to 54% of patients in group 2 and to 59,8% in patients in group 3 (p < 0.001) and at the age of 25 where the survival rate passed from 13.5% of patients in group 1 to 31.6% of patients in group 2 and to 49.2% in patients in group 3 (p < 0.001).
The causes of death were both cardiac and respiratory, with a prevalence of the respiratory ones till 1980s. The overall mean age for cardiac deaths was 19.6 years (range 13.4-27.5), with an increasing age in the last 15 years. The overall mean age for respiratory deaths was 17.7 years (range 11.6-27.5) in patients without a ventilator support while increased to 27.9 years (range 23-38.6) in patients who could benefit of mechanical ventilation.
This report documents that DMD should be now considered an adulthood disease as well, and as a consequence more public health interventions are needed to support these patients and their families as they pass from childhood into adult age.
PMCID: PMC3476854  PMID: 23097603
Duchenne; survival; cardiomyopathy
12.  The heart and cardiac pacing in Steinert disease 
Acta Myologica  2012;31(2):110-116.
Myotonic dystrophy (Dystrophia Myotonica, DM) is the most frequently inherited neuromuscular disease of adult life. It is a multisystemic disease with major cardiac involvement. Core features of myotonic dystrophy are myotonia, muscle weakness, cataract, respiratory failure and cardiac conduction abnormalities. Classical DM, first described by Steinert and called Steinert's disease or DM1 (Dystrophia Myotonica type 1) has been identified as an autosomal dominant disorder associated with the presence of an abnormal expansion of a CTG trinucleotide repeat in the 3' untranslated region of DMPK gene on chromosome 19. This review will mainly focus on the various aspects of cardiac involvement in DM1 patients and the current role of cardiac pacing in their treatment.
PMCID: PMC3476856  PMID: 23097601
myotonic dystrophy type 1; arrhythmias; cardiac pacing
13.  Cardiac resynchronization improves heart failure in one patient with Myotonic Dystrophy type 1. A case report 
Acta Myologica  2012;31(2):154-155.
We report an improvement in symptoms of heart failure, a reduced left ventricular dysfunction and induced reverse remodelling in one patient with Myotonic Dystrophy type 1, showing an early onset ventricular dysfunction secondary to a complete left bundle branch block (LBBB) who underwent cardioverter defibrillator CRT (ICD- CRT) implantation.
PMCID: PMC3476859  PMID: 23097608
myotonic dystrophy; cardiac resynchronization therapy; sudden death
14.  Diagnosis and Management of Atrial Fibrillation by Primary Care Physicians in Italy 
Clinical Drug Investigation  2012;32(11):771-777.
Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with a heavy burden of morbidity and mortality, mainly due to an increased risk of cerebrovascular events and cardiac failure. Oral anticoagulant (OAC) treatment prevents stroke and systemic thromboembolism in patients with AF and its use is strongly recommended in guidelines. However, its use in this patient group remains limited. Primary care physicians (PCPs) have an important role to play in this context.
The primary objective was to estimate prevalence and epidemiological features of AF in the primary care setting, focusing on ischaemic and bleeding risk assessment. A secondary objective was to examine the PCPs’ level of adherence to the guidelines for the prevention of thromboembolic risk in these patients.
This retrospective, observational study was based on data entered by 128 PCPs into the Health Search (HS) Thales database, identifying patients with a diagnosis of AF at the time of the analysis.
Out of 167,056 patients analysed, 2,173 (1.3 %) were diagnosed with AF, with 86 % at high risk for ischaemic stroke, according to CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years [doubled], diabetes, stroke [doubled], vascular disease, age 65–74 years, sex category [female]) stratification. After the diagnosis of AF, 84 % of patients were prescribed OAC treatment. However, at 2 years’ follow-up, only 29.6 % were still being treated with OACs.
The prevalence of AF in this analysis was consistent with previously reported Italian national epidemiological data. Adherence to the European Society of Cardiology AF guidelines by PCPs was low, despite the high levels of stroke risk. At the end of the observation period less than one-third of patients were still on OAC therapy. Awareness of the benefits of OACs in stroke prevention in AF patients needs to be improved.
PMCID: PMC3693438  PMID: 23018284
15.  A longitudinal study on BIO14.6 hamsters with dilated cardiomyopathy: micro-echocardiographic evaluation 
In recent years, several new technologies for small-animal imaging have been developed. In particular, the use of ultrasound in animal imaging has focused on the investigation of accessible biological structures such as the heart, of which it provides a morphological and functional assessment. The purpose of this study was to investigate the role of micro-ultrasonography (μ-US) in a longitudinal study on BIO14.6 cardiomyopathic hamsters treated with gene therapy.
Thirty hamsters were divided into three groups (n = 10): Group I, untreated BIO 14.6 hamsters; Group II, BIO 14.6 hamsters treated with gene therapy; Group III, untreated wild type (WT) hamsters. All hamsters underwent serial μ-US sessions and were sacrificed at predetermined time points.
μ-US revealed: in Group I, progressive dilation of the left ventricle with a change in heart morphology from an elliptical to a more spherical shape, altered configuration of the mitral valve and subvalvular apparatus, and severe reduction in ejection fraction; in Group II, mild decrease in contractile function and ejection fraction; in Group III, normal cardiac chamber morphology and function. There was a negative correlation between the percentage of fibrosis observed at histology and the ejection fraction obtained on μ-echocardiography (Spearman r: -0.839; p < 0.001).
Although histological examination remains indispensable for a conclusive diagnosis, high-frequency μ-echocardiography, thanks to the high spatial and contrast resolution, can be considered sufficient for monitoring therapeutic efficacy and/or the progression of dilated cardiomyopathy, providing an alternative tool for repeatable and noninvasive evaluation.
PMCID: PMC3254069  PMID: 22151912
μ-US; muscular dystrophy; gene therapy; animal model
16.  Worsening of Cardiomyopathy Using Deflazacort in an Animal Model Rescued by Gene Therapy 
PLoS ONE  2011;6(9):e24729.
We have previously demonstrated that gene therapy can rescue the phenotype and extend lifespan in the delta-sarcoglycan deficient cardiomyopathic hamster. In patients with similar genetic defects, steroids have been largely used to slow down disease progression. Aim of our study was to evaluate the combined effects of steroid treatment and gene therapy on cardiac function. We injected the human delta-sarcoglycan cDNA by adeno-associated virus (AAV) 2/8 by a single intraperitoneal injection into BIO14.6 Syrian hamsters at ten days of age to rescue the phenotype. We then treated the hamsters with deflazacort. Treatment was administered to half of the hamsters that had received the AAV and the other hamsters without AAV, as well as to normal hamsters. Both horizontal and vertical activities were greatly enhanced by deflazacort in all groups. As in previous experiments, the AAV treatment alone was able to preserve the ejection fraction (70±7% EF). However, the EF value declined (52±14%) with a combination of AAV and deflazacort. This was similar with all the other groups of affected animals. We confirm that gene therapy improves cardiac function in the BIO14.6 hamsters. Our results suggest that deflazacort is ineffective and may also have a negative impact on the cardiomyopathy rescue, possibly by boosting motor activity. This is unexpected and may have significance in terms of the lifestyle recommendations for patients.
PMCID: PMC3170375  PMID: 21931833
17.  Combined deficiency of alpha and epsilon sarcoglycan disrupts the cardiac dystrophin complex 
Human Molecular Genetics  2011;20(23):4644-4654.
Cardiomyopathy is a puzzling complication in addition to skeletal muscle pathology for patients with mutations in β-, γ- or δ-sarcoglycan (SG) genes. Patients with mutations in α-SG rarely have associated cardiomyopathy, or their cardiac pathology is very mild. We hypothesize that a fifth SG, ɛ-SG, may compensate for α-SG deficiency in the heart. To investigate the function of ɛ-SG in striated muscle, we generated an Sgce-null mouse and a Sgca-;Sgce-null mouse, which lacks both α- and ɛ-SGs. While Sgce-null mice showed a wild-type phenotype, with no signs of muscular dystrophy or heart disease, the Sgca-;Sgce-null mouse developed a progressive muscular dystrophy and a more anticipated and severe cardiomyopathy. It shows a complete loss of residual SGs and a strong reduction in both dystrophin and dystroglycan. Our data indicate that ɛ-SG is important in preventing cardiomyopathy in α-SG deficiency.
PMCID: PMC3209833  PMID: 21890494
18.  Disease Rescue and Increased Lifespan in a Model of Cardiomyopathy and Muscular Dystrophy by Combined AAV Treatments 
PLoS ONE  2009;4(3):e5051.
The BIO14.6 hamster is an excellent animal model for inherited cardiomyopathy, because of its lethal and well-documented course, due to a spontaneous deletion of delta-sarcoglycan gene promoter and first exon. The muscle disease is progressive and average lifespan is 11 months, because heart slowly dilates towards heart failure.
Methodology/Principal Findings
Based on the ability of adeno-associated viral (AAV) vectors to transduce heart together with skeletal muscle following systemic administration, we delivered human delta-sarcoglycan cDNA into male BIO14.6 hamsters by testing different ages of injection, routes of administration and AAV serotypes. Body-wide restoration of delta-SG expression was associated with functional reconstitution of the sarcoglycan complex and with significant lowering of centralized nuclei and fibrosis in skeletal muscle. Motor ability and cardiac functions were completely rescued. However, BIO14.6 hamsters having less than 70% of fibers recovering sarcoglycan developed cardiomyopathy, even if the total rescued protein was normal. When we used serotype 2/8 in combination with serotype 2/1, lifespan was extended up to 22 months with sustained heart function improvement.
Our data support multiple systemic administrations of AAV as a general therapeutic strategy for clinical trials in cardiomyopathies and muscle disorders.
PMCID: PMC2660610  PMID: 19333401

Results 1-18 (18)