Functional abilities, respiratory and cardiac function in a large cohort of adults with Duchenne muscular dystrophy treated with glucocorticoids.

BACKGROUND AND PURPOSE: The transition to adult services, and subsequent glucocorticoid management, is critical in adults with Duchenne muscular dystrophy. This study aims (1) to describe treatment, functional abilities, respiratory and cardiac status during transition to adulthood and adult stages; and (2) to explore the association between glucocorticoid treatment after loss of ambulation (LOA) and late-stage clinical outcomes. METHODS: This was a retrospective single-centre study on individuals with Duchenne muscular dystrophy (≥16 years old) between 1986 and 2022. Logistic regression, Cox proportional hazards models and survival analyses were conducted utilizing data from clinical records. RESULTS: In all, 112 individuals were included. Mean age was 23.4 ± 5.2 years and mean follow-up was 18.5 ± 5.5 years. At last assessment, 47.2% were on glucocorticoids; the mean dose of prednisone was 0.38 ± 0.13 mg/kg/day and of deflazacort 0.43 ± 0.16 mg/kg/day. At age 16 years, motor function limitations included using a manual wheelchair (89.7%), standing (87.9%), transferring from a wheelchair (86.2%) and turning in bed (53.4%); 77.5% had a peak cough flow <270 L/min, 53.3% a forced vital capacity percentage of predicted <50% and 40.3% a left ventricular ejection fraction <50%. Glucocorticoids after LOA reduced the risk and delayed the time to difficulties balancing in the wheelchair, loss of hand to mouth function, forced vital capacity percentage of predicted <30% and forced vital capacity <1 L and were associated with lower frequency of left ventricular ejection fraction <50%, without differences between prednisone and deflazacort. Glucocorticoid dose did not differ by functional, respiratory or cardiac status. CONCLUSION: Glucocorticoids after LOA preserve late-stage functional abilities, respiratory and cardiac function. It is suggested using functional abilities, respiratory and cardiac status at transition stages for adult services planning.

Effects of cardiac medications on ventricular function in patients with Duchenne muscular dystrophy-related cardiomyopathy.

INTRODUCTION/AIMS: The DMD Care Considerations Working Group Guidelines 2010 recommended treating cardiac dystrophinopathy with angiotensin-converting enzyme-inhibitor (ACEi) and beta-blocker (BB) therapy to prevent the progressive decline in left ventricular function expected from earlier, natural history studies. The aim of this research was to audit change in measures of left ventricular function over 8 years to 4 years before and 4 years after deploying an ACEi/BB combination systematically at a dedicated "cardiology-muscle" clinic. METHODS: This is an institutionally registered, retrospective, case-file-based audit of serial echocardiographic measures of left ventricular fractional shortening accumulated over the period 1995 to 2015. RESULTS: Data from 104 genetically confirmed Duchenne muscular dystrophy (DMD) patients, aged 22.2 ± 5.3 years at data censure, were included. Mean age at first detection of left ventricular dysfunction was 15.1 ± 4.2 years, but older in those on maintenance steroid therapy (16.8 ± 4.2 vs 14.5 ± 4.1 years; P = .04). Group mean fractional shortening fell by 1.5%/year over the 4 years before therapy, but this decreased to 0.9%/year over the first 4 years after starting therapy. Analysis of limited left ventricular ejection fraction measures showed similar but nonsignificant changes. Neither age at detection of left ventricular dysfunction nor fractional shortening percent at time of therapy initiation affected the beneficial response. DISCUSSION: The results support the international DMD recommendations of the time. This combination of cardiac medications helps stabilize heart function. For the best long-term effects, therapy needs to be initiated no later than on first detection left ventricular impairment.

Interventions for preventing and treating cardiac complications in Duchenne and Becker muscular dystrophy and X-linked dilated cardiomyopathy.

BACKGROUND: The dystrophinopathies include Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and X-linked dilated cardiomyopathy (XLDCM). In recent years, co-ordinated multidisciplinary management for these diseases has improved the quality of care, with early corticosteroid use prolonging independent ambulation, and the routine use of non-invasive ventilation signficantly increasing survival. The next target to improve outcomes is optimising treatments to delay the onset or slow the progression of cardiac involvement and so prolong survival further. OBJECTIVES: To assess the effects of interventions for preventing or treating cardiac involvement in DMD, BMD, and XLDCM, using measures of change in cardiac function over six months. SEARCH METHODS: On 16 October 2017 we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE and Embase, and on 12 December 2017, we searched two clinical trials registries. We also searched conference proceedings and bibliographies. SELECTION CRITERIA: We considered only randomised controlled trials (RCTs), quasi-RCTs and randomised cross-over trials for inclusion. In the Discussion, we reviewed open studies, longitudinal observational studies and individual case reports but only discussed studies that adequately described the diagnosis, intervention, pretreatment, and post-treatment states and in which follow-up lasted for at least six months. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed the titles and abstracts identified from the search and performed data extraction. All three authors assessed risk of bias independently, compared results, and decided which trials met the inclusion criteria. They assessed the certainty of evidence using GRADE criteria. MAIN RESULTS: We included five studies (N = 205) in the review; four studies included participants with DMD only, and one study included participants with DMD or BMD. All studied different interventions, and meta-analysis was not possible. We found no studies for XLDCM. None of the trials reported cardiac function as improved or stable cardiac versus deteriorated.The randomised first part of a two-part study of perindopril (N = 28) versus placebo (N = 27) in boys with DMD with normal heart function at baseline showed no difference in the number of participants with a left ventricular ejection fraction (LVEF%) of less than 45% after three years of therapy (n = 1 in each group; risk ratio (RR) 1.04, 95% confidence interval (CI) 0.07 to 15.77). This result is uncertain because of study limitations, indirectness and imprecision. In a non-randomised follow-up study, after 10 years, more participants who had received placebo from the beginning had reduced LVEF% (less than 45%). Adverse event rates were similar between the placebo and treatment groups (low-certainty evidence).A study comparing treatment with lisinopril versus losartan in 23 boys newly diagnosed with Duchenne cardiomyopathy showed that after 12 months, both were equally effective in preserving or improving LVEF% (lisinopril 54.6% (standard deviation (SD) 5.19), losartan 55.2% (SD 7.19); mean difference (MD) -0.60% CI -6.67 to 5.47: N = 16). The certainty of evidence was very low because of very serious imprecision and study limitations (risk of bias). Two participants in the losartan group were withdrawn due to adverse events: one participant developed an allergic reaction, and a second exceeded the safety standard with a fall in ejection fraction greater than 10%. Authors reported no other adverse events related to the medication (N = 22; very low-certainty evidence).A study comparing idebenone versus placebo in 21 boys with DMD showed little or no difference in mean change in cardiac function between the two groups from baseline to 12 months; for fractional shortening the mean change was 1.4% (SD 4.1) in the idebenone group and 1.6% (SD 2.6) in the placebo group (MD -0.20%, 95% CI -3.07 to 2.67, N = 21), and for ejection fraction the mean change was -1.9% (SD 9.8) in the idebenone group and 0.4% (SD 5.5) in the placebo group (MD -2.30%, 95% CI -9.18 to 4.58, N = 21). The certainty of evidence was very low because of study limitations and very serious imprecision. Reported adverse events were similar between the treatment and placebo groups (low-certainty evidence).A multicentre controlled study added eplerenone or placebo to 42 patients with DMD with early cardiomyopathy but preserved left ventricular function already established on ACEI or ARB therapy. Results showed that eplerenone slowed the rate of decline of magnetic resonance (MR)-assessed left ventricular circumferential strain at 12 months (eplerenone group median 1.0%, interquartile range (IQR) 0.3 to -2.2; placebo group median 2.2%, IQR 1.3 to -3.1%; P = 0.020). The median decline in LVEF over the same period was also less in the eplerenone group (-1.8%, IQR -2.9 to 6.0) than in the placebo group (-3.7%, IQR -10.8 to 1.0; P = 0.032). We downgraded the certainty of evidence to very low for study limitations and serious imprecision. Serious adverse events were reported in two patients given placebo but none in the treatment group (very low-certainty evidence).A randomised placebo-controlled study of subcutaneous growth hormone in 16 participants with DMD or BMD showed an increase in left ventricular mass after three months' treatment but no significant improvement in cardiac function. The evidence was of very low certainty due to imprecision, indirectness, and study limitations. There were no clinically significant adverse events (very low-certainty evidence).Some studies were at risk of bias, and all were small. Therefore, although there is some evidence from non-randomised data to support the prophylactic use of perindopril for cardioprotection ahead of detectable cardiomyopathy, and for lisinopril or losartan plus eplerenone once cardiomyopathy is detectable, this must be considered of very low certainty. Findings from non-randomised studies, some of which have been long term, have led to the use of these drugs in daily clinical practice. AUTHORS' CONCLUSIONS: Based on the available evidence from RCTs, early treatment with ACE inhibitors or ARBs may be comparably beneficial for people with a dystrophinopathy; however, the certainty of evidence is very low. Very low-certainty evidence indicates that adding eplerenone might give additional benefit when early cardiomyopathy is detected. No clinically meaningful effect was seen for growth hormone or idebenone, although the certainty of the evidence is also very low.

Cardiac involvement in female carriers of duchenne or becker muscular dystrophy.

INTRODUCTION: The significance of abnormal cardiac measures in asymptomatic females who harbor dystrophin gene mutations is controversial. METHODS: Echo-measures of ventricular function were compared with published norms in a cross-sectional study of 130 (age, 39 ± 15.7 years) "carriers" of Duchenne or Becker muscular dystrophy (DMD/BMD). Correlations between cardiomyopathy (CM) and mutation, creatine kinase (CK) levels, age, and muscle symptoms were investigated. RESULTS: Depending on definition, CM prevalence was 3-33%. Ejection fraction (Simpson method) was < 55% in 9 (13%) and < 40% in 2 (2.9%). Eleven (8.5%) had wall motion abnormalities. Left ventricular end-systolic dimensions were increased in 7 (5.7%) and end-diastolic in 17 (13.9%). CM did not correlate with mutation type, DMD or BMD phenotype, CK level, muscle symptoms, or age. CONCLUSIONS: Occult CM can be found by screening in DMD/BMD carriers. Its lack of age-correlation suggests that not all abnormalities progress. Optimum screening schedules require a better understanding of progressive CM. Muscle Nerve 55: 810-818, 2017.

Sudden adult death syndrome in m.3243A>G-related mitochondrial disease: an unrecognized clinical entity in young, asymptomatic adults.

AIMS: To provide insight into the mechanism of sudden adult death syndrome (SADS) and to give new clinical guidelines for the cardiac management of patients with the most common mitochondrial DNA mutation, m.3243A>G. These studies were initiated after two young, asymptomatic adults harbouring the m.3243A>G mutation died suddenly and unexpectedly. The m.3243A>G mutation is present in ∼1 in 400 of the population, although the recognized incidence of mitochondrial DNA (mtDNA) disease is ∼1 in 5000. METHODS AND RESULTS: Pathological studies including histochemistry and molecular genetic analyses performed on various post-mortem samples including cardiac tissues (atrium and ventricles) showed marked respiratory chain deficiency and high levels of the m.3243A>G mutation. Systematic review of cause of death in our m.3243A>G patient cohort showed the person-time incidence rate of sudden adult death is 2.4 per 1000 person-years. A further six cases of sudden death among extended family members have been identified from interrogation of family pedigrees. CONCLUSION: Our findings suggest that SADS is an important cause of death in patients with m.3243A>G and likely to be due to widespread respiratory chain deficiency in cardiac muscle. The involvement of asymptomatic relatives highlights the importance of family tracing in patients with m.3243A>G and the need for specific cardiac arrhythmia surveillance in the management of this common genetic disease. In addition, these findings have prompted the derivation of cardiac guidelines specific to patients with m.3243A>G-related mitochondrial disease. Finally, due to the prevalence of this mtDNA point mutation, we recommend inclusion of testing for m.3243A>G mutations in the genetic autopsy of all unexplained cases of SADS.

Characteristics of the atrial repolarization phase of the ECG in paroxysmal atrial fibrillation patients and controls.

OBJECTIVE: The aim of this study is to characterize the observable segment of the atrial repolarization (Ta wave) of the standard ECG during sinus rhythm in paroxysmal atrial fibrillation (PAF) patients and controls. METHODS: Ta and P waves were measured from signal-averaged recordings of a standard 12-lead ECG in 40 patients, 20 with PAF, but in SR at the time of recording, and 20 healthy controls. Wave amplitudes and morphologies were measured. RESULTS: There were no significant differences in Ta amplitude between the PAF patients and controls. A subgroup analysis of patients on and off anti-arrhythmic drugs also showed no significant differences in Ta amplitudes. For both groups Ta wave had opposite polarity to the monophasic P wave. Biphasic P waves had Ta polarity opposite to the initial phase of the P wave. Ta wave amplitudes were largest in leads II (mean ± SD, ­25 ± 16 µV), V2 (­22 ± 10 µV), V3 (­21 ± 10 µV) and V4 (­20 ± 8 µV). A significant correlation was found between Ta and P wave amplitudes, leads recording larger P waves also had larger Ta waves (PAF group: r = 0.15 (P = 0.02) PAF vs r = 0.33 (P = 0.002) HC). CONCLUSION: No differences in the amplitude of the observable section of the atrial repolarization phase of the ECG could be observed between patients with PAF and controls. Ta wave correlates with the corresponding P wave in both amplitude and polarity.

Understanding the Electrical Substrates Contributing to "Ablation-Resistant" Atrial Fibrillation?

Atrial fibrillation (AF) was largely ignored by cardiac electrophysiologists until it was first suggested in 1998 that it might be amenable to catheter ablation. In the 25 years since then, a vast body of knowledge has emerged, initially reporting the "hypes and hopes" that ablation was appropriate for all but more recently acknowledging that not all patients benefit from this approach. The AF "epidemic" and more holistic understanding of the complex contributors to its development question whether it is even meaningful to consider AF a single condition that is always responsive to ablation management. In this issue, Masuda et al11 provide novel insights into the electrophysiologic "footprints" that they found in the body of the left atrium of patients who underwent a second ablation procedure after achieving pulmonary vein isolation. In conclusion, the findings require prospective validation but may show a way of achieving antiarrhythmic success in a cohort of patients responding unpredictably to current ablation strategies.

Disease-associated comorbidities, medication records and anthropometric measures in adults with Duchenne muscular dystrophy.

We investigated the comorbidities, associated factors, and the relationship between anthropometric measures and respiratory function and functional abilities in adults with Duchenne muscular dystrophy (DMD). This was a single-centre cross-sectional study in genetically diagnosed adults with DMD (>16 years old). Univariate and multivariate analyses identified factors associated with dysphagia, constipation, Body Mass Index (BMI), and weight. Regression analysis explored associations between BMI, weight, and respiratory/motor abilities. We included 112 individuals (23.4 ± 5.2 years old), glucocorticoid-treated 66.1 %. The comorbidities frequency was 61.6 % scoliosis (61.0 % of them had spinal surgery), 36.6 % dysphagia, 36.6 % constipation, and 27.8 % urinary conditions. The use of glucocorticoids delayed the time to spinal surgery. The univariate analysis revealed associations between dysphagia and constipation with age, lack of glucocorticoid treatment, and lower respiratory and motor function. In the multivariate analysis, impaired cough ability remained as the factor consistently linked to both conditions. Constipation associated with lower BMI and weight. BMI and weight positively correlated with respiratory parameters, but they did not associate with functional abilities. Glucocorticoids reduce the frequency of comorbidities in adults with DMD. The ability to cough can help identifying dysphagia and constipation. Lower BMI and weight in individuals with DMD with compromised respiratory function may suggest a higher calories requirement.

Cardiac involvement in mitochondrial DNA disease: clinical spectrum, diagnosis, and management.

Mitochondrial disease refers to a heterogenous group of genetic disorders that result from dysfunction of the final common pathway of energy metabolism. Mitochondrial DNA mutations affect key components of the respiratory chain and account for the majority of mitochondrial disease in adults. Owing to critical dependence of the heart on oxidative metabolism, cardiac involvement in mitochondrial disease is common and may occur as the principal clinical manifestation or part of multisystem disease. Recent advances in our understanding of the clinical spectrum and genetic aetiology of cardiac involvement in mitochondrial DNA disease have important implications for cardiologists in terms of the investigation and multi-disciplinary management of patients.

Spatial pattern of P waves in paroxysmal atrial fibrillation patients in sinus rhythm and controls.

BACKGROUND: Measuring body surface potentials in the assessment of the electrical activity of the heart is the most commonly used noninvasive method for diagnosing cardiac arrhythmias. Paroxysmal atrial fibrillation (PAF) patients have disturbed cardiac electrophysiology but the detailed characteristics of atrial activation on the body surface are unknown. METHODS: P waves from 60 sites on the body surface were analyzed from 10 PAF patients in sinus rhythm (PAF group) and 10 healthy controls (HC group). Evolution of atrial depolarization was described qualitatively by maps of P-wave amplitudes. P-wave dipole evolution was described quantitatively by measuring the changing location (body site) and amplitude of the dipole positive and negative pole peaks. RESULTS: Both groups exhibited similar dipolar structure with an area of positive and an area of negative potentials. Over the depolarization cycle, there were significant changes in the location of the dipole with the positive pole rotating anteriorly right to left by two electrode sites (10 cm) (P = 0.001). There were significant differences between groups with the positive pole in PAF offset to the right of the chest by 0.43 (0.38) strips compared to HC (P < 0.007). Compared to controls, the PAF group positive poles reached peak amplitude sooner (49 [11] ms vs 65 [14] ms, P = 0.012) and negative poles reached peak amplitude later (74 [13] ms vs 62 [8] ms, P = 0.019). CONCLUSION: Atrial depolarization is characterized by a single dipole with time-varying amplitude and orientation with significant differences in dipole trajectory between patients with PAF and HCs.

Sudden cardiac death among competitive adult athletes: a review.

Sudden cardiac death is the leading cause of mortality among young athletes with an incidence of 1-2 per 100,000 athletes per annum. It is described as 'an event that is non-traumatic, non-violent, unexpected, and resulting from sudden cardiac arrest within six hours of previously witnessed normal health'. Most predisposed athletes have no symptoms and there is no warning for the impending tragic event. The majority of cases are caused by an underlying structural cardiac abnormality, most commonly hypertrophic cardiomyopathy. More recently, the understanding of non-structural causes such as long QT syndrome and Brugada syndrome has grown and diagnostic criteria have been developed. This review presents the known aetiologies of sudden cardiac death among athletes and outlines their identification and management including implications for future sporting participation as laid out in the consensus documents produced by the European Society of Cardiology and the 36th Bethesda Conference.

Arrhythmia prevalence and sudden death risk in adults with the m.3243A>G mitochondrial disorder.

AIMS: To define the prevalence of non-sustained tachyarrhythmias and bradyarrhythmias in patients with the m.3243A>G mitochondrial genotype and a previously defined, profile, associated with 'high sudden-death risk'. METHODS AND RESULTS: Patients at high risk of sudden death because of combinations of ventricular hypertrophy, mitochondrial encephalopathy, lactic acidosis and stroke-like episodes family phenotype, epilepsy or high mutation load, due to the m.3243A>G mutation, were identified from a mitochondrial cohort of 209 patients. All recruited had serial ECG and echo assessments previously according to schedule, had an ECG-loop recorder implanted and were followed for as long as the device allowed. Devices were programmed to detect non-sustained brady- or tachy-arrhythmias. This provided comprehensive rhythm surveillance and automatic downloads of all detections to a monitoring station for cardiology interpretation. Those with sinus tachycardia were treated with beta-blockers and those with ventricular hypertrophy received a beta-blocker and ACE-inhibitor combination.Nine consecutive patients, approached (37.2±3.9 years, seven males) and consented, were recruited. None died and no arrhythmias longer than 30s duration occurred during 3-year follow-up. Three patients reported palpitations but ECGs correlated with sinus rhythm. One manifest physiological, sinus pauses >3.5 s during sleep and another had one asymptomatic episode of non-sustained ventricular tachycardia. CONCLUSIONS: Despite 'high-risk' features for sudden death, those studied had negligible prevalence of arrhythmias over prolonged follow-up. By implication, the myocardium in this genotype is not primarily arrhythmogenic. Arrhythmias may not explain sudden death in patients without Wolff-Parkinson-White or abnormal atrioventricular conduction or, it must require a confluence of other, dynamic, proarrhythmic factors to trigger them.

Ablation of atrial tachyarrhythmias late after surgical repair of tetralogy of Fallot.

BACKGROUND: Patients with repaired tetralogy of Fallot may develop symptomatic and haemodynamic deterioration for many reasons such as arrhythmia, pulmonary regurgitation, and impairment in ventricular function. We describe a consecutive group of patients whose main clinical problem was atrial tachyarrhythmias. AIMS: To describe the clinical outcome of atrial tachyarrhythmias occurring late after surgical repair of tetralogy of Fallot; to define the circuits/foci responsible for these atrial tachyarrhythmias; to evaluate the outcome of computer-assisted mapping and catheter ablation in this patient group. METHODS AND RESULTS: Consecutive patients with surgically repaired tetralogy of Fallot and atrial tachyarrhythmias, who underwent catheter ablation between January, 2001 and June, 2007, were identified retrospectively from case records. Computer-assisted mapping was performed in all using either EnSite® (St Jude Medical Inc.) arrhythmia mapping and intra-cardiac catheter guidance system or CARTO™ (Biosense Webster Inc.) electroanatomical mapping systems. Ten patients (four males) with a median age of 39 plus or minus 8 years were studied. The total number of atrial tachyarrhythmias identified was 22 (six macro-reentrant, 16 micro-reentrant/focal). In nine patients, catheter ablation led to improvement in arrhythmia episodes and/or symptoms during follow-up of 41 plus or minus 20 months. Following ablation(s), five patients required pacing for pre-existing conduction disease and five needed further surgery for haemodynamic indications. All patients remained on anti-arrhythmic drugs. CONCLUSIONS: Patients with surgically repaired tetralogy of Fallot and atrial tachyarrhythmias typically have multiple arrhythmic circuits/foci arising from a scarred right atrium. Catheter ablation reduces arrhythmia frequency and improves symptoms. However, hybrid management is often required, comprising drugs, pacing, and further surgery tailored to the individual.

Preventing Cardiomyopathy in DMD: A Randomized Placebo-Controlled Drug Trial.

OBJECTIVE: To determine whether a combination of 2 heart medications would be tolerated and could prevent/delay the onset of cardiomyopathy in boys with Duchenne muscular dystrophy (DMD) compared with placebo. METHODS: This multicenter, parallel group, 1:1 patient randomized, placebo-controlled study of prophylactic perindopril and bisoprolol recruited boys with DMD aged 5-13 years, with normal ventricular function. Repeat assessments of left ventricular (LV) function, electrocardiogram, and adverse event reporting were performed 6 monthly. The primary outcome was change in ejection fraction between arms after 36 months. The study was approved by the National Research Ethics Service Committee East Midlands-Derby. RESULTS: Eighty-five boys were recruited (76% on steroid therapy) and randomized to combination heart drugs or matched placebo. Group change in left ventricular ejection fraction (LVEF%) at 36 months from baseline was -2.2% ± 6.0% and -2.9% ± 6.1% in active and placebo arms (adjusted mean difference: -2.1, 95% CI -5.2 to 1.1). There was no difference between treatment arms over repeated assessments (analysis of variance) up to 36 months (trial arms p = 0.53); arm-over-time (p = 0.44). Four participants on placebo but none on active therapy were withdrawn due to deteriorations in LV function. Secondary outcomes did not differ between arms either. Thirty-six serious adverse events occurred none due to cardiac events or trial medication. CONCLUSIONS: Combination therapy was well tolerated. Consistent with the previous prophylactic perindopril heart study, there was no evidence of group benefit after 36-month treatment. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that combination perindopril-bisoprolol therapy was well tolerated but did not change decline in LVEF significantly in boys with DMD.

Exploring the acceptability of implantable defibrillators in patients with cardiac dystrophinopathy and carers.

Objective: Unlike for patients with other forms of cardiomyopathies, those with severe ventricular dysfunction due to Duchenne muscular dystrophy (DMD) are not offered implantable cardioverter-defibrillator (ICD) therapy routinely. This prospective study aimed to determine the views of DMD-patients and their carers about discussing sudden death risk and their acceptance of ICDs. Design and setting: Adults with DMD (n=9) and parents/carers (n=9) participated in audio-recorded, 60-90 min focus group sessions (patients 2; parents/carers 2) conducted through either a face-to-face session at a neutral venue or a videoconference. Sessions were facilitated by a clinical psychologist, experienced in conducting focus group research. All participants understood the rationale for the study and the nature of ICD therapy. The same predefined themes were explored with each group. Recordings were transcribed, analysed thematically by two researchers, working independently and then agreed. Differences in responses between patient and carer groups were also studied and compared. Participants all provided informed written consent and the study had ethical approval. Results: Three main themes emerged: (1) access to/quality of information provided by professionals and patient engagement with them; (2) decision-making about ICDs; (3) individuals' own 'lived experience' of DMD. Conclusions: The main findings were: (1) patients with DMD want to have their risk of sudden arrhythmic death discussed, when relevant and (2) if ICD therapy were established as beneficial, they would welcome an individualised discussion about its appropriateness for them.

Paced ventricular electrogram fractionation predicts sudden cardiac death in hypertrophic cardiomyopathy.

AIMS: Paced electrogram fractionation analysis (PEFA) has been assessed for the prediction of sudden cardiac death (SCD) in a large-scale, prospective study of patients with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: We determined the positive predictive value (PPV) of PEFA in relation to other risk factors for SCD and outcomes in 179 patients with HCM and no prior history of cardiac arrest. Patients were followed over a mean 4.3 years (range: 1.1-6.3 years). Thirteen patients had SCD-equivalent events: four of these patients died suddenly, three were resuscitated from ventricular fibrillation (VF), and six had implantable cardioverter-defibrillator (ICD) discharges in response to VF. PEFA identified nine of these patients and another 14 non-VF patients yielding a censored PPV of between 0.19 and 0.59 that was greater than the PPV that was the formal stopping point of the trial (0.18). Eighty per cent of patients were followed for 4 years or more. The PPV for the identification of SCD in this group was 0.38 (0.17-0.59). The use of two or more conventional markers to predict SCD identified five patients with SCD-equivalent events in the 4-year follow-up group and 42 other patients without events yielding a PPV of 0.106 (confidence limits 0.02-0.15). CONCLUSION: PEFA identifies HCM patients at risk of SCD with greater accuracy than non-invasive techniques and may have an important role in determining indications for ICD prescription.

Randomised placebo-controlled trial of combination ACE inhibitor and beta-blocker therapy to prevent cardiomyopathy in children with Duchenne muscular dystrophy? (DMD Heart Protection Study): a protocol study.

INTRODUCTION: Although cardiologists were 'late-comers' to the multidisciplinary team-contributing to the complex care of patients with Duchenne muscular dystrophy (DMD), they now recognise the importance of systematic cardiac surveillance and timely therapy to prolonged survival in patients with DMD. Empirical deployment of cardioactive medications has already improved outcomes, but the evidence base for clinical decision making is weak. Fundamental questions remain as to whether prophylactic therapy is justified and convincingly superior to prompt deployment of the same therapies once left ventricular (LV) dysfunction is detected. Even if it were, at what age should therapy be introduced and with what specific drugs? METHODS AND ANALYSIS: We are conducting a multicentre, parallel group, randomised, placebo-controlled study of combination therapy with an ACE inhibitor (perindopril) and a beta-blocker (bisoprolol) in boys with DMD aged 5-13 years, with normal LV function by echocardiographic criteria at the time of recruitment. Boys are being followed-up for a minimum of 3 years and a maximum of 5 years and undergo repeat assessments of LV function, heart rate and ECG, forced expiratory volume in the 1 s and forced vital capacity, adverse event reporting and quality of life at 6 monthly intervals.The primary outcome is change in LV function between active and placebo-treated participants over the course of the study. ETHICS AND DISSEMINATION: The study was approved by 'NRES Committee East Midlands - Derby'. The results will be disseminated through manuscript publications, an international workshop and presentations to scientific meetings and parent forums. TRANSLATIONAL ASPECTS: The study seeks to establish the evidence for prophylactic heart therapies for children with DMD, define the optimum age for their introduction and identify any safety concerns. ARTICLE SUMMARY: The protocol describes the design of an ongoing multicentre, double-blind, randomised placebo-controlled study to establish the evidence for the use of prophylactic heart therapies in children with DMD, define the optimum age for their introduction and identify any safety concerns. TRIAL REGISTRATION NUMBERS: EudraCT2007-005932-10 and ISRCTN50395346; Pre-results.

Comparison of magnetocardiography and electrocardiography.

OBJECTIVE: Automated techniques were developed for the measurement of cardiac repolarisation using magnetocardiography. METHODS: This was achieved by collaboration with the Physikalisch-Technische Bundesanstalt (PTB), Berlin, Germany and the Grönemeyer Institute of Microtherapy, Bochum, Germany, to obtain recordings of magnetocardiograms (MCGs) in cardiac patients and healthy subjects. Manual and automated ventricular repolarisation measurements from MCGs were evaluated to determine the clinical relevance of these measurements compared with electrocardiograms (ECGs). RESULTS: Results showed that MCG and ECG T-wave shapes differed and that manual repolarisation measurement was significantly influenced by T-wave amplitude. Automatic measurements of repolarisation in both MCGs and ECGs differed between techniques. The effects of filtering on the waveforms showed that filtering in some MCG research systems could significantly influence the results, with 20 ms differences common. In addition, MCGs were better able to identify differences in the distribution of cardiac magnetic field strength during repolarisation and depolarisation between normal subjects and cardiac patients. Differences were also determined in ventricular repolarisation between MCGs and ECGs, which cannot be explained by channel/lead numbers or amplitude effects alone. CONCLUSION: The techniques developed are essential, because of the many extra MCG channels to analyse, and will encourage the use of MCG facilities.