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.

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.

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.

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.

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.

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.

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.

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.

Cardiac involvement in hereditary myopathy with early respiratory failure: A cohort study.

OBJECTIVE: To assess whether hereditary myopathy with early respiratory failure (HMERF) due to the c.951434T>C; (p.Cys31712Arg) TTN missense mutation also includes a cardiac phenotype. METHOD: Clinical cohort study of our HMERF cohort using ECG, 2D echocardiogram, and cross-sectional cardiac imaging with MRI or CT. RESULTS: We studied 22 participants with the c.951434T>C; (p.Cys31712Arg) TTN missense mutation. Three were deceased. Cardiac conduction abnormalities were identified in 7/22 (32%): sustained atrioventricular tachycardia (n = 2), atrial fibrillation (n = 2), nonsustained atrial tachycardia (n = 1), premature supraventricular complexes (n = 1), and unexplained sinus bradycardia (n = 1). In addition, 4/22 (18%) had imaging evidence of otherwise unexplained cardiomyopathy. These findings are supported by histopathologic correlation suggestive of myocardial cytoskeletal remodeling. CONCLUSIONS: Coexisting cardiac and skeletal muscle involvement is not uncommon in patients with HMERF arising due to the c.951434T>C; (p.Cys31712Arg) TTN mutation. All patients with pathogenic or putative pathogenic TTN mutations should be offered periodic cardiac surveillance.

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.

Effect of catheter ablation on quality of life in patients with atrial fibrillation and its correlation with arrhythmia outcome.

OBJECTIVE: To assess the effect of catheter ablation on atrial fibrillation (AF) symptoms and quality of life (QoL). METHODS: Patients with AF scheduled for ablation were recruited. Pulmonary vein isolation (PVI) was performed and complex fractionated atrial electrogram (CFAE)±linear ablation undertaken in patients in AF despite PVI. QoL and AF symptoms were assessed using SF-36 V2 and Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaires before and 3 months after ablation. Change in QoL scores after ablation was correlated with clinical parameters and the extent of ablation. Magnitude of QoL change was compared between AFEQT and SF-36 physical component summary (PCS) and mental component summary (MCS) scores and correlated with arrhythmia outcome. RESULTS: 80 patients were studied. Summative and individual health scores for both AFEQT (51.5±22.0 vs 81.3±18.2; p<0.01) and SF-36 (PCS 43.3±10.5 vs 47.9±11.3; p<0.01 and MCS 45.0±11.5 vs 51.5±9.4; p<0.01) improved significantly in patients who maintained sinus rhythm after ablation, but not in those with recurrent AF. Improvement in AFEQT (25.4±19) was significantly greater than change in PCS (6.8±6.4; p<0.01) and MCS (8.5±7.9; p<0.01) scores and correlated more closely with arrhythmia outcome (AFEQT r=0.55; PCS r=0.26; MCS r=0.30). CONCLUSIONS: Patients who maintained sinus rhythm after ablation had a significant improvement in AF symptoms and QoL; however, no improvement was observed in patients with recurrent AF. QoL change after ablation did not correlate with baseline clinical parameters or ablation strategy. AF specific QoL scales are more responsive to change and correlate better with ablation outcome.

Principal component analysis of atrial fibrillation: inclusion of posterior ECG leads does not improve correlation with left atrial activity.

BACKGROUND: Lead V1 is routinely analysed due to its large amplitude AF waveform. V1 correlates strongly with right atrial activity but only moderately with left atrial activity. Posterior lead V9 correlates strongest with left atrial activity. AIMS: (1) To establish whether surface dominant AF frequency (DAF) calculated using principal component analysis (PCA) of a modified 12-lead ECG (including posterior leads) has a stronger correlation with left atrial activity compared to the standard ECG. (2) To assess the contribution of individual ECG leads to the AF principal component in both ECG configurations. METHODS: Patients were assigned to modified or standard ECG groups. In the modified ECG, posterior leads V8 and V9 replaced V4 and V6. AF waveform was extracted from one-minute surface ECG recordings using PCA. Surface DAF was correlated with intracardiac DAF from the high right atrium (HRA), coronary sinus (CS) and pulmonary veins (PVs). RESULTS: 96 patients were studied. Surface DAF from the modified ECG did not have a stronger correlation with left atrial activity compared to the standard ECG. Both ECG configurations correlated strongly with HRA, CS and right PVs but only moderately with left PVs. V1 contributed most to the AF principal component in both ECG configurations.

Recurring patterns of atrial fibrillation in surface ECG predict restoration of sinus rhythm by catheter ablation.

BACKGROUND: Non-invasive tools to help identify patients likely to benefit from catheter ablation (CA) of atrial fibrillation (AF) would facilitate personalised treatment planning. AIM: To investigate atrial waveform organisation through recurrence plot indices (RPI) and their ability to predict CA outcome. METHODS: One minute 12-lead ECG was recorded before CA from 62 patients with AF (32 paroxysmal AF; 45 men; age 57±10 years). Organisation of atrial waveforms from i) TQ intervals in V1 and ii) QRST suppressed continuous AF waveforms (CAFW), were quantified using RPI: percentage recurrence (PR), percentage determinism (PD), entropy of recurrence (ER). Ability to predict acute (terminating vs. non-terminating AF), 3-month and 6-month postoperative outcome (AF vs. AF free) were assessed. RESULTS: RPI either by TQ or CAFW analysis did not change significantly with acute outcome. Patients arrhythmia-free at 6-month follow-up had higher organisation in TQ intervals by PD (p<0.05) and ER (p<0.005) and both were significant predictors of 6-month outcome (PD (AUC=0.67, p<0.05) and ER (AUC=0.72, p<0.005)). For paroxysmal AF cases, all RPI predicted 3-month (AUC(ER)=0.78, p<0.05; AUC(PD)=0.79, p<0.05; AUC(PR)=0.80, p<0.01) and 6-month (AUC(ER)=0.81, p<0.005; AUC(PD)=0.75, p<0.05; AUC(PR)=0.71, p<0.05) outcome. CAFW-derived RPIs did not predict acute or postoperative outcomes. Higher values of any RPI from TQ (values greater than 25th percentile of preoperative distribution) were associated with decreased risk of AF relapse at follow-up (hazard ratio ≤0.52, all p<0.05). CONCLUSIONS: Recurring patterns from preprocedural 1-minute recordings of ECG TQ intervals were significant predictors of CA 6-month outcome.

Atrial fibrillation associated with ivabradine treatment: meta-analysis of randomised controlled trials.

OBJECTIVE: To quantify any risk of atrial fibrillation (AF) associated with ivabradine treatment by meta-analysis of clinical trial data. METHODS: Medline, Embase, Web of Knowledge and the Cochrane central register of controlled trials were searched for double-blinded randomised controlled trials of ivabradine with a minimum follow-up period of 4 weeks. For studies where AF data were unpublished, safety data were obtained from the European Medicines Agency (EMeA) website and personal communications. Studies were appraised for risk of bias using components recommended by the Cochrane Collaboration. Meta-analyses were performed of relative risk of AF and absolute risk difference of AF per year of treatment. The main outcome measure was incident AF during the follow-up period. RESULTS: AF data were available from 11 studies: one from the published report, six from the EMeA and four from personal communications. Ivabradine treatment was associated with a relative risk of AF of 1.15 (95% CI 1.07 to 1.24, p=0.0027) among 21 571 patients in the meta-analysis. From this we estimated that the number needed to harm for ivabradine would be 208 (95% CI 122 to 667) per year of treatment. CONCLUSIONS: AF is a substantially more common side effect of ivabradine treatment than one patient in 10 000, the risk presently reported in the product literature. The incidence of AF has not routinely been reported in clinical trials of ivabradine.

Defining cardiac adaptations and safety of endurance training in patients with m.3243A>G-related mitochondrial disease.

BACKGROUND: Cardiac hypertrophic remodelling and systolic dysfunction are common in patients with mitochondrial disease and independent predictors of morbidity and early mortality. Endurance exercise training improves symptoms and skeletal muscle function, yet cardiac adaptations are unknown. METHODS AND RESULTS: Before and after 16-weeks of training, exercise capacity, cardiac magnetic resonance imaging and phosphorus-31 spectroscopy, disease burden, fatigue, quality of life, heart rate variability (HRV) and blood pressure variability (BPV) were assessed in 10 adult patients with m.3243A>G-related mitochondrial disease, and compared to age- and gender-matched sedentary control subjects. At baseline, patients had increased left ventricular mass index (LVMI, p<0.05) and LV mass to end-diastolic volume ratio, and decreased longitudinal shortening and myocardial phosphocreatine/adenosine triphosphate ratio (all p<0.01). Peak arterial-venous oxygen difference (p<0.05), oxygen uptake (VO2) and power were decreased in patients (both p<0.01) with no significant difference in cardiac power output. All patients remained stable and completed ≥80% sessions. With training, there were similar proportional increases in peak VO2, anaerobic threshold and work capacity in patients and controls. LVMI increased in both groups (p<0.01), with no significant effect on myocardial function or bioenergetics. Pre- and post-exercise training, HRV and BPV demonstrated increased low frequency and decreased high frequency components in patients compared to controls (all p<0.05). CONCLUSION: Patients with mitochondrial disease and controls achieved similar proportional benefits of exercise training, without evidence of disease progression, or deleterious effects on cardiac function. Reduced exercise capacity is largely mediated through skeletal muscle dysfunction at baseline and sympathetic over-activation may be important in pathogenesis.

Characteristics of atrial fibrillation cycle length predict restoration of sinus rhythm by catheter ablation.

BACKGROUND: Successful termination of atrial fibrillation (AF) during catheter ablation (CA) is associated with arrhythmia-free follow-up. Preablation factors such as mean atrial fibrillation cycle length (AFCL) predict the likelihood of AF termination during ablation but recurring patterns and AFCL stability have not been evaluated. OBJECTIVE: To investigate novel predictors of acute and postoperative ablation outcomes from intracardiac electrograms: (1) recurring AFCL patterns and (2) localization index (LI) of the instantaneous fibrillatory rate distribution. METHODS: Sixty-two patients with AF (32 paroxysmal AF; 45 men; age 57 ± 10 years) referred for CA were enrolled. One-minute electrogram was recorded from coronary sinus (CS; 5 bipoles) and right atrial appendage (HRA; 2 bipoles). Atrial activations were detected automatically to derive the AFCL and instantaneous fibrillatory rate (inverse of AFCL) time series. Recurring AFCL patterns were quantified by using recurrence plot indices (RPIs): percentage determinism, entropy of determinism, and maximum diagonal length. AFCL stability was determined by using the LI. The CA outcome predictivity of individual indices was assessed. RESULTS: Patients with terminated atrial fibrillation (T-AF) had higher RPI (P < .05 in CS7-8) and LI than did those with nonterminated atrial fibrillation (P < .005 in CS3-4; P < .05 in CS5-6, CS7-8, and HRA). Patients free of arrhythmia after 3-month follow-up had higher RPI and LI (all P < .05 in CS7-8). All indices except percentage determinism predicted T-AF in CS7-8 (area under the curve [AUC] ≥ 0.71; odds ratio [OR] ≥ 4.50; P < .05). The median AFCL and LI predicted T-AF in HRAD (AUC ≥ 0.75; OR ≥ 7.76; P < .05). The RPI and LI predicted 3-month follow-up in CS7-8 (AUC ≥ 0.68; OR ≥ 4.17; P < .05). CONCLUSIONS: AFCL recurrence and stability indices could be used in selecting patients more likely to benefit from CA.