Background/Objectives: Duchenne muscular dystrophy (DMD) is an X-linked inherited muscle disease. Patients with DMD demonstrate improved prognosis with angiotensin-converting enzyme inhibitors and beta-blockers at the time of cardiac dysfunction. However, most deaths due to DMD are due to cardiac dysfunction. Fragmented QRS (fQRS) is an abnormal finding that forms a notch in the QRS wave on electrocardiography (ECG) and is associated with fibrosis and scarring of the myocardium. Methods: Patients with DMD were examined for the number of leads of fQRS, their sites of appearance, changes in cardiac dysfunction, and age using the chest leads of a synthesized 18-ECG. A retrospective analysis of 184 patients under 20 years of age with DMD and known genetic mutations was performed; they were divided into three age groups: 3-10, 11-15, and 16-20 years. The chest leads of the ECG were defined as follows: V1-3, anterior leads; V4-6, lateral leads; V7-9, posterior leads; and V3R-V5R, right-sided chest leads. Cardiac dysfunction was defined as a left ventricular (LV) ejection fraction <53% on the same day, and echocardiography was performed. LV dilation was defined as dilation beyond the normal range, considering the body surface area. Results: In 167 of 184 patients (91%), fQRS was present in one or more chest leads. The number of fQRS leads in the anterior and lateral walls was significantly higher in 16-20-year-olds than in 3-10-year-olds. The total number of chest leads with fQRS was 4.9 ± 3.1 in the cardiac dysfunction group and 3.5 ± 2.5 in the preserved group. The cardiac dysfunction group had a significantly greater number of fQRS leads than did the preserved group (p = 0.003). The group with LV dilation had a significantly greater number of fQRS leads than did the non-dilation group (p = 0.009). Conclusions: The fQRS site is associated with age, cardiac dysfunction, and LV dilation. Multivariate regression analysis revealed that the number of anterior leads of the fQRS correlated with age and that of lateral leads of the fQRS with cardiac dysfunction and LV dilation. The number of fQRS leads on the lateral wall marks cardiac dysfunction and LV dilation.

Duchenne muscular dystrophy (DMD) is a genetic progressive neuromuscular disorder characterized by early-onset proximal muscle weakness and significant long-term pulmonary and cardiac involvement. Due to the early pharmacological treatments and the wider adoption of non-invasive ventilation, life expectancy has significantly increased in recent years, highlighting the relevance of DMD-related cardiomyopathy and fatal arrhythmias, especially in the late stage of the disease. Current guideline-derived evaluation of sudden cardiac death (SCD) in DMD lacks accuracy, leading to inadequate arrhythmic risk stratification and jeopardized SCD prevention strategies. This review aims to outline these critical issues, proposing an integrative approach encompassing manifold tools such as an imaging-derived systematic and comprehensive evaluation (speckle-tracking echocardiography and magnetic resonance imaging), the electrophysiological study, the 3-dimensional electroanatomic mapping, and a multidimensional clinical examination. This approach might lead to more personalized management along with an effective arrhythmia-prevention strategy aiming to balance clinical care goals, patient expectations, and ethical considerations.

Duchenne muscular dystrophy (DMD) patients exhibit a late left ventricular systolic dysfunction preceded by an occult phase, during which myocardial fibrosis progresses and some early functional impairments can be detected. These latter include electrocardiographic (ECG) and heart rate variability (HRV) abnormalities. This longitudinal study aimed at describing the sequence of ECG and HRV abnormalities, using Holter ECG in the GRMD (Golden retriever muscular dystrophy) dog model, known to develop a DMD-like disease, including cardiomyopathy. Most of the known ECG abnormalities described in DMD patients were also found in GRMD dogs, including increased heart rate, prolonged QT and shortened PR intervals, ventricular arrhythmias, and several of them could be detected months before the decrease of fractional shortening. The HRV was impaired like in DMD patients, one of the earliest evidenced abnormalities being a decrease in the very low frequency (VLF) component of the power spectrum. This decrease was correlated with the further reduction of fractional shortening. Such decreased VLF probably reflects impaired autonomic function and abnormal vasomotor tone. This study provides new insights into the knowledge of the GRMD dog model and DMD cardiomyopathy and emphasizes the interest to monitor the VLF power in DMD patients, still unexplored in this disease, whilst it is highly predictive of deleterious clinical events in many other pathological conditions.

Duchenne Muscular Dystrophy (DMD) is a rare inherited neuromuscular disease. At first, cardiac involvement may be asymptomatic. Therefore, assessing patients using non-invasive methods can help detect any changes.

Analyze the electrocardiogram (ECG) test and heart rate variability (HRV) of the DMD group and compare the information with that of the age-matched control group.

A prospective study with 27 male patients with DMD (11.9 years old), who underwent clinical evaluation, ECG, echocardiogram, and Holter monitoring. ECG (200% increase) was assessed by two independent observers. HRV was measured over time (24 h) and in the frequency domain, in the supine and sitting positions. The healthy group consisted of nine patients (11.0 years old). A value of p < 0.05 was considered statistically significant.

The mean ejection fraction (EF) was 60% (34 to 71%). The Kappa coefficient for ECG measurements ranged from 0.64 to 1.00. An increase in the R/S ratio in V1 was observed in 25.9% of the subjects, pathological Q wave in 29.6%, and fragmented QRS in 22.2% in inferior/high lateral regions, with a negative correlation with EF (p = 0.006). There was low HRV, without the influence of any variable, including treatment. With the change in position, there was an increase in HR (p = 0.004), but there was no change in HRV. The LF/HF ratio was 2.7 in the DMD group and 0.7 in the control group (p = 0.002).

In DMD subjects, prominent R waves in V1 and changes in the inferior/high lateral regions occurred in almost 30% of the cases. Lower vagal tone was observed without the influence of the variables age, ejection fraction, QT dispersion, and treatment. Despite the increase in HR, there was no adequate HRV response to the change in position.

LAMA2-related muscular dystrophy (LAMA2-MD) and SELENON-related myopathy (SELENON-RM) are two rare neuromuscular diseases characterized by proximal and axial muscle weakness, scoliosis, spinal rigidity, low bone quality and respiratory impairment. Cardiac involvement has previously been described in retrospective studies and case reports, but large case series and prospective studies in unselected cohorts are lacking.

The objective of this study is to conduct prevalence estimations, perform cardiac phenotyping, and provide recommendations for clinical care.

In this case series including two time points, we conducted comprehensive assessments with electrocardiography (ECG) and transthoracic echocardiography (TTE). ECGs were systematically assessed for a large subset of variables. TTE included left and right ventricular ejection fraction (LVEF/RVEF) and left ventricular global longitudinal strain (GLS), the latter being a more early and sensitive marker of left ventricular dysfunction.

21 LAMA2-MD (M = 5; 20±14 years) and 10 SELENON-RM patients (M = 7; 18±12 years) were included. In most patients, QRS fragmentation and Q waves, markers of heterogeneous ventricular activation, were present both at baseline and at follow-up. GLS was abnormal (age specific in children, > -18% in adults) in 33% of LAMA2-MD and 43% of SELENON-RM patients at baseline. Reduced LVEF (<52% in males, <54% in females and <55% in pediatric population) was observed in three LAMA2-MD patients at baseline and in none of the SELENON-RM patients. GLS and LVEF did not change between baseline and follow-up. RVEF was normal in all patients.

ECG abnormalities and abnormal GLS are prevalent in LAMA2-MD and SELENON-RM, yet abnormal LVEF was only seen in LAMA2-MD patients. One LAMA2-MD patient had a clinically relevant deterioration in LVEF during 1.5-year follow-up. We advise routine screening of all patients with LAMA2-MD or SELENON-RM with ECG and echocardiography at diagnosis, minimally every two years from second decade of life and if new cardiac signs arise.

LAMA2-related muscular dystrophy (LAMA2-MD) is a rare neuromuscular disease characterized by proximal and axial muscle weakness, rigidity of the spine, scoliosis, and respiratory impairment. No curative treatment options exist, yet promising preclinical studies are ongoing. Currently, there is a paucity on natural history data, and appropriate clinical and functional outcome measures are needed. We aim for deep clinical phenotyping, establishment of a well-characterized baseline cohort for prospective follow-up and recruitment for future clinical trials, improvement of clinical care, and selection of outcome measures for reaching trial readiness.

We performed a cross-sectional, single-center, observational study. This study included neurologic examination and functional measurements among others the Motor Function Measure 20/32 (MFM-20/32) as primary outcome measure, accelerometry, questionnaires, muscle ultrasound, respiratory function tests, electrocardiography and echocardiography, and dual-energy X-ray absorptiometry.

Twenty-seven patients with genetically confirmed LAMA2-MD were included (21 ± 13 years; M = 9; ambulant = 7). Axial and proximal muscle weakness was most pronounced. The mean MFM-20/32 score was 42.0% ± 29.4%, with domain 1 (standing and transfers) being severely affected and domain 3 (distal muscle function) relatively spared. Physical activity as measured through accelerometry showed very strong correlations to MFM-20/32 (Pearson correlation, -0.928, p < 0.01). Muscle ultrasound showed symmetrically increased echogenicity, with the sternocleidomastoid muscle most affected. Respiratory function was impaired in 85% of patients without prominent diaphragm dysfunction and was independent of age. Ten patients (37%) needed (non)invasive ventilatory support. Cardiac assessment revealed QRS fragmentation in 62%, abnormal left ventricular global longitudinal strain in 25%, and decreased left ventricular ejection fraction in 14% of patients. Decreased bone quality leading to fragility fractures was seen in most of the patients.

LAMA2-MD has a widely variable phenotype. Based on the results of this cross-sectional study and current standards of care for congenital muscular dystrophies, we advise routine cardiorespiratory follow-up and optimization of bone quality. We propose MFM-20/32, accelerometry, and muscle ultrasound for assessing disease severity and progression. For definitive clinical recommendations and outcome measures, natural history data are needed.

This study was registered at clinicaltrials.gov (NCT04478981, 21 July 2020). The first patient was enrolled in September 2020.

Patients with repaired Tetralogy of Fallot (rTOF) have risks of late life-threatening sequelae, including right ventricular (RV) dilation and failure, arrhythmias, and sudden death. QRS prolongation is a well-known ECG predictor of these outcomes but has poor sensitivity for mortality. Growing evidence demonstrates QRS fragmentation (fQRS) as a better prognostic marker for mortality in adults with rTOF, though the two markers have not been directly compared as correlates for CMR abnormalities. Additionally, fQRS has never been studied in pediatric TOF. This single institution retrospectively reviewed 138 CMRs in rTOF patients (median age 21.7 years) who had a corresponding 12-lead ECG within 1 year. fQRS was defined as ≥3 R-waves/notches in the R/S complex (>2 in right bundle branch block) in ≥2 contiguous leads. QRS prolongation was defined as QRS ≥160 ms. Nearly half (46%) the sample had fQRS (42.1% of pediatric subgroup), and 26% had QRS prolongation. Both markers were significantly associated with reduced RV ejection fraction (EF%) (p < 0.01) and larger RV end-diastolic volumes (p < 0.01). QRS prolongation alone predicted lower LV EF% (p = 0.02). Regression analyses showed both QRS prolongation (p < 0.01) and fQRS (p < 0.01) independently associated with reduced RV EF%; QRS prolongation alone predicted RV dilation (p < 0.01). We concluded that both QRS prolongation and fQRS are equivalent as significant markers of RV dysfunction in rTOF patients. QRS prolongation may be a better surrogate for RV dilation specifically. fQRS was frequently seen in children with rTOF and was significantly associated with similar late structural sequelae.

SELENON(SEPN1)-related myopathy (SELENON-RM) is a rare congenital neuromuscular disease characterized by proximal and axial muscle weakness, spinal rigidity, scoliosis and respiratory impairment. No curative treatment options exist, but promising preclinical studies are ongoing. Currently, natural history data are lacking, while selection of appropriate clinical and functional outcome measures is needed to reach trial readiness.

We aim to identify all Dutch and Dutch-speaking Belgian SELENON-RM patients, deep clinical phenotyping, trial readiness and optimization of clinical care.

This cross-sectional, single-center, observational study comprised neurological examination, functional measurements including Motor Function Measurement 20/32 (MFM-20/32) and accelerometry, questionnaires, muscle ultrasound, respiratory function tests, electro- and echocardiography, and dual-energy X-ray absorptiometry.

Eleven patients with genetically confirmed SELENON-RM were included (20±13 (3-42) years, 73% male). Axial and proximal muscle weakness were most pronounced. The mean MFM-20/32 score was 71.2±15.1%, with domain 1 (standing and transfers) being most severely affected. Accelerometry showed a strong correlation with MFM-20/32. Questionnaires revealed impaired quality of life, pain and problematic fatigue. Muscle ultrasound showed symmetrically increased echogenicity in all muscles. Respiratory function, and particularly diaphragm function, was impaired in all patients, irrespective of the age. Cardiac assessment showed normal left ventricular systolic function in all patients but abnormal left ventricular global longitudinal strain in 43% of patients and QRS fragmentation in 80%. Further, 80% of patients showed decreased bone mineral density on dual-energy X-ray absorptiometry scan and 55% of patients retrospectively experienced fragility long bone fractures.

We recommend cardiorespiratory follow-up as a part of routine clinical care in all patients. Furthermore, we advise vitamin D supplementation and optimization of calcium intake to improve bone quality. We recommend management interventions to reduce pain and fatigue. For future clinical trials, we propose MFM-20/32, accelerometry and muscle ultrasound to capture disease severity and possibly disease progression.

Cardiac magnetic resonance (CMR) is a unique tool for non-invasive tissue characterization, especially for identifying fibrosis.

To present the existing data regarding the association of electrocardiographic (ECG) markers with myocardial fibrosis identified by CMR - late gadolinium enhancement (LGE).

A systematic search was performed for identifying the relevant studies in Medline and Cochrane databases through February 2021. In addition, we conducted a relevant search by Reference Citation Analysis (RCA) (https://www.referencecitationanalysis.com).

A total of 32 studies were included. In hypertrophic cardiomyopathy (HCM), fragmented QRS (fQRS) is related to the presence and extent of myocardial fibrosis. fQRS and abnormal Q waves are associated with LGE in ischemic cardiomyopathy patients, while fQRS has also been related to fibrosis in myocarditis. Selvester score, abnormal Q waves, and notched QRS have also been associated with LGE. Repolarization abnormalities as reflected by increased Tp-Te, negative T-waves, and higher QT dispersion are related to myocardial fibrosis in HCM patients. In patients with Duchenne muscular dystrophy, a significant correlation between fQRS and the amount of myocardial fibrosis as assessed by LGE-CMR was observed. In atrial fibrillation patients, advanced inter-atrial block is defined as P-wave duration ≥ 120 ms, and biphasic morphology in inferior leads is related to left atrial fibrosis.

Myocardial fibrosis, a reliable marker of prognosis in a broad spectrum of cardiovascular diseases, can be easily understood with an easily applicable ECG. However, more data is needed on a specific disease basis to study the association of ECG markers and myocardial fibrosis as depicted by CMR.

Dystrophin deficiency results in the cardiomyopathy of variable onset and deficiency. Myocardial scarring commonly results in cardiac dysfunction, with both atrial and ventricular dysrhythmias. Heart failure, rather than arrhythmia burden, remains the strongest cardiac predictor of mortality in this patient population. Current data suggest the overall rate of sudden cardiac death in pediatric dilated cardiomyopathy is significantly lower than in adults. Specifically, in the Duchenne cardiomyopathy population, sudden death from an arrhythmic cause appears to be rare, even in patients with previously diagnosed arrhythmias. Despite this, recommendations for implantable cardioverter-defibrillator (ICD) placement in patients with Duchenne cardiomyopathy has traditionally been extrapolated from adult heart failure recommendations based on decreased left ventricular ejection fraction <35%. Early involvement of the cardiologist in the care for patients with dystrophin-deficient cardiomyopathy is recommended for this reason. The indications for ICD placement to prevent sudden death in patients with Duchenne cardiomyopathy are not well defined. There is little evidence to suggest that placement meaningfully prolongs life in this population, and should be carefully considered in accordance with the care goals of the patient and his family.

Fragmented QRS (fQRS) is a marker of local myocardial scar. This study aimed to analyze the relationship between fQRS and coronary collateral circulation (CCC) and evaluate the predictive value of fQRS for long-term clinical outcomes among patients with chronic total occlusion (CTO) and prior myocardial infarction (MI) who underwent percutaneous coronary intervention (PCI).

A total of 862 patients with a definite history of MI who had one CTO coronary artery and underwent PCI between 2013 and 2018 were continuously analyzed. Patients were divided into group A (no Q wave and fQRS, n = 206), group B (fQRS, n = 265), group C (Q wave, n = 391). All patients were followed up for 2 years.

The incidence rate of major adverse cardiovascular events (MACE) in group B was significantly lower than in group C (group B vs. C: 7.2% vs. 11.3%, P = 0.043). The percentage of good CCC was 94.2%, 88.3%, and 82.9% in group A, B, and C (p < .001), respectively. The improvement of cardiac function in group B and A were more significant than in group C. Multivariate Cox regression analysis showed fQRS was an independent protective factor of MACE after PCI within 2 years in CTO patients with prior MI (RR = 0.668, 95% CI [0.422-0.917], p = .001).

fQRS is an independent protective factor of prognosis in patients with prior MI and one CTO vessel who underwent PCI, presenting with a higher rate of good CCC, less occurrence of MACE, and better heart function than in Q wave patients.

ECG is a common diagnostic tool in medical practice. Sudden cardiac death (SCD) is a rare but devastating event. The most common cause of SCD in the young is a primary arrhythmic event, which is often produced by malignant ventricular arrhythmia. Several electrocardiographic markers for ventricular repolarization and depolarization have been proposed to predict this arrhythmic risk and SCD in children. Although many of these parameters can easily be used in clinical practice, some of them need specific techniques for interpretation. In this review, we summarized the current knowledge regarding the clinical importance and the ability of these ECG parameters to predict adverse cardiac events in the pediatric population.

Background: In acromegaly patients; it has been observed that heart failure may develop even in the absence of predisposing factors such as hypertension, diabetes mellitus, so a specific acromegalic cardiomyopathy has been suggested. We aimed to evaluate the fQRS frequency in acromegaly patients and the left ventricular (LV) functions of acromegaly patients with fQRS.Methods: Our study included 60 acromegalic patients. Each patient underwent conventional echocardiography and tissue Doppler imaging. The patients included were separated into two groups: those with (n:23) and without (n:37) fQRS.Results: Significant differences were identified between fQRS(+) and fQRS (-) groups with respect to disease duration (p < .001), Left ventricular end diastolic volume (EDV) (p < .001), E velocity (p < .001), E\A ratio (p < .001), E' velocity (p < .001), E/E' ratio (p < .001), isovolumic relaxation time (IVRT) (p < .001), MPI (p < .001). Disease duration (odds ratio [OR]: 2.120 (1.023-1.703 95% confidence interval [CI]), p = .002), E' (OR:3.029 (1.013-1.703 95% CI) p = .004) and fQRS (OR:4.59 (1.94-10.87 95% CI), p = .001) were identified as the independent predictors of myocardial performance index (MPI). However, disease duration (OR:1.078 (1.030-1.128 95% CI), p = .001), E/E' (OR: 1.43 (1.22-1.97 95% CI), p = .001), IVRT (OR:1.65 (1.32-2.06 95% CI), p = .001) and MPI (OR:1.014 (1.004-1.024 95% CI), p = .002) were the independent predictors of fQRS.Conclusions: fQRS was frequent and an independent predictor of MPI that was independelty associated with LV dysfunction in patients with acromegaly. In light of these findings the presence of fQRS is thought to be an indicator of acromegalic CMP development.

To evaluate cardiovascular function in boys with Duchenne (DMD) and Becker (BMD) muscular dystrophy, using cardiac magnetic resonance (CMR).

This is a single point cross sectional study of twenty-four boys with genetically ascertained DMD, and 10 with BMD, aged 10.5 ± 1.5 years (range 9-13), were prospectively evaluated by a 1.5 T system and compared with those of age-sex matched controls. The DMD patients were divided in 2 groups. Group A (N = 12) were under treatment with both deflazacort and perindopril, while Group B (n = 12) were under treatment with deflazacort, only. BMD patients did not take any medication. Biventricular function was assessed using a standard SSFP sequence. Late gadolinium enhancement (LGE) was assessed from T1 images taken 15 min after injection of 0.2 mg/Kg gadolinium DTPA using a 3D-T1-TFE sequence.

Group A and BMDs were asymptomatic with normal ECG, 24 h ECG recording and echocardiogram. Group B were asymptomatic but 6/12 had abnormal ECG and mildly impaired LVEF. Their 24 h ECG recording revealed supraventricular and ventricular extrasystoles (all at 12-13 yrs). LV indices in Group A and BMD did not differ from those of controls. However, LV indices in Group B were significantly impaired compared with controls, Group A and BMDs (p < 0.001). An epicardial LGE area = 3 ± 0.5% of LV mass was identified in the posterolateral wall of LV only in 6/12 patients of Group B, but in not in any BMD or Group A.

Children with either BMD or DMD under treatment with both deflazacort and perindopril present preserved LV function and lack of LGE. However, further large scale multicenter studies are warranted to confirm these data, including further CMR mapping approaches.

Duchenne muscular dystrophy (DMD) is a genetic, progressive neuromuscular condition that is marked by the long-term muscle deterioration with significant implications of pulmonary and cardiac dysfunction. As such, end-stage heart failure (HF) in DMD is increasingly becoming the main cause of death in this population. The early detection of cardiomyopathy is often challenging, due to a long subclinical phase of ventricular dysfunction and difficulties in assessment of cardiovascular symptomatology in these patients who usually loose ambulation during the early adolescence. However, an early diagnosis of cardiovascular disease in patients with DMD is decisive since it allows a timely initiation of cardioprotective therapies that can mitigate HF symptoms and delay detrimental heart muscle remodelling. Echocardiography and ECG are standardly used for screening and detection of cardiovascular abnormalities in these patients, although these tools are not always adequate to detect an early, clinically asymptomatic phases of disease progression. In this regard, cardiovascular magnetic resonance (CMR) with late gadolinium enhancement is emerging as a promising method for the detection of early cardiac involvement in patients with DMD. The early detection of cardiac dysfunction allows the therapeutic institution of various classes of drugs such as corticosteroids, beta-blockers, ACE inhibitors, antimineralocorticoid diuretics and novel pharmacological and surgical solutions in the multimodal and multidisciplinary care for this group of patients. This review will focus on these challenges and available options for HF in patients with DMD.