Cardiac Involvement in LAMA2-Related Muscular Dystrophy and SELENON-Related Congenital Myopathy: A Case Series.

Background Cirrhotic cardiomyopathy (CCM) in adults is now defined to include left ventricular (LV) global longitudinal strain (GLS) as a marker of subclinical systolic dysfunction.1 In children with biliary atresia (BA), cardiac involvement has been linked to adverse peri-transplant outcomes,2 but data on the significance of LVGLS in paediatric cirrhosis are sparse. Purpose This study aimed to assess the prevalence of abnormal LV GLS in children with BA listed for liver transplantation (LT) and its association with clinical outcomes. Methods We performed a retrospective study and included consecutive paediatric patients with BA listed for LT (2013–2021) at a quaternary paediatric institution. Patients with a pre-LT echocardiogram and adequate apical views for GLS measurement were included. GLS >-18% (between 0% and -18%) were considered abnormal.1,3 Primary outcomes included waitlist decompensation and overall mortality (death from listing to one year post-LT). Secondary outcome measures were ventilator-free days (VFD), post-operative ICU length of stay (LOS) and hospital LOS. Results Among 125 patients with BA listed for LT, 83 met the inclusion criteria (median age: 10 months [6, 17], 62% female). The median age at LT was 13 months [9, 24], including 42% (35/83) with waitlist decompensation and 14% (12/83) overall mortality (1 pre-LT and 11 post-LT). The median pre-LT LV GLS was -19.5% [-17, -23] and 31% (26/83) had abnormal LV GLS (>-18%). Patients with abnormal GLS had higher rates of waitlist decompensation (61% [16/26] vs. 33% [19/57]; OR = 3.2, 95% CI: 1.2, 8.3; p=0.019) and mortality (31% [8/26] vs. 7% [4/57]; OR = 5.9, 95% CI: 11.6, 21.9; p=0.007). VFD, ICU LOS, and hospital LOS did not differ significantly different between groups (Table 1). Abnormal GLS remained independently associated with mortality after adjusting for age, PELD score, and LV mass index (OR 23; 95% CI: 1.3-416; p = 0.03). Conclusions Abnormal LV GLS >-18% was present in 31% of children with BA listed for LT and was associated with waitlist decompensation and independently predictive of mortality. These findings highlight the potential role of GLS in evaluating CCM in paediatric cirrhosis. Further studies are warranted to refine CCM definition and improve risk stratification in paediatric cirrhosis.

Introduction: Atypical myocarditis, presenting as isolated chest pain, elevated troponin and preserved cardiac output in childhood is rare. Beyond small volume single center case series, limited data are reported on CMR characteristics at initial presentation and follow up. Methods: This is a pediatric multi-center retrospective study. Patients with chest pain and elevated cardiac troponin who underwent an echo and CMR within 30 days of each other were included. Clinical, echo and CMR parameters were collected at presentation and follow up. CMR global longitudinal strain (GLS) was performed with feature tracking technology (TomTec). Cases were divided into CMR myocarditis positive (Myo+) and CMR myocarditis negative (Myo-) based on Lake Louise criteria. Findings were compared to 19 age matched controls. Results: A total of 108 cases were included (88 Myo+ and 20 Myo-). Majority were male (88%) with average age of 15.6 ± 2.1 years. Median troponin was 13 (0.18-260.1 ng/mL), median BNP was 270.8 (12-3949 pg/ml). Abnormal ECG findings were present in 79% at presentation. While CMR LVEF did not differ between cases (56 ± 9%) and controls (60 ± 4%, p 0.06), GLS was significantly worse in cases (-16.2 ± 2.7%) compared to controls (-19.2 ± 2.1%, p <0.001). Unlike LVEF, GLS was significantly worse in Myo+ (-15.7 ± 2.8%) compared to Myo- cases (-18.0 ± 1.3%, p < 0.001). Fifty-four subjects had follow up data with 35 repeat CMRs. Median follow up was 204 (30-944) days. Late gadolinium enhancement (LGE) persisted in 82% of the Myo+ cases. Of the cases with abnormal GLS at presentation, 77% had persistent LGE. At follow up, 14% of cases were on heart failure medications, 33% had abnormal GLS and 39% had abnormal LVEF (<55%). Neither treatment with steroids or IVIG at presentation nor LGE on initial or follow up CMR were associated with the need for heart failure medications or persistent symptoms at follow up. Conclusions: In atypical myocarditis, CMR GLS can help differentiate between Myo+ and Myo- cases. Abnormal CMR GLS at presentation has higher association with persistence of LGE at follow up, irrespective of type of treatment. Future studies are needed to identify other characteristics that predict persistently abnormal findings important to clinical management and prognosis.

Introduction: Depressed left ventricular function is associated with mortality after pediatric cardiac arrest (CA). Echocardiographic global longitudinal strain (GLS) is more sensitive for poor outcomes than ejection fraction (EF) and shortening fraction (SF), with few studies in children. We aimed to identify the frequency of impaired GLS after pediatric CA and its association with hospital mortality. We hypothesized abnormal GLS is associated with mortality. Methods: This is a retrospective single-center cohort study of children < 18 years of age treated in the pediatric intensive care unit after in- and out-of-hospital CA, with echocardiogram performed within 24 hours of admission between 2013-2020. Patients with congenital heart disease, extracorporeal support, or inability to measure GLS were excluded. EF and SF measurements were abstracted and GLS measured post hoc by an investigator blinded to outcome. Abnormal left ventricular GLS was defined as >-18%. Correlation between GLS, EF and SF were calculated with Spearman’s rho. Logistic regression tested association of GLS with mortality. Area under the receiver operator characteristic (AUROC) curve was calculated for discriminative utility of GLS, EF, and SF with mortality. Results: GLS was measured in 124 subjects and abnormal in 49 (40%). Subjects with abnormal GLS were older (median 8 vs 2 years, p< 0.001), had more ventricular tachycardia/fibrillation as initial rhythm (18% vs 4%, p=0.008) and higher maximum troponin in 24 hours (median 2.6 ng/mL vs 0.5, p=0.002). There was no difference between arrest location or CPR duration based on GLS. Subjects with abnormal GLS had lower median EF (43% vs 63%) and SF (24% vs 37%), with strong inverse correlation between GLS and EF (rho -0.76) and SF (rho -0.71), all p< 0.001. Abnormal GLS had higher mortality (57% vs 33%, p=0.009) and GLS was associated with mortality when controlling for age and initial rhythm [aOR 1.17 per 1% increase in GLS (95% CI 1.09-1.26), p< 0.001]. GLS (AUROC 0.69), EF (0.71) and SF (0.71) had similar discrimination for mortality. Conclusions: Post-arrest GLS is a novel complementary metric, strongly correlated with EF and SF and associated with mortality. Future prospective studies should investigate the prognostic utility of GLS alongside SF and EF.

Introduction: The timing of surgical intervention in aortic stenosis (AS) is critical. Guidelines recommend aortic valve replacement in severe, asymptomatic AS with an ejection fraction (EF) less than 50%. Two-dimensional speckle tracking echocardiography is a relatively novel way to identify left ventricular dysfunction by measuring myocardial strain. Global longitudinal strain (GLS) is a measurement of deformation of the myocardium, and is considered a more sensitive marker for left ventricular dysfunction than EF. Hypothesis: Our aim was to determine if abnormal GLS predicts poor outcomes in severe, asymptomatic AS patients with a preserved EF. Methods: We conducted a meta-analysis and searched MEDLINE, EMBASE, Cochrane (2000 to 2015), supplemented by manual bibliographies of key relevant articles. We selected all cohort, cross-sectional, and case-control studies in which GLS was measured and major adverse cardiac events (MACE) were reported. In the case-control studies, we calculated the pooled standard mean difference (SMD) of GLS between those with MACE and those without MACE. In cohort studies, we calculated the pooled relative risk (RR) with the corresponding 95% confidence interval (CI) for incident MACE by using the fixed effects method. Results: Our search strategy identified 3 studies that met the inclusion criteria, and included 370 AS patients. Of the 3 studies, all reported data using a case-control design and 2 reported data using a cohort design. The median age of AS patients included was 72.6 years old, the median indexed aortic valve area was 0.44 (cm 2 /m 2 ), and the median ejection fraction was 64.2 (%). Of the 370 patients included in the analysis, 183 had MACE. Case-control studies revealed a pooled GLS SMD of 0.5 (95% CI: 0.30-0.69, p&lt;0.01) for patients with MACE compared to those without MACE. Cohort studies revealed a RR of MACE of 2.07 (95% CI: 1.59-2.69, p&lt;0.01) for those with abnormal GLS compared to those normal GLS. Conclusions: AS patients with a more positive global longitudinal strain value were more likely to have a major adverse cardiac event despite having a preserved EF and absence of symptoms. Therefore, if abnormal GLS is detected, earlier surgical intervention should be considered in severe, asymptomatic aortic stenosis.

10052 Background: Among survivors exposed to anthracycline or chest radiation (RT) who have an ejection fraction (EF) of ≥50%, the utility of GLS and NT-proBNP to identify survivors who are at highest risk for future CM is unknown. Methods: Survivors participating in the St. Jude Lifetime Cohort, ≥5 years from cancer diagnosis and at risk for CM per the International Guideline Harmonization Group (IGHG), underwent baseline surveillance echocardiography. A baseline GLS and NT-proBNP was also performed for survivors with an EF ≥50%. Multivariable Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of CM (graded per modified Common Terminology Criteria for Adverse Events v4.0) based on abnormal baseline GLS (≥ -18) and/or NT-proBNP (&gt;age-sex-specific 97.5th percentiles) adjusted for age at baseline assessment, age at diagnosis, sex, race, hypertension, diabetes, obesity, and IGHG risk group (Table footnote). Results: Among 1598 at-risk survivors (median age 35.1, range 9.4-68.8 years), all had GLS and 1110 NT-proBNP at baseline. 165 (10.3%) developed CM ≥ grade 2 at a median follow-up of 5.2 (0.7-10.0) years. IGHG moderate- and high-risk survivors exposed to anthracyclines were at increased risk of CM at follow-up if both baseline GLS and NT-proBNP were abnormal (HR=3.4, 95% CI: 1.9-5.8; Table) or GLS was abnormal and NT-proBNP not assessed (HR=3.8, 95% CI: 2.0-7.2), or when GLS was normal and NT-proBNP was abnormal (HR=1.9, 95% CI: 1.1-3.4). Abnormal GLS and/or NT-proBNP were not associated with increased risk of CM in IGHG low-risk survivors or in those defined as moderate- to high-risk due to chest RT only. Conclusions: Among long-term survivors of childhood cancer exposed to &gt;100 mg/m2 anthracycline, abnormal GLS and NT-proBNP identified those survivors at increased risk of future CM despite an EF ≥50% on surveillance echocardiography. Conditional surveillance strategies utilizing GLS and NT-proBNP may benefit moderate- to high-risk survivors. [Table: see text]

Backround: Left ventricular ejection fraction (LVEF) is traditionally used for cardiac risk stratification but may miss subclinical myocardial dysfunction. Left ventricular global longitudinal strain (GLS) may better reflect early systolic impairment. We investigated the association between GLS and major adverse cardiac events (MACE) in kidney transplant (KT) recipients with preserved pre-transplant LVEF (≥55%). We hypothesized that abnormal pre-transplant GLS would be associated with a higher incidence of MACE. Methods: In this retrospective study, KT recipients from January 2015 to December 2023 with LVEF ≥55% on pre-transplant echocardiograms were included. Investigators achieved ≥80% interobserver agreement with the principal investigator on a random sample before GLS measurement using TomTec software. Patients were grouped as abnormal GLS (AbGLS, worse than –16%) vs. normal GLS (NGLS) per current American Society of Echocardiography guidelines. The primary outcome was MACE: cardiovascular death, non-fatal myocardial infarction, stroke, revascularization, angina, heart failure hospitalization, or fatal arrhythmia. Multivariable logistic regression adjusted for significant pre-transplant group differences. Kaplan-Meier survival analysis was also performed. Results: Among 520 recipients, 309 had preserved LVEF (≥55%) and analyzable pre-transplant GLS; 153 had AbGLS and 156 had NGLS. Mean follow-up was 5.05 years in AbGLS and 5.38 years in NGLS. MACE occurred more frequently in AbGLS patients (27.5% vs. 15.4%, p=0.014). AbGLS patients were more likely to be male (62.7% vs. 48.1%, p=0.013), older (56.0 vs. 51.7 years, p=0.004), diabetic (45.8% vs. 27.6%, p=0.001), and have coronary artery disease (36.6% vs. 22.4%, p=0.009). Differences in LVEF, hypertension, smoking, stroke, heart failure, and arrhythmia were not significant. In multivariable regression, GLS as a continuous variable showed a trend toward predicting MACE (OR 0.94, 95% CI 0.87–1.01, p=0.075), and abnormal GLS as a binary variable also trended toward significance (OR 0.56, 95% CI 0.31–1.02, p=0.060). Coronary artery disease remained a significant predictor of MACE (OR 2.28, 95% CI 1.20–4.31, p= 0.011). Kaplan-Meier analysis showed significantly lower MACE-free survival in AbGLS vs. NGLS patients (p=0.0014). Conclusion: GLS can aid in risk stratifying MACE in KT candidates with preserved pre-transplant LVEF. Lower GLS values were associated with increased post-transplant cardiovascular risk.

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.

Introduction: Obstructive sleep apnea (OSA), a form of sleep disordered breathing (SDB), is associated with abnormal myocardial flow reserve (MFR), a precursor to heart failure with preserved ejection fraction (HFPEF). Sex differences have been reported in the prevalence of abnormal MFR and OSA. However, it is unknown if there are sex differences in the relationship between left ventricular (LV) global longitudinal strain (GLS) and abnormal MFR in a patient population with SDB. Methods: We compared LV GLS among patients in our institution who had sleep testing for obstructive sleep apnea (OSA), cardiac PET stress test and an echocardiogram between 2015 and 2019. We reprocessed the echocardiograms using a vendor neutral software to obtain the two-dimensional LV GLS. Results: Among the 148 participants, 59% were female. Compared with females, males had lower BMIs, a higher prevalence of prior myocardial infarction or revascularization, and a greater severity of nocturnal airway obstruction and hypoxia. Males also had a greater proportion with abnormal LV GLS (≥ -17). See Table. The prevalence of abnormal MFR (&lt; 2.0) was higher among participants with abnormal LV GLS ( P = 0.031). This association was persistent among males but was lost among females (see Figure ). In age and sex adjusted logistic regression persons with abnormal LV GLS had 2X the odds of abnormal MFR (OR 2.3; 95% CI: 1.02 - 5.03). Among males, this association was significant (OR 4.8; 95%CI:1.5 - 13.7). No association observed among females. Formal interaction analyses did not meet statistical significance ( P int = 0.106). Conclusions: In this patient population with SDB, there was a significant association between LV GLS and abnormal MFR. The sex differences in the relationship may be due to differences in the severity of OSA and prevalence of ischemic heart disease. Future studies should clarify these relationships and elucidate the drivers of the sex disparities observed in these findings.

Long term survivors of haematopoietic stem cell transplantation (HSCT) for β-thalassemia major are designated "ex-thalassaemics". Whether ex-thalassaemics continue to harbour residual myocardial dysfunction and thereby stand the risk of heart failure-related morbidity and mortality is unknown. The aim of this study was to assess the prevalence and predictors of subclinical left ventricular (LV) dysfunction in an apparently normal ex-thalassaemic population. We conducted a single centre cross-sectional study among 62 ex-thalassaemic patients, who had undergone HSCT for β-thalassaemia major at our centre. The primary outcome variable was LV systolic dysfunction, as assessed by 1) LV global longitudinal strain (GLS) derived by 2D speckle tracking echocardiography and 2) LV ejection fraction (EF) derived by 2D Simpsons Biplane method. Among the 62 patients included in the study, 7 [11.3%] were found to have LV systolic dysfunction, all of which were subclinical. Of these, 4 [6.5%] had abnormal GLS and LVEF, 2 [3.2%] had abnormal GLS with normal LVEF, and 1 [1.6%] had abnormal LVEF with low normal mean GLS. There were no statistically significant predictors of LV dysfunction in this cohort. There was a high prevalence of subclinical myocardial dysfunction in the ex-thalassaemic population reiterating the need for close follow up of these patients. 2D Speckle tracking echocardiography-derived LV global longitudinal strain is an effective tool in detecting subclinical myocardial dysfunction in this cohort.

Global Longitudinal Strain Reference Values in the Hispanic/Latino Population: Echocardiographic Study of Latinos (ECHO-SOL).

BackgroundAnthracyclines and radiotherapy involving the heart region are cardiotoxic, but the potential cardiotoxicity of vincristine remains unknown. We assessed cardiac function in vincristine-treated >5-year childhood cancer survivors (CCS). Methods and resultsWe cross-sectionally compared echocardiograms of 101 vincristine-treated CCS (median age 35 years [range: 17–53], median vincristine dose 63 mg/m2) from the national Dutch Childhood Cancer Survivor Study, LATER cohort, to 101 age- and sex-matched controls. CCS treated with anthracyclines, radiotherapy involving the heart region, cyclophosphamide or ifosfamide were excluded. Twelve CCS (14%) versus four controls (4%; p 0.034) had a decreased left ventricular ejection fraction (LVEF; men <52%, women <54%). Mean LVEF was 58.4% versus 59.7% (p 0.050). Global longitudinal strain (GLS) was abnormal in nineteen (24%) CCS versus eight controls (9%; p 0.011). Mean GLS was 19.0% versus 20.1% (p 0.001). No ≥grade 2 diastolic dysfunction was detected. In multivariable logistic regression analysis CCS had higher risk of abnormal GLS (OR 3.55, p 0.012), but not abnormal LVEF (OR 3.07, p 0.065), than controls. Blood pressure and smoking history contributed to variation in LVEF, whereas obesity and diastolic blood pressure contributed to variation in GLS. Cumulative vincristine dose was not associated with either abnormal LVEF or abnormal GLS in multivariable models corrected for age and sex (OR per 50 mg/m2: 0.88, p 0.85 and 1.14, p 0.82, respectively). ConclusionsVincristine-treated long-term CCS showed an abnormal GLS more frequently than controls. Their risk for future clinical cardiac events and the role of risk factor modification should be further elucidated.

Tracking Changes in Global Longitudinal Strain in Lung Cancer Patients Receiving Thoracic Radiation

Global Longitudinal Strain: A Potential Noninvasive Tool for Early Detection of Radiation-Induced Cardiac Dysfunction in Patients With Lung Cancer Receiving Thoracic Radiation Therapy.

Systolic dysfunction in patients with methamphetamine use and heart failure with preserved ejection fraction

To leverage baseline global longitudinal strain (GLS) and N-terminal-pro-B-type natriuretic peptide (NT-proBNP) to identify childhood cancer survivors with a normal left ventricular ejection fraction (LVEF) at highest risk of future treatment-related cardiomyopathy. St Jude Lifetime Cohort participants ≥5 years from diagnosis, at increased risk for cardiomyopathy per the International Guideline Harmonization Group (IGHG), with an LVEF ≥50% on baseline echocardiography (n = 1,483) underwent measurement of GLS (n = 1,483) and NT-proBNP (n = 1,052; 71%). Multivariable Cox regression models estimated hazard ratios (HRs) and 95% CIs for postbaseline cardiomyopathy (modified Common Terminology Criteria for Adverse Events ≥grade 2) incidence in association with echocardiogram-based GLS (≥-18) and/or NT-proBNP (>age-sex-specific 97.5th percentiles). Prediction performance was assessed using AUC in models with and without GLS and NT-proBNP and compared using DeLong's test for IGHG moderate- and high-risk individuals treated with anthracyclines. Among survivors (median age, 37.6; range, 10.2-70.4 years), 162 (11.1%) developed ≥grade 2 cardiomyopathy 5.1 (0.7-10.0) years from baseline assessment. The 5-year cumulative incidence of cardiomyopathy for survivors with and without abnormal GLS was, respectively, 7.3% (95% CI, 4.7 to 9.9) versus 4.4% (95% CI, 3.0 to 5.7) and abnormal NT-proBNP was 9.9% (95% CI, 5.8 to 14.1) versus 4.7% (95% CI, 3.2 to 6.2). Among survivors with a normal LVEF, abnormal baseline GLS and NT-proBNP identified anthracycline-exposed, IGHG-defined moderate-/high-risk survivors at a four-fold increased hazard of postbaseline cardiomyopathy (HR, 4.39 [95% CI, 2.46 to 7.83]; P < .001), increasing to a HR of 14.16 (95% CI, 6.45 to 31.08; P < .001) among survivors who received ≥250 mg/m2 of anthracyclines. Six years after baseline, AUCs for individual risk prediction were 0.70 for models with and 0.63 for models without GLS and NT-proBNP (P = .022). GLS and NT-proBNP should be considered for improved identification of survivors at high risk for future cardiomyopathy.