Time course of hypertension and myocardial dysfunction following anthracycline chemotherapy in pediatric patients.

Background: Anthracyclines are associated with cardiac dysfunction. Little is known about the interplay of pre-existing hypertension and treatment response. We aimed to investigate the relationship between hypertension and the development of cancer therapy-related cardiac dysfunction (CTRCD) in pediatric patients treated with anthracycline chemotherapy. Methods: Pediatric patients with cancer who received anthracycline chemotherapy from 2013 to 2021 were retrospectively included. Serial cardiac assessments were conducted during and after chemotherapy. The primary outcome was the development of CTRCD, classified as mild, moderate, or severe according to contemporary definitions. Results: Among 190 patients undergoing anthracycline chemotherapy, 34 patients (17.9 %) had hypertension (24 patients Stage 1, and 10 patients Stage 2) at baseline evaluation. Patients underwent chemotherapy for a median of 234.4 days (interquartile range 127.8-690.3 days) and were subsequently followed up. Hypertension was frequent during follow-up 31.3 % (0-3 months), 15.8 % (3-6 months), 21.9 % (0.5-1 years), 24.7 % (1-2 years), 31.1 % (2-4 years) and 35.8 % (beyond 4 years) (P for trend < 0.001). Freedom from mild CTRCD at 5 years was 45.0 %, freedom from moderate CTRCD was 87.8 % at 5 years. Baseline hypertension did not increase the risk of mild (HR 0.77, 95 % CI: 0.41-1.42, P = 0.385) or moderate CTRCD (HR 0.62, 95 % CI: 0.14-2.72, P = 0.504). Patients with baseline hypertension showed different global longitudinal strain (P < 0.001) and LVEF (P < 0.001) patterns during follow-up. Conclusions: Pediatric patients often develop CTRCD post-anthracycline chemotherapy. Those with pre-existing hypertension show a unique treatment response, despite no increased CTRCD risk, warranting further investigation.

Identifying responders to elamipretide in Barth syndrome: Hierarchical clustering for time series data.

BACKGROUND: Barth syndrome (BTHS) is a rare genetic disease that is characterized by cardiomyopathy, skeletal myopathy, neutropenia, and growth abnormalities and often leads to death in childhood. Recently, elamipretide has been tested as a potential first disease-modifying drug. This study aimed to identify patients with BTHS who may respond to elamipretide, based on continuous physiological measurements acquired through wearable devices. RESULTS: Data from a randomized, double-blind, placebo-controlled crossover trial of 12 patients with BTHS were used, including physiological time series data measured using a wearable device (heart rate, respiratory rate, activity, and posture) and functional scores. The latter included the 6-minute walk test (6MWT), Patient-Reported Outcomes Measurement Information System (PROMIS) fatigue score, SWAY Balance Mobile Application score (SWAY balance score), BTHS Symptom Assessment (BTHS-SA) Total Fatigue score, muscle strength by handheld dynamometry, 5 times sit-and-stand test (5XSST), and monolysocardiolipin to cardiolipin ratio (MLCL:CL). Groups were created through median split of the functional scores into "highest score" and "lowest score", and "best response to elamipretide" and "worst response to elamipretide". Agglomerative hierarchical clustering (AHC) models were implemented to assess whether physiological data could classify patients according to functional status and distinguish non-responders from responders to elamipretide. AHC models clustered patients according to their functional status with accuracies of 60-93%, with the greatest accuracies for 6MWT (93%), PROMIS (87%), and SWAY balance score (80%). Another set of AHC models clustered patients with respect to their response to treatment with elamipretide with perfect accuracy (all 100%). CONCLUSIONS: In this proof-of-concept study, we demonstrated that continuously acquired physiological measurements from wearable devices can be used to predict functional status and response to treatment among patients with BTHS.

Do you hear what you see? Utilizing phonocardiography to enhance proficiency in cardiac auscultation.

INTRODUCTION: Cardiac auscultation skills have proven difficult to train and maintain. The authors investigated whether using phonocardiograms as visual adjuncts to audio cases improved first-year medical students' cardiac auscultation performance. METHODS: The authors randomized 135 first-year medical students using an email referral link in 2018 and 2019 to train using audio-only cases (audio group) or audio with phonocardiogram tracings (combined group). Training included 7 cases with normal and abnormal auscultation findings. The assessment included feature identification and diagnostic accuracy using 14 audio-only cases, 7 presented during training, and 7 alternate versions of the same diagnoses. The assessment-administered immediately after training and repeated 7 days later-prompted participants to identify the key features and diagnoses for 14 audio-only cases. Key feature scores and diagnostic accuracy were compared between groups using repeated measures ANOVA. RESULTS: Mean key feature scores were statistically significantly higher in the combined group (70%, 95% CI 67-75%) compared to the audio group (61%, 95% CI 56-66%) (F(1,116) = 6.144, p = 0.015, ds = 0.45). Similarly, mean diagnostic accuracy in the combined group (68%, 95% CI 62-73%) was significantly higher than the audio group, although with small effect size (59%, 95% CI 54-65%) (F(1,116) = 4.548, p = 0.035, ds = 0.40). Time on task for the assessment and prior auscultation experience did not significantly impact performance on either measure. DISCUSSION: The addition of phonocardiograms to supplement cardiac auscultation training improves diagnostic accuracy and heart sound feature identification amongst novice students compared to training with audio alone.

The discerning ear: cardiac auscultation in the era of artificial intelligence and telemedicine.

Heart murmur, a thoracic auscultatory finding of cardiovascular origin, is extremely common in childhood and can appear at any age from premature newborn to late adolescence. The objective of this review is to provide a modern examination and update of cardiac murmur auscultation in this new era of artificial intelligence (AI) and telemedicine. First, we provide a comprehensive review of the causes and differential diagnosis, clinical features, evaluation, and long-term management of paediatric heart murmurs. Next, we provide a brief history of computer-assisted auscultation and murmur analysis, along with insight into the engineering design of the digital stethoscope. We conclude with a discussion of the paradigm shifting impact of deep learning on murmur analysis, AI-assisted auscultation, and the implications of these technologies on telemedicine in paediatric cardiology. It is our hope that this article provides an updated perspective on the impact of AI on cardiac auscultation for the modern paediatric cardiologist.

Exercise-Induced Abnormalities of Regional Myocardial Deformation in Anomalous Aortic Origin of the Right Coronary Artery.

AIMS: Congenital coronary artery anomalies are uncommon and may result in sudden death. Management of asymptomatic patients with anomalous aortic origin of the right coronary artery (AAORCA) remains controversial with a lack of evidence to guide decision-making. We hypothesized that patients with AAORCA may have exercise-inducible ischemia detectable as abnormalities in regional myocardial deformation on exercise stress echocardiography (ESE). METHODS: We reviewed clinical data, computed tomography angiography, and treadmill ESE from 33 AAORCA patients (21 unoperated, 12 operated) and 11 controls. Regional wall motion on ESE was visually assessed. Doppler tissue imaging was done pre and post exercise to evaluate regional myocardial wall deformation. The post- to pre-exercise time to peak systolic strain corrected for heart rate ratio (TPScR) for the left ventricular inferior and anterior walls of AAORCA patients was compared to controls. RESULTS: No regional wall motion abnormalities were noted. The TPScR of the inferior wall was higher in unoperated (0.96 ± 0.41) but not operated (0.84 ± 0.28) AAORCA patients compared to controls (0.76 ± 0.18, P = .03 vs .23, respectively). There was no significant difference in TPScR of the anterior wall between unoperated patients and controls (P = .08). CONCLUSION: In some AAORCA patients undergoing ESE, TPScR of the left ventricular inferior wall is elevated, suggestive of ischemia induced by exercise in myocardium supplied by the right coronary artery. Further work is needed to understand the potential role of this finding in risk assessment.

Feeding methods for infants with single ventricle physiology are associated with length of stay during stage 2 surgery hospitalization.

BACKGROUND: Tube feedings are often needed to achieve the growth and nutrition goals associated with decreased morbidity and mortality in patients with single ventricle anatomy. Variability in feeding method through the interstage period has been previously described, however, comparable information following stage 2 palliation is lacking. OBJECTIVES: To identify types of feeding methods following stage 2 palliation and their influence on length of stay. DESIGN: Secondary analysis of the National Pediatric Cardiology Quality Improvement Collaborative registry was performed on 932 patients. Demographic data, medical characteristics, postoperative complications, type of feeding method, and length of stay for stage 2 palliation were analyzed. RESULTS: Type of feeding method remained relatively unchanged during hospitalization for stage 2 palliation. Gastrostomy tube fed only patients were the oldest at time of surgery (182.7 ± 57.7 days, P < .001) and had the lowest weight-for-age z scores at admission (-1.6 ± 1.4, P < .001). Oral + gastrostomy tube groups had the longest median bypass times (172.5 minutes, P = .001) and longest length of stay (median 12 days, P < .001). Multivariable modeling revealed that feeding by tube only (P < .001), oral + tube feeding (P ≤ .001), reintubation (P < .001), and prolonged intubation (P < .001) were associated with increased length of stay. Neither age (P = .156) nor weight-for-age z score at admission (P = .066) was predictive of length of stay. CONCLUSIONS: Feeding methods established at admission for stage 2 palliation are not likely to change by discharge. Length of stay is more likely to be impacted by tube feeding and intubation history than age or weight-for-age z score at admission. Better understanding for selection of feeding methods and their impact on patient outcomes is needed to develop evidence-based guidelines to decrease variability in clinical practice patterns and provide appropriate counseling to caregivers.

Artificial Intelligence-Assisted Auscultation of Heart Murmurs: Validation by Virtual Clinical Trial.

Artificial intelligence (AI) has potential to improve the accuracy of screening for valvular and congenital heart disease by auscultation. However, despite recent advances in signal processing and classification algorithms focused on heart sounds, clinical acceptance of this technology has been limited, in part due to lack of objective performance data. We hypothesized that a heart murmur detection algorithm could be quantitatively and objectively evaluated by virtual clinical trial. All cases from the Johns Hopkins Cardiac Auscultatory Recording Database (CARD) with either a pathologic murmur, an innocent murmur or no murmur were selected. The test algorithm, developed independently of CARD, analyzed each recording using an automated batch processing protocol. 3180 heart sound recordings from 603 outpatient visits were selected from CARD. Algorithm estimation of heart rate was similar to gold standard. Sensitivity and specificity for detection of pathologic cases were 93% (CI 90-95%) and 81% (CI 75-85%), respectively, with accuracy 88% (CI 85-91%). Performance varied according to algorithm certainty measure, age of patient, heart rate, murmur intensity, location of recording on the chest and pathologic diagnosis. This is the first reported comprehensive and objective evaluation of an AI-based murmur detection algorithm to our knowledge. The test algorithm performed well in this virtual clinical trial. This strategy can be used to efficiently compare performance of other algorithms against the same dataset and improve understanding of the potential clinical usefulness of AI-assisted auscultation.

Cardiac Management of the Patient With Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) results in a progressive cardiomyopathy that produces significant morbidity and mortality. To improve the quality of life in patients with DMD, cardiac care is focused on surveillance and management, with the goal of slowing the onset and progression of heart failure complications. The current article is intended to be an expanded review on the cardiac management data used to inform the 2018 DMD Care Considerations recommendations as well as be a discussion on clinical controversies and future management directions. The new cardiac guidance includes changes regarding noninvasive imaging surveillance of cardiac function and pharmacologic therapy. Many emerging therapies lack sufficient evidence-based data to be recommended in the 2018 DMD Care Considerations. These are discussed in the present article as clinical controversies and future directions. Important emerging therapies include new heart failure medications, mechanical circulatory support with ventricular assist devices, heart transplantation, and internal cardiac defibrillators. Future research studies should be focused on the risks and benefits of these advanced therapies in patients with DMD. We conclude this review with a brief discussion on the relationship between the heart and the recently developed medications that are used to directly target the absence of dystrophin in DMD.

Electrophysiological effects of anthracyclines in adult survivors of pediatric malignancy.

BACKGROUND: Anthracycline use is limited by cardiotoxicity, including arrhythmias and left ventricular (LV) dysfunction. We aim to characterize the association between electrophysiological changes and LV dysfunction. METHODS: A retrospective chart review was conducted, including all 147 pediatric cancer survivors at our institution over 18 years of age and treated with an anthracycline. One hundred thirty-four patients who had at least one electrocardiogram (ECG) and echocardiogram were analyzed. The association between dysfunction and baseline characteristics, treatment history, and electrocardigraphic parameters were analyzed using multivariable logistic regression. Additionally, a longitudinal generalized estimating equation (GEE) model was used to examine the temporal association between repeated measure corrected QT (QTc) intervals and subsequent LV function. RESULTS: In our population, 24% of patients had LV dysfunction. The initial posttreatment QTc interval was longer in patients with LV dysfunction (438 ± 35 vs. 420 ± 20 msec, P = 0.002). In logistic regression analysis, QTc interval (P < 0.001) and cumulative radiation dose (P = 0.027) were associated with LV dysfunction. On ECGs performed prior to evidence of LV dysfunction, the QTc was longer than on ECGs preceding a normal echocardiogram (451 ± 32 msec vs. 423 ± 25 msec, P < 0.001). Mean time from QTc ≥ 450 msec to evidence of LV dysfunction was 1.8 ± 2.9 years. In the longitudinal GEE model, QTc prolongation was associated with subsequent decreased fractional shortening. CONCLUSIONS: Among adult survivors of pediatric cancer treated with anthracyclines, prolongation of the QTc interval was associated with subsequent LV dysfunction.

In defence of auscultation: a glorious future?

Auscultation of the heart using a simple stethoscope continues to be a central aspect of the cardiovascular examination despite declining proficiency and availability of competing technologies such as hand-held ultrasound. In the ears and mind of a trained cardiologist, heart sounds can provide important information to help screen for certain diseases such as valvar lesions and many congenital defects. Using emerging technology, auscultation is poised to undergo a transformation that will simultaneously improve the teaching and evaluation of this important clinical skill and create a new generation of smart stethoscopes, capable of assisting the clinician in quickly and confidently screening for heart disease. These developments have important implications for global health, screening of athletes and recognition of congenital heart disease.

Return of Viable Cardiac Function After Sonographic Cardiac Standstill in Pediatric Cardiac Arrest.

Sonographic cardiac standstill during adult cardiac arrest is associated with failure to get return to spontaneous circulation. This report documents 3 children whose cardiac function returned after standstill with extracorporeal membranous oxygenation. Sonographic cardiac standstill may not predict cardiac death in children.

What makes medical students better listeners?

Diagnosing heart conditions by auscultation is an important clinical skill commonly learnt by medical students. Clinical proficiency for this skill is in decline [1], and new teaching methods are needed. Successful discrimination of heartbeat sounds is believed to benefit mainly from acoustical training [2]. From recent studies of auditory training [3,4] we hypothesized that semantic representations outside the auditory cortex contribute to diagnostic accuracy in cardiac auscultation. To test this hypothesis, we analysed auditory evoked potentials (AEPs) which were recorded from medical students while they diagnosed quadruplets of heartbeat cycles. The comparison of trials with correct (Hits) versus incorrect diagnosis (Misses) revealed a significant difference in brain activity at 280-310 ms after the onset of the second cycle within the left middle frontal gyrus (MFG) and the right prefrontal cortex. This timing and locus suggest that semantic rather than acoustic representations contribute critically to auscultation skills. Thus, teaching auscultation should emphasize the link between the heartbeat sound and its meaning. Beyond cardiac auscultation, this issue is of interest for all fields where subtle but complex perceptual differences identify items in a well-known semantic context.

New targets for monitoring and therapy in Barth syndrome.

PURPOSE: Barth syndrome (BTHS), an X-linked disorder caused by defects in TAZ, is the only known single-gene disorder of cardiolipin remodeling. We hypothesized that through analysis of affected individuals, we would gain a better understanding of the range of clinical features and identify targets for monitoring and therapy. METHODS: We conducted a multidisciplinary investigation involving 42 patients with BTHS, including echocardiograms, muscle strength testing, functional exercise capacity testing, physical activity assessments, cardiolipin analysis, 3-methylglutaconic acid analysis, and review of genotype data. We analyzed data points to provide a quantitative spectrum of disease characteristics and to identify relationships among phenotype, genotype, and relevant metabolites. RESULTS: Echocardiography revealed considerable variability in cardiac features. By contrast, almost all patients had significantly reduced functional exercise capacity. Multivariate analysis revealed significant relationships between cardiolipin ratio and left ventricular mass and between cardiolipin ratio and functional exercise capacity. We additionally identified genotypes associated with a less severe metabolic and clinical profile. CONCLUSION: We defined previously unrecognized metabolite/phenotype/genotype relationships, established targets for therapeutic monitoring, and validated avenues for clinical assessment. In addition to providing insight into BTHS, these studies also provide insight into the myriad of multifactorial disorders that converge on the cardiolipin pathway.Genet Med 18 10, 1001-1010.

Stress echocardiography in paediatrics: implications for the evaluation of anomalous aortic origin of the coronary arteries.

Stress echocardiography in paediatrics is used to evaluate pre- and post-operative coronary artery conditions, as well as to gain haemodynamic information for a variety of diagnoses, although evidence regarding sensitivity, specificity, and predictive value is lacking. This review will consider the available literature with a focus on anomalous aortic origin of the coronary arteries and discuss a practical approach to test selection and use.

Total anomalous pulmonary venous connection in a neonate characterised by low-dose, high-pitch cardiac CT.

We describe the use of low-dose dual-source cardiac for the evaluation of a neonate with suspected total anomalous pulmonary venous connection. This novel technique obviates the need for sedation or breathholding. Radiation dose-reduction strategies result in sub-mSv-estimated effective doses, substantially lower than annual background radiation dose. Low-dose, high-pitch cardiac CT should be considered as an alternative to MRI or diagnostic cardiac catheterisation in neonates with complex CHD, requiring definitive anatomic evaluation.

Sildenafil does not improve cardiomyopathy in Duchenne/Becker muscular dystrophy.

OBJECTIVE: Duchenne and Becker muscular dystrophies (DBMD) are allelic disorders caused by mutations in dystrophin. Adults with DBMD develop life-threatening cardiomyopathy. Inhibition of phosphodiesterase 5 (PDE5) improves cardiac function in mouse models of DBMD. To determine whether the PDE5-inhibitor sildenafil benefits human dystrophinopathy, we conducted a randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov, number NCT01168908). METHODS: Adults with DBMD and cardiomyopathy (ejection fraction ≤ 50%) were randomized to receive sildenafil (20mg 3× daily) or placebo for 6 months. All subjects received an additional 6 months of open-label sildenafil. The primary endpoint was change in left ventricular end-systolic volume (LVESV) on cardiac magnetic resonance imaging. Secondary cardiac endpoints, skeletal muscle function, and quality of life were also assessed. RESULTS: An interim analysis (performed after 15 subjects completed the blinded phase) revealed that 29% (4 of 14) of subjects had a ≥10% increase in LVESV after 6 months of sildenafil compared to 13% (1 of 8) of subjects receiving placebo. Subjects with LVESV > 120ml at baseline were more likely to worsen at 12 months regardless of treatment assignment (p = 0.035). Due to the higher number of subjects worsening on sildenafil, the data and safety monitoring board recommended early termination of the study. There were no statistically significant differences in outcome measures between treatment arms. INTERPRETATION: Due to the small sample size, comparisons between groups must be interpreted with caution. However, this trial suggests that sildenafil is unlikely to improve cardiac function in adults with DBMD.

Evaluation of cardiac auscultation skills in pediatric residents.

UNLABELLED: Auscultation skills are in decline, but few studies have shown which specific aspects are most difficult for trainees. We evaluated individual aspects of cardiac auscultation among pediatric residents using recorded heart sounds to determine which elements pose the most difficulty. METHODS: Auscultation proficiency was assessed among 34 trainees following a pediatric cardiology rotation using an open-set format evaluation module, similar to the actual clinical auscultation description process. RESULTS: Diagnostic accuracy for distinguishing normal from abnormal cases was 73%. Findings most commonly correctly identified included pathological systolic and diastolic murmurs and widely split second heart sounds. Those least likely to be identified included continuous murmurs and clicks. Accuracy was low for identifying specific diagnoses. CONCLUSIONS: Given time constraints for clinical skills teaching, this suggests that focusing on distinguishing normal from abnormal heart sounds and murmurs instead of making specific diagnoses may be a more realistic goal for pediatric resident auscultation training.

Pathophysiology and therapy of cardiac dysfunction in Duchenne muscular dystrophy.

Cardiac dysfunction is a frequent manifestation of Duchenne muscular dystrophy (DMD) and a common cause of death for individuals with this condition. Early diastolic dysfunction and focal fibrosis proceed to dilated cardiomyopathy (DCM), complicated by heart failure and arrhythmia in most patients. Improvements in the management of respiratory insufficiency in DMD have improved lifespan and overall prognosis, but heart failure and sudden death continue to impact survival and quality of life for people with DMD. Since the specific mechanisms resulting in heart failure for people with DMD are poorly understood, current treatments are not targeted, but rely on approaches that are considered standard for DCM. These approaches include angiotensin-converting enzyme (ACE) inhibitors and ß-adrenoceptor antagonists. Data from one trial in DMD support the use of ACE inhibitors before the onset of left ventricular dysfunction. Angiotensin receptor blockers have shown similar efficacy to ACE inhibitors in numerous studies of dilated cardiomyopathy, and are a good choice for patients who cannot tolerate ACE inhibition. The pathogenesis of DMD-associated cardiomyopathy may be similar to other genetic disorders of the cytoskeletal complex of ventricular myocytes, though unique features offer targeted opportunities to impact treatment. Novel areas of investigation are focused on the regulatory role of dystrophin in relation to neuronal nitric oxide synthase (nNOS) and transient receptor potential canonical channels (TRPC). Inhibition of phosphodiesterase-5 (PDE5) addresses several aspects of regulatory dysfunction induced by dystrophin deficiency, and studies with PDE5-inhibitors have shown benefits in murine models of DMD. PDE5-inhibitors are currently under investigation in at least one study in humans. This article focuses on mechanisms of cardiac dysfunction, as well as potential targets for pharmacologic manipulation to prevent or improve cardiomyopathy in DMD.