Qureshi, M. Yasir

Congenital heart diseases, including single ventricle circulations, are clinically challenging due to chronic pressure overload and the inability of the myocardium to compensate for lifelong physiological demands. To determine the clinical relevance of autologous umbilical cord blood–derived mononuclear cells (UCB-MNCs) as a therapy to augment cardiac adaptation following surgical management of congenital heart disease, a validated model system of right ventricular pressure overload due to pulmonary artery banding (PAB) in juvenile pigs has been employed. PAB in a juvenile porcine model and intramyocardial delivery of UCB-MNCs was evaluated in three distinct 12-week studies utilizing serial cardiac imaging and end-of-study pathology evaluations. PAB reproducibly induced pressure overload leading to chronic right ventricular remodeling including significant myocardial fibrosis and elevation of heart failure biomarkers. High-dose UCB-MNCs (3 million/kg) delivered into the right ventricular myocardium did not cause any detectable safety issues in the context of arrhythmias or abnormal cardiac physiology. In addition, this high-dose treatment compared with placebo controls demonstrated that UCB-MNCs promoted a significant increase in Ki-67-positive cardiomyocytes coupled with an increase in the number of CD31+ endothelium. Furthermore, the incorporation of BrdU-labeled cells within the myocardium confirmed the biological potency of the high-dose UCB-MNC treatment. Finally, the cell-based treatment augmented the physiological adaptation compared with controls with a trend toward increased right ventricular mass within the 12 weeks of the follow-up period. Despite these adaptations, functional changes as measured by echocardiography and magnetic resonance imaging did not demonstrate differences between cohorts in this surgical model system. Therefore, this randomized, double-blinded, placebo-controlled pre-clinical trial establishes the safety of UCB-MNCs delivered via intramyocardial injections in a dysfunctional right ventricle and validates the induction of cardiac proliferation and angiogenesis as transient paracrine mechanisms that may be important to optimize long-term outcomes for surgically repaired congenital heart diseases.

Background: Echocardiographic (echo) functional assessment of single systemic right ventricle (RV) lacks a reliable parameter and does not provide a substitute of volumetric ejection fraction (EF). RV volumes by 3D-echo are challenging and not widely used. Apical RV fractional area change (FAC) has shown some relation to CMR EF, but the strength of correlation has been suboptimal. Adding additional planes to apical FAC may improve this correlation. Our objective was to assess correlation of triplane FAC (apical, short-axis, and inflow-outflow) with CMR EF and to compare the tri- and single plane methods of measuring FAC to each other. Methods: Subjects with hypoplastic left heart syndrome (after superior or total cavopulmonary anastomosis) were prospectively recruited. CMR was performed and right ventricular ejection fraction was calculated. Transthoracic echo studies were performed close to the time of the CMR scan (median interval: 1 d). FAC was measured in apical 4-chamber view, parasternal short axis view at the mid ventricular level, and para-apical right ventricular inflow-outflow view. Triplane FAC was calculated by the average of the three FAC. Comparison was made between FAC and CMR-derived ejection fraction. Results: A total of 25 subjects underwent testing. Triplane FAC could not be assessed in 5, due to lack of optimal acoustic windows. Mean age was 10 ± 8 y (range 9 m to 24 y). Out of the uniplanar methods, apical FAC had the closest relationship to CMR EF. Triplane FAC showed even better correlation coefficient and R 2 values; although in this small group the difference did not reach significance. Results are summarized in the Table. Conclusion: In patients with single systemic RV, triplane FAC offers improved correlation with CMR EF relative to single plane evaluations. This approach may be useful if 3D echo is unavailable or of suboptimal quality and warrants further study.

Background: Hypoplastic left heart syndrome (HLHS) with risk of poor outcome has been linked to MYH6 variants, implicating overlap in genetic etiologies of structural and myopathic heart disease. Methods: Whole genome sequencing was performed in 197 probands with HLHS, 43 family members, and 813 controls. Data were filtered for rare, segregating variants in 3 index families comprised of an HLHS proband and relative(s) with cardiomyopathy. Whole genome sequencing data from cases and controls were compared for rare variant burden across 56 cardiomyopathy genes utilizing a weighted burden test approach, accounting for multiple testing using a Bonferroni correction. Results: A pathogenic MYBPC3 nonsense variant was identified in the first proband who underwent cardiac transplantation for diastolic heart failure, her father with left ventricular noncompaction, and 2 fourth-degree relatives with hypertrophic cardiomyopathy. A likely pathogenic RYR2 missense variant was identified in the second proband, a second-degree relative with aortic dilation, and a fourth-degree relative with dilated cardiomyopathy. A pathogenic RYR2 exon 3 in-frame deletion was identified in the third proband diagnosed with catecholaminergic polymorphic ventricular tachycardia and his father with left ventricular noncompaction and catecholaminergic polymorphic ventricular tachycardia. To further investigate HLHS-cardiomyopathy gene associations in cases versus controls, rare variant burden testing of 56 genes revealed enrichment in MYH6 ( P =0.000068). Rare, predicted-damaging MYH6 variants were identified in 10% of probands in our cohort—4 with familial congenital heart disease, 4 with compound heterozygosity (3 with systolic ventricular dysfunction), and 4 with MYH6 – FLNC synergistic heterozygosity. Conclusions: Whole genome sequencing in multiplex families, proband-parent trios, and case-control cohorts revealed defects in cardiomyopathy-associated genes in patients with HLHS, which may portend impaired functional reserve of the single-ventricle circulation.

Ebstein anomaly has a breadth of presentations, including “typical” and “atypical,” and can be confused with congenital tricuspid dysplasia. We summarize how to differentiate within this spectrum of disease. Both typical and atypical Ebstein have an underlying failure of delamination, but atypical Ebstein does not have ≥8mm/m 2 apical septal leaflet displacement. In congenital tricuspid dysplasia, delamination is normal, while the leaflets and subvalvar apparatus are abnormal. To summarize, the sine qua non feature of Ebstein anomaly, present in both typical and atypical, is the failure of delamination. These are distinct from congenital tricuspid valve dysplasia in which the pathology is in the leaflet itself.

Abstract Background (+)‐Epicatechin (EPI) induces mitochondrial biogenesis and antioxidant metabolism in muscle fibers and neurons. We aimed to evaluate safety and efficacy of (+)‐EPI in pediatric subjects with Friedreich's ataxia (FRDA). Methods This was a phase II, open‐label, baseline‐controlled single‐center trial including 10 participants ages 10 to 22 with confirmed FA diagnosis. (+)‐EPI was administered orally at 75 mg/d for 24 weeks, with escalation to 150 mg/d at 12 weeks for subjects not showing improvement of neuromuscular, neurological or cardiac endpoints. Neurological endpoints were change from baseline in Friedreich's Ataxia Rating Scale (FARS) and 8‐m timed walk. Cardiac endpoints were changes from baseline in left ventricular (LV) structure and function by cardiac magnetic resonance imaging (MRI) and echocardiogram, changes in cardiac electrophysiology, and changes in biomarkers for heart failure and hypertrophy. Results Mean FARS/modified (m)FARS scores showed nonstatistically significant improvement by both group and individual analysis. FARS/mFARS scores improved in 5/9 subjects (56%), 8‐m walk in 3/9 (33%), 9‐peg hole test in 6/10 (60%). LV mass index by cardiac MRI was significantly reduced at 12 weeks ( P = .045), and was improved in 7/10 (70%) subjects at 24 weeks. Mean LV ejection fraction was increased at 24 weeks ( P = .008) compared to baseline. Mean maximal septal thickness by echocardiography was increased at 24 weeks ( P = .031). There were no serious adverse events. Conclusion (+)‐EPI was well tolerated over 24 weeks at up to 150 mg/d. Improvement was observed in cardiac structure and function in subset of subjects with FRDA without statistically significant improvement in primary neurological outcomes. Synopsis A (+)‐epicatechin showed improvement of cardiac function, nonsignificant reduction of FARS/mFARS scores, and sustained significant upregulation of muscle‐regeneration biomarker follistatin.

Background: Coarctation of aorta (COA) results in chronic left ventricular (LV) pressure overload and subsequently leads to LV diastolic dysfunction and heart failure over time. The goal of COA intervention is to prevent these complications. The timing of COA interventions is based on the presence of these COA severity indices: doppler mean COA gradient, systolic blood pressure, upper-to-lower-extremity SBP gradient, aortic isthmus ratio, presence of collaterals, and exercise-induced hypertension. Although these indices are physiologically intuitive, the relationship between these indices and LV diastolic dysfunction and exertional symptoms has not been studied. The purpose of this study was to evaluate the association between the indices of COA severity and LV diastolic function and symptoms. Methods: In this cross-sectional study, multivariate linear and logistic regression analyses were used to assess the correlation between indices of COA severity, LV diastolic function (average e’ and E/e’), and exertional symptoms (NYHA II–IV and peak oxygen consumption). Results: Of all the COA indices analyzed in 546 adult COA patients, aortic isthmus ratio had the strongest correlation with e’ (β [95% CI]: 3.11 [2.02–4.31]; P =0.014) per 1 cm/second; E/e’ (−13.4 [−22.3 to −4.81]; P =0.009) per 1 unit; peak oxygen consumption (4.05 [1.97–6.59] per 1% change, P =0.019), and NYHA II to IV symptoms (odds ratio, 2.16 [1.65–3.18]; P =0.006). Conclusions: Of all the COA severity indices stipulated in the guidelines, aortic isthmus ratio had the strongest correlation with LV diastolic function and exertional symptoms. As LV diastolic dysfunction typically precede heart failure symptoms, we anticipate that the results of this study will improve and simplify patient selection for COA intervention and potentially improve long-term outcomes.

Hypoplastic left heart syndrome is one of the most complex congenital heart diseases and requires several cardiac surgeries for survival. The diagnosis is usually established prenatally or shortly after birth. Each stage of surgery poses a unique hemodynamic situation that requires deeper understanding to manage common pediatric problems such as dehydration and respiratory infections. Careful multidisciplinary involvement in the care of these complex patients is improving their outcome; however, morbidity and mortality are still substantial. In this review, we focus on the hemodynamic aspects of various surgical stages that a primary care provider should know to manage these challenging patients.