Asaki, S. Yukiko

While significant progress has been made in reducing disparities within the US health care system, notable gaps remain. This article explores existing disparities within pediatric congenital heart disease care. Congenital heart disease, the most common birth defect and a leading cause of infant death, has garnered substantial attention, revealing certain disparities within the US health care system. Factors such as race, ethnicity, insurance coverage, socioeconomic status, and geographic location are all commonalities that significantly affect health disparities in pediatric congenital heart disease. This comprehensive review sheds light on disparities from diverse perspectives in pediatric care, demonstrates the inequities and inequalities leading to these disparities, presents effective solutions, and issues a call to action for providers, institutions, and the health care system. Recognizing and addressing these disparities is imperative for ensuring equitable care and enhancing the long‐term well‐being of children affected by congenital heart disease. Implementing robust, evidence‐based frameworks that promote responsible and safe interventions is fundamental to enduring change.

Background: Sex hormones influence the arrhythmogenic risk for various genetic heart diseases (GHDs) including long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and idiopathic ventricular fibrillation (IVF). Although exogenous hormones are used frequently in transgender medicine for gender-affirming hormone therapy (GAHT), the effect of such treatments on sudden cardiac death (SCD) risk in transgender patients with a GHD is unknown. Objective: To describe the prevalence and spectrum of transgender patients with GHD and to evaluate the impact of GAHT on the treatment and outcomes of their underlying GHD. Methods: We performed a retrospective review of all patients seen and evaluated in Mayo Clinic’s Windland Smith Rice Genetic Heart Rhythm Clinic from January 1999-2022 to identify transgender patients. Clinical notes were reviewed for sex, gender identity, GAHT, and details of their GHD, therapy, and outcomes. Results: Among 1990 patients with a GHD, we found 7 patients (0.35%) who self-identify as a gender different from their chromosomal sex (transgender). Specifically, there were 4 patients who identified as transgender women (XY males at birth) and 3 as transgender men (XX females at birth). Five of seven patients (71%) have used forms of GAHT, with 2 patients on estradiol and 3 patients on testosterone. GHDs identified include LQT1 (2 transgender women), LQT3 (1 transgender man), LQT3/BrS overlap syndrome (1 transgender woman), genotype negative LQTS (1 transgender man), CPVT (1 transgender woman), and IVF (1 transgender man). Guideline-directed GHD therapy was optimized, not altered nor escalated, for all patients and no patients were advised against initiating GAHT due to perceived interactions. One of seven patients (transgender man with IVF) experienced a breakthrough cardiac event (BCE) while on GAHT, while the other 6 patients have had no BCEs. Conclusion: Although less than 0.5% of patients seen over 20+ years self-identified as transgender, their holistic care must include a careful discussion of the possible cardiac risks associated with GAHT. Additional studies are needed to determine the potential pro-arrhythmic risk of GAHT.

Background: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration. Methods: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. Results: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P <0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6–52.2]; P =0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3–10.8], P =0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%). Conclusions: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.