Dearani, Joseph A.

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: Optimal management of cardiac implantable electronic devices (CIEDs) in patients with Ebstein anomaly during tricuspid valve (TV) surgery is unknown. Thus, we aimed to characterize CIED management/outcomes in patients with Ebstein anomaly undergoing TV surgery. Methods: Patients at the Mayo Clinic from 1987 to 2020 with Ebstein anomaly and CIED procedure were reviewed for procedural details, complications, echocardiogram, and lead parameters. Five-year cumulative incidence of CIED complications were estimated using the Kaplan-Meier method. Results: Ninety-three patients were included; 51 were female, and mean age was 40.7±17.5 years. A new CIED was implanted in 45 patients at the time of TV surgery with the majority receiving an epicardial (n=37) CIED. Among 34 patients who had preexisting CIED (11 epicardial, 23 transvenous) at time of TV surgery, 20 had a transvenous right ventricular lead managed by externalizing the lead to the TV (n=15) or extracting the transvenous lead with epicardial lead implantation (n=5). Fourteen patients underwent CIED implantation (4 epicardial, 10 transvenous) without concurrent surgery. Placement of lead across the TV was avoided in 85% of patients. The 5-year cumulative incidence of CIED complications was 24% with no significant difference between epicardial and transvenous CIEDs (26% versus 23%, P =0.96). Performance of lead parameters was similar in epicardial and transvenous leads during median (interquartile range) follow-up of 44.5 (61.1) months. Conclusions: In patients with Ebstein anomaly undergoing TV surgery, the use of epicardial leads and externalization of transvenous leads to the TV can avoid lead placement across the valve leaflets. Lead performance and CIED complications was similar between epicardial and transvenous CIEDs.

Background Patients with heterotaxy syndromes (right and left atrial isomerism) are at high risk of poor outcomes after single-ventricle palliation. However, the long-term outcomes and specific parameters associated with poor outcomes are incompletely understood. Methods A retrospective review was performed of all patients with atrial isomerism who had a Fontan at our institution from 1973 to 2020. Standard demographic, as well as pre-, peri-, and postoperative parameters were collected. Features and outcomes of patients with polysplenia were compared to asplenia. Outcomes were analyzed for effect during 4 eras: (1: 1973-1984; n = 27), (2: 1985-1994; n = 93), (3: 1995-2004; n = 28), and (4: 2005-2020; n = 10). Results Of the 1176 patients who had a Fontan operation, 158 (14%) had a heterotaxy syndrome. The median age at the time of Fontan was 8 (9) years. Early mortality was 20% and was greater in patients with asplenia compared to polysplenia (27% vs. 12%, p = .019). But it substantially improved over time (61% in era 1 vs. 7%-10% in the more recent eras ( p < .001)), as did transplant-free survival (22% at 10 years in era 1 vs. 88% in era 4, p < .001). Transplant-free survival was significantly lower in patients with asplenia versus those with polysplenia ( p = .014), and patients with heterotaxy had lower survival than nonheterotaxy ( p = .01). This was largely due to the asplenia group ( p < .001) (hazard ratio = 3.05, p = .007). Conclusions After Fontan operation, patients with heterotaxy, particularly asplenia, continue to demonstrate worse transplant-free survival than nonheterotaxy patients. Early mortality and long-term transplant-free survival have improved in more recent eras.

Abstract OBJECTIVES This study analyzes the safety and outcomes of mitral valve repair for degenerative mitral valve regurgitation in patients 75 years of age or older. METHODS We retrospectively reviewed the clinical results of 343 patients aged ≥75 years who underwent mitral valve repair for degenerative mitral valve regurgitation as a primary indication between January 1998 and June 2017. RESULTS The median (interquartile range) age of the patients was 79.4 (76.9, 82.9) years, and 132 (38.5%) patients were women. Concomitant procedures were performed in 123 patients: tricuspid surgery in 68 (19.8%) and a maze procedure or pulmonary vein isolation in 55 (16.0%). Operative mortality was 1.2%. Operative complications included atrial fibrillation in 37.9%, prolonged ventilation in 7.0%, pacemaker implantation in 3.8, renal failure requiring dialysis in 1.5 and stroke in 3 (0.9%). The median follow-up was 7.4 years (interquartile range, 3.5–14.1 years). The cumulative incidence rates of mitral valve reoperation were 2.2%, 3.2% and 3.2% at 1, 5 and 10 years, respectively. Overall survival at 1, 5 and 10 years were 95%, 83% and 51%, respectively. Older age, smoking and over and underweight were associated with increased risk of mortality, while higher left ventricular ejection fraction and hypertension were associated with reduced risk. CONCLUSIONS Mitral valve repair in elderly patients can be accomplished with low operative mortality and complications. Mitral valve repair in the elderly remains the preferred treatment for degenerative mitral regurgitation.

Introduction: Hypertrophic cardiomyopathy (HCM) is one of the most common genetic heart diseases characterized by asymmetric left ventricular hypertrophy (LVH) and vast clinical and genetic heterogeneity. Several transcriptional studies in HCM heart tissues have shown severe alterations in gene expression. However, these earlier studies relied on microarray technology or were limited by small sample size or lack of genotype-specific analyses. Methods: We obtained flash-frozen cardiac tissue from patients with HCM undergoing surgical myectomy/septal reduction therapy for relief of left ventricular outflow tract obstruction. RNA-sequencing (RNAseq) was performed using paired-end index reading on 97 myectomy tissues (44 female [45%]; mean age at surgery of 47 ± 18 years) and 23 control tissues (10 female [43%]; mean age at death of 43 ± 12 years) to identify differentially expressed genes (DEGs) using edgeR and pathways in HCM using Ingenuity Pathway Analysis. Additionally, genome sequencing (GS) was performed and HCM patients were divided into genotype-based subgroups to compare the transcriptional profile across different genotypes. Results: Overall, 43% had a pathogenic, HCM-associated variant including 23% with MYBPC3-HCM and 15% with MYH7-HCM. Among the 15,634 genes expressed in the cardiac tissue,1,246 genes (8%) were upregulated and 738 genes (3%) were downregulated significantly in HCM vs. controls. Pathway analysis showed alterations in 126 pathways with downregulation of 44 pathways and upregulation of 1 pathway. There were notable transcriptional alterations of most canonical, pro-hypertrophic pathways, including statistically and biologically significant downregulation of five pathways [-log (BH p-value)≥ 1.3; Z-score≤ -2]: ERK/MAPK, p38 MAPK, ERK5, IL6, and NF-κB signaling. Far less DEGs were observed between genotypic subgroups, with only 37 DEGSs identified between sarcomere positive- and genotype negative-HCM. Conclusions: At the time of surgical myectomy, the ventricular myocardium’s transcriptome, independent of genotype, reveals widespread downregulation of pro-hypertrophic pathways. Whether these counter regulatory measures can be targeted therapeutically warrants further investigation.