Long-term outcomes following valve-sparing root replacement with concomitant mitral repair.

OBJECTIVES: To examine the late outcomes of valve-sparing root replacement and concomitant mitral valve repair in patients who have been followed prospectively for more than 2 decades. METHODS: From 1992 to 2020, 54 consecutive patients (mean age, 47 ± 16 years; 80% men) underwent valve-sparing root replacement (45 reimplantation and 9 remodeling) with concomitant repair of the mitral valve. Patients were followed prospectively for a median of 9 years (IQR, 3-14 years). RESULTS: No patient experienced perioperative death or stroke. There were 3 late deaths and the 15-year overall survival was 96.0% (95% CI, 74.8%-99.4%), similar to the age- and sex-matched population. Over the follow-up period, 6 patients had reoperation of the aortic valve and 3 on the mitral valve. Of those, 2 had reoperation on both aortic and mitral valves for a total of 7 reoperations in this cohort. The cumulative proportion of reoperation at 10 years of either or both valves were as follows: aortic valve 11.4% (95% CI, 3.9%-33.3%), mitral valve 4.2% (95% CI, 0.6%-28.4%), and both valves 11.4% (95% CI, 3.9%-33.3%). The estimated probability of developing moderate/severe aortic insufficiency at 15 years was 18.5% (95% CI, 9.0%-34.2%). On final echocardiographic follow-up, none of the patients had developed moderate/severe mitral regurgitation. CONCLUSIONS: In this single-center series of concomitant valve-sparing root replacement and mitral valve repair, we observed excellent clinical outcomes with a low risk of death or valve-related complications. Continued surveillance of late valve function is necessary.

Risk of Sudden Death in Patients With RASopathy Hypertrophic Cardiomyopathy.

BACKGROUND: Genetic defects in the RAS/mitogen-activated protein kinase pathway are an important cause of hypertrophic cardiomyopathy (RAS-HCM). Unlike primary HCM (P-HCM), the risk of sudden cardiac death (SCD) and long-term survival in RAS-HCM are poorly understood. OBJECTIVES: The study's objective was to compare transplant-free survival, incidence of SCD, and implantable cardioverter-defibrillator (ICD) use between RAS-HCM and P-HCM patients. METHODS: In an international, 21-center cohort study, we analyzed phenotype-positive pediatric RAS-HCM (n = 188) and P-HCM (n = 567) patients. The between-group differences in cumulative incidence of all outcomes from first evaluation were compared using Gray's tests, and age-related hazard of all-cause mortality was determined. RESULTS: RAS-HCM patients had a lower median age at diagnosis compared to P-HCM (0.9 years [IQR: 0.2-5.0 years] vs 9.8 years [IQR: 2.0-13.9 years], respectively) (P < 0.001). The 10-year cumulative incidence of SCD from first evaluation was not different between RAS-HCM and P-HCM (4.7% vs 4.2%, respectively; P = 0.59). The 10-year cumulative incidence of nonarrhythmic deaths or transplant was higher in RAS-HCM compared with P-HCM (11.0% vs 5.4%, respectively; P = 0.011). The 10-year cumulative incidence of ICD insertions, however, was 5-fold lower in RAS-HCM compared with P-HCM (6.9% vs 36.6%; P < 0.001). Nonarrhythmic deaths occurred primarily in infancy and SCD primarily in adolescence. CONCLUSIONS: RAS-HCM was associated with a higher incidence of nonarrhythmic death or transplant but similar incidence of SCD as P-HCM. However, ICDs were used less frequently in RAS-HCM compared to P-HCM. In addition to monitoring for heart failure and timely consideration of advanced heart failure therapies, better risk stratification is needed to guide ICD practices in RAS-HCM.

Early and mid-term outcomes after aortic valve intervention in patients with previous stentless or stented bioprostheses.

BACKGROUND: Limited data are available concerning comparative outcomes of redo aortic valve interventions, including surgery after aortic valve replacement (AVR) with either stented or stentless bioprostheses. We investigated the comparative outcomes of redo aortic valve interventions, including surgery after AVR with either stented or stentless bioprostheses. METHODS: The cohort consisted of 112 patients who underwent aortic valve intervention for infective endocarditis or structural valve deterioration between 2001 and 2020. One hundred patients received a stented valve (stented group) and 12 patients received a stentless valve (stentless group) during the initial surgery. Early and late outcomes were evaluated. RESULTS: The mean [IQR] ages during the current interventions were 66 [54, 77] years in the stented group and 74 [67, 79] years in the stentless group (P = 0.13). In the stented group, aortic valve interventions included redo AVRs with stented valves (n = 54), mechanical valves (n = 26), stentless valves (n = 16), and transcatheter aortic valve implantations (n = 4). In the stentless group, redo AVRs were performed with stented valves (n = 4), mechanical valves (n = 2), stentless valves (n = 1), and transcatheter valve implantations (n = 5). Hospital mortality was observed in 2 (2%) patients in the stented group and 1 (8%) patients in the stentless group (P = 0.29). The 5-year survival was 80.8% [66.8, 88.5] in the stented group and 91.7% [53.9, 98.8] in stentless group. Statistically significant differences in thromboembolisms were observed between the groups. CONCLUSIONS: No significant differences in early and mid-term outcomes (except thromboembolism) after aortic valve interventions were detected between patients with stented and stentless AVRs.

Outcomes of Reimplantation of the Aortic Valve in Patients With Aortic Cusp Fenestration.

BACKGROUND: Aortic cusp fenestrations are common in patients with aortic root aneurysm, and their management during aortic valve repair remains controversial. We believe that fenestrations in the area of the commissures may rupture after reimplantation of the aortic valve because this operation increases the mechanical stress on the cusps. For this reason we have reinforced the free margin of the aortic cusp with fenestration with fine Gore-Tex sutures (WL Gore). This study examines the outcomes of reimplantation of the aortic valve in patients who had cusp fenestration reinforced with Gore-Tex sutures. METHODS: A review of all patients who had reimplantation of the aortic valve for aortic root aneurysm disclosed 111 patients who had at least 1 cusp fenestration reinforced with a double layer of a fine Gore-Tex suture. The outcomes of these patients were examined and compared with a group of patients without fenestration using propensity score analysis. All patients were followed prospectively with images of the heart. RESULTS: The median follow-up was 8.3 years. Overall the cumulative incidence of aortic valve reintervention at 15 years was 4.8% and the cumulative incidence of aortic insufficiency of moderate or severe degree was 9.2%. Comparison of outcomes of patients with and without fenestrations showed similar results up to 15 years of follow-up. CONCLUSIONS: Reinforcement of the free margins of cusps with fenestrations using Gore-Tex sutures is safe and does not seem to adversely affect the durability of reimplantation of the aortic valve.

Improved Outcomes of Reimplantation vs Remodeling in Marfan Syndrome: A Propensity-Matched Study.

BACKGROUND: Valve-sparing root replacement (VSRR) has excellent outcomes when performed in experienced centers in well-selected patients. It is suggested that reimplantation of the aortic valve may have better durability than remodeling in patients with Marfan syndrome (MFS), although long-term comparative data are limited. METHODS: Between 1988 and 2018, 194 patients with MFS underwent VSRR at our institution. From these, we derived a propensity-matched cohort of 68 patients (44 who underwent reimplantation and 24 who had remodeling). Early outcomes included death and perioperative complications. Late outcomes were survival, probability of aortic insufficiency, and reintervention up to 20 years of follow-up. Median follow-up was 17.8 years (interquartile range, 12.0-20.6 years) for the entire matched cohort. RESULTS: Baseline variables were similar between reimplantation and remodeling patients after matching: age (39 ± 12 vs 40 ± 13 years, P = .75) and male sex (28 [64%] vs 15 [63%], P = 1.0). Similar 20-year survival was observed after reimplantation compared with remodeling (82% vs 72%, P = .20), whereas the probability of developing greater than mild aortic insufficiency at 20 years was increased after remodeling (5.8% vs 13%, P = .013). More patients underwent reoperation on the aortic valve after a remodeling procedure than after reimplantation of the aortic valve (18% vs 0%, P = .018). CONCLUSIONS: VSRR provides excellent long-term survival and freedom from valve-related complications outcomes in patients with MFS. Reimplantation of the aortic valve was associated with a lower risk of aortic valve reoperation and aortic insufficiency than the remodeling procedure after 2 decades of follow-up.

Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors have been demonstrated to promote reverse cardiac remodeling in people with diabetes or heart failure. Although it has been theorized that sodium-glucose cotransporter 2 inhibitors might afford similar benefits in people without diabetes or prevalent heart failure, this has not been evaluated. We sought to determine whether sodium-glucose cotransporter 2 inhibition with empagliflozin leads to a decrease in left ventricular (LV) mass in people without type 2 diabetes or significant heart failure. METHODS: Between April 2021 and January 2022, 169 individuals, 40 to 80 years of age, without diabetes but with risk factors for adverse cardiac remodeling were randomly assigned to empagliflozin (10 mg/d; n=85) or placebo (n=84) for 6 months. The primary outcome was the 6-month change in LV mass indexed (LVMi) to baseline body surface area as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and LV end-systolic volumes indexed to baseline body surface area and LV ejection fraction. RESULTS: Among the 169 participants (141 men [83%]; mean age, 59.3±10.5 years), baseline LVMi was 63.2±17.9 g/m2 and 63.8±14.0 g/m2 for the empagliflozin- and placebo-assigned groups, respectively. The difference (95% CI) in LVMi at 6 months in the empagliflozin group versus placebo group adjusted for baseline LVMi was -0.30 g/m2 (-2.1 to 1.5 g/m2; P=0.74). Median baseline (interquartile range) NT-proBNP (N-terminal-pro B-type natriuretic peptide) was 51 pg/mL (20-105 pg/mL) and 55 pg/mL (21-132 pg/mL) for the empagliflozin- and placebo-assigned groups, respectively. The 6-month treatment effect of empagliflozin versus placebo (95% CI) on blood pressure and NT-proBNP (adjusted for baseline values) were -1.3 mm Hg (-5.2 to 2.6 mm Hg; P=0.52), 0.69 mm Hg (-1.9 to 3.3 mm Hg; P=0.60), and -6.1 pg/mL (-37.0 to 24.8 pg/mL; P=0.70) for systolic blood pressure, diastolic blood pressure, and NT-proBNP, respectively. No clinically meaningful between-group differences in LV volumes (diastolic and systolic indexed to baseline body surface area) or ejection fraction were observed. No difference in adverse events was noted between the groups. CONCLUSIONS: Among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, sodium-glucose cotransporter 2 inhibition with empagliflozin did not result in a meaningful reduction in LVMi after 6 months. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04461041.

A Double-Blind, Randomized, Controlled Crossover Trial of Cannabis in Adults with Tourette Syndrome.

Background: The number of effective evidence-based treatment options for patients with Tourette syndrome (TS) is limited. Emerging evidence shows cannabinoids as promising for the treatment of tics. Objectives: To compare the efficacy and tolerability of single doses of three vaporized medical cannabis products and placebo in reducing tics in adults with TS. Methods: In a randomized, double-blind, crossover design, each participant received a vaporized single 0.25 g dose of Δ9-tetrahydrocannabinol (THC) 10%, THC/cannabidiol (CBD) 9%/9%, CBD 13%, and placebo at 2-week intervals. Our primary outcome was the Modified Rush Video-Based Tic Rating Scale (MRVTRS), taken at baseline and at 0.5, 1, 2, 3, and 5 h after dose administration. Secondary measures included the Premonitory Urge for Tics Scale (PUTS), Subjective Units of Distress Scale (SUDS), and Clinical Global Impression-Improvement (CGI-I). Correlations between outcomes and cannabinoid plasma levels were calculated. Tolerability measures included open-ended and specific questions about adverse events (AEs). Results: Twelve adult patients with TS were randomized, with nine completing the study. There was no statistically significant effect of product on the MRVTRS. However, there was a significant effect of THC 10%, and to a lesser extent THC/CBD 9%9%, versus placebo on the PUTS, SUDS, and CGI-I. As well, there were significant correlations between plasma levels of THC and its metabolites, but not CBD, with MRVTRS, PUTS, and SUDS measures. There were more AEs from all cannabis products relative to placebo, and more AEs from THC 10% versus other cannabis products, particularly cognitive and psychomotor effects. Most participants correctly identified whether they had received cannabis or placebo. Conclusions: In this pilot randomized controlled trial of cannabis for tics in TS, there was no statistically significant difference on the MRVTRS for any of the cannabis products, although the THC 10% product was significantly better than placebo on the secondary outcome measures. Also, THC and metabolite plasma levels correlated with improvement on all measures. The THC 10% product resulted in the most AEs. ClinicalTrials.gov ID: NCT03247244.

Platelet preservation in cardiac surgery using minimally invasive extracorporeal circulation versus optimized cardiopulmonary bypass.

BACKGROUND: Minimally invasive extracorporeal circulation (MiECC) is employed as a strategy to attenuate the physiologic disturbance caused by cardiopulmonary bypass. The aim of this study was to compare the coagulation profile of MiECC to an optimized conventional extracorporeal circuit (OpECC) with regards to platelet function, rotational thromboelastometry and blood product usage. METHODS: A retrospective analysis of coronary artery bypass grafting operations using either MiECC or OpECC was performed at a single institution. RESULTS: A total of 112 patients were included, with 61 receiving MiECC and 51 OpECC patients. OpECC patients had a significantly larger BSA (1.95+/- 0.22m2 vs 1.88 +/- 0.18m2, p = 0.034), than those who received MiECC. No difference between groups was observed regarding red blood cell, plasma, and platelet transfusions. Functional platelet count during the warming phase of cardiopulmonary bypass was found to be higher in the MiECC group ((136 (102-171) x109/L vs 109 (94-136) x109/L), p = 0.027), as were functional platelets as a percent of total platelet count ((86 (77-91)% vs 76 (63-82)%), p = 0.003). There were no significant differences between other outcomes such as operative mortality, incidence of stroke, and intensive care unit length of stay. CONCLUSION: While we did not see a difference in blood transfusions, MiECC resulted in a statistically significant advantage over OpECC with regards to preservation of functional platelets.

The PROMIZING trial enrollment algorithm for early identification of patients ready for unassisted breathing.

BACKGROUND: Liberating patients from mechanical ventilation (MV) requires a systematic approach. In the context of a clinical trial, we developed a simple algorithm to identify patients who tolerate assisted ventilation but still require ongoing MV to be randomized. We report on the use of this algorithm to screen potential trial participants for enrollment and subsequent randomization in the Proportional Assist Ventilation for Minimizing the Duration of MV (PROMIZING) study. METHODS: The algorithm included five steps: enrollment criteria, pressure support ventilation (PSV) tolerance trial, weaning criteria, continuous positive airway pressure (CPAP) tolerance trial (0 cmH2O during 2 min) and spontaneous breathing trial (SBT): on fraction of inspired oxygen (FiO2) 40% for 30-120 min. Patients who failed the weaning criteria, CPAP Zero trial, or SBT were randomized. We describe the characteristics of patients who were initially enrolled, but passed all steps in the algorithm and consequently were not randomized. RESULTS: Among the 374 enrolled patients, 93 (25%) patients passed all five steps. At time of enrollment, most patients were on PSV (87%) with a mean (± standard deviation) FiO2 of 34 (± 6) %, PSV of 8.7 (± 2.9) cmH2O, and positive end-expiratory pressure of 6.1 (± 1.6) cmH2O. Minute ventilation was 9.0 (± 3.1) L/min with a respiratory rate of 17.4 (± 4.4) breaths/min. Patients were liberated from MV with a median [interquartile range] delay between initial screening and extubation of 5 [1-49] hours. Only 7 (8%) patients required reintubation. CONCLUSION: The trial algorithm permitted identification of 93 (25%) patients who were ready to extubate, while their clinicians predicted a duration of ventilation higher than 24 h.

Improved Outcomes Following the Ross Procedure Compared With Bioprosthetic Aortic Valve Replacement.

BACKGROUND: The ideal aortic valve substitute for young and middle-aged adults remains elusive. OBJECTIVES: This study sought to compare the long-term outcomes of patients undergoing the Ross procedure and those receiving bioprosthetic aortic valve replacements (AVRs). METHODS: Consecutive patients aged 16-60 years who underwent a Ross procedure or surgical bioprosthetic AVR at the Toronto General Hospital between 1990 and 2014 were identified. Propensity score matching was used to account for differences in baseline characteristics. The primary outcome was all-cause mortality. Secondary outcomes included valve reintervention, valve deterioration, endocarditis, thromboembolic events, and permanent pacemaker implantation. RESULTS: Propensity score matching yielded 108 pairs of patients. The median age was 41 years (IQR: 34-47 years). Baseline characteristics were similar between the matched groups. There was no operative mortality in either group. Mean follow-up was 14.5 ± 7.2 years. All-cause mortality was lower following the Ross procedure (HR: 0.35; 95% CI: 0.14-0.90; P = 0.028). Using death as a competing risk, the Ross procedure was associated with lower rates of reintervention (HR: 0.21; 95% CI: 0.10-0.41; P < 0.001), valve deterioration (HR: 0.25; 95% CI: 0.14-0.45; P < 0.001), thromboembolic events (HR: 0.15; 95% CI: 0.05-0.50; P = 0.002), and permanent pacemaker implantation (HR: 0.22; 95% CI: 0.07-0.64; P = 0.006). CONCLUSIONS: In this propensity-matched study, the Ross procedure was associated with better long-term survival and freedom from adverse valve-related events compared with bioprosthetic AVR. In specialized centers with sufficient expertise, the Ross procedure should be considered the primary option for young and middle-aged adults undergoing AVR.

Trajectory of Left Ventricular Remodeling in Children With Valvar Aortic Stenosis Following Balloon Aortic Valvuloplasty.

BACKGROUND: Aortic valve stenosis is the most common type of congenital left ventricular (LV) outflow tract obstruction. Balloon aortic valvuloplasty (BAV) has become the first-line treatment pathway in many centers. Our aim was to assess the trajectory of LV remodeling following BAV in children and its relationship to residual aortic stenosis (AS) and insufficiency (AI). METHODS: Children <18 years of age who underwent BAV for isolated aortic stenosis from 2004 to 2012 were eligible for inclusion. Those with AI before BAV, other complex congenital heart lesions, or <2 accessible follow-up echocardiograms were excluded. Baseline and serial echocardiographic data pertaining to aortic valve and LV size and function were retrospectively collected through December 2017 or the first reintervention. Longitudinal data was assessed using per-patient time profiles with superimposed trend lines using locally estimated scatterplot smoothing. Associations with reintervention or death were also evaluated. RESULTS: Among the 98 enrolled children, the median (interquartile range) age at BAV was 2.8 months (0.2-75). The median (interquartile range) follow-up was 6.8 years (1.9-9.0). Children with predominantly residual AI (n=11) demonstrated progressive increases in their LV end-diastolic dimension Z score within the first 3 years after the BAV, followed by a plateau (P<0.001). Their mean LV circumferential and longitudinal strain values remained within the normal range but lower than in the non-AI group (P<0.001 and P=0.001, respectively). Children with predominantly residual aortic stenosis (n=44) had no changes in LV dimensions but had a rapid early increase in mean LV circumferential and longitudinal strain. The cumulative proportion (95% CI) of reintervention at 5 years following BAV was 33.7% (23.6%-42.4%). CONCLUSIONS: Our study demonstrates that LV remodeling occurs mainly during the first 3 years in children with predominantly residual AI after BAV, with no subsequent significant functional changes over the medium term. These data improve our understanding of expected patient trajectories and thus may inform decisions on the timing of reintervention.

Outcomes of combined aortic and mitral valve replacement with reconstruction of the fibrous skeleton of the heart.

OBJECTIVES: The objectives of this study were to examine operative and long-term results of combined aortic and mitral valve replacement when reconstruction of the fibrous skeleton of the heart is needed because of calcification, abscess, previous operations, or patient-prosthesis mismatch. METHODS: From 1985 to 2020, 182 consecutive patients underwent combined aortic and mitral valve replacement with reconstruction of the intervalvular fibrous skeleton in all cases and also the posterior mitral annulus in 63 patients. Bovine pericardium or Dacron grafts were used for the reconstructions. Median follow-up was 7.5 (interquartile range, 2.1-12.6) years and 98% complete. RESULTS: Patient mean age was 62 years; 69% had 1 or more previous valve operations, and 92% were functional class III or IV. The indications for reconstruction were extensive calcification of the fibrous skeleton in 34%, abscess in 13%, tissue damage secondary to previous operations in 39%, and patient-prosthesis mismatch of the mitral valve in 13%. Bovine pericardium was used in two-thirds of cases and Dacron grafts in one-third. Operative mortality was 13.2% and postoperative complications were common. Survival at 1, 10, and 20 years was 81.8%, 51.1%, and 23.7%, respectively. Fourteen patients required reoperation and 3 transcatheter interventions. The cumulative probability of reinterventions at 1, 10, and 20 years were 3.3%, 5.8%, and 9.1%, respectively. Most patients experienced symptomatic improvement postoperatively. CONCLUSIONS: Reconstructions of the fibrous skeleton of the heart are associated with high operative mortality but the long-term results are satisfactory because most patients would not have survived without surgical intervention.

Early outcomes of the Bentall procedure after previous cardiac surgery.

OBJECTIVES: We sought to evaluate the early outcomes of patients undergoing a Bentall procedure after previous cardiac surgery. METHODS: From 1990 to 2014, 473 patients underwent a Bentall procedure after previous cardiac surgery with a composite valve graft at a single institution: composite valve graft with a mechanical prosthesis (n = 256) or composite valve graft with a bioprosthesis (n = 217). Patients were excluded if their index operation was less than 30 days before the reoperation. The primary outcome was 30-day mortality. The secondary outcome was a composite of major morbidity and operative mortality: stroke, renal failure, prolonged mechanical ventilation, deep sternal infection, or reoperation during the same admission. Multivariable logistic regression was used to identify risk factors associated with the primary and secondary outcomes of interest. RESULTS: Median age was 57 (interquartile range, 44-67) years, and 349 patients (74%) were male. Median time between index surgery and reoperation was 13 (interquartile range, 8-21) years. A total of 178 patients (38%) underwent urgent or emergency intervention, 61 patients (13%) had active endocarditis/abscess, 87 patients (19%) had left ventricular ejection fraction less than 40%, and 262 patients (55%) had undergone more than 1 previous operation. Previous operations (not mutually exclusive) included coronary artery bypass grafting (n = 58, 12%), aortic valve/root replacement (n = 376, 80%) or repair (n = 36, 8%), and other surgical interventions (n = 245, 52%). Ninety-six patients (20%) had undergone coronary reimplantation during the previous operation, which consisted of a Bentall procedure in 81 patients, a Ross operation in 8 patients, a valve-sparing root replacement in 4 patients, and an arterial switch in 3 patients. At the time of the reoperative Bentall, both coronary arteries were reimplanted directly in 357 patients (77%), whereas 79 patients (17%) received at least 1 interposition graft. In 26 patients (5%), at least 1 of the native coronary arteries was oversewn and a vein graft bypass was performed. Thirty-day mortality occurred in 37 patients (7.8%), and 152 patients (32%) had major morbidity and operative mortality. On multivariable analysis, risk factors associated with increased 30-day mortality included older age and coronary reimplantation by a technique other than direct anastomosis. Indirect coronary reimplantation was also associated with a higher incidence of major morbidity and operative mortality, as were more than 1 previous cardiac operation and preoperative New York Heart Association functional class III/IV or greater. CONCLUSIONS: In the largest reported cohort of aortic root replacement after previous cardiac surgery, the reoperative Bentall procedure was associated with a significant operative risk. The need for complex coronary reimplantation techniques was an important factor associated with adverse perioperative events.

A progress report on reimplantation of the aortic valve.

OBJECTIVE: To examine the late outcomes of reimplantation of the aortic valve (RAV) in patients followed prospectively since surgery. METHODS: All 465 patients who had RAV from 1989 to 2018 were followed prospectively with periodic clinical and echocardiographic assessments. Mean follow-up was 10 ± 6 years and 98% complete. RESULTS: Patients' mean age was 47 ± 5.1 years, and 78% were men. The aortic root aneurysm was associated with Marfan syndrome in 164 patients, Loeys-Dietz syndrome in 13, bicuspid aortic valve (BAV) in 67, and type A aortic dissection in 33. Aortic insufficiency (AI) was greater than mild in 298 patients. Concomitant procedures were performed in 105 patients. There were 5 operative and 51 late deaths. At 20 years, 69.1% of patients were alive and free from aortic valve reoperation, and the cumulative probability of aortic valve reoperation with death as a competing risk was 6.0%, and the cumulative probability of developing moderate or severe AI was 10.2%. Only time per 1-year interval was associated with the development of postoperative AI by multivariable analysis (hazard ratio, 1.06; 95% confidence interval, >1.02-1.10; P = .006). Gradients across preserved BAV increased in 5 patients, and 1 required reoperation for aortic stenosis. Distal aortic dissections occurred in 22 patients, primarily in those with associated genetic syndromes. CONCLUSIONS: RAV provides excellent long-term results, but there is a progressive rate of AI over time, and patients with BAV may develop aortic stenosis. Patients with genetic syndromes have a risk of distal aortic dissections. Continued surveillance after RAV is necessary.

Comparison of Heart Transplantation Outcomes: Adult Congenital Heart Disease vs Matched Cardiac Patients in a Quaternary Reference Centre.

BACKGROUND: The number of transplantations performed for adult congenital heart disease (ACHD) patients is increasing. We sought to compare survival and post-transplantation complications, including graft failure, rejection, dialysis, and use of a right ventricular assist device, between ACHD and a cohort of dilated (DCM) and ischemic (ICM) cardiomyopathy patients matched by age and year of transplantation. METHODS: We retrospectively reviewed our single-institution heart transplantation database and selected all patients who had surgery from 1988 to 2017. In our primary analysis, we looked at survival and post-transplantation complications across cardiomyopathy groups. Our secondary analysis was matched to mitigate era effects as well as differences in age at transplant. RESULTS: We analyzed a cohort consisting of 303 heart transplant patients with cardiomyopathy due to either 1) ACHD (n = 38), 2) ICM (n = 110), or 3) DCM (n = 155). Kaplan-Meier analysis and a multivariable Cox proportional hazard regression model were used for all-cause mortality, and cause-specific hazard regression for cause-specific mortality and morbidity. There was no statistically significant survival difference across groups. The 1-year survival was 68.5% for ACHD, 85.4% for ICM, and 85.5% for DCM. In multivariable analysis, ICM and DCM patients showed a 66% lower risk of death relative to the ACHD group. The matched analysis showed no significant difference in survival across groups. CONCLUSIONS: ACHD patients represent a growing high-risk patient cohort referred for transplantation. To improve survival outcomes we need to address modifiable risk factors.

A Validated Model for Sudden Cardiac Death Risk Prediction in Pediatric Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy is the leading cause of sudden cardiac death (SCD) in children and young adults. Our objective was to develop and validate a SCD risk prediction model in pediatric hypertrophic cardiomyopathy to guide SCD prevention strategies. METHODS: In an international multicenter observational cohort study, phenotype-positive patients with isolated hypertrophic cardiomyopathy <18 years of age at diagnosis were eligible. The primary outcome variable was the time from diagnosis to a composite of SCD events at 5-year follow-up: SCD, resuscitated sudden cardiac arrest, and aborted SCD, that is, appropriate shock following primary prevention implantable cardioverter defibrillators. Competing risk models with cause-specific hazard regression were used to identify and quantify clinical and genetic factors associated with SCD. The cause-specific regression model was implemented using boosting, and tuned with 10 repeated 4-fold cross-validations. The final model was fitted using all data with the tuned hyperparameter value that maximizes the c-statistic, and its performance was characterized by using the c-statistic for competing risk models. The final model was validated in an independent external cohort (SHaRe [Sarcomeric Human Cardiomyopathy Registry], n=285). RESULTS: Overall, 572 patients met eligibility criteria with 2855 patient-years of follow-up. The 5-year cumulative proportion of SCD events was 9.1% (14 SCD, 25 resuscitated sudden cardiac arrests, and 14 aborted SCD). Risk predictors included age at diagnosis, documented nonsustained ventricular tachycardia, unexplained syncope, septal diameter z-score, left ventricular posterior wall diameter z score, left atrial diameter z score, peak left ventricular outflow tract gradient, and presence of a pathogenic variant. Unlike in adults, left ventricular outflow tract gradient had an inverse association, and family history of SCD had no association with SCD. Clinical and clinical/genetic models were developed to predict 5-year freedom from SCD. Both models adequately discriminated between patients with and without SCD events with a c-statistic of 0.75 and 0.76, respectively, and demonstrated good agreement between predicted and observed events in the primary and validation cohorts (validation c-statistic 0.71 and 0.72, respectively). CONCLUSION: Our study provides a validated SCD risk prediction model with >70% prediction accuracy and incorporates risk factors that are unique to pediatric hypertrophic cardiomyopathy. An individualized risk prediction model has the potential to improve the application of clinical practice guidelines and shared decision making for implantable cardioverter defibrillator insertion. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT0403679.

Left Ventricular Size and Outcomes in Patients With Left Ventricular Ejection Fraction Less Than 20.

BACKGROUND: The interactive relationship between left ventricular (LV) ejection fraction (LVEF) and LV size in predicting perioperative outcomes after cardiac surgery has not been clarified. METHODS: This study reviewed all patients who underwent cardiac surgery between 2010 and 2016 with either preserved LVEF (>60%; n = 5685) or severely reduced LVEF (<20%; n = 143). LV size was categorized by using either LV end-diastolic or end-systolic diameter or a qualitative assessment, as follows: normal, smaller than 4 cm; mildly enlarged, 4.1 to 5.4 cm moderately enlarged, 5.5 to 6.5 cm; and severely enlarged, larger than 6.5 cm. Using propensity-score analysis, we matched patients with LVEF less than 20% (n = 143) in a 3:1 ratio with patients with LVEF greater than 60% (n = 429). RESULTS: There were significant differences in mortality, major morbidity, and operative mortality and prolonged length of stay between patients with LVEF less than 20% and LVEF greater than 60%. In patients with LVEF less than 20%, there were no significant differences in outcomes between those with an LV size of 5.4 cm or smaller and an LV size of 5.5 cm or larger. In patients undergoing isolated coronary artery bypass grafting (CABG), LV size predicted mortality, major morbidity, and operative mortality (odds ratio, 5.5 [95% confidence interval, 2.0 to 15.7]; P < .001) and prolonged length of stay (odds ratio, 3.4 [95% confidence interval, 1.2 to 10.3]; P = .026), respectively. CONCLUSIONS: LVEF is more important than LV size in predicting outcomes after cardiac surgery. However, in patients undergoing isolated CABG, LV size has an interactive effect with LVEF and can potentially aid the decision-making process. Risk adjustment models using only LVEF may be inaccurate, particularly with respect to isolated CABG procedures.

Machine Learning Identifies Clinical and Genetic Factors Associated With Anthracycline Cardiotoxicity in Pediatric Cancer Survivors.

BACKGROUND: Despite known clinical risk factors, predicting anthracycline cardiotoxicity remains challenging. OBJECTIVES: This study sought to develop a clinical and genetic risk prediction model for anthracycline cardiotoxicity in childhood cancer survivors. METHODS: We performed exome sequencing in 289 childhood cancer survivors at least 3 years from anthracycline exposure. In a nested case-control design, 183 case patients with reduced left ventricular ejection fraction despite low-dose doxorubicin (≤250 mg/m2), and 106 control patients with preserved left ventricular ejection fraction despite doxorubicin >250 mg/m2 were selected as extreme phenotypes. Rare/low-frequency variants were collapsed to identify genes differentially enriched for variants between case patients and control patients. The expression levels of 5 top-ranked genes were evaluated in human induced pluripotent stem cell-derived cardiomyocytes, and variant enrichment was confirmed in a replication cohort. Using random forest, a risk prediction model that included genetic and clinical predictors was developed. RESULTS: Thirty-one genes were differentially enriched for variants between case patients and control patients (p < 0.001). Only 42.6% case patients harbored a variant in these genes compared to 89.6% control patients (odds ratio: 0.09; 95% confidence interval: 0.04 to 0.17; p = 3.98 × 10-15). A risk prediction model for cardiotoxicity that included clinical and genetic factors had a higher prediction accuracy and lower misclassification rate compared to the clinical-only model. In vitro inhibition of gene-associated pathways (PI3KR2, ZNF827) provided protection from cardiotoxicity in cardiomyocytes. CONCLUSIONS: Our study identified variants in cardiac injury pathway genes that protect against cardiotoxicity and informed the development of a prediction model for delayed anthracycline cardiotoxicity, and it also provided new targets in autophagy genes for the development of cardio-protective drugs. (Preventing Cardiac Sequelae in Pediatric Cancer Survivors [PCS2]; NCT01805778).