Citations

Introduction: Machine learning models (MLM) hold promise for improved risk stratification and to guide personalized care. Hypothesis: MLM would outperform conventional statistical (CS) methods and existing iScore for predicting composite of recurrent stroke or death at 90 days and 3 years after ischemic stroke (IS) Methods: We built 3 MLM (random forest [RF], support vector machine [SVM], and extreme gradient boosting decision trees [XGBoost]) and two CS models (logistic regression [LR] and least absolute shrinkage and selection operator [LASSO]) to predict composite outcome at 90 days or 3 years after AIS in a retrospective cohort of 721 adults. The performance of these models was evaluated against the existing iScore to predict outcomes after AIS. Results: Composite outcome occurred in11% at 90 days and in 34% at 3 years after AIS. Performance metrics for predicting 90-day and 3-year composite outcome were comparable across all study models except SM LR. Measurements for the area under the receiver operating characteristic curve for each model in validation set was as follow. 1) 90-day prediction: 0.779 for RF, 0.771 for SVM, 0.772 for EXBOOST, 0.613 for LR, 0.811 for LASSO, and 0.720 for iScore; 2) 3-year prediction: 0.743 for RF, 0.777 for SVM, and 0.773 for EXBOOST, 0.724 for LR, 0.790 for LASSO, and 0.710 for iScore. Conclusions: ML-based algorithms did not improve prediction of composite outcome at 90 days or 3 years after AIS compared with CS-based LASSO. iScore was successfully validated and compared broadening its generalizability and applicability.

Introduction: Studies on leadless pacemakers (LP) are very limited and they often fail to reflect real population outcomes. Hypothesis: We sought to evaluate the effect of leadless pacemaker implantation on the echocardiographic parameters including ventricular function and valvular competence. Methods: A retrospective review including 162 patients (81 Micra Leadless pacemaker implant and 81 dual-chamber transvenous pacemakers) from 3 centers were included. Follow-up clinical, echocardiographic, and pacing characteristics were obtained over a median of 14+/-2 months. Results: baseline demographics and clinical characteristics were comparable between the 2 groups including age (78.6+/-9.9, Range 35-95) and gender (49 males, 69.5%). Compared to conventional pacemakers, LP patients had worsening tricuspid regurgitation noted on follow-up echo in 59.3% of patients compared to baseline(P<0.001). This difference was independent of the RV pacing percentage and device location. In addition, LP implantation resulted in a reduction of RV function (P=0.003) and left ventricular ejection fraction (P=0.03). The RV Pacing burden in LP patient patients was not associated with a change in LVEF during the follow-up period (95% CI -0.24, 0.20, p = 0.846). Conclusions: LP therapy is associated with worsening tricuspid valve regurgitation and biventricular dysfunction over a mean 1 year of follow-up. Additional prospective randomized studies are warranted to further evaluate these findings.

Background: Long QT syndrome (LQTS) stems from cardiac action potential duration (APD) prolonging pathogenic variants in KCNQ1 (LQT1), KCNH2 (LQT2), or SCN5A (LQT3). Sodium/glucose co-transporter 2 inhibitor (SGLT2i), a class of drugs used to treat type II diabetes and all forms of heart failure, reduces cardiac late sodium channel current. Objective: To test the ability of three commercially available SGLT2i to reduce APD in patient-specific induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) models of LQT1, LQT2, and LQT3. Method: Patient-specific iPSC-CMs and a CRISPR/Cas9 gene-edited variant corrected, isogenic control (IC) iPSC-CMs were generated. The variant-corrected IC was used to determine the curative APD in order to establish the degree of APD attenuation. The SCN5A-P1332L (LQT3) and IC iPSC-CMs were tested with 10 μM of either canagliflozin (CANA), dapagliflozin (DAPA), or empagliflozin (EMPA). An ATXII (5μM)-induced APD prolongation iPSC-CM model, mimicking drug-induced LQT3, was also treated. The APD was measured 30 minutes, 1 hour, and 2 hours after treatment using local extracellular action potential recordings on multielectrode array. The efficacy of these SGLT2i were also tested in KCNQ1-V254M (LQT1) and KCNH2-G604S (LQT2) iPSC-CMs. Results: The APD90 was prolonged in SCN5A-P1332L iPSC-CMs compared to its IC (469 ± 4 ms vs 305 ± 2 ms, p<0.0001). While 10 μM of SGLT2i had no APD shortening effect on the KCNQ1-V254M or KCNH2-G604S iPSC-CMs, all three SGLT2i compounds shortened the APD90 of the SCN5A-P1332L iPSC-CMs after 1 hour of treatment from 463±5 ms to 432±6 ms (EMPA, 18.8% attenuation, p=0.0002), 459±8 ms to 430±5 ms (CANA, 17.5%, p=0.004), and 453±6 ms to 434±4 ms (DAPA, 11.4%, p=0.01). Additionally, IC iPSC-CMs treated with 5 μM of ATXII induced significant APD prolongation from 318±9 ms to 379±12 ms (p=0.0003) after 30 min incubation. However, co-incubation of ATXII and SGLT2i abolished the APD prolonging effect of ATXII. Conclusions: Therapeutically inhibiting SGLT2 effectively shortens the cardiomyocyte APD in human heart cell models of the LQT3, but not LQT1 or LQT2. This pre-clinical data compels further assessment of SGLT2i as a novel therapy for patients with congenital LQT3.

Introduction: Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) is associated with increased risk of periprocedural complications. Estimating the risk of complications facilitates risk-benefit assessment and procedural planning. Methods: We analyzed the Prospective Global Registry for the Study of Chronic Total Occlusion Intervention (PROGRESS-CTO, NCT02061436) and created a risk score for in-hospital all-cause mortality. Logistic regression prediction modeling was used to identify independently associated variables and the model was internally validated with bootstrapping. Results: Of the 10,480 CTO PCI cases performed between 2012-2022 at 40 US and non-US centers, in-hospital mortality occurred in 47 (0.45%). The final prediction model identified 4 independent predictors of mortality: Age ≥65 years, Odds Ratio [OR]: 2.83 (95% confidence interval [CI], 1.30-6.16), 1-point; Left ventricular ejection fraction ≤45%, OR: 2.13 (95% CI, 1.14-3.98), 1-point; Moderate-severe calcification, OR: 2.45 (95% CI, 1.18-5.08), 1-point; and Antegrade dissection re-entry, OR: 2.81 (95% CI, 1.06-7.43), 1-point; or Retrograde strategy, OR: 3.51 (95% CI, 1.67-7.37), 1-point; with a bootstrap corrected c-statistics of 0.71 (95% confidence interval: 0.63-0.81). The calculated risk percentages for mortality based on the PROGRESS-CTO mortality score ranged from 0.05-2.42% for mortality, and 63% of patients in the PROGRESS-CTO cohort had PROGRESS-CTO mortality score of 1 or 2, corresponding to a mortality risk of 0.1-0.5% (Figure 1). Conclusions: The PROGRESS-CTO in-hospital mortality risk score can facilitate risk-benefit assessment and procedural planning in patients undergoing CTO PCI.

Introduction: It has been previously demonstrated that cardiomyopathy predisposing common genetic variation in SMARCB1 is associated with interstitial myocardial fibrosis (MF) as determined by cardiac MRI (CMR) linking the development of cardiomyopathy with MF. SMARCB1 is known to be a tumor suppressor, but it’s role in the pathophysiology of MF and fibroblast physiology has not been functionally validated. Hypothesis: SMARCB1 plays an important role in regulating human cardiac fibroblast (HCF) differentiation/activation and collagen deposition, which are the critical steps in the development of MF. Methods: Cultured HCFs were treated with TGF-β1 (10ng/ml) for 48hrs to transdifferentiate into myofibroblasts, which are characterized by increased expression of α-smooth muscle actin (α-SMA, ACTA2) and collagen I (COL1A1). HCFs were transfected by siRNA using Lipofectamine™ RNAiMAX Transfection Reagent to knock-down (KD) the expression of SMARCB1 . Total RNA and protein were extracted from cell lysate followed by qPCR and Western blot (WB) to quantify the expression level of SMARCB1, ACTA2 and COL1A1. Triplicate experiments were performed using biologically independent samples. For statistical analysis, a paired two-tail t-test was used. Results: HCFs treatment with TGF-β1, resulted in a significant decrease in expression of SMARCB1 (p=0.031) with accompanying significant increase in expression of ACTA2 (p=0.025) and COL1A1 (p=0.0015) as compared to control by qPCR and WB. SMARCB1 KD resulted in a further significant increase in expression of ACTA2 (p=0.018) and COL1A1 (p=0.028) as compared to non-target siRNA control group at both the transcript and protein level. Conclusion: We demonstrate for the first time that a gene associated with the development of cardiomyopathy SMARCB1 mediates TGF-β1 induced cardiac fibrosis. These findings suggest SMARCB1 as a potential therapeutic target to attenuate MF in cardiomyopathy.

Introduction: Breathing efficiency (V E /VCO 2 slope or nadir) predicts mortality in heart failure (HF). The usual pattern of V E /VCO 2 vs. exercise intensity is a characteristic “shallow bowl” configuration allowing estimate of a V E vs. VCO 2 slope both in normal controls (C) and HF patients. Slope or nadir in HF is generally > 33 vs. 25-30 in C. This pattern of V E /VCO 2 may not be true for other CV diseases. Objective: Compare V E /VCO 2 versus exercise time curves in patients with history of chronic thromboembolic pulmonary hypertension type 4 (PHT4) to HF and C referred for dyspnea on exertion. Methods: We identified 40 consecutive cases of PHT4 versus 40 HF and 40 C over the same age range retrospectively selected from our cardiopulmonary exercise test (CPX) database. V E /VCO 2 was plotted against exercise time (minutes of exercise ≈ METs), and groups were compared statistically for V E /VCO 2 and peak VO 2 by ANOVA followed with Tukey test, with significance set at P < .05. Results: Figure shows higher V E /VCO 2 in PHT4 vs. HF and C with a different pattern vs. exercise intensity. In severe cases (example shown) V E /VCO 2 may increase continuously without plateau reaching peak values > 80. There was statistically significant difference between peak VO 2 between C group vs HF and PHT4, but not among HF and PHT4, although V E /VCO 2 was significant different among the three groups. Age and sex was not different among them. Conclusion: V E /VCO 2 was elevated in PHT4 compared to HF and C. We interpret continuously increasing V E /VCO 2 as a marker of progressively worsening ventilation: perfusion mismatch. Interpretation of V E /VCO 2 in PHT4 cannot be based simply on nadir or slope as in HF, but a plot of the data should be visually examined to gain full understanding of the ventilatory abnormality.

Introduction: The Safety and efficacy of DOACs is unknown in patients with left ventricular thrombus as these patients were excluded from DOAC trials. Hypothesis: The safety and efficacy of DOACs is comparable to vitamin K antagonists Methods: Databases including Medline, Scopus and Cochrane Central Registration of Controlled Trials were queried from inception to March 30 th 2022. Studies reporting efficacy and safety outcomes were selected for the analysis. Results: We included 11 studies comprising 1920 patients with left ventricular thrombus. The mean age in the DOAC group was 57.5 years (SD 12.8) and 58.6 years (SD 13.0) in the VKA group; 26.8% were females. Pooled results showed no difference in mortality (RR, 0.64 [95% CI, 0.16-2.52]) embolic events (RR, 0.94 [95% CI, 0.59-1.50]) or major bleeding (RR, 0.95[95% CI, 0.66-1.36]) in the DOACs compared to VKA groups. Event rate for DOAC group compared to VKA group was 12.7 vs 17.5 per 100 patient-years (mean follow up of 4.0 months) for mortality, 19.5 vs 26.5 per 100 patient-years (mean follow up of 8.9 months) for embolic events and 8.0 vs 10.0 per 100 patient-years (mean follow up of 9.5 months) for major bleeding. Conclusions: These data, from observational and randomized studies, demonstrate promising safety and efficacy of DOACs for treatment of left ventricular thrombus. Elevated embolic and mortality rates regardless of anticoagulant choice emphasize the need for further research to improve outcomes for patients with this complication.

Introduction: Patients with sickle cell disease are at risk for many types of cardiac complications. We present a case of endocarditis of the superior vena cava (SVC) in a 22-year-old male with sickle cell disease. Case study: A 22 year old male with sickle cell disease presented to the hospital with 3 days of fever, night sweats, generalized body pains, vomiting and poor oral intake. 6 weeks ago, he had been admitted to an outside hospital for Methicillin related Staphylococcus aureus (MRSA) bacteremia. At that time an implanted venous access port in the patient’s chest was removed and 4 weeks of intravenous(iv) vancomycin were administered. He was admitted to the hospital for sepsis. Blood cultures were drawn which were positive for MRSA. A transesophageal echocardiogram revealed a large mobile vegetation in the SVC ( Fig. 1) The proximal end of the vegetation extended beyond the echocardiographic field of view, so a CT scan of the chest with contrast was performed (Fig. 2) This showed intraluminal filling defects in the distal SVC along with pulmonary emboli in the lower lobes of the lungs bilaterally. His antibiotics were changed to iv daptomycin and ceftaroline but he remained persistently bacteremic for 14 days. Therefore, removal of the SVC vegetation/thrombus was performed using AngioVac venous drainage cannula system. This was followed by resolution of bacteremia, and he was discharged from the hospital 9 days later. Conclusion: Echocardiographic evaluation of endocarditis should involve a comprehensive evaluation of all cardiac structures and not be limited to valves only. AngioVac venous drainage cannula system can be used to remove infected vegetations/thrombus.

Introduction: Ebstein’s anomaly (EA) is a rare congenital anomaly of the tricuspid valve associated with heart failure and arrhythmias. Currently available imaging modalities like transthoracic echocardiography, cardiac magnetic resonance imaging (MRI), or computerized tomography (CT) are not viable for screening large asymptomatic populations. Hypothesis: A deep learning algorithm, implemented using a convolutional neural network (CNN) applied to the standard 12-lead ECG can be used as an accurate screening tool for EA in children and adults. Method: We identified 1,154 EA patients and 21,430 age- and sex-matched controls (1:20 ratio) between 1987 - 2020. A CNN was trained, validated and tested using digital 12-lead ECGs in 70%, 10% and 20% of the cohort respectively, divided by random shuffling. Results: The mean age was 26.68±19.23 years (41.8% aged < 18 years, 56.41% female) for the EA cohort and 28.36±18.65 years (37.2% aged <18 years, 55.67% female) for the control cohort. Following training and validation the area under the curve (AUC) for detecting EA in the testing cohort was 0.976 (95% CI 0.962 - 0.989) with prediction accuracy of 0.959. In subgroup analysis, the AUC was comparable in males (0.970, 95% CI 0.946-0.995) and females (0.979, 95% CI 0.964-0.994), those <18 (0.980, 95% CI 0.958-1.000) and ≥18 years old (0.972, 95% CI 0.954-0.989), as well as in those with right bundle branch block (RBBB) (0.969, 95% CI 0.950-0.989) and without RBBB (0.950, 95% CI 0.922-0.978) on ECG. Conclusion: Artificial intelligence enhanced ECG based detection of EA is possible with high diagnostic accuracy. Following further refinement and external validation, this algorithm can facilitate early detection of EA using ECGs, a widely available and inexpensive tool. Figure: Receiver operating characteristic (ROC) curve for the performance of the artificial intelligence CNN in detecting EA in the test cohort stratified by (A) age (< 18 and ≥ 18 years) and sex and (B) presence of RBBB.

Introduction: The role of hypertriglyceridemia (HTG) in cardiovascular disease (CVD) remains controversial, especially in persons with well-controlled low-density lipoprotein cholesterol (LDL-C). Hypothesis: We aimed to evaluate the association between triglyceride (TG) levels and CVD mortality according to LDL-C and age in a general population. Methods: From the Korean National Health Insurance Service database, 15,672,028 participants aged 18-99 who underwent routine health examinations were followed up for CVD mortality. Hazard ratios (HRs) for CVD mortality were calculated using Cox models after adjusting for various confounders. Results: During a mean 8.8 years of follow-up, 105,174 individuals died from CVD. There was a clear log-linear association between TG and overall CVD mortality down to 50 mg/dL. Each two-fold increase in TG was associated with 1.10-fold (overall CVD), 1.22-fold (ischemic heart disease [IHD]), 1.24-fold (acute myocardial infarction [AMI]), and 1.10-fold (ischemic stroke) higher CVD mortality. Hemorrhagic stroke and heart failure were not associated with TG levels. The impact of HTG on CVD weakened but remained present in persons with LDL-C <100 mg/dL, in whom each two-fold higher TG was associated with 1.05-fold (overall CVD), 1.12-fold (IHD), 1.15-fold (AMI), and 1.05-fold (ischemic stroke) higher CVD mortality. The younger population (18 to 44 years) had stronger associations between TG levels and mortality from overall CVD, IHD, and AMI than the older population. Conclusions: HTG independently increases CVD mortality. There are residual risks of HTG in both young and older individuals with a low level of LDL-C. HTG management might be beneficial in individuals with well-controlled LDL-C.