Noseworthy, Peter A.

Abstract The objective of this study is to describe application of the Observational Medical Outcomes Partnership (OMOP) common data model (CDM) to support medical device real-world evaluation in a National Evaluation System for health Technology Coordinating Center (NESTcc) Test-Case involving 2 healthcare systems, Mercy Health and Mayo Clinic. CDM implementation was coordinated across 2 healthcare systems with multiple hospitals to aggregate both medical device data from supply chain databases and patient outcomes and covariates from electronic health record data. Several data quality assurance (QA) analyses were implemented on the OMOP CDM to validate the data extraction, transformation, and load (ETL) process. OMOP CDM-based data of relevant patient encounters were successfully established to support studies for FDA regulatory submissions. QA analyses verified that the data transformation was robust between data sources and OMOP CDM. Our efforts provided useful insights in real-world data integration using OMOP CDM for medical device evaluation coordinated across multiple healthcare systems.

Despite the global COVID-19 pandemic, during the past 2 years, there have been numerous advances in our understanding of arrhythmia mechanisms and diagnosis and in new therapies. We increased our understanding of risk factors and mechanisms of atrial arrhythmias, the prediction of atrial arrhythmias, response to treatment, and outcomes using machine learning and artificial intelligence. There have been new technologies and techniques for atrial fibrillation ablation, including pulsed field ablation. There have been new randomized trials in atrial fibrillation ablation, giving insight about rhythm control, and long-term outcomes. There have been advances in our understanding of treatment of inherited disorders such as catecholaminergic polymorphic ventricular tachycardia. We have gained new insights into the recurrence of ventricular arrhythmias in the setting of various conditions such as myocarditis and inherited cardiomyopathic disorders. Novel computational approaches may help predict occurrence of ventricular arrhythmias and localize arrhythmias to guide ablation. There are further advances in our understanding of noninvasive radiotherapy. We have increased our understanding of the role of His bundle pacing and left bundle branch area pacing to maintain synchronous ventricular activation. There have also been significant advances in the defibrillators, cardiac resynchronization therapy, remote monitoring, and infection prevention. There have been advances in our understanding of the pathways and mechanisms involved in atrial and ventricular arrhythmogenesis.

AbstractBackgroundAccurate automated wide QRS complex tachycardia (WCT) differentiation into ventricular tachycardia (VT) and supraventricular wide complex tachycardia (SWCT) can be accomplished using calculations derived from computerized electrocardiogram (ECG) data of paired WCT and baseline ECGs.ObjectiveDevelop and trial novel WCT differentiation approaches for patients with and without a corresponding baseline ECG.MethodsWe developed and trialed WCT differentiation models comprised of novel and previously described parameters derived from WCT and baseline ECG data. In Part 1, a derivation cohort was used to evaluate five different classification models: logistic regression (LR), artificial neural network (ANN), Random Forests [RF], support vector machine (SVM), and ensemble learning (EL). In Part 2, a separate validation cohort was used to prospectively evaluate the performance of two LR models using parameters generated from the WCT ECG alone (Solo Model) and paired WCT and baseline ECGs (Paired Model).ResultsOf the 421 patients of the derivation cohort (Part 1), a favorable area under the receiver operating characteristic curve (AUC) by all modeling subtypes: LR (0.96), ANN (0.96), RF (0.96), SVM (0.96), and EL (0.97). Of the 235 patients of the validation cohort (Part 2), the Solo Model and Paired Model achieved a favorable AUC for 103 patients with (Solo Model 0.87; Paired Model 0.95) and 132 patients without (Solo Model 0.84; Paired Model 0.95) a corroborating electrophysiology procedure or intracardiac device recording.ConclusionAccurate WCT differentiation may be accomplished using computerized data of (i) the WCT ECG alone and (ii) paired WCT and baseline ECGs.

Abstract Background Accurate automated wide QRS complex tachycardia (WCT) discrimination between ventricular tachycardia (VT) and supraventricular wide complex tachycardia (SWCT) can be accomplished using novel calculations derived from computerized electrocardiogram (ECG) data from paired WCT and baseline ECGs. Purpose Our aim was to develop and trial novel WCT discrimination approaches for WCT patients with and without a corresponding baseline ECG. Central to this analysis was the creation and use of a novel parameter (i.e., percent monophasic time-voltage area [PMonoTVA] [%]) that may be derived from computerized ECG measurements present on the WCT ECG alone. Methods In a two-part study, we derived and tested WCT differentiation models comprised of novel and previously established parameters formulated from computerized data of paired WCT and baseline ECGs. In Part 1, novel and established parameters generated from WCT and baseline ECG data were used to derive, validate, and compare five different binary classification models: (i) logistic regression [LR], (ii) artificial neural network [ANN], (iii) Random Forests [RF], (iv) support vector machine [SVM], and (v) ensemble learning (EL). In Part 2, two unique LR models were derived, validated, and compared using parameters generated from computerized data of the (i) WCT ECG alone (i.e., Solo Model) and (ii) paired WCT and baseline ECGs (i.e., Paired Model). Results In Part 1, among 103 patients with VT or SWCT diagnoses established from corroborating electrophysiology studies or intra-cardiac device recordings, favorable diagnostic performance was achieved by all modeling technique subtypes: LR (area under the receiver operating characteristic curve [AUC] 0.95), ANN (AUC 0.91), RF (AUC 0.97), SVM (AUC 0.98), and EL (AUC 0.97). In Part 2, among 235 patients with a VT or SWCT diagnosis established with (Gold Standard cohort) or without (Non-Gold Standard cohort) a corroborating electrophysiology procedure or intra-cardiac device recording, favorable diagnostic performance was achieved by the Solo Model (AUC 0.86) and Paired Model (AUC 0.95) (Table). Conclusion Accurate WCT discrimination may be accomplished using novel parameters derived from computerized data of the WCT ECG alone and paired WCT and baseline ECGs. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institute of Health

Abstract Background Pregnancy related cardiomyopathy is a significant cause of maternal morbidity and mortality globally. A presumed overlap between normal pregnancy-associated symptoms and clinical symptoms of cardiomyopathy contributes to delays in diagnosis and increased risk of maternal mortality. Purpose We sought to evaluate the association between patient-reported cardiovascular symptoms and the presence of cardiomyopathy among pregnant and postpartum patients. We hypothesize that individual cardiovascular symptoms are unrelated to the presence of cardiomyopathy. We also evaluated the use of a novel adaptation of a validated health status questionnaire in relation to cardiomyopathy. Methods We enrolled 48 pregnant (>13 weeks) and postpartum (up to 12 months) participants in a prospective study between October 2021 and February 2022. All study participants completed a baseline questionnaire, which included current cardiovascular symptoms, an assessment of health status using an adapted version of the Kansas City Cardiomyopathy Questionnaire (KCCQ-12), followed by a resting transthoracic echocardiogram on the same day. We defined cardiomyopathy as a left ventricular ejection fraction (LVEF) <50% based on 2-D echocardiography. Fisher's exact and Wilcoxon rank-sum tests were employed to evaluate the association between reported cardiovascular symptoms, the adapted KCCQ-12 (KCC-A) score, and cardiomyopathy. Results At the time of enrollment, 67% were pregnant and 33% postpartum. Forty-eight percent identified as White, 31% as Black, 10% as Asian, and 10% as other race. The median age was 31 years (Q1: 28, Q3: 35) and 6% had an LVEF <50%. We found no statistically significant association between four reported cardiovascular symptoms (shortness of breath, orthopnea, fast breathing, and episodes of “asthma” that did not improve with inhalers or other treatment) and cardiomyopathy or medial E/e' ratio. KCC-A scores were low in the study population overall (median 52; Q1:40, Q3: 61). We demonstrated a significantly lower KCC-A score among women with LVEF <50% (median 24; Q1: 15, Q3: 44) compared to women with LVEF ≥50% (median 54; Q1: 44, Q3: 61) p=0.02. Conclusions We showed no significant association between individual cardiovascular symptoms and cardiomyopathy in an obstetric population. However, we demonstrate for the first time that an adapted KCCQ-12 questionnaire for health status assessment could potentially identify women with a high-likelihood of cardiomyopathy during the peripartum period who may benefit from additional evaluation including echocardiography. Larger studies are needed to validate this finding. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): This study was funded by a research grant from the Miami Heart Research Institute, Florida Heart Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health

Abstract Background Atrial fibrillation (AF) is diagnosed in up to 50% of patients with heart failure. However, the prevalence of AF among patients with peripartum cardiomyopathy (PPCM) ranges from only 2–10%, with the lowest rates in Black women. An artificial intelligence enhanced electrocardiogram (AI-ECG) has previously been shown to be effective in detecting AF while in sinus rhythm, and for AF risk prediction in a population-based study. Purpose Our objective was to evaluate the use of an AI-ECG for AF risk stratification among women of reproductive age (18 to 49 years) with PPCM compared to other forms of cardiomyopathy. Methods We identified 59 reproductive age women with a diagnosis of PPCM between January 2007, and October 2018 and included matched controls in a 3:1 fashion. Matching was performed based on sex, age, race, and left ventricular ejection fraction. We excluded patients with a diagnosis of AF prior to cardiomyopathy diagnosis date. AI-ECG prediction probabilities were generated for ECGs performed within a 30-day window prior to the patient's first cardiomyopathy diagnosis date for the entire study cohort. Results A total of 236 patients were included in the final analysis (59 cases, 177 controls). Overall, the median age at cardiomyopathy diagnosis was 31.7 years (IQR: 18.5, 49.4), 76.3% were White, 8.5% were Black, and 15.3% represented other or unknown race. Over the period studied, 3.4% of women with PPCM developed AF compared to 5.6% of women with other cardiomyopathies. The frequency of positive AI-ECG predictions for AF was more common among women with other cardiomyopathies (40.7%) compared to women with PPCM (20.3%). The predicted odds ratio for AF development following a cardiomyopathy diagnosis based on AI-ECG results was 0.37 (95% CI: 0.18, 0.73) for PPCM compared to other cardiomyopathies (p=0.006). Conclusion We demonstrated that an AI-ECG model for AF prediction may play a potential role in arrhythmia risk stratification/prediction among young women with PPCM who have a demonstrable lower risk for AF compared to women with other cardiomyopathies. Mechanisms for lower AF risk among patients with PPCM remain unknown. Further studies evaluating mechanistic pathways will be essential. Funding Acknowledgement Type of funding sources: None.

Abstract Background Current approaches utilizing non-invasive methods to screen for cardiac allograft rejection (gene expression profiling and cell free DNA) have yet to be broadly integrated into heart transplant management and have shown limited discrimination (AUCs of 0.68 and 0.77, respectively). Changes in the electrocardiogram (ECG) have been reported at the time of severe cardiac rejection, including low voltages and conduction abnormalities. It remains unknown if subtle ECG changes correlating with cardiac allograft rejection can be detected earlier using machine learning methods. Purpose We sought to develop an artificial intelligence (AI) model to detect cardiac allograft rejection based on the 12 lead ECG. Methods We identified all patients who underwent a heart transplant at 3 hospital sites within a single health system from Jan 1998 through Apr 2021 and extracted digital 12-lead ECG data as well as endomyocardial biopsy pathology results from the electronic medical record. We partitioned our data into a training (80%), validation (10%), and test set (10%) based on a group stratification sampling. Each patient was present in only one set and each set had a positivity rate of 2.6% with 6,074/758/758 ECGs belonging to 1,146/140/141 unique patients in each set respectively. Cardiac allograft rejection was defined as moderate or severe acute cellular rejection based on International Society for Heart and Lung Transplantation (ISHLT) guidelines. A convolutional neural network, using the 12-lead ECG data as input, was trained with hyperparameter optimization for regularization, learning rate adjustments, and class weights. Model performance metrics were based on the test data and estimated using the final model architecture. Results 1,587 heart transplant recipients who had at least one endomyocardial biopsy were evaluated for inclusion. We limited our sample to ECGs performed within 30 days of the biopsy date (7,590 ECGs, representing 1,425 unique patients). Our study population had a median age of 55.8 years and 28.7% were female. The median number of ECG-biopsy pairs per patient was 5. The majority of endomyocardial biopsy results were classified as none or mild rejection (97.1%), and 2.9% had moderate/severe rejection. The ECG-based AI model detected cardiac allograft rejection with an area under the receiver operative curve (AUC) of 0.84 in the test set. The sensitivity, specificity, positive and negative predictive values were 95%, 52.6%. 5.2% and 99.7% respectively. Conclusions An AI-ECG model appears to outperform novel non-invasive laboratory tests (gene expression profiling and cell free DNA) for detecting cardiac allograft rejection and does not require a blood draw or the additional complexities surrounding sample processing. This model relies on a readily available and relatively inexpensive test, the ECG. In addition, AI predictions can be made available within a few minutes following ECG acquisition. Funding Acknowledgement Type of funding sources: Private hospital(s). Main funding source(s): Mayo Clinic

Abstract Objective To emulate the GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) trial using real world data before its publication. GRADE directly compared second line glucose lowering drugs for their ability to lower glycated hemoglobin A 1c (HbA 1c ). Design Observational study. Setting OptumLabs® Data Warehouse (OLDW), a nationwide claims database in the US, 25 January 2010 to 30 June 2019. Participants Adults with type 2 diabetes and HbA 1c 6.8-8.5% while using metformin monotherapy, identified according to the GRADE trial specifications, who also used glimepiride, liraglutide, sitagliptin, or insulin glargine. Main outcome measures The primary outcome was time to HbA 1c ≥7.0%. Secondary outcomes were time to HbA 1c >7.5%, incident microvascular complications, incident macrovascular complications, adverse events, all cause hospital admissions, and all cause mortality. Propensity scores were estimated using the gradient boosting machine method, and inverse propensity score weighting was used to emulate randomization of the treatment groups, which were then compared using Cox proportional hazards regression. Results 8252 people were identified (19.7% of adults starting the study drugs in OLDW) who met eligibility criteria for the GRADE trial (glimepiride arm=4318, liraglutide arm=690, sitagliptin arm=2993, glargine arm=251). The glargine arm was excluded from analyses owing to small sample size. Median times to HbA 1c ≥7.0% were 442 days (95% confidence interval 394 to 480 days) for glimepiride, 764 (741 to not calculable) days for liraglutide, and 427 (380 to 483) days for sitagliptin. Liraglutide was associated with lower risk of reaching HbA 1c ≥7.0% compared with glimepiride (hazard ratio 0.57, 95% confidence interval 0.43 to 0.75) and sitagliptin (0.55, 0.41 to 0.73). Results were consistent for the secondary outcome of time to HbA 1c >7.5%. No significant differences were observed among treatment groups for the remaining secondary outcomes. Conclusions In this emulation of the GRADE trial, liraglutide was statistically significantly more effective at maintaining glycemic control than glimepiride or sitagliptin when added to metformin monotherapy. Generating timely evidence on medical treatments using real world data as a complement to prospective trials is of value.

Background This study aimed to compare percutaneous left atrial appendage occlusion (LAAO) with non‐vitamin K antagonist oral anticoagulants among patients with atrial fibrillation. Methods and Results Using a US administrative database, 562 850 patients with atrial fibrillation were identified, among whom 8397 were treated with LAAO and 554 453 were treated with non‐vitamin K antagonist oral anticoagulants between March 13, 2015 and December 31, 2018. Propensity score overlap weighting was used to balance baseline characteristics. The primary outcome was a composite end point of ischemic stroke or systemic embolism, major bleeding, and all‐cause mortality. The mean age was 76.4±7.6 years; 280 097 (49.8%) were female. Mean follow‐up was 1.5±1.0 years. LAAO was associated with no significant difference in the risk of the primary composite end point (hazard ratio [HR], 0.93 [0.84–1.03]), or the secondary outcomes including ischemic stroke/systemic embolism (HR, 1.07 [0.81–1.41]), and intracranial bleeding (HR, 1.08 [0.72–1.61]). LAAO was associated with a higher risk of major bleeding (HR, 1.22 [1.05–1.42], P =0.01) and a lower risk of mortality (HR, 0.73 [0.64–0.84], P <0.001). The lower risk of mortality associated with LAAO was most pronounced in patients with a prior history of intracranial bleeding. Conclusions In comparison to non‐vitamin K antagonist oral anticoagulants, LAAO was associated with no significant difference in the risk of the composite outcome and a lower risk of mortality, which suggests LAAO might be a reasonable option in select patients with atrial fibrillation. The observation of higher bleeding risk associated with LAAO highlights the need to optimize postprocedural antithrombotic regimens as well as systematic efforts to assess and address bleeding predispositions.

AbstractAimsAn artificial intelligence algorithm detecting age from 12-lead electrocardiogram (ECG) has been suggested to reflect ‘physiological age’. An increased physiological age has been associated with a higher risk of cardiac mortality in the non-transplant population. We aimed to investigate the utility of this algorithm in patients who underwent heart transplantation (HTx).Methods and resultsA total of 540 patients were studied. The average ECG ages within 1 year before and after HTx were used to represent pre- and post-HTx ECG ages. Major adverse cardiovascular event (MACE) was defined as any coronary revascularization, heart failure hospitalization, re-transplantation, and mortality. Recipient pre-transplant ECG age (mean 63 ± 11 years) correlated significantly with recipient chronological age (mean 49 ± 14 years, R = 0.63, P &lt; 0.0001), while post-transplant ECG age (mean 54 ± 10 years) correlated with both the donor (mean 32 ± 13 years, R = 0.45, P &lt; 0.0001) and the recipient ages (R = 0.38, P &lt; 0.0001). During a median follow-up of 8.8 years, 307 patients experienced MACE. Patients with an increase in ECG age post-transplant showed an increased risk of MACE [hazard ratio (HR): 1.58, 95% confidence interval (CI): (1.24, 2.01), P = 0.0002], even after adjusting for potential confounders [HR: 1.58, 95% CI: (1.19, 2.10), P = 0.002].ConclusionElectrocardiogram age-derived cardiac ageing after transplantation is associated with a higher risk of MACE. This study suggests that physiological age change of the heart might be an important determinant of MACE risk post-HTx.