Citations

Introduction: Cardiac arrhythmias are common in continuous flow left ventricular assist device (LVAD) recipients. The impact of axial vs. intrapericardial centrifugal LVAD pumps on arrhythmia incidence and associated clinical outcomes is unclear. Hypothesis: This multicenter study evaluated the impact of LVAD type (axial vs. centrifugal) on incidence of atrial and ventricular arrhythmias, ICD shocks and mortality in LVAD patients. Methods: Analysis was done on 536 patients who underwent LVAD implantation at 5 US centers from 2008 to 2016. The groups were divided based on their LVAD type (axial - HeartMate II [HMII, n=433] vs. centrifugal - HeartWare (HW, n=103). Baseline characteristics as well as incidence of post-LVAD atrial arrhythmias (PL-AA), ventricular arrhythmias (PL-VA) and ICD shocks were analyzed in these groups. Multivariable Cox Regression analysis was used to identify predictors of survival. Results: Of 536 patients, 433 had HMII axial LVAD and 103 had HW centrifugal VAD implant. At baseline, HMII group had more males, higher proportion of CRT-D and higher prevalence of AA (Table 1A). Left ventricular dimensions were similar between groups. During a median follow-up of 537 days of LVAD support, incidence of PL-VA and ICD shocks were significantly higher in the HM2 group compared to HW group whereas incidence of PL-AA was not significantly different (Table 1A). In multivariable Cox Regression analysis, LVAD indication was the only variable that predicted survival (Table 1B). Type of LVAD (axial vs. centrifugal) was not associated with survival (HMII vs. HW - HR 1.04, P=0.48). Conclusions: In this multi-center continuous flow LVAD cohort, axial HM2 VAD patients had a higher incidence of PL-VA and ICD shocks. Type of LVAD (axial vs. centrifugal) was not associated with survival.

Background: Patients with ccTGA have a high incidence of atrial arrhythmias and premature failure of the systemic right ventricle. We sought to better define this risk. Methods: A retrospective review of all clinical data for patients with ccTGA followed at a large tertiary care institution was performed. The primary outcome was a composite of death and cardiac transplantation. Results: A cohort of 165 patients (age 41±16 years, 53% male) were followed for 11±8 years; 41 patients died, 7 underwent cardiac transplantation, and 4 underwent VAD placement. Male sex (HR 2.7, p=0.002), older age (HR 1.04, p<0.001), clinical heart failure symptoms (HR 7, p<0.001), heart failure hospitalization (HR 4.9, p<0.001), syncope (HR 1.8, p=0.04) and pulmonary hypertension (HR 2.77, p<0.001) were significant predictors of the primary outcome. Atrial fibrillation (HR 3.5, p=0.002), atrial flutter (HR 3.05, p=0.04), and prolonged QRS duration (HR 1.01, p=0.004) on the first ECG, as well as right and left atrial enlargement (HR 4, p<0.001 and 3.7, p<0.003) and severe systemic AV valve regurgitation (HR 3.8, p=0.03) on the first echocardiogram were associated with poor outcomes. Atrial arrhythmias occurred in 110(67%) patients: atrial fibrillation in 75(45%), atrial flutter in 50(30%), and supraventricular tachycardia in 16(9.7%) patients. Arrhythmias were largely asymptomatic in 109(66%) patients, while 25(14.5%) experienced palpitations, dizziness or presyncope, and 10(6%) presented with decompensated heart failure. Cardioversion and antiarrhythmic therapy were utilized in 53(32%) patients. Surgical pulmonary vein isolation or atrial MAZE were performed in 15(9%) patients, cryoablation of the CTI in 3 patients, and surgical ablation of an accessory pathway in 2 patients. One or more catheter ablation procedures were also performed in 18(11%) patients. Conclusions: Atrial fibrillation and flutter, heart failure, prolonged QRS duration, systemic AV valve regurgitation and pulmonary hypertension predict worse outcomes in ccTGA. Although asymptomatic in a majority of patients, atrial arrhythmias are associated with significant morbidity and mortality. Whether a rhythm control strategy even in asymptomatic patients may improve outcomes remains unknown.

Introduction: Calmodulin (CaM)-mediated long QT syndrome (CaM-LQTS) is a genetic arrhythmia disorder characterized by a high prevalence of life-threatening ventricular arrhythmias occurring very early in life, frequent T-wave alternans, markedly prolonged QT intervals (QTc > 600 ms), and intermittent 2:1 AV block. Three distinct genes ( CALM1 , CALM2 , and CALM3 ) all encode for the identical CaM protein. Conventional LQTS pharmacotherapies fail to adequately protect against potentially lethal cardiac events in patients with CaM-LQTS. Here, we developed a CALM1 “ suppression-replacement (SupRep)” gene therapy with the goal of rescuing the prolonged cardiac action potential duration (APD) and increased Ca 2+ amplitude (ΔF/F0) in patient-derived induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from a patient with CALM1 -mediated LQTS. Methods: Custom designed CALM1 -targeting shRNAs were tested for knockdown efficiency using TSA201 cells and RT-qPCR. A dual-component SupRep CALM1 gene therapy was created by cloning into a single construct a custom-designed CALM1 shRNA that produces knockdown (suppression) and a “shRNA-immune” (shIMM) CALM1 cDNA (replacement). Patient-specific CALM1-F142L iPSC-CMs were generated from a patient with severe LQTS (QTc = 515 ms). FluoVolt voltage-sensing dye was used to measure the APD at 90% repolarization (APD 90 ). Calcium transient amplitude was measured using Fluo-4 indicator. Results: Overall, 6 unique candidate CALM1 -targeting shRNAs were tested for knockdown efficiency in a transient transfection CALM1 over-expression TSA201 cell system. One candidate shRNA had an 80% knockdown efficiency of CALM1. Following transfection with CALM1 -SupRep gene therapy, the APD 90 was significantly decreased in F142L iPSC-CMs compared to untreated cells (F142L: 665 ± 9 ms [n=40] vs F142L + SupRep: 353 ± 9 ms [n=20], p<0.0001). Ca 2+ amplitude was significantly decreased following SupRep transfection when compared to untreated cells (0.99 ± 0.04 vs 0.8 ± 0.06, p=0.02). Conclusions: Here, we provide the first proof-of-principle SupRep gene therapy for CALM1-mediated LQTS. CALM1 -SupRep gene therapy shortened significantly the pathologically prolonged APD 90 in CALM1 -F142L patient-derived iPSC-CMs.

Introduction: Heart failure with preserved ejection fraction (HFpEF) is an increasingly common clinical syndrome with diagnostic challenges and no effective treatment. The high heterogeneity of HFpEF clinical syndrome demands novel technologies to distinguish from heart failure with reduced ejection Fraction (HFrEF). Currently, invasive hemodynamic exercise testing is performed to evaluate for HFpEF with right heart catheterization. Hypothesis: We hypothesize that a deep learning model can noninvasively detect patients with HFpEF using phonocardiogram (PCG). Methods: Eligible patients undergoing right heart catheterization were recruited after IRB approval. Eko duo stethoscope was used to record simultaneous ECG & PCG at the mitral area on the patients prior to right heart catheterization at baseline. Each recording was 30 seconds in length with a frequency range between 250 - 5000 Hz. R-wave peak detection was performed & beat to beat PCG annotations were performed. The annotated PCG signals were converted into Mel-frequency cepstral coefficients (MFCC) and padded to account for the difference in lengths. Deep Learning model was developed using a Sequential Neural Network with 80% data to train and validate the model and 20% hold out data was used for testing accuracy of the model. Receiver operating curve (ROC) was obtained to estimate area under the curve (AUC) for performance analysis. Results: 42 patients were enrolled with 25 patients diagnosed as HFpEF by right heart catheterization and 17 were reported as controls. 2544 & 1771 individual PCG annotations for HFpEF and controls were used for model training/validation and testing. The model performed reasonably well with accuracy of 0.89, F1 score of 0.88, precision of 0.80 and recall of 0.97 on the test data. ROC was obtained with AUC of 0.94. Conclusions: The results demonstrate the ability of the deep learning model to noninvasively detect HFpEF using PCG. Larger study is needed to validate these findings.

Senescence induced by various stresses reprograms cancer cells to acquire senescence-associated (SA) cell growth (SACG), which allows them to escape senescence-induced cell cycle arrest with enhanced growth potential. ERK5 is a dual kinase-transcription factor, containing an N-terminal kinase domain and transactivation domains in the C-terminal half. Recent data have raised questions regarding the functional role of ERK5 kinase inhibitors in cancer and inflammatory diseases. We aimed to investigate how ERK5 reprograms myeloid cells (MC) to the SA secretory phenotype (SASP) and SACG, consequently leading to atherosclerosis (AthS). AthS was inhibited in ERK5 S496A knock-in (KI) mice. Single-cell analysis of p53 and Ki67 with imaging mass cytometry revealed three groups of MCs with different p53 and Ki67 expression patterns in the plaque. One group showed that p53 and Ki67 were co-expressed lineally, suggesting that this group of cells escaped from the growth-suppression effects of p53, which is also known as a senescence marker. The % of ERK5 S496A KI cells in this group was significantly lower than in wild-type (WT). Also, we found an increase of SA β-gal (SAβ-gal) + Ki67 + and 53BP1 + Ki67 + cells in bone narrow-derived macrophage (BMDMs) isolated from hypercholesterolemia (H-chol) WT mice, suggesting H-chol-induced MC SACG. MC SACG were significantly inhibited in ERK5 S496A KI mice, supporting the role of ERK5 S496 phosphorylation on SACG. RNA sequencing analysis identified the ERK5 S496 phosphorylation-dependent AHR induction by H-chol, and AHR depletion significantly inhibited SACG. We also discovered a critical effect of ERK5 S496 phosphorylation on SUMOylation at a novel site of NRF2 (i.e., K518), which inhibited NRF2 transcriptional activity without affecting ERK5 kinase activity and antagonized oxidized LDL (oxLDL)-induced SASP. Specific ERK5 kinase inhibitors (AX15836 and XMD8-92) inhibited oxLDL-induced ERK5 S496 phosphorylation, suggesting that ERK5 S496 phosphorylation was involved at least in part of the effects of these inhibitors. We have discovered a novel mechanism in which ERK5 S496 phosphorylation directly inhibits NRF2 activity by upregulating NRF2 K518 SUMOylation and AHR induction, subsequently inducing SACG and AthS.

Introduction: The mechanistic link between early coronary artery disease (CAD) and atrial fibrillation (AF) continues to be explored. Clonal hematopoiesis of indeterminate potential (CHIP) is increasingly recognized as a risk factor for cardiovascular disease. We hypothesize CHIP further increases the risk for AF in early CAD. Methods: 184 participants underwent invasive coronary angiogram with endothelial function testing. Buffy coat was used for whole exosome sequencing to identify CHIP (variant allele frequency > 2% and minor allele frequency ≤ 0.1%). Early CAD was defined by the presence of coronary endothelial dysfunction (CED) in the absence of obstructive CAD. Invasive coronary angiography with endothelial function testing characterized CED as ≥ 20% increase in coronary artery diameter or ≤ 50% increase in coronary blood flow in response to acetylcholine. AF was identified by ICD-10 code or patient survey and confirmed by an independent investigator by chart review. Cox proportional hazard regression was adjusted for age, sex, and conventional cardiovascular comorbidities (hypertension, diabetes, and total cholesterol). Results: Of the 184 participants, we identified 23 cases with both early CAD and CHIP and 62 normal controls without CHIP or CAD. Case patients were significantly older (mean 60 ±9 vs 52 ±10 years, p = 0.004 years) and predominantly female (74% vs 81%, p = 0.506). AF was more likely among case participants when compared to normal controls (29% vs 10%, p = 0.036). Mean time to AF or last follow-up was 11 ±7 years. Case patients with both early CAD and CHIP were nearly 10 times more likely to develop AF when compared to normal controls in a Cox regression model adjusted for age, sex, and conventional cardiovascular comorbidities (HR 9.52, 95% CI 1.93 - 47.02, p = 0.006). The risk for AF was not significant if we defined cases by only the presence of CHIP (n = 30) or early CAD (n = 122). Conclusions: Patients with both CHIP and early CAD may have greater risk for developing AF beyond the presence of CHIP or CAD alone. Our findings suggest an added mechanistic role of CHIP that further increases the risk for AF in early CAD.

Introduction: Post-transcatheter aortic valve replacement (TAVR) outcome of patients is an important research topic. To accurately assess post-TAVR mortality, we examined a family of new echo-parameters (augmented systolic blood pressure (AugSBP) and arterial mean pressure parameters (AugMAP)) derived from blood pressure and aortic valve gradient ( Figure 1 ). Methods: Patients in the Mayo Clinic National Cardiovascular Diseases Registry-TAVR database who underwent TAVR between January 1, 2012, and June 30, 2017, were identified to retrieve baseline clinical, echocardiographic, and mortality data. The median of AugSBP and AugMAP were used to stratify patients in Kaplan-Meier analysis. Results: The final cohort contained 974 patients with a mean age of 81.4±8.3 years old, and 56.6% were male. The mean Society of Thoracic Surgeons risk score was 8.2±5.2. The median follow-up duration was 354 days, and the one-year all-cause mortality rate was 14.2%. Detailed characteristics are summarized in Table 1. AugMAP1 < 102.5 mmHg (median) was associated with a 3-fold risk of all-cause mortality post-TAVR at 1 year (hazard ratio 3.0, 95%confidence interval 2.0-4.5, p<0.0001)( Figure 1 ). Conclusions: Augmented mean arterial pressure provides clinicians with a simple but effective approach to quickly identify patients at risk and potentially improve post-TAVR prognosis.

Background: The prognostic implications of exercise induced hypertension (EIH) in adults with repaired coarctation of aorta (COA) and treated hypertension are unknown. The purpose of this study was to assess the relationship between EIH and cardiovascular events, and to determine whether exercise blood pressure (BP) improved risk stratification in this population. Methods: Retrospective study of patients with COA on antihypertensive therapy that underwent exercise testing (2003-2019). BP was measured at rest in 3 different clinical settings and averaged to determine the resting BP. EIH was defined as systolic BP (SBP) >210 (males) or >190 (females) at peak exercise. Cardiovascular event was defined as atrial fibrillation, ventricular tachycardia, heart failure hospitalization, heart transplant, and cardiovascular death. Results: Of 327 patients (age 35±13 years), 116 (35%) had EIH. Although the resting BP was similar between patients with versus without EIH, the EIH group had higher pulsatile arterial load, more advanced left ventricular remodeling, and were less likely to be on angiotensin converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB). EIH was associated with cardiovascular events (HR 1.06 [95%CI 1.02-1.08]) independent of resting SBP, and improved prognostic accuracy above resting SBP (C-statistic 0.671 [95%CI 0.645-0.694] to 0.727 [95%CI 0.709-0.750], p=0.01). ACEI/ARB was associated with a lower risk of cardiovascular events. Conclusions: EIH was associated with cardiovascular events independent of resting BP, and patients receiving ACEI/ARB had lower risk of EIH and cardiovascular events. These data suggest that exercise BP could be used to assess adequacy of antihypertensive therapy, and to guide titration of antihypertensive therapy.

Introduction: Increasingly, catheter ablation for atrial fibrillation (AF) has been utilized for rhythm control and to improve quality of life (QoL). Data are limited on patient-centered ablation outcomes in individuals with chronic kidney disease (CKD). Objective: To examine clinical outcomes and QoL following AF ablation in CKD patients from a large patient-reported outcomes (PRO) database. Methods: All patients undergoing AF ablation (2013-2016) at our center were enrolled and assessed for outcomes using automated PRO surveys (baseline, 3 and 6 months after ablation, every 6 months thereafter). This analysis captured data at 1- and 3-year follow-up. CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min using the 2021 CKD-EPI equation. The atrial fibrillation symptom severity scale (AFSSS) was used as the main measure for QoL assessment. In addition, data were collected on clinical improvement by patient report, AF burden, and healthcare utilization. Results: A total of 488 patients were identified (66% male, mean age 68.5, 56.2% persistent AF). QoL was significantly improved from baseline median (IQR) AFSSS of 14 (6-19.5) to 3 (0-9) at 1-year and 4 (0-9.5) at 3-year; P≤0.0001 for both. About 90% of patients reported improvement in their overall AF-related symptoms both at 1- and 3-year follow up. The proportion of patients in AF at the time of completion of the baseline survey was 51.2%, and this decreased to 6.2% at 1-year and 9.7% at 3-year follow up (P<0.0001 for both). AF burden was significantly reduced at 1-year and 3-year including frequency and duration of episodes (P<0.05 for both), with associated decrease in ER visits and hospitalizations; P<0.0001 for all comparisons. The proportion of patients on antiarrhythmics decreased from 61.8% at baseline to 35.6% and 22.7% at 1-year and 3-year, respectively (P<0.0001 for both). Conclusions: In a large AF-specific PRO system, catheter ablation for AF was associated with a significant improvement of QoL in most patients with CKD; with a decrease in AF burden and healthcare utilization.

Background: The 2021 ACC/AHA chest pain guidelines recommend risk scores such as HEAR (History, Electrocardiogram, Age, Risk Factors) for short term risk-stratification yet limited data exists integrating them with high-sensitivity cardiac troponin T (hs-cTnT). Methods: Retrospective, multicenter (n=2), observational, U.S. cohort study of consecutive ED patients without ST-elevation myocardial infarction (MI) who had at least one hs-cTnT (limit of quantitation, LoQ, <6 ng/L, and sex-specific 99 th percentiles of 10 ng/L for women and 15 ng/L for men) measurement on clinical indication in whom HEAR scores (0-8) were calculated. The composite major adverse cardiovascular (MACE) outcome was 30-day MI and death. Results: Among 1,979 ED patients undergoing hs-cTnT measurement, 1045 (53%) were classified as low-risk (0-3), 914 (46%) as intermediate-risk (4-6), and 20 (1%) as high-risk (7-8) based on HEAR scores. HEAR scores were not associated with an increased risk of 30-day MACE after adjusted analyses. Outcomes according to risk-strata based on HEAR scores and baseline hs-cTnT are shown in Table 1. Patients with quantifiable hs-cTnT (LoQ-99 th ) had an increased risk for 30-day MACE (3.4%) despite being estimated to be low-risk (0-3) per HEAR scores. Conversely, those with serial hs-cTnT<99 th percentile remained at low-risk (range 0% to 1.2%) for 30-day MACE across HEAR score strata. Conclusions: HEAR scores are of limited value in those with baseline hs-cTnT<LoQ or hs-cTnT>99 th percentile where hs-cTnT identifies very low and high-risk patients irrespective of HEAR scores. In those with baseline quantifiable hs-cTnT within the reference range (<99 th percentile), a higher risk (>1%) for 30-day MACE exists even in those with low HEAR scores. With serial hs-cTnT measurements, HEAR scores overestimate risk when hs-cTnT remains <99 th percentile.