Citations

Introduction: In the current study, we examined the temporal trends in mortality across gender, race, and 10-year age groups over last two-decades. Methods: We conducted a retrospective population-based study using Centers for Disease Control and Prevention database. Subjects with underlying cause of death from AMI were identified using validated ICD10 codes. Age adjusted mortality rates were calculated for gender and race whereas crude rates were calculated for 10-year age group. Using Poisson regression, we estimated the rate ratio between race/ethnicity pairs adjusting for age and sex in order to analyze temporal trend. Results: We identified 2,709,173 subjects with reported underlying cause of death as AMI between January-2000 to December-2019 of which 54.7% were males (n=1,483,163). The age adjusted mortality rate per 100,000 was higher in males compared to females (52.4% vs 30.7%, OR: 1.66 [1.45-1.89]). Among ethnicities African American (AA) population had the highest age adjusted mortality rate per 100,000 [Table 1]. As expected, age group >85 years had the highest mortality rate per 100,000 constituting 30% of total deaths (78% of total deaths were noted in >65yr age group). AMI age adjusted mortality rates/100,000 showed significant decline across gender and race with highest decline in female population (66.5% decline). Highest percentage decline in mortality was noted in AA female population (68.2%) whereas in males it was the white population (62%). In females, highest percentage decline in mortality was noted in 75-84 age-group (70%) while it was >85 age-group (67%) in males. Conclusion: Over last two decades there has been a significant decline in AMI mortality rates across gender and race. AA continue to have higher age adjusted mortality rate among both male and female population (38% and 22% respectively). Further studies are needed to identify and provide targeted prevention and intervention strategies in high-risk populations.

Introduction: Long QT syndrome (LQTS) is an autosomal dominant disorder characterized by a prolonged QT interval on a 12-lead electrocardiogram (ECG). Cascade genetic testing for LQTS is standard of care, including in infants, but takes 2-4 weeks for return of results. For newborns of parent with confirmed LQTS, the ECG is obtained after birth as an initial assessment, but QTc values during the immediate newborn period may be misleading. Thus, our objective was to determine the ECG’s diagnostic accuracy in the first 48 hours of life for neonates born to a parent with LQTS. Methods: We performed a retrospective review of the electronic medical records of neonates born to a parent with ≥ 1 pathogenic variant in a LQTS-causative gene for which at least 1 ECG in the first 48 hours of life was obtained. Clinical data was collected on all neonates with focus on the 12-lead ECG, family history, and genetic testing results. The sensitivity and specificity of the diagnostic ECG were calculated using QTc thresholds of 440, 460, and 470 ms. Results: Overall, 70 infants (35 [50%] females) met inclusion criteria and the mean QTc on the first ECG was 484 ± 61 ms. Following genetic testing, a LQTS-causing variant was identified in 46 infants (66%), including 22 (48%) with LQT1 ( KCNQ1 ), 12 (26%) with LQT2 ( KCNH2 ), and 8 (17%) with LQT3 ( SCN5A ). Mean QTc in the first 48 hours of life for neonates that ultimately were genotype-positive was 502 ± 59 ms compared to 451 ± 50 ms (p < 0.001) for genotype-negative neonates. When using a recommended threshold QTc of ≥ 440 ms, 6/46 genotype-positive neonates (13%) were missed (underdiagnosed) and 13/24 genotype-negative neonates (54%) were overdiagnosed (sensitivity: 87%, specificity: 45%). At a QTc threshold ≥ 460 ms, 15 (21%) were classified erroneously (sensitivity: 85%, specificity: 67%) while at a threshold of ≥ 470 ms, 18 (26%) were misclassified (sensitivity: 76%, specificity: 71%). Conclusions: Although a baseline ECG should still be obtained before a newborn’s dismissal, reliance solely on the QTc for diagnosing LQTS and initiating therapy will result in an unacceptable number of misclassifications. Thus, genetic testing must be initiated prior to the baby’s discharge and proper anticipatory guidance is vital while awaiting genetic test results.

Introduction: Hypertrophic cardiomyopathy (HCM) is a major cause of sudden cardiac death in the young and especially in young athletes. The treadmill exercise test (TEST) has an important role in the functional assessment of patients with HCM. Herein, TEST-derived peak oxygen uptake (VO2 max) is a proxy for cardiopulmonary fitness. However, the correlation between symptoms and VO2 - especially in active young patients with HCM - is unclear. Objective: To explore the relationship between TEST-derived VO2 and symptomology in athletes and non-athletes with HCM. Methods: Overall, 91 patients (40% female) with HCM and a TEST with VO 2 data were included in this case-control study. Data were abstracted from the electronic health record using the first TEST performed at Mayo Clinic. Patients were defined as an athlete if they participated in an organized, competitive sport. Results: Overall, 60 HCM patients (33% female) were categorized as an athlete. HCM athletes were younger (17 vs. 27 years; p<0.0001) and less likely to be symptomatic at the time of their TEST (OR=0.24; p=0.01). Additionally, athletes had a higher VO2 max (86% vs. 68% of predicted; p<0.0001) and reached higher exercise times (93% vs 76% of predicted; p<0.0001) compared to the non-athletes with HCM. When comparing symptomatic (n = 18) to asymptomatic patients (n = 73), symptomatic patients had i) a reduced exercise time (68% vs. 92% of predicted; p=0.002) and ii) lower VO2 max (62% vs 84% of predicted; p<0.001). Finally, among the 27 patients (30%) with a VO 2 max < 70% predicted (n=27), they i) more likely had a history of cardiac arrest (4 vs 0; p=0.006) and ii) were more likely to be symptomatic (OR=7.7; p< 0.0001) than those with VO2 ≥ 70% of predicted (n=64). Importantly, however, 15/27 (56%) patients (8 athletes/7 non-athletes) with a VO2 max < 70% were asymptomatic. Conclusions: Reduced exercise capacity is common in athletes with HCM and does not correlate with symptom status. However, if the TEST-derived VO2 max is < 70%, treatment intensification may be necessary as it may portend an adverse outcome both arrhythmically and mechanically.

Introduction: Type 2 long QT syndrome (LQT2) is caused by loss-of-function variants in the KCNH2 -encoded K v 11.1 potassium channel which is essential for the rapid delayed rectifier channel (I Kr ) that governs phase 3 of cardiac action potential (AP). No current therapies target the molecular cause of LQT2. Methods: A dual-component “suppression-and-replacement” (SupRep) KCNH2 gene therapy was created by cloning into a single construct a custom-designed KCNH2 shRNA that produces ~80% knockdown (suppression) and a “shRNA-immune” (shIMM) KCNH2 cDNA modified by the introduction of synonymous single nucleotide substitutions within the shRNA target site (replacement). The ability of KCNH2-SupRep gene therapy to suppress and replace LQT2-causative variants in KCNH2 was evaluated via heterologous expression in TSA201 cells. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated from two patients with LQT2 (KCNH2-G604S and -N633S). CRISPR-Cas9 corrected isogenic control iPSC-CMs were made. Both lines were treated with KCNH2-SupRep or non-targeting control shRNA (shCT). FluoVolt voltage dye was used to measure the APD. Results: KCNH2-SupRep achieved mutation-independent suppression of wild-type KCNH2 and both LQT2-causative variants with simultaneous replacement of KCNH2-shIMM as measured by allele-specific qRT-PCR. Treatment with KCNH2-SupRep resulted in shortening of the pathologically prolonged APD at 90% repolarization (APD 90 ) to near isogenic control APD 90 levels (G604S: isogenic controls, 424 + 39 ms and N633S: isogenic controls, 433 + 16 ms) compared to treatment with non-targeting shCT (G604S: SupRep treated, 399±105 ms vs. shCT treated, 577±39 ms, p<0.0001; N633S: SupRep treated, 432±85 ms vs. shCT treated, 483±65 ms, p<0.005). Conclusions: We provide the first proof-of-principle gene therapy for correction of LQT2. Like our sentinel discovery of SupRep gene therapy for LQT1, KCNH2-SupRep successfully suppressed and replaced KCNH2 to normal wild-type levels. In TSA201 cells, co-transfection of LQT2 variants and KCNH2-SupRep caused mutation-independent suppression-and-replacement of KCNH2 . In LQT2 iPSC-CMs, KCNH2-SupRep shortened the APD, thereby eliminating the pathognomonic feature of LQT2.

Introduction: LMNA encodes the nuclear envelope proteins lamin A/C that are involved in ageing processes. Mutations in LMNA cause a spectrum of phenotypes which include muscular dystrophy, arrhythmogenic dilated cardiomyopathy, peripheral neuropathy, progeroid syndrome and overlap syndrome. Early diagnosis is crucial to prevent sudden cardiac death. We hypothesized that LMNA mutations result in an ECG biological age older than chronological age. Methods: In this study, we used AI-enabled ECG network to investigate standard digital 12-lead ECGs in genetically characterized LMNA patients. Results: We identified 33 LMNA patients with 331, 12-lead ECG available for analysis. Median age at symptoms onset was 23.5 (range: <1 to 61 years;15 females). Mean follow up time was 86 months (range: <1 to 367 months). Symptoms at onset included muscle weakness (n=10) or cardiac symptoms (n=18) and asymptomatic (n=5). We included a total of 1532 age sex matched controls. We found significant differences in positive age-gap (biologically older than chronological age) comparing LMNA patients (median of 17.5) versus controls (4.9 years; p<0.001, Figure 1 ). AI-ECG age with 10 years or higher age-gap was observed in 73% of LMNA patients compared to 27% in the controls (p<0.001). Consecutive serial analysis for all ECG’s in the study versus predicted age showed faster aging when comparing the rates of age-gap overtime in the LMNA group compared to controls (p<0.0001, Figure 2 ). Moreover, the subset analysis of 23 ECG in the 5 asymptomatic patients versus controls also showed significantly higher AI-ECG age-gap (p=0.004) Conclusions: An AI-ECG algorithm to detect biological age effectively demonstrates accelerated aging in patients with LMNA mutations related to physiological aging. Our findings further validate the role of AI-ECG to detect accelerated aging, expanding previous studies demonstrating higher mortality among individuals with in increased positive age-gap.

Background: Many cardiac implantable devices have the capability of monitoring the volume status in patients with heart failure by tracking the intra-thoracic impedance changes over time measured by OptiVol fluid index. Objective: The aim of this study is to evaluate the association between the intra-thoracic impedance measured by OptiVol fluid index and the onset of tachyarrhythmias. Methods: We searched Medline and EMBASE databases through January 2021 looking for studies evaluating intra-thoracic impedance measured by OptiVol with either ventricular tachycardia/ventricular fibrillation (VT/VF) or atrial tachycardia/atrial fibrillation (AT/AF). After extracting the data from each study, we calculated the odds ratio with 95% confidence intervals using RevMan 5 software. Results: Ten studies met our inclusion criteria with a total of 118,504 patients were included in our analysis. Seven studies measured VT/VF included 94,816 patients and 5 studies measured AT/AF included 23,688 patients. Two studies measured both AT/AF and VT/VF. The odds ratio for developing VT/VF with OptiVol fluid index crossing a threshold of 60 Ω-days was 1.55 (95% CI 1.35, 1.78) (P<0.00001) and for developing AT/AF was 1.79 (95% CI 1.43, 2.24) (P<0.00001) {Figure1} Conclusion: The decrease in intra-thoracic impedance measured by OptiVol fluid index threshold crossing of 60 Ω-days is associated with higher risk for developing new onset AT/AF and VT/VF. Key Words: intra-thoracic impedance; OptiVol; tachyarrhythmia Figure1: Forest Plot for risk of developing VT/VF Figure: Forest Plot for risk of developing AT/AF

Introduction: The survival impact of impaired multi-chamber longitudinal strain in significant tricuspid aortic valve stenosis(TAV-AS) and its relation to cardiac damage staging(CDS) is unknown. Hypothesis: Impaired strain improves prognostication of CDS in significant TAV-AS. Methods: We performed 2D-semi-automated strain analysis in a retrospective cohort of consecutive patients with TAV-AS with mean pressure gradient≥30mmHg on echocardiogram. The outcome was all-cause death. Cutoffs of impaired left-ventricular global longitudinal strain(

Background: Owing to reduced bleeding risks, radial is favored over femoral for access site selection in patients referred for coronary angiography, with specific benefits in patients presenting with acute coronary syndrome. However, studies were often limited to patients without coronary artery bypass grafts (CABG), given the technical challenges of the radial approach in these patients. Methods: We evaluated patients with prior CABG undergoing coronary angiography with or without percutaneous coronary intervention (PCI) from 2015-2020 at our institution. We reviewed access site and bleeding outcomes as defined in the NCDR CathPCI registry. Additional outcomes included procedural duration, fluoroscopy time, contrast volume, and clinical events. Results: Of the 1,546 patients studied, 280 (18%) patients had radial access while 1,266 (82%) patients had femoral access. Over the study time period, frequency of radial access for post CABG catheterization procedures increased from 0% in 2015 to 45% in 2020. There were no statistically significant differences in comorbidities, bleeding events, complications, or mortality between radial vs femoral (Table). Fluoroscopy time was higher for radial vs femoral (14.9 mins vs 13.3 mins, p=0.04). Conclusion: Over time, radial access choice in post CABG patients increased, without significant differences with respect to bleeding events or complications as compared to femoral, though at increased fluoroscopy times.

Objective: Stress cardiomyopathy(SCM) occurs between 4-15% in aneurysmal sub-arachnoid hemorrhage(aSAH). Predictors and prognostic implications of SCM in aSAH remains incompletely known. Methods: Adult patients between January 2006-December 2019 with diagnosis of aSAH and echocardiogram during same admission were identified from a prospectively maintained aSAH registry. Presence of SCM was confirmed using the echocardiographic criteria. Severity of aSAH was categorized using the modified Fisher(mFisher) and the World Federation of Neurological Scale(WFNS). Results: Among 570 aSAH patients during study period, 194 aSAH cases had echocardiography and 37(19%) of them had SCM. In comparison to aSAH without SCM, aSAH with SCM were mainly females(76% vs 62%; p= 0.12) and postmenopausal(57±12 vs 59±13 years; p= 0.39). Echocardiographic findings in Table . aSAH with SCM was associated with WFNS grade>3(68% vs 42%; p= 0.005) and mFisher grade>2(87% vs 81%; p= 0.39), intraventricular hemorrhage(IVH)(81% vs 64%; p= 0.04) and larger size of the ruptured aneurysm(8±5 vs 6±4; p= 0.04). Medical management, microsurgical clipping and endovascular coil embolization rates were similar in patients with and without SCM, yet patients with SCM had lower rates of disposition to home(8% vs 27%; p =0.02) and higher in-hospital mortality(41% vs 25%, p= 0.05). On multivariate analysis, ruptured ophthalmic artery aneurysms had 13-times higher odds for formation of SCM(OR 13.43 [1.22-147.8]; p= 0.02). Conclusion: aSAH with SCM predominantly occurred in postmenopausal females with larger aneurysms, and higher severity of bleeds. Ophthalmic artery aneurysms were associated with substantially increased risk of SCM after adjustment for aSAH severity. Despite similar treatment rates, SCM was associated with higher in-hospital mortality. These findings will require further confirmation in a larger subset of aSAH with SCM patients.

Background: Although genetic testing (GT) in dilated cardiomyopathy (DCM) enables molecular diagnosis, family screening and provides prognostic information, it is underutilized. Our hypothesis was that systemic intervention (INT) in the heart failure (HF) clinic could increase the frequency of GT for DCM. Methods: Eligible DCM patients in a 17-month period before and after the INT were compared for frequency of genetic counseling and GT uptake. The INT comprised of the following: 1. Pre-emptive cardiovascular genomics e-consult (with a specialist in genetic DCM) for all new HF patients that could be canceled by the treating physician if the patient was considered ineligible or was uninterested. If eligible and patient was willing, 2. They were shown a video in person on genetic testing for DCM prepared by a genetics counselor 3. A trained HF clinic nurse provided answers to questions and completed the test requisition 4. Educational material was provided to the patient 5. Results were reviewed electronically and communicated to the patient via letter or phone call by the physician completing the e-consult. Clinical genetics consultation was available throughout the study period. Standard commercially available cardiomyopathy gene panels were used for GT. Results: There were 162 eligible DCM patients before and 194 after the INT. DCM patients were more likely to undergo genetic counseling post-INT versus (vs) pre-INT (33.5% vs 14.8%, OR 2.9, 95% CI 1.7-4.8, P <.0001). Similarly, DCM patients were more likely to undergo GT post-INT vs pre-INT (27.3% vs 13%, OR 2.5, 95% CI 1.4-4.3, P =.001). Consequently, the total number of patients who were diagnosed to have likely pathogenic or pathogenic DCM-related genetic variants increased from 2 pre-INT to 6 post-INT. These variants were detected in the following genes: FLNC (n=2), TTN (n=2), DES , LMNA , PLN and TNNT2 . Conclusion: An intervention that was pre-emptive, easily accessible and available to the healthcare provider was successful in raising the rates of genetic counseling and testing in DCM patients seen in the HF clinic. Whether such low-cost interventions will enhance cascade screening and provide an opportunity for precision medicine remains to be determined.