Citations

Introduction: The prevalence of diabetes mellitus (DM) is increasing, and it is associated with cardiorenal dysfunction. Natriuretic peptides (NPs) have cardiorenal protective actions and enhance insulin sensitivity. We designed a dual-action bispecific peptide (CRRL 094) that simultaneously activates the natriuretic peptide system and induces insulin secretion. Methods: To test the in vivo effects of the peptide, Wistar rats (male, 6-8-week-old) were made diabetic by intraperitoneal Streptozotocin (STZ) injection (65 mg/kg). One week after STZ injection, diabetes was confirmed (fasting blood glucose > 350 mg/dL). Rats were then divided into 2 groups: controls (Ctrl group, n=6) and treatment group (Tx group, n= 9). The peptide (1 pmol/kg/min) was infused in the Tx group for 150 min. Results: After 150 minutes of peptide infusion, plasma insulin (mean± standard deviation) increased more than 3.7x among the Tx group compared to the Ctrl group (0.294± 0.199 ng/mL vs 0.078± 0.021 ng/mL, p=0.01). Additionally, plasma glucose decreased among Tx group (405.3±96.4 mg/dL) compared to Ctrl group (545.6± 52.8 mg/dL, p=0.003). Furthermore, the rate of natriuresis increased significantly among the Tx group compared to controls (1.582±0.7 vs 0.639±0.21, p= 0.009), as did the rate of kaliuresis (3.1± 1.1 vs 2.0±0.6, p=0.045). Importantly, the glomerular filtration rate increased by 1.5x among the Tx group compared to the controls (1.6±0.5 vs 1.0±0.3, p= 0.03). There were no significant differences in mean arterial pressure or heart rate. Conclusions: The dual-action insulin-secreting natriuretic peptide (CRRL 094) was effective in increasing endogenous insulin secretion, enhancing natriuresis, and improving renal clearance. Further studies are warranted to assess its long-term safety and efficacy in diabetes.

Background: Long-term outcomes of lead management strategies of lead abandonment (LA) or transvenous lead extraction (TLE) during cardiac implantable electronic devices (CIED) procedures requiring lead addition or replacement remain unclear. Hypothesis: We hypothesized that there is no difference in long-term (10-year) outcomes of LA versus TLE during CIED procedures requiring lead addition. Methods: We performed a retrospective cohort study of a population residing in seven adjacent counties of southeastern Minnesota with follow-up at the Mayo Clinic and its health systems. Patients who underwent LA or TLE for sterile leads from January 1, 2000, to January 1, 2011, and had follow-up for at least 10-years or until their death were included. Outcomes were identified through a detailed chart review of the electronic health record from within the Mayo Clinic system. Results: A total of 172 patients were included in the study with 153 patients who underwent LA and 19 who underwent TLE for sterile leads. In long-term follow-up, indications for subsequent lead extraction arose in 9.1% (n=14) of patients with initial LA and 5.3% (n=1) in patients with initial TLE, after an average of 7-years. Moreover, out of 14 patients, who required secondary extraction in the LA cohort, 28.6% did not proceed with the extraction. Of the remaining 10 patients, 60% had clinical success and 40% had a clinical failure with the extraction. Subsequent device upgrades or revisions were performed in 18.3% of patients in the LA group and 31.6% in the TLE group, with no significant differences in procedural challenges such as requiring balloon venoplasty or serial dilation (5.2% vs. 5.3%, P=1.0). There was no difference in 10-year survival probability among LA group and TLE group (P=0.64). Conclusion: Indications for subsequent extraction arose in 9.1% of patients with the initial LA approach for sterile leads after an average of 7.3 years and 28.6% did not proceed with the extraction. Of the patients who underwent the subsequent extraction, 60% had clinical success and 40% had a clinical failure. There was no difference in 10-year survival probability between patients with the initial LA approach or TLE approach.

Introduction: Shared decision-making (SDM) about anticoagulant treatment in patients with atrial fibrillation (AF) is widely recommended but its effectiveness is unclear. We assessed the extent to which using an SDM tool promotes high-quality SDM. Hypothesis: SDM will improve communication quality, knowledge, and decisional conflict and will translate to improved medication adherence and outcomes. Methods: In this multicentre encounter-randomized trial, we included patients with nonvalvular AF considering starting/reviewing anticoagulation, and their clinicians. We compared usual care with or without ANTICOAGULATION CHOICE, an SDM conversation tool for use during the clinical encounter that presents individualized risk estimates and compares anticoagulation options across patient important issues. Results: We enrolled and video-recorded 922 patient-clinician encounters. So far, our data have shown that participants in both arms reported near-optimal communication quality, knowledge, and decisional conflict (JAMA IM-2020). Patients in intervention-arm estimated their stroke risks more accurately and were more involved in decision-making (JAMA IM-2020), clinicians were more satisfied (JAMA IM-2020), and cost conversation were more common (JAMA NO-2021). Use of the intervention had no effect on treatment decisions, encounter duration (JAMA IM-2020), treatment adherence, clinical outcomes (JAHA-epub) or patient-perceived sense of the care plan (PEC-epub). New analyses have shown that compared to eligible white participants, black participants more frequently did not enrol to the study. Enrolment of Black, indigenous, and people of colour benefited most form including and prioritizing practices most likely to care for them. We found no evidence of contamination (tool use, functional, or learned) between study arms. Conclusions: Use of an SDM tool improved some measures of SDM quality, without affecting treatment decisions and their sensibility, encounter duration, patient adherence, or clinical outcomes. Our results should calibrate expectations as to what could be accomplished by implementing SDM tools about anticoagulation in the care of patients with AF

Introduction: Hypoplastic left heart syndrome (HLHS) is a severe form of single ventricle congenital heart disease characterized by the underdeveloped left ventricle. Early serial postmortem examinations revealed a high rate of coronary artery abnormalities in HLHS fetal hearts (e.g., thickened wall and kinking arteries). However, the intrinsic defect in HLHS coronary vessels and its genetic basis remain unclear. Methods: We profiled human fetal heart with an underdeveloped left ventricle (ULV) and induced pluripotent stem cells derived endothelial cells (iPSC-ECs) from HLHS patients at single-cell resolution. CD144 + / NPR3 - vascular ECs were selected and classified as venous, arterial, and late arterial populations. To study the arterial EC phenotypes, we generated iPSC-arterial ECs (AECs, CDH5 + CXCR4 + NT5E -/low ) derived from 3 HLHS patients and 3 age-matched controls, and evaluated their functionalities including cell cycle regulation, angiogenesis, and inflammatory response. Results: Revealed by single cell RNA-seq and subsequent gene ontology analysis, ULV late arterial EC population showed significant defects in EC development, proliferation, angiogenesis, and Notch signaling compared to the control. Consistently, HLHS iPSCs exhibited impaired AEC differentiation judged by the reduced CXCR4 + NT5E -/low AEC progenitors. Mature HLHS iPSC-AECs showed reduced angiogenesis and enhanced G0/G1 cell cycle arrest with downregulated cell cycle-related genes (e.g., Ki67, CCND1/2 ). Healthy human aortic smooth muscle cells exhibited abnormal proliferation and synthetic phenotypes when co-cultured with HLHS iPSC-AECs. Additionally, NOTCH pathway genes (e.g., DLL4, HEY1, GJA5 ) were suppressed in both ULV AECs and HLHS iPSC-AECs. HLHS de novo variant KMT2D directly regulated the transcription of NOTCH targeted genes involved in arterial development and proliferation via H3K4me2. Intriguingly, the treatment of NOTCH ligands (Jag1, Dll1) significantly improved the proliferation of HLHS AECs. Conclusions: Our study revealed that HLHS coronary AECs were dysfunctional in angiogenesis, proliferation, and EC-SMC interaction. KMT2D-NOTCH signaling may contribute to the impaired development and proliferation of HLHS AECs.

Introduction: Previously, miR-425 have been implicated in the inhibition of the cardiac natriuretic peptide (NP) ANP gene expression with their role on BNP undefined. The mechanism by which miR-425 modulates NP expression remains to be explored. In heart failure (HF), adrenergic and neurohormone pathways are aberrantly activated. Our goal was to investigate the role of miR-425 and its downstream target Cofilin 2 (CFL2) on ANP and BNP expression in human CV disease (CVD). Hypothesis: We hypothesized miR-425, via CFL2, supresses NPs expression in vitro. MiR-425, CFL2 and NP levels were also determined in CVD patients. Methods: In vitro, human cardiomyocytes (HCM) were treated with vehicle (Veh), catecholamine isoproterenol (ISO) and cytokine endothelin (ET), miR-425 mimic. Cells were transfected with CFL2 plasmid or CFL2 siRNA. Normal (NM, n=100), Hypertension (HTN, n=30) and Acute HF (AHF, n=74) cohorts were studied. A confirmatory cohort was recruited. Plasma NT-proBNP, miR-425 were measured. In left ventricles (LV) from NM or HF (n=5 each), NP, CFL2 and miR-425 expression were assessed. Data expressed as means±SEM. * p<0.05 vs NM or Veh. Results: In vitro in HCM, treatment with ISO or ET in HCM reduced miR-425 and elevated NP mRNA levels. Furthermore, miR-425 mimic reduced Nppa (Veh: 1.0±0.03, mimic: 0.7±0.02*) and Nppb levels (Veh: 1.0±0.03, mimic: 0.5±0.01*). We showed that a top predicted target of miR-425, CFL2, was also reduced by the mimic. Further, NP mRNA was elevated by CFL2 overexpression and reduced by the knockdown of CFL2. In humans, MiR-425 was lower in HTN and AHF patients (NM: 0.15±0.03, HTN: 0.03±0.005*, HF: 0.01±0.003*) than NM. MiR-425 negatively correlates with NT-proBNP in NM and AHF cohorts. Downregulation of miR-425 was validated in a second AHF cohort. Similarly, in HF LV tissues, miR-425 (NM: 2.5±0.5, HF: 1.0±0.5*) was lower than NM group, while CFL2 and NP gene and protein expression were increased. Conclusion: In vitro, cardiac stress hormones downregulate miR-425 and increase NP gene expression, potentially through a novel target, CFL2. In CVD patients, miR-425 is lower, accompanied by an elevation of CFL2 and NP. Our findings implicate the pathway of stress hormones/miR-425/CFL2/NP production in CVD.

Background: An electrocardiogram (ECG)-based artificial intelligence (AI) algorithm has shown good performance in detecting hypertrophic cardiomyopathy (HCM AI-score). However, its clinical application may be challenging due to the low disease prevalence and potentially high false-positive rate when screening unenriched cohorts. Aims: To identify clinical characteristics associated with false-positive HCM AI-score results to improve screening tool application. Methods: From a cohort of 20,677 patients with a digital 12-lead ECG in routine clinical practice in 2021, we performed a detailed chart review of the 200 patients with highest HCM AI-score to determine their HCM status and collect clinical data. Stepwise forward logistic regression was used to create a clinical variable-based “candidacy for HCM screening” score (CHS score), differentiating true- and likely true-positive from likely false-positive HCM AI-score results. We then validated the CHS score in 200 patients with the highest HCM AI-scores from an independent cohort of 15,147 patients with an ECG in 2022. Results: Among the 200 patients in 2021 (median age 71 years, 48% female), 96 (48%) were likely false-positive HCM AI-score results, 71 (36%) definite or likely true-positive results, and 33 (16%) indeterminate. The CHS score included a history of surgical septal myectomy, coronary artery bypass graft surgery, cardiac valve replacement, and pacemaker, and had an AUC of 0.88 (95% CI 0.83-0.92) for the differentiation of true- versus false-positive AI results. In the 2022 cohort, the CHS score had an AUC of 0.82 (95% CI 0.76 - 0.88). After limiting the cohort to HCM candidates identified by the CHS score, the false-positive results rate was reduced to 27/114 (24%). Conclusions: By applying the CHS score to patients with positive HCM AI-screening results, the false-positive rate decreased from 49% to 24%. Utilizing a clinical model used in tandem with an AI model improved diagnostic yield.

Background: The bicuspid aortic valve (BAV) exhibits abnormal geometry and transvalvular flow and is susceptible to calcification with subsequent cardioembolic stroke from calcific embolic material. However, the description of embolic ischemic strokes in patients with BAV is limited to case reports. Methods: Consecutive patients from 1975-2015 with BAV (n=5401) at our institution were retrospectively identified. Patients with ischemic stroke before aortic valve replacement (AVR) were analyzed, and the stroke was characterized. Patients were grouped according to stroke etiology: calcific embolism from a BAV (BAV stroke); large artery atherosclerotic or lacunar stroke (LA stroke); and non-BAV, non-large artery embolic stroke (nLA stroke). Results: There were 83/5401 (1.5%) patients with ischemic stroke. Mean age was 54 ± 12 years and 28% were female. Stroke etiology was BAV stroke in 26/83 (31%), LA stroke in 23/83 (28%), nLA stroke in 30/83 (36%), and other in 4/83 (5%). Stroke was embolic in 72/83 (87%), as shown in Figure 1. CHA 2 DS 2 -VASc score was not different in patients with BAV stroke (1.4 ± 1.2) versus nLA stroke (1.8 ± 1.2, p=0.188) but was higher in LA stroke (2.3 ± 1.2, p=0.005 vs. BAV stroke). Recurrent stroke occurred in 41% overall (50% BAV stroke vs. 30% LA stroke vs. 47% nLA stroke, both p=NS vs. BAV stroke). BAV stroke was more commonly located in the retinal circulation (39% BAV stroke vs. 13% LA stroke [p=0.044] vs. 0% nLA stroke [p=0.002]). Patients with BAV and LA stroke were more likely to have moderate-to-severe aortic stenosis and undergo AVR sooner after stroke compared to patients with nLA stroke. Conclusions: Stroke is an important complication in patients with BAV. The most common type of stroke in BAV is embolic. Greater than one-third of embolic stroke resulted from embolism from a calcific aortic valve. Patients with BAV stroke commonly have a history of recurrent cerebral ischemic events, severe valvular disease, and proceed to AVR soon after stroke.

Background: Safety net hospitals treat a large burden of uninsured, or Medicaid insured patients, and have been linked to worse outcomes across several medical and surgical conditions. Currently, there is limited data on the effect of safety net burden on outcomes of inpatient cardiopulmonary resuscitation (CPR) for patients that suffered in-hospital cardiac arrest (IHCA) in the US. Hypothesis: Patients that experience IHCA in high burden safety net hospitals (HBH) will have worse outcomes compared to low burden safety net hospitals (LBH). Methods: Using the National Inpatient Sample database, from 2008 – 2018, we identified patients aged ≥ 18 years who experienced IHCA, using International Classification of Diseases (ICD) codes. Hospitals’ safety net burden was calculated from the proportions of Medicaid and uninsured patients using previously published methodology and categorized into LBH and HBH. Multivariate regression models were used to estimate the odds of key clinical outcomes Result: From 2008 to 2018, an estimated 555,016 unweighted adult hospitalizations underwent CPR for IHCA, out of which 19.2 % occurred at LBH and 55.2 % occurred at HBH. Compared with LBH, patients at HBH on average were younger 62 years ± 20 vs 67 years ± 17), less likely to be of White race, and more likely to be in the lowest median household income. On multivariate regression analysis, HBH was associated with lower chances of survival to hospital discharge (aOR 0.88; 95% CI 0.85 – 0.96) and lower odds of routine discharge (aOR 0.6; 95% CI 0.47 – 0.75)), compared to LBH. Patients who suffered IHCA in safety net hospitals with medium and large hospital bed size (aOR 0.96; 95% CI 0.94 – 0.98) and those publicly owned (aOR 0.95; 95% CI 0.92 – 0.98) were less likely to survive to hospital discharge. Median household income of patients in the 26 th – 100 th quartile and hospital location in the Midwest and Southern region were associated with better odds of hospital survival. Conclusion: Our study suggests that patients who experience IHCA at HBH had lower rates and odds of in-hospital survival and also less likely to be routinely discharged home. Patients’ income level and hospital-level characteristics appear to contribute to survival.

Background: Diastolic dysfunction (DD) is frequently present in patients with hypertrophic cardiomyopathy (HCM) due to abnormal left ventricular (LV) relaxation, wall hypertrophy, increased LV filling pressures and myocardial disarray and fibrosis, even though ejection fraction (EF) remains preserved until late stages. Our aim was to investigate in a large cohort whether contemporary markers of DD and increased filling pressures are associated with outcomes in these patients. Methods: We screened consecutive patients with HCM who had transthoracic echocardiography and no significant valvular heart disease. The associations of septal/lateral e’ velocity, E/e’, left atrial volume index (LAVi), and tricuspid regurgitant velocity (TR) with all-cause mortality were tested. A diastolic score (DS) was also calculated (1 point for each abnormality in e’, E/e’, TR, LAVi). Results: 1,496 patients with HCM were studied (mean age 52±15 yrs; 61% men; LV EF 69±7%; Table). Diastolic abnormalities were highly prevalent in these patients ( Table ). In the subset without septal reduction therapy (SRT; n=900), at a median followup of 9 years (IQR 7-11 yrs; n=78 deaths), increased E/e’ and DS were strongly associated with mortality (log-rank P <.0001 for both; Figure ). However, E/e’ did not remain significant in multivariable models after adjustment for known cardiac risk factors or other significant confounders ( Table ). In contrast, DS >2 remained independently associated with ~2-fold higher mortality risk (adjusted HR 1.91 [1.14-3.20, P =.01]; n=693; Table). In patients who underwent SRT (n=596), these associations showed the same trend but attenuated. Conclusion: In HCM patients who did not require SRT, the severity of DD was associated with mortality, independent of cardiac pump function or known cardiac risk factors. The composite score was more powerful than E/e’. Further studies are needed to fully understand the impact of DD in these patients with and without SRT.

Background: High-sensitivity (hs) cardiac troponin (cTn) assays quantifies cTn in most healthy men and women. Whether quantifiable cTn concentrations below the 99 th percentile upper-reference limit have short term prognostic implications in emergency department (ED) patients remains uncertain. Methods: Multicenter (n=22) United States (US) cohort of ED patients undergoing at least one hs-cTnT measurement (CV Data Mart Biomarker cohort). For this assay, the lowest reportable concentration is <6 ng/L. Sex-specific 99 th percentiles of 10 ng/L for women and 15 ng/L for men were used. The primary outcome was index hospitalization mortality. Results: A total of 85610 patients were examined, including 43043 women and 42567 men. A total of 775 index hospitalization deaths (0.91%) occurred, including 361 (0.84%) in women and 414 (0.97%) in men. Among women, baseline hs-cTnT concentrations were non-quantifiable (<LoQ) in 37.5%, quantifiable (LoQ-99 th ) in 21.6%, and increased >99 th percentile in 40.9%. Among men, baseline hs-cTnT concentrations were non-quantifiable (<LoQ) in 20.0%, quantifiable (LoQ-99 th ) in 37.4%, and increased >99 th percentile in 42.6%. Patients with higher concentrations were more likely to be older and had more comorbidities. Continuous baseline hs-cTnT (log) were associated with a higher odds of index hospitalization mortality (OR 1.26, 95% CI 1.24-1.28). Following multivariable analyses, quantifiable hs-cTnT (LoQ-99 th ) also were associated with index hospitalization mortality in all patients (OR 2.07, 95% 1.22-3.53), and in both women (OR 3.13, 95% CI 1.51-6.50) and men (OR 2.17, 95% 1.28-3.69) (Figure). Conclusions: Hs-cTnT concentrations within the reference range are more common in men than in women. Quantifiable hs-cTnT concentrations within the sex-specific reference range are associated with a higher risk of index hospitalization mortality, with a larger prognostic effect in women than in men.