Citations

Introduction: Asymptomatic LV systolic dysfunction is often underdiagnosed, leading to missed opportunities for treatment. In a recently completed pragmatic RCT, an AI algorithm performed on the ECGs ordered as part of routine practice increased early diagnosis of low EF. The current study aimed to understand whether the effectiveness of the AI algorithm integrated into routine care differed by the socioeconomic status of the patient. Methods: The main findings of the RCT were previously published. Clinicians in the intervention group had access to AI results (i.e., a positive or negative screening result, with positive results indicating a high likelihood of low EF). When a positive result was found, clinicians in the intervention group received an alert that encouraged them to order TTE if considered clinically appropriate. Clinicians in the control group did not have access or received alerts. Area deprivation index (ADI) was used to measure area-level social determinants of health. This study included 16,992 patients (control 8,225; intervention: 8,767) who had ECG performed for any indications between 8/5/2019 and 3/31/2020, no prior HF, and a valid address to derive ADI. The primary endpoint was a new diagnosis of EF≤50% within 3 months. Results: The mean age was 60.5±17.6 y. AI increased the diagnosis of low EF in the overall cohort (OR 1.42 [1.13, 1.78], p=0.01). The magnitude of benefit was greater in patients with higher socioeconomic status, e.g., living in an area that is less deprived (OR 1.88 [1.16, 3.05]), with higher median income, lower poverty rate, higher education level, better housing conditions, and higher proportion of white-collar workers, although the interaction was not statistically significant (Figure). Conclusions: AI enables early diagnosis of low EF and the magnitude of benefit might be numerically greater in patients with higher socioeconomic status, possibly due to variations in access to or referral for subsequent testing.

Introduction: Peripheral artery disease impacts 202 million patients worldwide and is commonly diagnosed via ankle-brachial index. PAD is associated with endothelial dysfunction, which is also common to venous thromboembolism formation. Despite the suspected overlap in pathogenesis, few studies exist investigating the association between these pathologies. We investigated whether PAD with low or elevated ABI is an independent risk factor for VTE. Methods: We reviewed medical records of patients ≥18 years old undergoing ABI measurement with or without PAD symptoms from 01/01/1996 to 08/31/2018 and classified patients by ABI: severely low (ABI 0.00-0.39), moderately low (0.40-0.69), mildly low (0.70-0.90), borderline (0.91-0.99), normal (1.00-1.40), and elevated (>1.40). The primary outcome was incident VTE event after ABI measurement, defined as deep vein thrombosis or pulmonary embolism. Multivariable Cox proportional regression was used to calculate hazard ratios (HR) with 95% confidence intervals after adjusting for age, sex, active smoking, cancer or VTE history, thrombophilia, anticoagulation, and revascularization within 14 days of VTE. Results: In 39,384 unique patients (mean age 66.3±14.2 years, median follow-up 34 months), 5,141 VTE events were observed. Increased VTE risk was observed in PAD patients with severely low ABI (HR 1.26, 95%CI [1.02, 1.29]) compared to patients with normal ABI after multivariable regression. Patients with elevated ABI did not demonstrate an increased risk of VTE. Conclusions: Patients with severe PAD are at higher risk for VTE than patients with normal ABI, which may be due to a multifactorial pathophysiology of profound endothelial injury as well as immobility due to claudication. Further exploration of VTE incidence in patients with severe PAD stratified by functional status is warranted to determine the optimal strategy to minimize thromboembolic morbidity and mortality in this population.

Introduction: Elastin-like polypeptides (ELP) are novel drug delivery vectors that can be fused to therapeutic agents and cell penetrating peptides (CPPs), slowing their plasma clearance and increasing uptake by target tissues. We developed a CPP-ELP fusion to a specific inhibitor of the p50 subunit of NF-kB (SynB1-ELP-p50i). We developed a swine model of chronic kidney disease (CKD) that also fosters hypertension, cardiac remodeling, and diastolic dysfunction, and observed that cardiac abnormalities associate with increased cardiac expression of NF-kB, a ubiquitous transcription factor that modulates cardiac inflammation, fibrosis, and vascular remodeling. Hypothesis: We aimed to define the feasibility and efficacy of intra-coronary (IC) SynB1-ELP-p50i administration to test whether a targeted inhibition of NF-kB can improve cardiac abnormalities in CKD. Methods: We first performed a biodistribution study (BDS) in 3 pigs, 4 hours after IC injection of fluorescently labeled SynB1-ELP-p50i (10 mg/kg). Then, CKD was induced in 6 pigs (bilateral renovascular disease and dyslipidemia), treated with a single IC SynB1-ELP-p50i or placebo at 6 weeks and observed for 8 more weeks. Cardiac morphology and function were quantified before/after treatment by echocardiography. After completion of the studies, pigs were euthanized and hearts excised for ex vivo studies. Results: Using IVIS technology, the BDS showed significant retention of SynB1-ELP-p50i in the heart. In the efficacy study, a single IC administration of IC SynB1-ELP-p50i reduced cardiac NF-kB expression, improved cardiac relaxation, and remodeling compared to untreated CKD (Figure). Conclusions: We show for the first time the feasibility of a targeted inhibition of cardiac NF-kB using ELP technology in a translational model of CKD and diastolic dysfunction. Our study may set the stage for a new therapeutic strategy using unique drug-delivery technology never tested before to protect the heart.

Introduction: Ventricular arrhythmias, including ventricular tachycardia (VT) and ventricular fibrillation (VF), are associated with high mortality and morbidity. Sedation through agents like benzodiazepines, propofol, and opiates are mainstays of treatment but are limited by side effects. Dexmedetomidine is a α2-presynaptic receptor agonist with a safe and efficacious sedative profile. Furthermore, it has been recently proposed as a sedative agent in VT due its additional antiarrhythmic properties. Methods: A systemic literature review was conducted of MEDLINE, EMBASE, Cochrane, and Scopus. Randomized controlled trials comparing the incidence of ventricular arrhythmias of dexmedetomidine with placebo or an alternative sedative agent were included. Two researchers independently extracted the data and performed quality assessments. Results: We identified 6 studies that met the selection criteria. Our meta-analysis demonstrated significant reduction of the overall risk of ventricular arrhythmias in patients receiving dexmedetomidine (RR 0.35, 95% CI 0.16, 0.76). Furthermore, there was no significant difference in risk of mortality (RR 0.59 95% CI 0.12, 3.02). Dexmedetomidine also significantly increased the risk of bradycardia (RR 2.78 95% CI 2.00, 3.87). There was no significant difference in risk of tachycardia (RR 0.59 95% CI 0.12, 3.02) or hypotension (RR 1.07 95% CI 0.64, 1.81). Conclusions: Our study demonstrates that the dexmedetomidine reduces the risk of VA by 65% compared to control. Further prospective research is necessary to clarify the antiarrhythmic and sedative properties of dexmedetomidine and its potential effect on patient outcomes.

Introduction: Left atrial appendage closure (LAAC) device for stroke prevention is a safe and effective alternative to oral anticoagulation (OAC) in patients with atrial fibrillation (AF). The safety of performing LAAC on uninterrupted warfarin (UW) compared to interrupted warfarin (IW) is currently unknown. Hypothesis: Complication rates of performing LAAC on UW vs. IW will be similar. Methods: We reviewed the data from the second half of PROTECT-AF trial, PREVAIL trial, CAP and CAP2 registries. Patients were categorized to the UW group if INR on the day of the procedure was ≥2 and to the IW group if INR was <2. Procedural complications within 7 days of LAAC were reviewed. An association between complications and AC strategy was analyzed. Results: Data from 1580 patients were reviewed and 294 patients (18.6%) received LAAC on UW. The UW group had a mean INR of 2.4±0.4 and IW group had a mean INR of 1.3±0.3. There were several differences in baseline characteristics: lower BMI in the UW group (28.6±5.3 vs 29.5±6.0, p=0.01), fewer patients with hypertension in the UW group (87.1% vs 91.1%, p=0.04), lower HAS-BLED score in the UW group (2.0±1.0 vs 2.1±1.0, p<0.01), and more patients with persistent AF in the UW group (37.1% vs 26.4%, p<0.01). Overall, there were no significant differences in total or individual complication rates between the two groups (UW 5.1% vs IW 6.1%, p=0.59). Although not statistically significant, lower event rates were noted in the UW group for the following: stroke (0% vs 0.3%, p>0.99), pericardial effusion requiring intervention (1.7% vs 1.8%, p>0.99), pseudoaneurysm (0% vs 0.4%, p=0.59), hematoma (0% vs 0.2%, p>0.99), and device embolism (0% vs 0.2%, p=1.0). The UW group had statistically insignificant higher events rates of AV fistula (0.3% vs 0%, p=0.19) and major bleeding requiring transfusion (1% vs 0.5%, p=0.38). In addition, there was no significant difference in periprocedural ischemic stroke (0% vs 0.3%, p>0.99). Conclusion: In this retrospective analysis, no significant difference was observed in procedural complication rates when performing LAAC on UW vs. IW. These results suggest that LAAC can be safely performed without interruption of OAC.

Introduction: The endothelium controls coronary blood flow (CBF) by regulating microvascular tone, which is an important index of microcirculatory health. The difference in vasomotor response of the microvasculature between males and females is not well described. Hypothesis: Males and females react differently to different doses of intracoronary (IC) acetylcholine (Ach) injections. Methods: Patients with angina and non-obstructive coronary artery disease (<50% stenosis) that underwent coronary reactivity study were enrolled. A doppler wire was positioned and incremental IC Ach doses were injected (10 -6 , 10 -5 , and 10 -4 mol/L). CBF (mL/min) was then calculated from CAD and doppler-derived flow velocity. Comparisons between the 2 sexes were performed. Results: A total of 1927 patients (mean age 51±13 years, 67% females) were included. Males were significantly younger (49±13 vs 53±12, P<0.0001) than females and had a higher smoking exposure rate (56% vs 41%, P<0.0001). Baseline (B) CBF was significantly lower in males (27.7 [19.2; 40.8] vs 30.2 [20.6; 43.4], P=0.04). The gap between females and males widened the first 2 doses, but then diminished after the highest dose (41.2 [24.5; 67.8] vs 44.5 [25.9; 72.0], P=0.09) (Fig 1A) . On multivariable analyses, female sex was an independent predictor of higher CBF at all doses (Estimate±StdError) (B= 1.14±0.53; 10 -6 : 1.59±0.61; 10 -5 : 2.54±0.82; 10 -4 : 2.70±1.2; P<0.05 for all). When calculating the %ΔCBF, females had a significantly larger augmentation of flow after the first 2 doses of IC Ach (10 -6 : 3 [-14; 24] vs. -2 [-16; 19], P=0.02; 10 -5 : 21 [-7;68] vs. 12 [-10; 50], P=0.003). However, with the highest Ach dose, there was an equalization of overall augmentation (10 -4 : 49 [-1; 109] vs. 46 [-5; 106], P=0.46) (Fig 1B). Conclusions: Females had higher CBF regardless of given Ach concentration. Females have a higher sensitivity to Ach at smaller doses, while males exhibit a greater vasodilatory reaction at higher doses.

Introduction: Coronary microvascular dysfunction (CMD) is associated with increased morbidity and mortality. Anemia is an important predictor of outcomes in several cardiovascular diseases, such as heart failure and coronary artery disease (CAD), however its significance in patients with non-obstructive CAD is not fully elucidated. Hypothesis: We hypothesized that anemia would be associated with CMD and future adverse outcomes. Methods: We enrolled 1334 patients with signs and/or symptoms of ischemia and with non-obstructive CAD (<50% angiographic stenosis) who underwent invasive CMD evaluation and had follow-up data. CMD was defined as coronary flow reserve (CFR) (hyperemic flow/baseline flow as measured by the doppler wire) of ≤2 in response to intracoronary adenosine injection. Anemia was defined as a Hgb < 13.0 g/L in males and <12.0 g/L in females. MACE was defined as any incidence of myocardial infarction, cardiac revascularization (PCI, CABG) and all-cause mortality. Results: Overall mean age was 51.3±12.4 years, 66% were female. Patients with anemia were more likely to be female and have diabetes mellitus. Anemics were more likely to be diagnosed with CMD (Odds Ratio 2.01, 95% Confidence Interval [1.14-3.54]; P = 0.02). This relationship remained significant even after adjusting for cardiovascular risk factors like age, sex, hypertension, diabetes mellitus and dyslipidemia (OR 1.84, 95% CI [1.03-3.29], P = 0.04). Furthermore, patients with anemia were more likely to experience MACE (OR 1.86, 95% CI [1.30-2.66], P = 0.001), independent of possible confounders (OR 1.84, 95% CI [1.27-2.69], P = 0.002). Conclusions: Anemia is an independent predictor of CMD and future adverse cardiovascular events in patients with NOCAD. Moreover, it was associated with an increased risk of future adverse events. Further studies are needed to elucidate whether treatment of anemia in this population translates into outcomes.

Introduction: Changes in coronary artery diameter (CAD) and coronary blood flow (CBF) in reaction to acetylcholine are important surrogates of endothelial health, and abnormalities in these parameters might represent early atherosclerosis. Menopause is associated with an increased risk of coronary artery disease, yet the role of menopause on the endothelium is not well described. Hypothesis: The vasodilatory response of the endothelium to acetylcholine (Ach) decreases after menopause. Methods: A total of 1271 (42% pre-menopausal) females with angina and non-obstructive coronary artery disease (<50% angiographic stenosis) that underwent coronary reactivity study were enrolled. A doppler wire was positioned and incremental Ach doses were injected (10 -6 , 10 -5 , and 10 -4 mol/L). CBF was then calculated from CAD and doppler-derived flow velocity. Comparisons between the pre-and post-menopause groups were performed. Results: Mean age of the pre-menopausal group was 44±10 years, while that of the post-menopausal 59±9 years. Pre-menopausal females had higher baseline CAD as compared to post-menopausal females (2.22 [1.90; 2.65] vs. 2.20 [1.85; 2.55] mm, P=0.03). However, this difference was nullified with subsequent doses of Ach (Figure 1A&B ). Pre-menopausal females had a higher baseline CBF than post-menopausal females (32.1 [21.7; 44.9] vs. 29.2 [19.8; 42.0] mL/min; P=0.01). This difference progressively increased with successive doses of Ach (10 -4 :49.5 [30.3; 77.0] vs. 41.7 [24.4; 69.0] mL/min; P=0.0002), revealing a greater microvascular vasodilatory response in pre-menopausal females (Cumulative %ΔCBF after highest dose= 60 [2.6; 122] vs 45 [-4; 98], P=0.002) ( Figure 1C&D ). Conclusions: Premenopausal females have greater sensitivity of the microvascular endothelium to Ach compared to post-menopausal, suggesting a possible role for estrogen in mediating the effect of stress on the microvasculature through the endothelium.

Introduction: Most of long QT syndrome (LQTS) is explained by pathogenic variants in KCNQ1 , KCNH2 , or SCN5A . However, ~10-20% of LQTS index cases remain genetically elusive following commercial genetic testing. Here, we identified and functionally characterized a novel LQTS genetic substrate in a multi-generational, “genotype negative” LQTS pedigree. Methods: The index case was a 40-year-old female with a history of syncope, seizures, ventricular fibrillation, and a family history of LQTS and sudden death. Although anticipated to have KCNH2- mediated LQT2, commercial genetic testing of all LQTS-causative genes was negative. Genome sequencing and variant analysis was performed on 6 affected family members. Patient-specific and CRISPR/Cas9 “gene-corrected” isogenic control induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated. RT-PCR was used to determine the effects of the identified variant on splicing. Action potential duration (APD) and field potential duration (FPD) were measured using voltage-sensing dye (Fluovolt) and microelectrode array, respectively. Results: No ultra-rare, nonsynonymous heterozygous variants co-segregated among the 6 LQTS phenotype-positive individuals. Instead, a deep intronic KCNH2 variant (c.3331-316 G>T) was present in all affected individuals. RT-PCR analysis of patient-specific iPSC-CM-derived RNA revealed that c.3331-316 G>T creates a novel 89 base-pair exon residing between canonical exons 14 and 15 of KCNH2 that results in a frame-shift variant annotated as p.S1112Pfs*171. The APD 90 was significantly longer in p.S1112Pfs*171-iPSC-CMs (647 ± 12 ms, n=50) compared to isogenic control iPSC-CMs (412 ± 10 ms, n=50, p < 0.0001). Further, the FPD was significantly longer in p.S1112Pfs*171-iPSC-CMs (349 ± 8 ms, n=48) compared to isogenic control iPSC-CMs (209 ± 10 ms, n=20, p < 0.0001). Conclusions: A novel deep intronic KCNH2 variant was identified in a multi-generational genetically elusive LQTS pedigree. The patient-derived and isogenic control iPSC-CMs establish that the p.S1112Pfs*171-KCNH2 variant is the monogenetic cause for this family’s LQTS. As suggested by the phenotype, this family indeed has KCNH2 -mediated LQT2 albeit stemming from a deep intronic variant .

Introduction: Diabetes mellitus and insulin resistance are associated with accelerated vascular injury and progression of coronary atherosclerosis. CD34 + progenitor cells are mobilized and recruited to repair the endothelial and vascular damage. Hypothesis: We hypothesized that the interaction of insulin levels and retention of CD34+ progenitors in the coronary arteries will be different between patients with and without insulin resistance. Methods: In patients with no obstructive coronary artery disease (NOCAD: <40% angiographic stenosis), blood samples were collected concurrently from the proximal aorta and the coronary sinus, and CD34+ cells counted using flow cytometry. CD34+ cells gradient was calculated by subtracting aortic from coronary sinus cell counts, with a higher gradient reflecting lower retention. Patients on antidiabetic medications were excluded. Insulin resistance (IR) was estimated as HOMA-IR index ([insulin]*[glucose]/405)) ≥2. Results: Of 128 patients (mean age 51±11 years, 77% females), 60 (47%) had IR (mean age 51±10 years, 73% females) and 68 (53%) did not (mean age 50±13 years, 79% females). The groups did not differ in age, sex or LDL cholesterol. The IR group had higher BMI and triglyceride levels and lower HDL cholesterol. CD34 + cell gradient correlated directly significantly with insulin levels in patients without IR (r=0.25, p=0.04) (Fig1A) , but inversely in those with IR (r=-0.39, p=0.01) (Fig1B) . Both associations remained significant after adjustment for age, sex, and BMI (IR: r=-0.39, p=0.02; no IR: r=29, p=0.04). Conclusions: In NOCAD patients with IR, higher levels of serum insulin were associated with increased retention of CD34 + cells in the coronary arteries. The current study supports a potential role for CD34 + cells for vascular repair in patients with IR.