Citations

Introduction: Platelets are heavily implicated in angiogenesis; however, the underlying mechanism remains relatively uncharacterized. The goal of this study was to evaluate the angiogenic potency of a platelet-derived regenerative exosome product (PEP) in an effort to develop a novel treatment for peripheral arterial disease. Here, we evaluated the mechanistic basis of PEP in angiogenesis and it’s use In Vivo in a rodent hind limb ischemia model. Methods/Results: Under Current Good Manufacturing Practices, conditioned medium from apheresis platelet cultures was purified to acquire the exosomes. PEP, enriched in exosome markers CD63, CD9 and Flotillin, induced human umbilical vein endothelial cell (HUVEC) proliferation, migration, and vascular tube formation In Vitro. Proteomic evaluation of PEP highlighted receptor tyrosine kinase (RTK) pathways and western blot validation demonstrated induction of phospho-MAPK and phospho-AKT following PEP treatment of HUVECs. Systematic evaluation of RTK receptor involvement was performed using small molecule inhibitors and receptor knock-down in HUVECs, ruling out RTK activation as a mode of action. However, small molecule inhibition of PI3 kinase demonstrated elimination of PEP-induced AKT phosphorylation and reduction in PEP-induced angiogenesis In Vitro measured by HUVEC proliferation and migration. In Vivo, evaluation of angiogenesis was performed in a rodent model of hindlimb ischemia treated with PEP embedded in fibrin glue (PEP/TISSEEL). Blood flow was evaluated by SPY angiography on day 0 pre- and post-operation, day 21, and day 28. Animals treated with PEP/TISSEEL showed a significant increase in blood flow compared to sham and TISSEEL treated animals (percent perfusion at 28 days: sham 40.9%, TISSEEL 44.3%, PEP/TISSEEL 100.2%), with significant increase in vascular area on histology (at 28 days vascular area (μm 2 )/muscle area(μm 2 ): healthy control 12.71, sham 4.66, TISSEEL 4.76, PEP/TISSEEL 15.54). Conclusions: Exosome driven activation of PI3 kinase can induce angiogenesis both In Vitro and In Vivo. PEP provides a novel, clinical-grade, off-the-shelf therapy to promote angiogenesis for the treatment of peripheral arterial disease.

Background: Little is known about the relationship between carotid plaque formation and cognitive function in a middle-aged population. Hypothesis: We hypothesize that there will be an association between carotid atherosclerotic burden and cognitive function in middle-aged adults. Aim: The purpose of the present study is to examine the relationship between carotid artery (CA) plaque and cognitive function in middle-aged white and black men and women from the Bogalusa Heart Study (BHS) cohort. Methods: We included a total of 1,107 BHS participants with echocardiography and carotid ultrasound performed between 2013 and 2016. Cognitive function was quantified in a global cognitive score (GCS) comprised of the z standardized sum of 7 neuropsychiatric tests. CA plaque was defined by carotid intima media thickness ≥1.5mm in any segment of the CA including right and left common artery (RCC/LCC), bulbs (RCB/LCB) as well as right and left internal carotid artery (RIC/LIC). We compared demographic, clinical, and echocardiographic characteristics in participants with or without CA plaque and used linear regression analysis for the association between CA and GCS adjusted for age, sex, race and education. Results: Among all, 373 (33.7%) of participants had one or more CA plaque. The most common locations of CA plaque formation differed according to laterality, with 230 (61.7%), 189 (50.7%), 108 (29.0%), 92 (24.7%), 83 (22.3%), 10 (2.7%) participants having plaque in the RCB, LCB, LCA, RIC, LIC, and RCA, respectively. Participants with CA plaque were likely to be older (49.9 vs. 47.2 years), male (52 vs.38.9%), white (70.2 vs.63.4%,), have larger left ventricular (LV) end-diastolic volume (97.4 vs.94 ml) and LV mass index (83.4 vs.76.3 g/m 2 , all p -value<0.01), but similar LV ejection fraction (60.1 vs.60.0%) as compared to those without CA plaque. Moreover, CA is associated with poorer cognitive function (GCS, standardized β coefficient=-0.07; p =0.02) adjusted for age, sex, and race. However, the association was attenuated after adjusting for education. Conclusion: CA plaque was highly prevalent and inversely associated with cognitive function. The association was attenuated by education emphasizing the importance of social determinants in cognitive health.

Introduction: Atrial fibrillation (AF) is the most prevalent arrhythmia, placing a substantial burden on the healthcare system. Patients with AF are cared for in a variety of settings including primary care and cardiology clinics, while some require cardiac electrophysiology (EP) clinics offering specialized drugs or procedures. Appropriate triage of AF referrals to these specific clinics will lead to timely and appropriate care and reduce inefficiency in the health system. Goal: To develop a machine learning (ML) model to triage AF referrals to a large Cardiology center to either the Cardiology or EP clinic based on likelihood of requiring an invasive EP procedure or initiation of antiarrhythmic drug. Methods: We retrospectively analyzed 6,755 patients who were referred to CV with referral diagnosis of AF (mean age 70 ± 11 years, 66% male). We employed multiple input variables to predict the suitability for EP clinic defined as need for initiating an antiarrhythmic drug or an invasive EP procedure. These encompassed patient demographics, relevant comorbidities, medications, prior procedures, medical notes analyzed using natural language processing (NLP), and Holter monitoring data. Results: For internal referrals, XG boost model performed the best with AUC at 79%, accuracy at 72%, and F1 score at 68%. This model produces true positive (TP) at 68% and true negative (TN) at 74%, which was better in comparison with triaging using NLP only (AUC = 69%, TP = 58%, TN = 61%), Holter only (AUC = 52%, TP = 51%, TN = 77%), and NLP/Holter (AUC = 67%, TP = 60%, TN = 60%). When supplementing ML model with Holter readings on average HR ≥ 100 and maximum HR ≥ 150, the results can be improved to TP at 70% and TN at 73%. Conclusions: Our model effectively identifies patients who are more likely to require specialized EP care, enabling the automation and increased efficiency of the AF referral triage process. Prospective validation studies are paramount in determining the true value of this tool.

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been demonstrated to improve outcomes in congestive heart failure (HF). However, their effect in hypertrophic cardiomyopathy (HCM) is unknown. Research Question: Can SGLT2i improve clinical outcomes in HCM patients? Methods: Using TriNetX Global Research Network from March 2013 to February 2021, patients diagnosed with HCM (ICD-10 codes I42.1, I42.2) were identified and categorized into 2 groups: those on SGLT2i vs. those who are not. To avoid inclusion of other causes of left ventricular hypertrophy, patients with aortic stenosis or systemic hypertension were excluded. Propensity score matching (PSM) was used to limit confounders. Primary outcome was all-cause mortality and secondary outcomes were HF exacerbation, all-cause hospitalization, and documented cardiovascular symptoms (chest pain, dyspnea, palpitations, or leg edema) over a 2-year follow-up period. Results: A total of 27,561 HCM patients were identified; 408 (1.5%) on SGLT2i and 27,153 (98.5%) were not. Patients on SGLT2i were older (55 ± 15 vs. 48 ± 19, p<0.01) and had more comorbidities, including a nearly 6-fold higher prevalence of diabetes mellitus (44% vs. 7%, p<0.01) and congestive HF (65% vs. 10%, p<0.01). After PSM, each group consisted of 355 patients. HCM patients on SGLT2i had lower rates of all-cause mortality (OR 0.22 [95% CI: 0.12, 0.39]; p<0.01), hospitalizations (OR 0.72 [95% CI: 0.53, 0.98]; p=0.04), and cardiovascular symptoms (OR 0.71 [95% CI: 0.52, 0.97]; p=0.029) when compared to patients not on SGLT2i. There was no statistical difference in the rate of HF exacerbation (OR 0.82 [95% CI: 0.54, 1.24]; p=0.3). Conclusion: In this large dataset, SGLT2i use in a select subset of HCM patients was associated with improved survival, less hospitalizations, and fewer cardiovascular symptoms. These data support future randomized trials to evaluate the efficacy and safety of SGLT2i in more diverse HCM patient populations.

Background: Catheter ablation is an effective tool to reduce ventricular tachycardia (VT) burden. There is a lack of robust data studying the characteristics and outcomes of VT ablation in patients with ischemic (ICM) versus non-ischemic cardiomyopathy (NICM). Aims: The aim of this study was to assess the impact of ICM vs NICM on outcomes of VT ablation. Methods: A single-center, retrospective study of patients undergoing catheter ablation for VT was conducted. Results: A total of 168 patients, undergoing 200 VT ablation procedures, were included in this study. NICM group (112 procedures) was compared to ICM group (88 procedures). Patients in the ICM group were older (66.6 ± 13.4 vs 58.9 ± 14.4 years) and had higher rates of prior myocardial infarction (65.9% vs 3.6) and coronary artery bypass graft surgery (40.9% vs 1.8%). Overall, ICM group had more comorbidities like hypertension (80.7% vs 52.7%), diabetes mellitus (23.9% vs 12.5%), chronic kidney disease (45.5% vs 35.7%), stroke (17% vs 7.1%), and lower left ventricular ejection fraction (36.8 ± 13.2% vs 43.1 ± 14.7%). The ICM group had lower incidence of prior cardiac valvular surgery (9.1% vs 29.5%). The inducibility of VT (93% vs 93.5%; p= 1.0) and the number of different VT morphologies induced during the case (1.9 ± 1.5 vs 2.3 ± 2.5; p=0.19) was similar between the two groups. There was no acute mortality in either group. There was a non-significant trend towards greater VT recurrence in the NICM group (43.2% vs 33.3%, p= 0.19). However, patients with NICM had a lower VT-free survival as determined by Kaplan-Meier analysis (p=0.05) [Figure]. Long term mortality was higher in ICM group when compared to NICM group (18.2% vs 8.9%, p<0.01). Conclusion: Patients undergoing VT ablation in the NICM group when compared to the ICM group were noted to be younger, had fewer comorbidities, and lower long-term mortality. However, they had significantly less VT-free survival, likely owing to more challenging substrate responsible for VT.

Introduction: Patients with coronary artery disease (CAD) not amenable to revascularization are reported to have a 3-year mortality >14%. Advances in treatment modalities including medical management, rotational atherectomy, balloon lithotripsy, and drug-eluting stents work for focal disease but poorly treat diffuse CAD. In a porcine model of in-stent restenosis, we here evaluated whether a pro-angiogenic platelet-derived exosome product (PEP) could be delivered into the perivascular space to foster collateral vessel formation. Methods/Results: Cobalt chromium stents were placed and were oversized by 1 mm in the left anterior descending (LAD) and posterior descending arteries (PDA) of sus scrofa domesticus pigs. In-stent restenosis was angiographically visualized at the 2-month timepoint, with hemodynamic significance documented with fractional flow reserve (FFR) of <0.8. To document feasibility of PEP delivery into the perivascular space, exosomes were labeled with a far-red fluorescent tag and delivered into the perivascular bed. Here, the Bullfrog® micro-infusion catheter was positioned either in the great cardiac vein or the middle cardiac vein and PEP was delivered with the microneedle pointed towards the LAD or the PDA. Biodistribution demonstrated exosome retention and uptake around cardiac veins. Using the Bullfrog® technique, PEP was delivered in the perivascular space adjacent to areas of significant coronary stenosis. Initial results 1-month post-treatment demonstrated improved FFR of treated stenotic vessels (from 0.68 to 0.85), while untreated vessels demonstrate no change from previous FFR measurement (from 0.79 to 0.78). Conclusions: Here, exosome-mediated angiogenesis in the perivascular space improved coronary blood flow, distal to areas of stenosis. In patients with diffuse CAD, delivery of biotherapy in cardiac veins running anatomically parallel to stenosed epicardial arteries provides a novel therapeutic opportunity to supplement the existing armamentarium of therapies available for in-stent restenosis.

Background: We have previously demonstrated by performing a genome-wide association study that a genetic locus resulting in ↓CDCP1 expression was associated with myocardial recovery in patients with dilated cardiomyopathy (DCM). We have subsequently shown that ↓CDCP1 decreases human cardiac fibroblast proliferation in vitro , however, its potential role in modulating cardiac fibrosis and function in vivo is unknown. Methods: A Cdcp1 knock-out (KO) mouse was generated on FVB/NJ background. Angiotensin II/Phenylephrine (AngII/PE) or saline was infused by an osmotic pump into mice ( Cdcp1 KO n=20; wild type/wt n=18) for 4 weeks. Echocardiography was performed at 0 and 4 weeks. Picrosirius red (PSR) staining was performed on cross-sectional heart tissue to identify cardiac fibrosis, which was quantified, using ImageJ software, as a percentage of left ventricular (LV) area stained by PSR. Results: LV mass index (LVMI) significantly increased in AngII/PE wt mice as compared to saline wt (figure a. 3.65±0.15 mg/g vs 3.05±0.17mg/g, p=0.01), however, AngII/PE Cdcp1 KO mice had significantly decreased LVMI as compared to AngII/PE wt mice (figure a. 3.17±0.09 mg/g vs 3.65±0.15 mg/g, p=0.01). In addition, fractional shortening trended higher in AngII/PE Cdcp1 KO mice as compared to AngII/PE wt mice (figure b. 50.36±2.06% vs 45.48±1.43%, p=0.07). Extent of cardiac fibrosis was significantly higher in AngII/PE wt mice as compared to saline wt (figure c. 15.79±0.49% vs 7.93±0.39%, p<0.0001), however AngII/PE Cdcp1 KO mice had significantly reduced cardiac fibrosis as compared to AngII/PE wt mice (figure c. 9.41±0.43%, p<0.0001). Conclusions: CDCP1 KO significantly reduces pressure over-load induced LV hypertrophy and cardiac fibrosis. Its role as a novel therapeutic target in attenuating fibrosis and improving cardiac function in DCM needs to be further explored.

Introduction: Rate of aortic stenosis (AS) progression in patients with concurrent atrial fibrillation (AF) has not been previously described. Objectives: To describe changes over time in aortic valve area (AVA) and associated hemodynamics during AS progression in patients in AF versus sinus rhythm (SR). Methods: Patients with AVA ≤ 1 cm 2 and preserved left ventricular ejection fraction ≥50% were identified from the Mayo Clinic Echocardiographic Laboratory Database. Serial echocardiograms prior to the development of AVA ≤ 1 cm 2 (Time 0) were examined. Inverse probability weighting was used for statistical analysis. Results: A total of 166 patients were included (SR=79 and AF=87), mean age 78.1 ± 7.8 years, females 31%. The rates of AVA reduction (-0.14±0.01 vs -0.12±0.01 cm2/year, p=0.31) and increase in trans-aortic peak velocity (+0.23 ± 0.02 vs +0.22 ± 0.02 m/sec, p=0.55) and mean gradient (MG) (3.9 ± 0.3 vs 3.8 ± 0.4 mmHg, p=0.83) did not differ between AF and SR (Figure 1). However, AF was associated with systematically lower forward stroke volume index (SVi), peak velocity and MG for the same AVA compared to SR (p<0.04 for all) throughout AS progression. When AVA reached 1 cm 2 , SVi (38.8±6.6 vs 45.7 ±8.9, p=0.02), peak velocity (3.9 ± 0.6 vs 4.1 ± 0.6 m/sec, p=0.04) and MG (36.6±10.9 vs 41±12.8 mmHg, p=0.03) were lower in AF compared to SR. Conclusions: The rate of AS progression was not different in AF versus SR. However, forward flow was systematically lower in AF resulting in discordant AS during AS progression and when AVA reached 1 cm 2 . Doppler velocity and MG criteria for severe AS appear to be lower in AF versus SR which has implications for timely diagnosis of severe AS and patient management.

Background: Recently, our team developed an end-to-end artificial intelligence (AI) framework that can successfully estimate left ventricular ejection fraction (LVEF) from echocardiogram videos. However, this framework requires specific views (A2C and PLAX), and cannot estimate LVEF for studies from which these views are missing. Goal: To develop a deep learning model to estimate LVEF from any type and number of echocardiogram video(s). Methods: We built a deep learning model for B-mode echocardiogram videos of the left ventricle (A2C, A3C, A4C, or PLAX views), using retrospective transthoracic echocardiography (TTE) data. The model was evaluated with two test datasets: one with random valid (i.e., showing the left ventricle) views, and one with preselected views (both having 433 patients). Later, the model was tested with a prospective patient cohort that had both TTE and point-of-care ultrasound (POCUS) data collected simultaneously (393 patients). Results: On the retrospective TTE test set, we observed excellent performance (five random valid views per study: RMSE of 6.87% and Pearson correlation (PC) of 0.82 on LVEF estimation, and an AUC of 0.96 (95% CI: of 0.94-0.98) on low LVEF classification (<=40%); preselected views: RMSE of 6.75%, PC of 0.83, and an AUC of 0.96 (95% CI: 0.94-0.98)). For both TTE and POCUS data from the prospective cohort, we also observed strong performance (TTE: RMSE of 5.62%, PC of 0.87, and an AUC of 0.97; POCUS: RMSE of 6.12%, PC of 0.84, and an AUC of 0.96). For the prospective test sets as well as for the retrospective TTE test set with preselected views, results reflect the estimated LVEF average of A2C, A3C, A4C, and PLAX videos from each patient. Conclusions: For both TTE and POCUS data, the current model showed strong performance which was comparable to that of our previously established view-specific model. Alongside this comparable performance, the current model surpasses our previous model in terms of flexibility, as it isn't dependent on view classification and allows a broader selection in terms of the number and types of videos per study or patient. This innovative approach could prove particularly beneficial in point-of-care situations in which it may not be feasible to obtain high-quality, view-specific videos.

Introduction: Data on use of ICE guidance in TEER procedure is limited to case reports and small case series. Our study aims to assess the feasibility, safety, utilization patterns and clinical outcomes of mitral TEER procedure with ICE guidance using a nationally representative real-world cohort of patients.Hypothesis: There is no difference between ICE-guided TEER and TEE-guided TEER in the clinical outcomes and complications. Methods: This study used the National Inpatient Sample database from quarter 4 of 2015 to 2020. We used a propensity-matched analysis and adjusted odds ratios for in-hospital outcomes/complications. A P value of <0.05 was considered significant. Results: A total of 38,770 weighted cases of mitral TEER were identified. Of the included patients 665 patients underwent ICE-guided TEER while 38,105 had TEE-guided TEER. There were no differences in the in-hospital mortality between both groups (2.5% vs. 3.0%, p=0.58). Adjusted odds of in-hospital mortality (aOR 0.83, 95%CI [0.42-1.64]) were not significantly different. There were no differences in periprocedural complications including cardiac (aOR 0.85, 95%CI [0.54-1.35]), bleeding (aOR 1.45, 95%CI [0.93-2.33]), respiratory (aOR 0.88, 95%CI [0.61-1.25]), and renal (aOR 0.89, 95%CI [0.66-1.20]) complications between patients undergoing ICE-guided versus TEE-guided TEER. There was no difference in GI complications between both groups (aOR 1.11, 95%CI [0.46-2.70]). The adjusted length of stay was less among ICE-guided TEER (median: 1 vs. 2, p<0.01) with no differences in costs of hospitalization ($137,312 vs. $153,773, p=0.06), Conclusions: In conclusion, ICE-guided mitral TEER is safe when compared with TEE guided TEER with no significant differences in in-hospital mortality, cardiac, bleeding, respiratory, and renal complications. The length of stay in ICE group is shorter as compared with the TEE group.