bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 21351: Intravascular Ultrasound-Guided vs. Angiography-Guided Intervention in Coronary CTO: Report From a Seven Year National Data
Authors: Patel Prashant , Patel Nirali , Lahewala Sopan , Arora Shilpkumar , Tripathi Byomesh , Kumar Varun , Badheka Apurva
Published: March 2022

Background:
Intravascular ultrasound (IVUS) has been used for a long time to guide percutaneous coronary intervention in different subsets of coronary lesions and could be used to navigate guidewire within the CTO segment. However, previously published national data demonstrating the role of IVUS in CTO appears sparse.

Methods:
HCUP’s Nationwide Inpatient Sample (NIS) database from 2008-2014 was utilized to identify CTO (414.2), IVUS (00.24) and PCI using appropriate ICD-9 codes. Logistic regression analysis was used to adjust for confounders for our outcome variable of inpatient mortality.

Result:
878112 CTO admissions were identified during study period, of which 47.6% went for revascularization with PCI (26.7% female, 69.8% white, and 51.1% age ≥ 65). IVUS was used in 5.4 %(22730) of these CTO PCI. Univariate anlaysis revealed significantly different distribution of baseline risk factors (Table 1a). In hospital mortality was lower (1.86% vs 2.99%, p<0.0001) in IVUS group. Cost of care was higher in IVUS group while there was no difference in length of stay. After adjusting for confounders, in our multivariable analsis, use of IVUS was associated with reduced odds (0.64, CI 0.49-0.84, p=0.0012) of in hospital mortality(Table 1b).

Conclusion:
Intravascular ultrasound imaging was associated with lower in-hospital mortality compared to conventional angiographic approach in recanalization of CTO in this large national representative sample. Further research exploring role of IVUS in other outcomes such as procedural complications may establish it as an intergral part of CTO PCI.
Abstract 21353: Ccn5 Gene Therapy Suppresses Arrhythmias by Reversing Fibrosis in Mice With Chronic Angiotensin II Infusion
Authors: Raad Nour , Jeong Dongtak , Park Woo Jin , Akar Fadi G
Published: March 2022

Background:
Increased angiotensin II (ANG) levels elicit profibrotic effects which promote ventricular tachyarrhythmias (VT).

Hypothesis:
Gene delivery of the matricellular protein CCN5 ameliorates ANG related VT by reversing fibrosis.

Methods:
8-10 wk old mice underwent ANG infusion (3mg/Kg/d) for 2wk after which they received 5E11 drp AAV9.CCN5 (ANGII+CCN5, n=8) or empty vector (ANGII, n=8) and were maintained for another 2wk. Optical mapping was performed in hearts that were challenged with right atrial (RA) burst trains (20Hz, 5-20 sec) to determine VT propensity. Fibrosis was assessed using trichrome staining.

Results:
VT was induced in 6/8 ANG, 2/8 ANG+CCN5, and 1/3 control hearts. A total of 34 trains elicited 13 VT episodes (38.4% rate) in ANG whereas 150 trains yielded only 6 episodes in ANG+CCN5 (4.0%). ANG increased the transepicardial APD gradient by causing selective APD prolongation on the RV side which was partially reversed by CCN5. No differences in the APD gradient were found between VT (+) and VT (-) hearts. Activation mapping revealed fixed lines of conduction block leading to onset of VT in ANG hearts. In contrast, RA trains caused shifting ventricular activation patterns that were normalized following the train in ANG+CCN5 (Fig). Extensive fibrotic lesions in ANG were reversed by CCN5 (Fig).

Conclusions:
Reversal of fibrosis by chronic CCN5 gene therapy suppresses the incidence of ANG related VT.
Abstract 21362: The Combination Antiretroviral Therapy (cart) Inhibits Efferocytosis-Related Gene Expression via Activating P90rsk and Accelerates Atherosclerosis
Authors: Le Nhat Tu , Singh Meera V. , Ko Kyung Ae , Heo Kyung-sun , Tao Yunting , Medina Jan , Thomas Tamlyn , Stirpe Nicole E. , Lu Wang , Tyrell Alicia , Gates Kathleen J. , Qui Xing , Fujiwara Keigi , Maggirwar Sanjay B. , Schifitto Giovanni , Abe Jun-ichi
Published: March 2022

Background:
Increased incidence of cardiovascular disease (CVD) in HIV patients has been established, but the consequence of anti-HIV therapies in CVD is unclear. The activation of p90RSK in endothelial cells is a critical event in atherosclerosis, but its role in macrophage is unknown.

Hypothesis:
macrophage p90RSK plays a role in anti-HIV drug-induced CVD and atherosclerosis.

Methods and Results:
In macrophages, efferocytosis-related signaling was upregulated and inflammatory gene expression was down-regulated in a p90RSK activity-dependent manner. Using Lysm-Cre dominant negative (DN) p90RSK transgenic mice in LDLR
-/-
background fed a high-cholesterol diet, we found that p90RSK activation increases plaque formation, inducing pro-atherogenic phenotypes and enhancing M1 polarization. Every cART regimen we tested, except backbone regimen, activated macrophage p90RSK, reduced efferocytosis, and increased M1-type related gene expression. In human, peripheral monocytes were isolated from HIV infected individuals on stable cART for at least 1 year and with viral load ≤50 copies/mL and also from HIV negative and non-cART treated controls matched for age, gender, environment and Reynolds CVD risk score. We found significantly increased p90RSK activation in the cART-treated group, and additional treatment of low dose of H
2
O
2
(200 nM) accelerated p90RSK activation more in the macrophage isolated from cART-treated patients than those in control patients
in vitro
.

Conclusions:
Our results demonstrate that p90RSK is robustly activated by anti-HIV drug treatments known to be a high CVD risk. This activation culminates in reduced activity of macrophage efferocytosis, thereby accelerating atherosclerotic plaque formation. Monocyte/macrophage p90RSK can be a good target and an excellent biological marker to prevent and predict drugs-induced CVD.
Abstract 21363: Etiologies and Trends of Readmission in Patients With Takotsubo Cardiomyopathy
Authors: Kundoor Vishwa , Tripathi Byomesh , Arora Shilpkumar , Nalluri Nikhil , Kumar Varun , Lahewala Sopan , Patel Nirali , Patel Neil , Patel Prashant , Badal Madan , Gopalan Radha , Patel Nileshkumar , Deshmukh Abhishek
Published: March 2022

Introduction:
Takotsubo cardiomyopathy (TTC) is diagnosed in 1-2% of the patients presenting with troponin positive suspected acute coronary syndromes(ACS). Rising trends of adverse events in patients with TTC, makes it imperative to explore causes and predictors of readmission in this patient population.

Methods:
National Readmission Data (NRD) 2013-14 was utilized to select study cohort. International Classification of Diseases, 9th Revision (ICD-9-CM) diagnostic code 429.83 was used to identify takotsubo cardiomyopathy. Admissions within 90 day of index admission were considered as early readmissions. Readmission etiologies were identified by ICD-9-CM code in primary diagnosis field of readmissions. Hierarchical multivariate models were used to evaluate predictors of early readmission.

Results:
A total of 12255 patients were identified during study period out of which 23.92% (n=2932 with 4224 readmissions) patients were readmitted within 90 days of discharge following index admission. Most common etiologies for readmission were cardiac (18.56%), respiratory (17.20%), GI renal (9.10%), infections (13.12%) and neurological complications (5.88%). Among cardiac complications acute heart failure was the most common etiology (7.48%). Highest number of readmissions happened on first day after discharge (n=125) and within 33 days after discharge, >50% of readmissions took place (n=2136).

Conclusions:
Patients with TTC are highly likely to be readmitted with first month after discharge, most likely secondary to cardiac or respiratory complications. These findings warrant close post discharge transition to reduce morbidity and improve health care outcomes.
Abstract 21365: Intralipid Fails to Rescue Liposomal Bupivacaine (Exparel)-Induced Cardiac Arrest in Rats
Authors: Bernardo Marsha , Cao Nancy , Moazeni Shayan , Marijic Buljubasic Anamaria , Marijic Buljubasic Andriana , Rahman Siamak , Eghbali Mansoureh , Umar Soban
Published: March 2022

Background:
Exparel is a formulation of bupivacaine encapsulated in multi-vesicular liposomes, developed for post-surgical anesthesia. The liposomes have been shown to increase the drug’s stability and extend its duration of action. Exparel may prevent accumulation of bupivacaine in blood and/or tissue; thus, decreasing risk of central nervous or cardiovascular toxicities. However, administration of Exparel has its risks. The maximum dosage of Exparel for adults is ~266 mg, but the maximum mg/kg dosing limit is unknown. The role of Intralipid (ILP, 20%) for reversal of Exparel toxicity is not known. Our aim is to determine toxic dose of Exparel in mg/kg and if ILP can reverse its cardiotoxic effects in rats.

Methods:
Female rats (~250 gm, n=6) were used for the study. Asystole was attempted with different IV doses of Exparel (25 mg/kg, 15 mg/kg, 7.5mg/kg over 10 seconds). For the second part of the study, asystole was induced with Exparel (15 mg/kg over 10 sec, IV), and resuscitation with ILP (5 ml/kg bolus and 0.5 ml/kg/min maintenance) was started immediately along with chest compressions. Heart rate (HR, beats per min) and ejection fraction (EF, %) were measured using echo at 1, 5, and 10 min.

Results:
We found that a dose of 25 mg/kg of Exparel caused cardiac arrest immediately. Next we decreased the dose of Exparel to 15 mg/kg, that also caused immediate cardiovascular collapse. Exparel 7.5 mg/kg did not induce cardiac arrest; instead, it caused wide complex tachycardia that self resolved in 5 min. ILP rescue of Exparel cardiotoxicity was found to be unpredictable (n=3). EF, HR and EKG improved after cardiac arrest the most at 1 min after ILP. At 1 min, EF was 42.8+/-15% and HR was 169.3 +/- 25 bpm. ILP rescue of Exparel cardiotoxicity was not sustained contrary to ILP’s rescue of Bupivacaine cardiotoxicity in rats. EF and HR continued to deteriorate when measured at 5 and 10 min, with 2 out of 3 rats with EF=0 at 5 and 10 min.

Conclusion:
We found a dose of Exparel that reliably induced cardiotoxicity in rats. ILP is unreliable in rescuing Exparel induced cardiotoxicity at the dosage regimen typically used for rats with Bupivacaine cardiotoxicity. More experiments are needed to determine ILP’s dosage that can reliably reverse Exparel cardiotoxicity.
Abstract 21372: Women Undergoing Coronary Artery Bypass Graft Surgery Do Not Follow Any Recommended Guidelines for Breast Cancer Screening
Authors: Lopez Javier E , Sarma Nandini , Shakeri Tara , Aminololama-Shakeri Shadi
Published: March 2022

Introduction:
In the United States, 1 in 4 women dies of heart disease. Severe coronary artery disease is usually treated with coronary artery bypass graft (CABG) surgery to prolong a patient’s life span. To maintain the significant survival benefit derived from this procedure, vigilant post-care counseling is performed to prevent further health complications. Current post-CABG care guidelines include counseling on exercise, diet, and medical management but do not explicitly contain recommendations for other primary preventative care. Screening mammography (SM) for primary prevention is an effective measure that reduces women's mortality due to breast cancer by ~30%.

Hypothesis:
We hypothesize that women change the frequency of screening mammography following CABG surgery.

Methods and Results:
Using electronic medical record data, we identified a retrospective cohort of 170 women who underwent CABG surgery and SMs between 2002-2012. Recommended guidelines during these years varied between 0.5-1 SM per year (SM/year). The rate of SM/year prior to- and following CABG were calculated. We performed the same analysis on a second cohort of 400 women who underwent a cardiac catheterization (Cath) during the same time period and were found to have preserved heart function without CAD as a control group. The mean (95% CI) age of the CABG women at first screening mammogram, CABG procedure and last follow-up was, respectively, 61 (60-63), 67 (65-68), and 73 (71-74). The median SM/year before CABG procedure was 0.51 compared to 0.28 following CABG procedure (p<0.0001). The median SM/year for Cath women ranged from 0.64 to 0.45 following Cath procedure.

Conclusion:
Women following CABG have the lowest breast cancer screening rates and are not meeting any recommended screening guidelines for mammography. These results indicate that further study of patient, provider, and/or system-related factors resulting in this change of preventative care is warranted.
Abstract 21374: Adenovirus Targets Cardiac Gap Junctions to Facilitate Viral Replication
Authors: Calhoun Patrick J , Phan Allen V , Taylor Jordan , Zeitz Michael J , Smyth James W
Published: March 2022

Myocarditis is a leading cause of sudden cardiac death in young adults, accounting for 20% of cases under 40 years of age in the United States. Adenovirus is a major etiological agent in this disease yet much remains unknown regarding pathogenesis and predisposition to infection. During adenoviral infection, viral proteins uncouple cell cycle checkpoints for viral DNA genome replication to occur. Connexin43 (Cx43) gap junctions play an essential role in propagation of action potentials to precipitate each heartbeat. Cx43 has also been implicated in cell cycle regulation, leading us to hypothesize that adenovirus targets Cx43 to facilitate viral replication, resulting in arrhythmogenic alterations in cardiac intercellular communication. We find reduced Cx43 expression at the mRNA and protein level within 24 hours of infection with adenovirus type 5 (Ad5) in human epithelial cells. Studies in human induced pluripotent stem cell-derived cardiomyocytes reveal alterations in calcium transient propagation and reduced Cx43 protein levels. Growth factor signaling is activated by early Ad5 proteins and is known to negatively regulate gap junction coupling. We performed genetic screens and have identified the viral protein E4-ORF1 as sufficient in suppression of Cx43 expression and modulation of cardiac transcription factors. siRNA-mediated knockdown of Cx43 protein enhances viral genome replication while transient overexpression of Cx43 significantly inhibits late viral protein synthesis and genome replication. Finally, using dominant-negative trafficking-dead and closed-channel Cx43 mutants, we conclude that inhibition of Ad5 replication by Cx43 is gap junction dependent. Together, these data provide novel insight into molecular mechanisms underlying arrhythmogenic viral myocarditis in addition to understanding the role of Cx43 in adenoviral pathogenesis. Revealing viral mechanisms of gap junction dissolution will contribute not just to the development of novel antiviral therapeutics, but will also provide insight into fundamental Cx43 biology relevant to other forms of heart disease.
Abstract 21384: UNOS 1A Listing Trends in LVAD (Left Ventricular Assist Device) Recipients
Authors: Salimbangon Anthony , Vucicevic Darko , Chang Amy , Deng Mario C , DePasquale Eugene
Published: March 2022

Introduction:
LVAD utilization has increased in the face of continuing donor shortage. These patients may remain at the highest urgency status of UNOS 1A electively for 30 days. Upon completion of this time, LVAD patients may only regain this status with device complications. Trends in device complications of those undergoing HT have not been well-described. We sought to assess the trend of 1A exceptions in this population.

Methods:
3551 HT recipients bridged with LVAD of 10,634 were identified from UNOS (2000-2015) were stratified by UNOS 1A listing exception: device infection, thromboembolism, device malfunction, life-threatening ventricular arrhythmia or other. Exclusions: age<18, re-HT & lost to follow up. Survival was censored at 12y. UNOS 1A listing exceptions over time were assessed via a nonparametric test for trend.

Results:
3551 HT recipients bridged with LVAD with the following 1A exceptions: device infection (n=1516), thromboembolism (n=517), device malfunction (n=585), life-threatening ventricular arrhythmia (n=196) and other (n=737). During the study period, listing for each of these complications increased over time (Figure). Overall survival in patients listed with MCS exception was (1, 5 & 10y): 87, 74 & 56%. Survival by 1A exception is shown in Figure. Survival was significantly reduced in those with device infection (1, 5 & 10y: 85, 70, 50%; log rank, p=0.007).

Conclusions:
UNOS 1A listing exceptions in LVAD patients have increased over time. Despite this increase, short and long-term survival does not appear to be impacted with the exception of device infection. Further study is warranted to explore this increase in exceptions and impaired outcomes in the device infection population.
Abstract 21385: Presenting Features in Suspected Cardiac Sarcoid
Authors: Acharya Gayatri , Bois John , Rodriguez-Porcel Martin , Chareonthaitawee Panithaya
Published: March 2022

Background:
Sarcoidosis is multi-system disease characterized by non-caseating granulomas, often presenting with pulmonary involvement. However, in the United States at least one-fourth of sarcoid patients have cardiovascular involvement. Sarcoid can also present as isolated cardiac sarcoidosis (CS), with symptoms that include heart failure (HF), advanced atrioventricular (AV) nodal block, ventricular tachycardia (VT), or sudden cardiac death. Consequently, it has been suggested that CS should be considered in patients presenting with high grade AV block, VT, or heart failure, with a non-ischemic presentation. Here, we present the CS experience at a tertiary medical center.

Methods:
Patients who underwent
18
F-FDG (2-deoxy-2-[fluorine-18]fluoro-D-glucose) PET/CT to assess perfusion and inflammation for clinical suspicion of CS between 2009-2015 at a tertiary referral center were included in the study. These patients were retrospectively assessed for frequency of presenting features.

Results:
Inclusion criteria were met by 71 patients. VT was the most common presenting symptom seen in 40 of 71 patients (56%). High grade AV block was seen in 24 of 71 patients (34%). VT and high grade AV block was seen concomitantly in 9 (13%). An abnormal PET result was seen in 51 out of 71 patients (72%) with 30 of 51 having VT (59%) and 21 of 51 having AV block (41%). Of the patients with both VT and AV block, 8 of 9 had abnormal PET studies. In 34 of 71 (47%) patients with known extracardiac sarcoid, 18 (53%) had VT and 11 (32%) had AV block. HF symptoms (New York Heart Association class II-IV) were seen in 24 (34%). An abnormal resting ECG was seen in 64 out of 71 patients (90%).

Conclusions:
In our retrospective cohort VT is the most common presenting symptom in patients with suspicion of CS, and the combination of AV block with VT should raise concerns for an infiltrative process. In patients with extracardiac sarcoid and rhythm disturbance, cardiac involvement should be suspected and screened. Early identification of cardiovascular involvement is critical to ensure that appropriate management of the source of rhythm disturbance or heart failure is addressed before cardiovascular dysfunction is sustained.
Abstract 21392: Comparison Between Overweight With Preserved versus Reduced Muscle Mass in Young Trained Athletes
Authors: Cho Jae Yeong , Kim Kye Hun , Park Hyukjin , Hornsby Kyle , Lawrence Rink
Published: March 2022

Introduction:
The characteristics of the echocardiographic parameters in young trained athletes in comparison to healthy young general population need to be studied further. The aim of the present study was to compare the clinical and echocardiographic results between preserved versus reduced muscle mass in young trained athletes.

Methods:
A total of 1,186 athletes (22.5±6.3 years, 498 males) from 170 countries participated in the [Check-up Your Heart Program] during Summer Universiade. As an interim analysis, echocardiographic data of 380 trained athletes were included for this analysis. There were divided in to two groups; Overweight with preserved muscle mass (OPMM) (n=119) vs. non-OPMM (n=1,067). OPMM was defined as overweight athletes with proportion of muscle mass to body weight >40% for male and >35% for female. Echocardiographic parameters were compared between athletes group vs. normal control group.

Results:
OPMM was observed in 119 athletes (10.0%). Compared with normal control, athlete showed overweight more frequently (19.2% vs. 11.5%, p=0.014). Fat mass was higher in OPMM group (12.6±3.3 vs. 11.3±7.1 kg, p=0.001). OPMM group was more likely to be a caucasian than other ethnic groups (Caucasian 45.8% vs. Asian 16.1% vs. African 4.2% vs. Latin 17.8% vs. Middle Eastern 2.5% vs. others 13.6%, linear p=0.222), but significant racial difference was not observed. Intensity of sports had no significant influence on OPMM (11.8% vs. 16.4%, p=0.190). Also there was no difference between types of sports according to oxygen consumption (linear p=0.056). OPMM group showed larger left ventricular dimension (LVEDD 54.0±4.3 vs. 49.4±4.9 mm, p<0.0001; LVESD 34.5±3.8 vs. 31.6±4.3, p<0.0001; LAD 37.4±3.4 vs. 32.6±4.0, p<0.0001) and thicker interventricular septum (9.4±2.3 vs. 8.4±1.5, p<0.0001). Also LV mass index was higher in OPMM group (88.2±22.6 vs. 78.8±20.4, p=0.026). However, left atrial volume index and right ventricular dimension showed no difference between the two groups (p=0.105).

Conclusions:
LV size and mass were bigger in overweight athletes with preserved muscle mass, but LA and RV did not show such differences. There may be an association between body composition and cardiac structural change in trained young athletes.
Abstract 21394: Socioeconomic and Racial Disparities in Outcomes Among Patients Listed for Heart Transplant in the United States
Authors: Wayda Brian , Clemons Autumn , Givens Raymond C , Takeda Koji , Takayama Hiroo , Latif Farhana , Restaino Susan , Naka Yoshifumi , Farr Maryjane A , Colombo Paolo C , Topkara Veli K
Published: March 2022

Background:
Socioeconomic and racial disparities in outcomes among patients with heart failure are well-documented. Whether such disparities exist among patients awaiting heart transplant (HT) is unclear. We aimed to characterize the associations of socioeconomic status (SES) and race with outcomes among patients listed for HT.

Methods:
Patients listed for heart transplant between 1994 and 2014 were included (n = 64,276). SES indicators included insurance status, education, and neighborhood SES (nSES), measured by zip code using a composite index. The primary outcome was a composite of death or delisting and the secondary outcome was transplant. Multivariate analyses were employed to adjust for race, SES, comorbidity, and clinical severity at time of listing.

Results:
Non-white race, low education, Medicare, Medicaid, and lower nSES (Figure 1) were associated with higher unadjusted risks of death or delisting. After adjustment, the associations with less than high school (HR=1.39) and college education (HR=0.93), Medicare (HR=1.22), Medicaid (HR=1.16), and lowest nSES quartile (HR=1.06) remained significant (p < 0.05; Figure 2). Risks associated with black race and low nSES decreased significantly over time. Adjusted incidence of transplant was significantly lower among blacks (HR = 0.90), but higher among other non-white patients.

Conclusions:
Low SES is associated with poorer outcomes during HT listing, and there are racial disparities in the likelihood of transplant. Some of these disparities have narrowed over time. Further research is needed to identify the underlying cause of these disparities, which are not explained by measured clinical characteristics.
Abstract 21405: Dynamic Enhancement Pattern is Different Between Unstable and Stable Coronary Plaque: Analysis With 320-Row Area Detector Computed Tomography
Authors: Kameyama Tomoki , Ihori Hiroyuki , Ohara Kazumasa , Nonomura Makoto , Inoue Hiroshi
Published: March 2022

Introduction:
Intraplaque neovascularization is a marker of unstable coronary plaque. We investigated a difference in dynamic enhancement pattern of coronary plaque between stable and unstable angina pectoris, using 320-row area detector computed tomography (CT), which enables whole-heart volumetric acquisition in a single gantry rotation.

Hypothesis & Methods:
We analyzed 106 coronary plaque segments in 38 patients (mean age 69.8±8.3 years, 32 male) with angina pectoris (13 stable, 25 unstable) who underwent coronary CT and percutaneous coronary intervention (PCI). Coronary plaques were evaluated using 320-row area detector CT with and without contrast enhancement. Culprit plaques (PCI target) of unstable patients were defined as unstable plaque(n=35), whereas culprit plaques of stable patients and non-culprit plaque were defined as stable plaque(n=71). Coronary plaque without contrast enhancement, corresponding to the plaque detected by contrast enhanced CT, was identified using unique calcification as a landmark. The mean Hounsfield unit (HU) in the coronary plaque was measured, and the presence of positive vascular remodeling was evaluated. Coronary artery stenosis was quantified by coronary angiography.

Results:
Unstable patients were younger than stable patients (66.6±7.2 vs 76.1±6.7 years, p<0.01). Positive vascular remodeling and spotty calcification was more frequently observed in unstable than stable patients (68.4% vs 15.4%, p< 0.01 and 45.5% vs 86.4%, p<0.05 respectively). Coronary artery stenosis was not different between the 2 groups. In CT without contrast enhancement, plaque HU was not different between the 2 groups (unstable: 25.0±32.4 vs stable: 24.9±33.1). With contrast enhancement, plaque HU was significantly elevated in both groups from those without contrast enhancement to 53.9±24.1 (unstable: p<0.01) and to 42.6±33.5 (stable: p<0.01). Unstable plaque showed higher enhancement (delta HU) than stable plaque (28.9±23.5 vs 17.7±25.5, p=0.024).

Conclusions:
Dynamic enhancement pattern is different between unstable and stable coronary plaque. Compared to stable plaque, unstable plaque shows higher contrast enhancement, suggesting the increased neovascularization in the plaque.
Abstract 21406: The Impact of Continuous flow LVAD Device Related Complications on Patient Outcomes While on the Heart Transplant Wait List- Analysis of the UNOS Database
Authors: Fugar Setri , Okoh Alexis , Al-Ogaili Ahmed , Vondee Noble , Ayoub Ali , Desai Parth
Published: March 2022

Continuous Flow LVAD(CF-LVAD) are widely used as BTT among patients with Advance Heart Failure. The current study aimed to determine the impact of device related complications on waitlist mortality or delisting due to worsening clinical conditions.

Methods:
Patients who were bridged to heart transplant with a continuous flow LVAD (CF-LVAD) between April 2008 and September 2015 were identified from the UNOS heart transplant registry. They were then categorized by the presence or absence of CF-LVAD complications while on the wait list. Cox proportional hazards and Kaplan Meier survival curves were used for time-to-event analysis for the primary outcome.

Results:
Out of 7070 patients who were bridged to heart transplant, 4434(63%) got transplanted and 2510(36%) developed device related complications while on the waiting list. The primary outcome was present in 1631(23%) patients. Independent predictors of primary outcome were Age (HR/increasing unit: 1.01, 95% CI: 1.01-1.02, p value: <0.0001.), ABO blood group(O vs. A HR: 1.20, 95% CI: 1.20-1.36, p value: 0.003), Etiology of cardiomyopathy (Congenital vs. Ischemic HR: 3.46, 95% CI: 3.46(2.15-5.27, p value: <0.0001, Restrictive vs. Non-ischemic HR: 2.66, 95% CI: 1.67-3.99, p value: 0.0001), history of diabetes mellitus(HR: 1.18, 95% CI: 1.05-1.34, p value: 0.006). Developing one device-related complication was associated with a HR of 2.59 of having the primary outcome, (p<0.0001). The hazard risk however increased to 3.45 when ≥ 2 of the defined complications occurred.

Conclusion:
In conclusion, findings from the current study add to the existing literature: the incidence of morbidity and mortality in the current BTT era. While the development of any device-related adverse event is significantly associated with waitlist mortality or delisting, the occurrence of ≥ 2 almost doubles the risk. Improvement in clinical management strategies is needed to ensure optimal benefit of CF-LVADs for BTT therapy.
Abstract 21416: Variation Across Centers and Predictors of Initial Immunosuppression Strategy After Heart Transplant
Authors: Wayda Brian , Clemons Autumn , Givens Raymond C , Takeda Koji , Takayama Hiroo , Latif Farhana , Restaino Susan , Naka Yoshifumi , Garan A. Reshad , Yuzefpolskaya Melana , Farr Maryjane A , Colombo Paolo C , Topkara Veli K
Published: March 2022

Background:
There are multiple accepted immunosuppressive medication (ISM) strategies after heart transplant (HT) and evidence of their relative efficacy is limited. As a result, ISM strategies may vary considerably depending on local protocols. We aimed to characterize center-level variation and predictors of ISM strategy.

Methods:
Using data from the UNOS registry, we included 38,826 patients undergoing HT at 124 US centers from 1994 to 2014; centers with less than 30 transplants during this span were excluded (n=53). ISM strategies included 1) use of anti-lymphocyte induction therapy, 2) omission of corticosteroids (“steroid-free”) in the initial maintenance regimen, and 3) initial inclusion of mTOR inhibitors. Associations between the utilization of each strategy and other center-level characteristics were determined using chi-squared and Pearson correlation tests.

Results:
The mean center-level proportions of patients receiving induction, steroid-free, and mTOR inhibitor regimens were 50.2% (standard deviation (SD) = 24.6%), 4.3% (SD = 5.6%), and 2.4% (SD = 3.2%) respectively (Figure 1). Many centers (16.1%) used induction in nearly all (> 80%) of their patients and a similar proportion (21.0%) used induction infrequently (in < 20% of patients). While use of mTOR and steroid-free regimens was rare, 10 centers used one or both of these regimens in more than 10% of patients. Centers in the northeast less often used induction and steroid-free regimens were more often used in higher-volume centers (p <= 0.05).

Conclusions:
There is substantial variation across centers in ISM strategy after HT, particularly in the use of induction. This degree of variation is unlikely to be explained by differences in patient mix, and more likely stems from differences in provider preference. Further studies are needed to assess the underlying drivers and clinical impact of this variation.
Abstract 21417: Fragmented QRS Complex as a Predictor of Exercise-Related Sudden Cardiac Death
Authors: Toukola Tomi M.
Published: March 2022

Objective:
Our aim was to identify electrocardiographic (ECG) changes related to exercise-induced sudden cardiac death (SCD).

Methods and Results:
The Finnish Study of Genotype and Phenotype Characteristics of SCD (FinGesture) includes 3,989 consecutive sudden cardiac deaths in northern Finland between 1998 and 2012. Previously recorded ECGs were acquired manually from archives of Oulu University Hospital. A total of 647 SCD had a previously recorded ECG. In 276 of these cases the death was witnessed, and the activity at the time of death could be divided into either rest or physical exercise; in 40 (14%) cases SCD was exercise-related (PE group) and in 236 (86%) cases death took place at rest (R group). A total of 371 (57%) deaths were unwitnessed or the cases did not meet the criteria of either exercise or rest. Fragmented QRS (fQRS) complex in at least 2 consecutive leads within anterior leads (V1-V3) was more common in the exercise-group compared to rest-group (17/40, 43% vs. 51/236, 22%, p=0.005). Pathologic Q wave in anterior leads was somewhat more common in the PE group (9/40, 23% vs. 26/236, 11%; p=0.044). QRS duration, QTc interval or the prevalence of inverted T-waves did not differ significantly between the 2 groups.

Conclusions:
Fragmented QRS complex in the anterior leads is associated with an increased risk of SCD during physical exercise.
Abstract 23073: Cardiovascular Efficacy of PCSK9 Inhibition Among 1,578 Patients With Familial Hypercholesterolemia: The SPIRE Clinical Trials FH Analysis
Authors: Ridker Paul M ,   Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE) Investigators
Published: March 2022

Background:
Familial hypercholesterolemia (FH) is a genetic disorder with elevations of low-density lipoprotein cholesterol (LDLC) and premature atherosclerotic events. Therapeutic monoclonal antibodies that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) are indicated for the reduction of LDLC in patients with FH, but placebo-controlled outcome data for FH patients are not available.

Objective:
To estimate the efficacy of PCSK9 inhibition with bococizumab on future cardiovascular events among FH and non-FH patients enrolled in the four 1-year SPIRE Lipid Lowering trials or in the two cardiovascular outcomes trials (SPIRE-1 and SPIRE-2).

Design, Setting, and Participants:
Six multinational, randomized, placebo-controlled trials inclusive of 1,578 patients with FH (molecular analysis or Simon Broome criteria) and 15,959 patients without FH and levels of LDLC ≥100 mg/dL or non-HDLC ≥130 mg/dL at trial entry.

Intervention:
Bococizumab 150 mg SC every 2 weeks or matching placebo. The median follow-up period was 49 weeks.

Main Outcomes and Measures:
Incident major adverse cardiovascular events (MACE) including nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death.

Results:
Among FH patients, MACE occurred in 18 allocated to bococizumab and 22 to placebo (hazard ratio [HR]=0.83; 95% confidence interval [CI] 0.44-1.54, P=0.55). In the subgroup of 620 FH patients with LDLC ≥160 mg/dL, MACE occurred in 9 allocated to bococizumab and 13 to placebo (HR=0.74; 95% CI 0.31-1.75, P=0.49). For the 1,065 FH patients specifically enrolled in SPIRE-1 or SPIRE-2, MACE occurred in 11 allocated to bococizumab and 18 allocated to placebo (HR=0.64, 95% CI 0.30-1.35, P=0.24). These effect estimates are similar in magnitude to that observed in the 15,959 patients without FH (HR=0.79, 95% CI 0.64-0.97, P=0.023).

Conclusions and Relevance:
Statin-treated FH patients given the PCSK9 inhibitor bococizumab have a similar magnitude of risk reduction for hard cardiovascular events as do patients without FH. These data have importance for clinical practice and guidelines for cardiovascular disease prevention.

Trial Registration:
ClinicalTrials.gov: NCT01968954, NCT01968967, NCT02100514, NCT01968980, NCT01975376, NCT01975389
Abstract 23080: Increased Pulmonary Peripheral (But Not Central) Blood Flow Correlates With Decreased Right Ventricular Volume in Acute Pulmonary Embolism Treated With Ultrasound-Facilitated, Catheter-Directed Fibrinolysis
Authors: PIAZZA Gregory , Rahaghi Farbod N , Goldhaber Samuel Z , Estepar Raul S , Minhas Jasleen , Ross James , Washko George R
Published: March 2022

Introduction:
Ultrasound-facilitated, catheter-directed fibrinolysis improves right ventricular (RV) function in patients with acute pulmonary embolism (PE). Resolution of central pulmonary arterial thrombotic obstruction has been hypothesized as the principal mechanism for RV recovery.

Hypothesis:
We postulated that improved peripheral blood flow rather than central blood flow correlates with reversal of RV enlargement due to PE.

Methods:
Using a 3-dimensional quantitative reconstruction technique that allows resolution of the distal pulmonary arteries, we analyzed the computed tomographic (CT) pulmonary angiograms of 60 submassive and massive PE patients treated with ultrasound-facilitated, catheter-directed, low-dose fibrinolysis. We correlated the change in blood volume of the pulmonary arteries (<10 mm
2
vs. >40 mm
2
cross sectional area) from baseline to 48 ± 6 hours with change in CT-measured RV volume.

Results:
Forty-five patients demonstrated reduction in RV volume (mean change was -31 ml). Increase in total lung blood volume/lung volume correlated with decreased RV volume/lung volume (R
2
= 0.26). RV volume-to-left ventricular volume ratio decreased by 26% (
Figure, Panel A
). Decreased RV volume correlated with increased blood volume through <10 mm
2
pulmonary arteries (R
2
= 0.28) but not larger pulmonary arteries (> 40 mm
2
) (R
2
= 0.00003) (
Figure, Panel B1
and
B2
).

Conclusion:
Total lung blood volume increases following ultrasound-facilitated, catheter-directed fibrinolysis. Increased blood volume through the peripheral, but not central, pulmonary artery vasculature correlates with reduction in RV volume after ultrasound-facilitated catheter-directed fibrinolysis.
Abstract 23087: Applying the FOURIER Trial amongst Real-world Cardiovascular Disease Patients: The Cardiovascular Health in Ambulatory Care Research Team (CANHEART) PCSK9 Study
Authors: Ko Dennis T , Khan Anam M , Kotrri Gynter , Koh Maria , Chu Anna , Austin Peter C , Wijeysundera Harindra C , Tu Jack V
Published: March 2022

Background:
FOURIER demonstrated a 15% reduction in cardiovascular CV events for patients with CVD. With its high cost, healthcare systems are faced with the potential impact of adopting PCSK9 inhibitors in practice. The goal of this study was to evaluate eligibility, preventable events and incremental costs if FOURIER is applied to the real-world.

Methods:
The CANHEART cohort is a population-based database of the entire Ontario adult population created by merging multiple individual-level data sources (www.canheart.ca). CVD patients who were alive and 40- 85 years as of January 1
st
2008, and had a cholesterol measurement were included. Similar eligibility for PCSK9 inhibitors with FOURIER was applied. Our primary outcome was a composite of CV death, MI, unstable angina, stroke or coronary revascularization. Number of preventable events was estimated by applying FOURIER’s observed hazard ratio to our cohort’s survival function. The cost to prevent an event was calculated as the cumulative healthcare cost for each patient, assuming PCSK9 inhibitor costs $8,000 CAD (~$6,000 USD)/yr.

Results:
Of 1.5 million individuals in CANHEART, 62,729 (4.3%) had a history of CVD and 38,348 (2.6% of entire population, 61% of CVD patients) met FOURIER eligibility. Mean age was 66 years, 69% were men, 78% had a history of MI, and 31% were on high dose statins. Within 3 years, 11.9% of patients experienced a primary outcome. PCSK9 inhibitor uptake by all CVD patients was estimated to reduce primary events by 1.9% (746 events avoided) at a cost of $1.14 million CAD per event. Projected event rates, absolute risk reductions and PCSK9 associated costs are shown in the
Table
.

Conclusions:
In this large population-based cohort, 2.6% of individuals and 61% of CVD patients fulfil FOURIER criteria for PCSK9 inhibitor use. While the absolute anticipated benefit of adopting this new therapy was similar to that observed in clinical trials, it is associated with substantial costs to prevent each event.
Abstract 23931: Selective Inhibition Of Hdac3 Prevents Diabetic Cardiomyopathy In Ove26 Mice Via Mir-200a-mediated Nrf2 Activation
Authors: xu zheng , zheng yang , zhang zhiguo , SUN JIAN , Cai Lu
Published: March 2022

Although histone deacetylases (HDACs) was are the promising target for the initiation and development of diabetic cardiomyopathy (DCM), which isoform of them plays the key role remains unclear. The present study was designed to determine whether DCM could be prevented by selective inhibition of HDAC3 and the underlying mechanism. Male type 1 diabetic OVE26 and age-matched wild-type mice were given the selective HDAC3 inhibitor (HDAC3i) RGFP966 or vehicle for 3 months before the cardiac function was examined with Echo. Results indicated that HDAC3i treatment improved cardiac function in the diabetes group. HDAC3 activity was significantly increased in the heart of diabetic mice, which was blocked by the treatment of HDAC3i. Oxidative stress as a major cause of DCM is also inhibited by HDAC3i. Mechanistically cardiac miR-200a, which targets and destabilizes
kelch-like ECH-associated protein 1 (KEAP1)
mRNA, was significantly up-regulated and KEAP1 expression was markedly inhibited by HDAC3i in the diabetic mouse. Immunoprecipitation shows that the binding of KEAP1 in the diabetic heart was decreased by the treatment of HDAC3i when we pull down nuclear factor-E2-related factor 2 (NRF2). Meanwhile, the nuclear localization of NRF2 and its downstream anti-oxidative stress genes, NADPH quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), were markedly up-regulated in the HDAC3i treated diabetic mouse group. These results suggest that HDAC3i prevents DCM likely via miR-200a-mediated degradation of KEAP1 and consequently activation of the Nrf2-regulated antioxidant pathway.
Abstract 24010: Muscle-specific A-Kinase Anchoring Protein Polymorphisms Pre-dispose Humans to Cardiovascular Diseases by Affecting cyclic AMP/PKA Signaling
Authors: Suryavanshi Santosh , Jadhav Shweta , Anderson Kody , Katsonis Panagiotis , Lichtarge Olivier , McConnell Bradley K
Published: March 2022

In-depth understanding of key cardiac signaling pathways is crucial in finding new targets for cardiovascular diseases (CVDs), the no. 1 cause of deaths globally. One of such pathways is cAMP-dependent PKA signaling which is modulated by scaffold proteins, A-kinase anchoring proteins (AKAPs). Muscle-specific AKAP (mAKAP) regulates expression of hypertrophic factors partly by controlling cardiac cAMP levels. Furthermore, published literature revealed a strong correlation between single nucleotide polymorphisms (SNPs) in proteins and risk of developing CVDs by varying cAMP/PKA signaling. This aspect of AKAPs has been largely unexplored. Hence, we hypothesized that mAKAP SNPs alter cAMP/PKA signaling making individuals susceptible to CVDs. We analyzed selected mAKAP SNPs found often in human patients with CVDs through multiple online tools that predict functional effects of SNPs to finalize two SNPs, Ser(S)1653Arg(R) in PDE4D3 binding domain and Glu(E)2124Gly(G) in 3’-PKA binding domain of mAKAP. After making both mAKAP mutant plasmids from WT using site-directed mutagenesis, we studied them in HEK 293T cells. Four separate samples were used for each experiment. In immunoprecipitation studies, S1653R mutant showed increased binding to PDE4D3 at baseline but significantly reduced binding after stimulation with 1 μM isoproterenol as compared to WT. Similarly, E2124G mutant exhibited significantly lower PKA binding at baseline and higher binding after stimulation. cAMP levels and PKA activity were significantly lower at baseline but higher after stimulation in S1653R mutant cells. Also, E2124G expressed cells showed no significant change in cAMP levels when compared to WT but PKA activity was significantly lower at baseline followed by abrupt increase after stimulation. PDE activity assay was in congruent with cAMP changes in S1653R mutant cells. Fluorometric assay showed higher intracellular calcium in E2124G mutant cells after stimulation. Lastly, immunoblotting data showed altered phosphorylation of hypertrophic markers in both mutants. To conclude, human mAKAP SNPs may pre-dispose humans to the risk of developing CVDs by affecting cAMP/PKA signaling and thus confirming the clinical significance of PKA-mAKAP-PDE4D3 interaction.
Abstract 24011: Inducible Depletion of Calpain-2 Attenuates Obesity-accelerated Abdominal Aortic Aneurysms in mice
Authors: Javidan Aida , Jiang Weihua , Moorleghen Jessica J. , Subramanian Venkateswaran
Published: March 2022

Background and Objective:
Recent clinical studies demonstrated that abdominal adiposity is associated with increased risk of abdominal aortic aneurysm (AAA) development. Calpains are non-lysosomal calcium dependent cysteine proteases that are highly expressed in human and experimental AAAs. Using a pharmacological inhibitor and genetically deficient mice, we identified that calpain-2 (a major ubiquitous isoform) plays a critical role in Angiotensin II (AngII)-induced AAA formation in mice. In addition, calpain inhibition strongly suppressed adipose tissue inflammation in obese mice. The purpose of this study was to determine the functional contribution of calpain-2 in obesity-accelerated AAA.

Methods and Results:
Calpain-2 floxed mice that were hemizygous for β-actin Cre-ERT2 were produced by breeding male Cre-ERT2 to female calpain-2 floxed mice. At 8 weeks of age, male non-Cre littermates (Cre-) and Calp-2 x Cre-ERT2 (Cre+) mice were injected with tamoxifen (25 mg/kg, i.p.) daily for 5 consecutive days. After 2 weeks, Western blot analyses showed a complete depletion of calpain-2 protein in the aorta and periaortic adipose tissue from Cre+ mice compared to non-Cre littermates. Mice were fed a high fat diet (60% Kcal) for 20 weeks. After 16 weeks of diet feeding, mice were infused with AngII (1,000 ng/kg/min) by osmotic minipumps for 4 weeks. Depletion of calpain-2 had no effect on high fat diet-induced body weight gain, fat mass, glucose and insulin tolerance. Interestingly, calpain-2 depletion significantly attenuated AngII-induced expansion of ex-vivo maximal diameter of abdominal aortas in obese mice (Cre-: 1.4 ± 0.14; Cre+: 0.9 ± 0.04 mm; P<0.001). In addition, calpain-2 depletion significantly reduced the incidence of AngII-induced AAAs in mice (Cre-: 75%, Cre+: 7%; P< 0.001).

Conclusion:
These findings suggest that calpain-2 plays a critical role in AngII-induced AAA development in diet-induced obese mice.
Abstract 24031: Machine Learning Detection of Obstructive Hypertrophic Cardiomyopathy Using a Wearable Biosensor
Authors: Green Eric M , van Mourik Reinier , Wolfus Charles , Heitner Stephen B , Dur Onur , Semigran Marc J
Published: March 2022

Introduction:
Hypertrophic cardiomyopathy (HCM) is a heart muscle disease characterized by left ventricular (LV) hypertrophy without a systemic etiology and is associated with heart failure, stroke and sudden death. Disease prevalence is estimated at 1:500, but ~84% remain undiagnosed. Patients with obstructive HCM (oHCM) have dynamic obstruction of the LV outflow tract and characteristic abnormalities in arterial bloodflow patterns.

Hypothesis:
Arterial pulsewaves recorded with a wearable biosensor and analyzed with machine learning algorithms could identify a signature of oHCM when compared to unaffected controls.

Methods:
We compared baseline arterial pulse wave morphology, obtained by photoplethysmography using an investigational wristworn biosensor (Wavelet Health, Mtn. View, CA), from oHCM patients enrolled in a digital health substudy of PIONEER HCM (NCT02842242) to unaffected controls from a Wavelet Health database. Five minute recordings were obtained at rest, and data sets were divided into training and validation cohorts. A beat-by-beat machine learning model was developed using a predefined feature set to calculate an HCM probability score, and an optimal threshold score was determined. The model was evaluated using summary statistics and an ROC area-under-curve metric.

Results:
Arterial pulsewave recordings were obtained from 14 patients with oHCM at rest and 81 unaffected controls. An oHCM machine learning classifier was developed based on 42 calculated metrics. After training and cross-validation (n=9 oHCM, n=48 control), the model achieved 98% accuracy. Application of this model to a validation cohort (n=5 oHCM, n=33 control) confirmed an increased probability in oHCM patients compared to unaffected controls (0.40 ± 0.13 vs. 0.18 ± 0.10; p=0.006). Analysis of the ROC curve in the pooled cohort shows an area under the curve of 0.88.

Conclusion:
This first-of-its-kind study suggests that a signature of arterial bloodflow in oHCM can be identified with the combination of a wristworn biosensor and machine learning algorithms. These data raise the possibility of a novel approach to the non-invasive detection of oHCM.