bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 9511: Implication of the KATP SUR2B/kir6.1 in the Physiopathology of Pulmonary Arterial Hypertension
Authors: Le Ribeuz Helene , Dutheil Mary , capuano veronique , Mercier Olaf M , Humbert Marc , Montani David , Antigny Fabrice
Published: April 2022

Introduction:
PAH is a severe and rare cardiopulmonary disease which is defined by an elevation of the mean pulmonary artery pressure >25mmHg. ABCC9 mutations are responsible of Cantu syndrome, a disease characterised by several cardiac disorders and for some case pulmonary hypertension (PH). ABCC9 gene encodes for SUR2 protein, a regulatory subunit of KATP channels. KATP are composed of SUR1 or SUR2 and Kir6.1 or Kir6.2 subunits. We hypothesized that SUR2 / Kir6.1 channel contributes to PAH pathogenesis and could be a therapeutic target against PAH.

Methods:
Using a combination of
in vitro
,
ex vivo
and
in vivo
approaches, we analysed the localisation and expression of SUR2A, SUR2B and Kir6.1 in pulmonary vasculature from control and PAH patients as well as in experimental PH rat-models. We also analysed the role of SUR2/Kir6.1 in PAH physiopathology (PASMCs proliferation, migration and contraction). Finally, we deciphered the consequences of
in vivo
pharmacological activation of SUR2/Kir6.1 in experimental model of PH.

Results:
We demonstrated that SUR2A, SUR2B and Kir6.1 are expressed (mRNA and protein) in lungs from control and PAH patients and in MCT induced-PH model.Myograph experiments demonstrated that pharmacological activation of SUR2 by pinacidil induced pulmonary arterial relaxation in human and rat isolated pulmonary arteries. PA relaxation was still present in PA from MCT-rats but reduced compared to control rats.
In vitro
experiments on human PASMCs (hPASMCs) from control and PAH patients show a decrease of the cell proliferation and migration after SUR2 activation (pinacidil). Using Patch-clamp technique, we demonstrated that SUR2 activator (pinacidil) in adult rat RV cardiomyocytes reduces RV action potential. Finally, pharmacological activation
in vivo
of SUR2 by pinacidil (1mg/kg/day) on MCT induced-PH rats show an improvement of the hemodynamic parameters as the mean right ventricular systolic pressure during preventive and curative protocol.

Conclusions:
We demonstrated that SUR2A, SUR2B and Kir6.1 are expressed in hPASMCs and hPECs from control and iPAH patients. The in vivo SUR2 activation by pinacidil treatment reduced MCT induced-PH phenotype suggesting that SUR2 pharmacological activation should be considered for PAH.
Abstract 9517: Under-Utilization of Conventional Guideline-Directed Medical Therapy Among Patients Eligible for the Recent Large-Scale Clinical Trials of Heart Failure With Reduced Ejection Fraction
Authors: Shoji Satoshi , Kohsaka Shun , Shiraishi Yasuyuki , Sawano Mitsuaki , Ikemura Nobuhiro , Niimi Nozomi , Kohno Takashi , Goda Ayumi , Nagatomo Yuji , Saji Mike , Takei Makoto , Nakano Shintaro , Fukuda Keiichi , Yoshikawa Tsutomu
Published: April 2022

Introduction:
Recent large-scale clinical trials of novel heart failure (HF) agents (angiotensin receptor-neprilysin inhibitor, sodium-glucose cotransporter 2 inhibitor, and ivabradine) emphasize the use of baseline conventional guideline-directed medical therapy (GDMT; angiotensin-converting enzyme inhibitor, beta-blocker and mineral corticosteroid receptor antagonist); however, its use among real-world trial-eligible patients remains unclear.

Objectives:
To evaluate the prescription rate of GDMT and its association with long-term outcomes in patients that met enrollment criteria of recent large-scale clinical trials within hospitalized HF patients.

Methods:
We examined 1631 consecutive patients with HF with reduced ejection fraction (HFrEF) discharged after an episode of acute heart failure in the multicenter registry in Japan. We assessed the use of GDMT among patients that met PARADIGM-HF/ DAPA-HF enrollment criteria and SHIFT enrollment criteria. We then examined the association between the use of GDMT and long-term outcomes within each enrollment criteria.

Results:
Overall, 63.2% (n=1030) and 34.9% (n=569) of the patients met the enrollments criteria of PARADIGM/DAPA-HF and SHIFT trials. Within each patient subset, 32.5% (n=335) and 29.2% (n=166) had full GDMT, respectively. Although 82.6% (n=470) of patients that met SHIFT enrollment criteria received beta-blockers, only 21.3% (n=121) and 4.4% (n=25) patients were on >50% or higher dose (recommended dose). The use of GDMT was associated with lower rates of 2-year mortality and HF readmission in both of these populations (HR 0.85, 95% CI 0.81-0.89; HR 0.90, 95% CI 0.85-0.95, respectively).

Conclusions:
The underutilization of GDMT was observed among patients meeting the enrollment criteria of novel trials within Japanese multicenter registry of HF patients. Further effort to optimize the conventional GDMT before initiating novel therapeutics needs to be implemented.
Abstract 9521: Improvement of Left Ventricular Ejection Fraction After Surgical Revascularization in Patients Eligible for Implantable Cardioverter Defibrillator
Authors: Naksuk Niyada , Carlson Selma , Gravely Amy , Buelt-Gebhardt Melissa , Madjid Mohammad , Adabag Selcuk
Published: April 2022

Introduction:
Left ventricular ejection fraction (LVEF) ≤35% is the cornerstone criterion for implantable cardioverter-defibrillator (ICD) eligibility. But improvement in LVEF may occur in ICD-eligible patients after coronary artery bypass graft surgery (CABG).

Methods:
We studied the incidence, predictors, and outcomes of LVEF improvement among patients with LVEF ≤35% who underwent CABG as part of the Surgical Treatment for Ischemic Heart Failure (STICH) trial and had pre- and post-operative (4 months) LVEF assessment using the same cardiac imaging modality. Improvement in LVEF was defined as post-operative EF >35% and >5% absolute improvement from baseline.

Results:
Of the 427 patients (mean age 62±10 and 50 women), 125 (29.2%) had LVEF improvement from 26.8%±5.8% to 43.3%±6.5%; p<0.001. Improvement in LVEF occurred in 20% and 38% of patients with pre-operative LVEF <25% and 30-35%, respectively (Figure). Post-operative improvement in LVEF was 2.20 times more likely in patients with pre-operative LVEF ≥25% (95% CI 1.41-3.43; p<0.001) than those with pre-operative EF <25%. The odds of post-operative LVEF improvement were 1.96 times higher (95% CI 0.91-4.23, p=0.09) in patients with myocardial viability. After adjusting for age, sex, and pre-operative LVEF, improvement in LVEF was associated with a 42% lower risk of all-cause mortality (HR 0.58, 95% CI 0.35-0.96; p=0.03) and 69% lower risk of heart failure mortality (HR 0.31, 95% CI 0.11-0.87; p=0.03).

Conclusions:
Nearly 1/3
rd
of patients with LVEF ≤35% who underwent CABG had a significant improvement in left ventricular systolic function, obviating the need for primary prevention ICD implantation. Post-operative LVEF improvement was associated with a lower risk of death. These results provide patients and clinicians data on the likelihood of ICD eligibility after CABG and support the practice of reassessment of LVEF after revascularization.
Abstract 9524: The Challenge of Treating a Previously Surgical Revascularized Patient With Acute ST-Elevation Myocardial Infarction (STEMI) and Coronary-Subclavian Steal Syndrome
Authors: Trombini Pinesi Henrique , Marins Pedro H , Balzan Hadrien F , Cetinic Habrum Fabio , Matuck Bruna R , de Medeiros Marina A , Pitta Fabio G , Lima Eduardo G , Garzillo Cibele L , Serrano Carlos V
Published: April 2022

Introduction:
Coronary-subclavian steal syndrome (CSSS) is a rare cause of myocardial ischemia after coronary artery bypass grafting (CABG), due to significant stenosis of the proximal portion of the left subclavian artery. It is characterized by blood flow inversion in the left internal thoracic artery, diverting the blood flow from the coronary artery to the left medio-distal subclavian artery. We report a case of a patient who underwent complex surgery to correct the CSSS.

Case report:
A 70-year-old male patient, with history of both percutaneous coronary intervention (PCI) of the right coronary artery and CABG, was admitted to the emergency room with STEMI and complete atrioventricular block. He was initially managed to the cath lab where a transvenous pacemaker was implanted and coronary angiography showed occlusion of the left main, proximal right coronary and left subclavian arteries. Only saphenous vein - second marginal graft was patent and, despite severe stenosis in the proximal portion of the circumflex artery, this artery was responsible for irrigation of the entire left coronary system, as well as retrograde filling of the left internal thoracic artery - anterior descending artery graft. A conservative approach was proposed. For a better anatomically interpretation, coronary angiotomography was indicated and showed obstruction of the left subclavian artery after its origin, with 2.2cm length and refilling before the origin of the ipsilateral vertebral and internal mammary arteries. In addition, most visceral branches demonstrated severe atherosclerosis, and the right common iliac artery and left external iliac artery were occluded. After discussion with the Heart Team, it was decided to perform a left carotid-subclavian graft with a segment of the saphenous vein. The procedure was successful, with no complications and lasted 5 hours. The patient was discharged from hospital one week later.

Discussion:
CSSS is rare and difficult to treat. The most common treatment is angioplasty of the subclavian artery, which was not possible in this case due to the lack of femoral access and the extension of the occlusion. In this patient, with a high risk of death, the bypass surgical revascularization with saphenous graft became the only feasible treatment.
Abstract 9533: ‘Youthful’ Phenotype of C-kit+ Cardiac Fibroblasts
Authors: Firouzi Fareheh , Echeagaray Oscar H , Esquer Carolina Y , Gude Natalie A , Sussman Mark A
Published: April 2022

Introduction:
Fibroblasts are critical contributors to myocardial development, tissue homeostasis and remodeling. Cardiac fibroblast population heterogeneity and plasticity present a challenge for categorization of biological and functional properties. Distinct molecular markers and associated signaling pathways provide valuable insight for cardiac fibroblast biology and interventional strategies to influence injury response and remodeling. Receptor tyrosine kinase c-Kit mediates cell survival, proliferation, migration, and is activated by pathological injury. However, the biological significance of c-Kit within cardiac fibroblast population has not been addressed.

Approach:
An inducible c-Kit reporter mouse detects promoter activation with Green Fluorescent Protein (GFP) expression in cardiac interstitial cells (CICs). Coincidence of GFP and c-Kit with the DDR2 fibroblast marker was confirmed at protein level using flow cytometry and immunohistochemistry. Subsequently, cardiac fibroblasts expressing DDR2 with or without c-Kit were isolated and characterized
in vitro
.

Results:
A subset of DDR2
+
cardiac fibroblasts also express c-Kit with coincidence in ~8% of total CICs. Pathological injury induces coincidence as well as expression of c-Kit and DDR2. Cultured cardiac DDR2+ fibroblasts that are c-Kit+ exhibit youthful morphological and functional phenotypes compared to c-Kit- cells including 1) significantly smaller size, 2) higher cellular motility, 3) enhanced proliferation, 4) less multinucleation, 5) decreased senescence-associated β-galactosidase staining, and 6) down-regulation of p53 senescence marker. Mechanistically, c-Kit expression correlates with signaling implicated in proliferation and cell migration including phospho-ERK and pro-Caspase 3.

Conclusion:
The phenotype of c-kit+ on DDR2+ cardiac fibroblasts correlates with multiple characteristics of ‘youthful’ cells. To our knowledge, this represents the first evaluation of c-Kit biology within DDR2+ cardiac fibroblast population and provides a fundamental basis for future studies to influence myocardial biology, cardiac remodeling, and response to pathological injury.
Abstract 9536: Prediction of Drug-Induced QTc Prolongation With an ECG Based Machine Learning Model
Authors: Morland Thomas , Raghunath Sushravya , Kelsey Christopher R , Ruhl Jeffrey , Steinhubl Steven R , Monfette Mariya P , Pfeifer John , Chen Ruijun , Zimmerman Noah , Delisle Brian P , Storm Randle , Haggerty Christopher M , Fornwalt Brandon
Published: April 2022

Introduction:
Initiation of QTc-prolonging medications may lead to the rare but potentially catastrophic event, torsades de pointes (TDP). At present, no adequate, generalizable tools exist to predict drug-induced long QTc (LQT); machine learning from ECG data is a promising approach.

Hypothesis:
Prediction of drug-induced LQT using an ECG-based machine learning model is feasible, and outperforms a model trained on baseline QTc, age, and sex alone.

Methods:
We identified baseline 12-lead ECGs with QTc values < 500 ms for patients who had not received any known, conditional, or possible QTc prolonging medication per CredibleMeds at the time of ECG or within the past 90 days. We matched these with ECGs from the same patients while they were taking at least one CredibleMeds drug (“on-drug” ECGs). Using 5-fold cross-validation, we trained and tested two machine learning models using the baseline ECGs of the 92,848 resulting pairs to predict drug-induced LQT (≥500 ms) in the on-drug ECGs: a deep neural network using ECG voltage data, and a gradient-boosted tree using the baseline QTc. Age and sex were also inputs to both models.

Results:
On-drug LQT prevalence was 16%. The ECG model demonstrated superior performance in predicting on-drug LQT (area under the receiver operating characteristic curve (AUC) = 0.756) compared to the QTc model (0.710). At a potential operating point (Figure), the ECG model had 89% sensitivity and 95% negative predictive value. Even in the subset of patients with baseline QTc < 470/480 ms (male/female; post-drug LQT prevalence = 14%), the ECG model demonstrated good performance (AUC = 0.736).

Conclusions:
An ECG-based machine learning model can stratify patients by risk of developing drug-induced LQT better than a model using baseline QTc alone. This model may have clinical value to identify high-risk drug starts that would benefit from closer monitoring and others who are at low risk of drug-induced LQT.
Abstract 9539: Treatment of Hyperlipidemia: Assessment of Providers’ Competency With Edocate® Virtual Patient Simulation Application
Authors: Iancu Igal , DRAZNIN Boris
Published: April 2022

Management of hyperlipidemia (HL) in patients with Type 2 diabetes (T2DM) has been taught extensively but the real-life competency is difficult to evaluate. Edocate’s proprietary virtual patient simulation smartphone and web-based application (APP) allows an innovative way of learning and objective assessment of the provider’s proficiency in approach to and management of a given medical condition. We utilized this novel educational APP to analyze the real-life knowledge of 894 healthcare providers (HCP) in several projects within multiple geographies in the management of HL in patients with T2DM. The HCP managed 1-3 patients with T2DM and HL in their virtual clinic. HCP chose medications, made diagnostic adjustments, and ordered laboratory tests of their choice. Based on their selections, the APP simulated the course of diabetes and hyperlipidemia throughout multiple virtual visits, requiring diverse management decisions and addressing medications’ side effects, while adhering to guidelines and accepted standards of care.

Results:

Conclusions:
1. Innovative patient simulation-based learning APP revealed adequate but not perfect HL management skills. 2. NP - DM have the best guideline-recommended approach to therapy, followed by practicing MD/DO. 3. Intensive therapy achieving LDL levels below 50 or even 70 mg/dl remains elusive. 4. Edocate’s patient simulation-based learning application helps identify knowledge gaps, prescription patterns and HCP decision-making processes. 5. This APP accurately assesses the “real-life” knowledge and patterns of practice while offering cutting-edge ways of learning to dramatically improve competency levels.
Abstract 9541: Sex Disparities in In-Hospital Outcomes of Left Ventricular Aneurysm Complicating Acute Myocardial Infarction: A United States Nationwide Analysis
Authors: Pajjuru Venkata Siva Kumar , Thandra Abhishek , Walters Ryan , Papudesi Bhavani Nagendra N , Vallabhajosyula Saraschandra , Alla Venkata M , Goldsweig Andrew M
Published: April 2022

Background:
Previous studies have reported sex-specific differences in the presentation, mechanisms, and outcomes of acute myocardial infarction (AMI).

Objective:
To assess differences in the incidence and in-hospital outcomes of left ventricular (LV) aneurysm complicating AMI in women and men.

Methods:
We used the National Inpatient Sample database (NIS) from 2000 to 2017, to identify adult hospitalizations with a primary diagnosis of AMI and concomitant LV aneurysm. Incidence and trends in in-hospital mortality, complications, length of stay and costs were analyzed in women and men.

Results:
A total of 16,334 AMI hospitalizations with LV aneurysm were identified including 6,994 (42.8%) women and 9,340 (57.2%) men. Women had a higher incidence of LV aneurysm compared to men (0.16% vs. 0.14%; p<0.001). Compared to men, women were older (73 [63-81] vs 65 [56-75]; p<0.001), black race (9.6% vs 7.4%; p=0.1), and have higher elixhauser comorbidity index (2 [-1 to 9] vs 0 [-1 to 8]; p=0.014). Unadjusted in-hospital mortality was higher in women than men (12.7% vs. 7.2%; p<0.001). After adjusting for demographic and baseline characteristics and excluding inter-hospital transfers, women with AMI complicated by LV aneurysm had 49% greater odds of in-hospital mortality than men (aOR 1.49, 95% Confidence Interval 1.06-2.10, p=0.02). Women with LV aneurysm were less likely than men to undergo percutaneous coronary intervention (28.5% vs. 35.4%; p<0.001), bypass surgery (15.8% vs. 25.1%; p<0.001), coronary atherectomy (0.8% vs. 1.9%; p=0.009) and LV aneurysm surgery (7.8% vs. 11.1%; p=0.001).

Conclusions:
In this large population-based cohort study, women had a slightly higher incidence but dramatically higher in-hospital mortality associated with LV aneurysm complicating AMI compared to men. Further research is necessary to validate strategies to ensure that women receive guideline-directed therapy for AMI and LV aneurysm to address the sex disparity in mortality.
Abstract 9547: Prevalence and Characteristics of Registered Diabetes Clinical Trials With Cardiovascular Outcomes: An Analysis of Clinicaltrials.gov
Authors: Zheutlin Alexander R , Caldwell David , Chaitoff Alexander , Niforatos Joshua
Published: April 2022

Introduction:
Cardiovascular disease (CVD) is a well-known sequela of diabetes. Interventions to address diabetes often fail to assess clinically-relevant cardiovascular event reduction. Recently, emphasis has shifted to include CVD events in diabetes trials. We characterized diabetes trials that include CVD events as a primary or secondary outcome.

Methods:
Interventional (non-observational) clinical trials registered to ClinicalTrials.gov from 1/1/2009 through 12/31/2019 were abstracted. Diabetes trials and characteristics were selected from the “Clinical Trials Transformation Initiative” SQL database, using the United States National Library of Medicine medical subject heading terms (MeSH). Trials were restricted based upon inclusion of CVD (Major Adverse Cardiac Events [MACE], cardiovascular death, fatal stroke, fatal myocardial infarction [MI], non-fatal MI, non-fatal stroke) outcomes as identified in primary or secondary outcome fields.

Results:
Among 2470 diabetes trial, only 49 (1.9%) included CVD events as a primary or secondary outcome. Median trial size was 571 (range 12, 934000), with 40.8% including multiple sites and 42.9% including a site in the US and another country. Most trials had been completed (53.1%) and were Phase 3 or 4 (36.7% and 20.4%, respectively). Trials were predominantly randomized (91.8%), parallel assignment (89.8%), masked (75.5%), included a control arm (87.8%), and industry-funded (59.2%). Over half did not report results on ClinicalTrials.gov (55.1%). Only 2 diabetes trials with CVD outcomes were registered in both 2009 and 2019 each (range 2-7).

Conclusions:
Despite increased emphasis on clinically-relevant outcomes, particularly with new therapeutics, <2% of diabetes trials registered to ClinicalTrials.gov included CVD outcomes, which did not meaningfully increase from 2009. However, diabetes trials with CVD outcomes were primarily industry funded and well-designed. Given the importance of clinically-relevant outcomes, particularly the increased risk of CVD seen with diabetes, greater emphasis on CVD outcomes in diabetes-specific trials is needed.
Abstract 9549: Role of Troponin Levels, Grace Score, and Timi Score in Predicting Mortality in Covid-19 Related Myocardial Injury
Authors: raj Kavin , mahajan pranav , Shah Monarch , Jose Jemin , Watts Abi , Kiran Aedma Surya , Dhobale Swati , Upadhyay Riddhi , Rizkalla Adam , Sharma Suyansh , khanam rukhsaar , Bin Farooq Talha , Keval Patel , Martin Randolph , Manohar Hasitha
Published: April 2022

Introduction:
COVID-19 infection is associated with troponin elevation, which is associated with increased mortality. We wanted to evaluate whether troponin levels, GRACE scores, and TIMI scores were independently associated with mortality in COVID-19 patients.

Methods:
Out of 1500 COVID-19 patients admitted to our hospitals, 217 patients with troponin levels were included. Key variables were collected manually, and survival analysis was done.

Results:
Mortality was 26.5% in the normal troponin group and 54.6% in the elevated troponin group. Patients with elevated troponins had increased frequency of hypotension (P=0.01), oxygen support (P<0.01), low absolute lymphocyte count (P<0.01), elevated blood urea nitrogen (P<0.01), higher C-reactive protein (P<0.01), higher D-dimer (P<0.01), higher lactic acid (P<0.01), and higher qSOFA, SOFA, TIMI, and GRACE scores (all scores P<0.01). On cox regression, troponin elevation (HR 1.85, 95% CI 1.18-2.88, P<0.01), TIMI score >3 (HR 1.79, 95% CI 1.11-2.75, P=0.01), GRACE score >140 (HR 2.27, 95% CI 1.45-3.55, P<0.01) were highly associated with mortality whereas cardiovascular disease (HR 1.40, 95% CI 0.89-2.21, P=0.129) and cardiovascular risk factors (HR 1.15, 95% CI 0.73-1.81, P=0.52) were not. We created four separate multivariate cox regression models for troponin, GRACE score, TIMI score, and SOFA score while adjusting for age, use of non-rebreather or high flow nasal cannula, hemoglobin<8.5, suspected or confirmed source of infection, and qSOFA score. GRACE (HR 1.02, 95% CI 1.01-1.04, P<0.01) and SOFA scores (HR 1.19, 95% CI 1.08-1.31, P<0.01) were independently associated with mortality whereas Troponin (HR 1.08, 95% CI 0.63-1.85, P=0.76) and TIMI score (HR 1.02, 95% CI 0.99-1.06, P=0.12) were not. SOFA scores are positively correlated with GRACE scores (r=+0.39).

Conclusion:
Troponin elevation in COVID-19 patients is mostly due to demand ischemia rather than acute coronary syndrome-related. This was shown by the association of troponin with a higher degree of systemic inflammation and end-organ dysfunction. We recommend SOFA scores and GRACE scores in risk stratifying COVID-19 patients with myocardial injury.
Abstract 9552: RNA Sequencing of Cardiac and Renal Tissue in a Rat Model of Chronic Kidney Disease Reveals Chronodisruption as Common Pathway
Authors: Van Den Eynde Jef , Jacquemin Xander , Gillijns Hilde , Gsell Willy , Himmelreich Uwe , Luttun Aernout , McCutcheon Keir , Janssens Stefan P , Oosterlinck Wouter
Published: April 2022

Introduction:
Chronic kidney disease (CKD) is often accompanied by cardiovascular disease, which is referred to as type 4 cardiorenal syndrome. Management is challenging due to the multifactorial nature of the condition, and treatment of one organ may negatively impact the other.

Hypothesis:
More insights into the common molecular disease processes in the heart and kidney might provide a source for new therapies. We used RNA sequencing to identify pathways that were dysregulated in both organs.

Methods:
Cardiac and renal tissue samples from four 5/6
th
partial nephrectomized (NX) and four sham-operated (SHAM) female Sprague-Dawley rats were analyzed using RNA sequencing. Strand-specific and rRNA depleted cDNA libraries were generated and were sequenced on NovaSeq (Ilumina) with 20 million reads per library.

Results:
In comparison to SHAM, the kidneys of NX animals had 290 differentially expressed genes (DEGs), showing increased expression of genes that map to Gene Ontology terms including collagen
fibril organization
,
circadian regulation of gene expression
,
mitotic cell cycle
,
neutrophil chemotaxis
, and
inflammatory response
. Within the hearts of NX animals, 8 DEGs were found, including those related to
circadian regulation of gene expression (Per2, Per3, Arntl/Bmal1, BHLHE41)
, as well as the
Adra1d
,
C2cd4b
,
Ubtd1
, and
Atp2b2
genes. Four genes were differentially expressed in both organs. Three of them were related to circadian rhythm, with
Per2
and
Per3
being downregulated and
Arntl/Bmal1
being upregulated. Furthermore,
Adra1d
was downregulated in both organs.

Conclusions:
This comprehensive RNA sequencing in a rat model of type 4 cardiorenal syndrome identified chronodisruption as a common pathway, suggesting that circadian rhythms could be a novel target for intervention.
Figure Legend.
(A) Venn diagram with number of DEGs and vulcano plots for heart (left) and kidney (right). (B) GO terms for heart. (C) GO terms for kidney.
Abstract 9556: Dipeptidyl Peptidase-4 Inhibitors Significantly Reduce the Incidence of First Cardiovascular Events in Diabetic Patients
Authors: Soejima Hirofumi , Morimoto Takeshi , Okada Sadanori , Matsumoto Chisa , Nakayama Masafumi , Jinnouchi Hideaki , Masuda Izuru , Waki Masako , Saito Yoshihiko , Ogawa Hisao
Published: April 2022

Background:
Many studies have reported that dipeptidyl peptidase (DPP)-4 inhibitors do not significantly reduce cardiovascular events (CVE). We sought to evaluate whether DPP-4 inhibitors effected the incidence of CVE in diabetic patients with no history of atherosclerotic events.

Methods:
The Japanese primary prevention of atherosclerosis with aspirin for diabetes (JPAD) trial was a multicenter, prospective, randomized, open label, blinded, end-point study done from 2002 to 2008. After completion of the JPAD trial, we followed up with the patients until 2019. We defined the cardiovascular events as the following: acute myocardial infarction; stable angina; unstable angina; sudden cardiac death; stroke; transient ischemic attack; heart failure requiring hospitalization; aortic disease; and peripheral artery disease. JPAD patients were divided into a DPP-4 Group and a non-DPP-4 Group based on whether or not they were taking DPP-4 inhibitors at the 2013 follow-up. We investigated the incidence of CVE in 1,107 JPAD patients who had had at least one follow-up by 2019.

Results:
During the observation period from 2013 to 2019, there were 37 (7%) CVE in the DPP-4 Group (n=520) and 66 (11%) in the non-DPP-4 Group (n=587). The incidence of CVE was significantly lower in the DPP-4 Group than in the non-DPP-4 Group (Log-Rank P=0.0074, Figure). Cox proportional hazards model analysis revealed that use of DPP-4 inhibitors (HR, 0.65: 0.43-0.98, P=0.04) was an independent factor after adjustment for age ≥65 years, hypertension, dyslipidemia, and, insulin usage (Figure).

Conclusions:
Our study demonstrated that the use of DPP-4 inhibitors was associated with a reduced incidence of CVE after adjustment in diabetic patients without a history of atherosclerotic events. It is necessary to be aware of the cardiovascular event-suppressing effect of DPP-4 inhibitors on diabetic patients.
Abstract 9559: Clinical Outcomes and Predictors of All-Cause Mortality After Complex High-risk and Indicated Revascularization Using Percutaneous Coronary Intervention
Authors: Satake Akinori , Uchida Yasuhiro
Published: April 2022

Introduction:
The concept of complex and high-risk indicated procedures using percutaneous coronary intervention (CHIP-PCI) has recently been defined. However, few studies have investigated the prognosis of patients after CHIP-PCI.

Methods:
CHIP-PCI was defined as a procedure satisfying at least one criterion each for both patient and procedure characteristics, as follows: patient characteristics [age (≥ 75 years old), low left ventricular ejection fraction (LVEF), diabetes mellitus, acute coronary syndrome, previous coronary artery bypass surgery, peripheral arterial disease, severe chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), and severe valvular disease] and procedure characteristics [unprotected left main disease, degenerated saphenous or radial artery grafts, severely calcified lesions, last patent conduit, chronic total occlusions, multivessel disease, and use of mechanical circulatory support]. Between January 2017 and December 2018, we performed PCI for 695 consecutive patients in our hospital. Of these patients, CHIP-PCI was performed for 322 consecutive patients.

Results:
The survival rate was significantly lower in CHIP-PCI group than non-CHIP-PCI group (log-rank P < 0.01, Figure). Moreover, on Cox multivariate hazard analysis, age (≥ 75 years old) (hazard ratio: 4.01, 95% confidence interval: 1.92-8.38, p < 0.01), COPD (hazard ratio: 2.95, 95% confidence interval: 1.38-6.32, p < 0.01), low LVEF (hazard ratio: 3.35, 95% confidence interval: 1.55-7.22, p < 0.01), severe CKD (hazard ratio: 3.02, 95% confidence interval: 1.44-6.36, p < 0.01), and use of mechanical circulatory support (hazard ratio: 5.97, 95% confidence interval: 2.72-13.10, p < 0.01) remained significant predictors of mortality after CHIP-PCI..

Conclusions:
The presence of advanced age, COPD, low LVEF, severe CKD, and mechanical circulatory support use might lead to worse clinical outcomes after CHIP-PCI.
Abstract 9562: Prediction of Post-TAVR Pacemaker Implantation Using Machine Learning on Pre-TAVR ECG
Authors: Hajjari Jamal , Tsushima Takahiro , Janus Scott , Wheat Heather , Baeza Cristian R , Thal Sergio , Attizzani Guilherme , Al-Kindi Sadeer
Published: April 2022

Introduction:
Transcatheter Aortic Valve Replacement (TAVR) is increasingly performed with a decreasing overall complication rate. The risk of complete heart block requiring pacemaker implant (PPI) remains an important complication. Simple and accurate pre-TAVR risk stratification is essential to identify the patients who are at high risk for PPI. Unfortunately, an accurate risk prediction tool is not established yet.

Hypothesis:
We hypothesized that a pre-existing “electrical fingerprint” on electrocardiography (ECG) is associated with the need for post-TAVR PPI and that using machine learning (ML) approaches on pre-TAVR ECG can predict the need for post-TAVR PPI.

Methods:
This is a single-center retrospective study of 1032 patients who underwent TAVR from March 2011 to November 2019 at University Hospitals Cleveland Medical Center. Patients with preexisting cardiac implantable electronic devices were excluded. Pre-TAVR ECGs were obtained within 90 days prior to TAVR and a total of 637 features were extracted using ECG MUSE system (GE Healthcare; Milwaukee, WI). We applied hierarchical clustering on 637 ECG features and explored the incidence of post-TAVR PPI in each cluster. Using supervised machine learning, we trained and tested 25 ML algorithms using 445 ECG features (66:34 train:test split). We explored the accuracy of the best 5 ML algorithms on clinical data alone, 26 pre-TAVR clinical variables+ECG, and ECG alone to predict PPI after TAVR. Analysis was done using R Studio (Vienna, Austria) and Waikato Environment for Knowledge Analysis (WEKA, NZ).

Results:
Hierarchical clustering identified two distinct clusters (cluster 1 has 69% of the patient and cluster has 31% of the patient). The incidence of PPI was 13% in cluster 1 and 33% in cluster 2 (P<0.0001). The best performing supervised ML had an accuracy of 83% and AUC-ROC of 0.76 with no significant improvement with including clinical variables.

Conclusions:
A pre-existing “electrical fingerprint” accounts for significant variation in post-TAVR PPM implant. Unsupervised and supervised ML approaches can be helpful in predicting PPI without the need for inclusion of clinical data. ML-based models can be broadly applied to automatically-extracted ECG features with minimal data preparation
Abstract 9564: Zeb2 Shapes the Epigenetic Landscape of Atherosclerosis and Modulates the Risk of Myocardial Infarction
Authors: Cheng Paul , Wirka Robert , Zhao Quanyi , Kim Juyong B , Nguyen Trieu , CLARKE Shoa L , Kundu Ramendra K , Sharma Disha , Kim Hyun-jung , Shi Huitong , Assimes Themistocles L , Quertermous Thomas
Published: April 2022

Smooth muscle cells (SMC) transition into a number of different phenotypes during atherosclerosis, including those that resemble fibroblasts and chondrocytes, and make up the majority of cells in atherosclerotic plaque. To better understand the epigenetic and transcriptional mechanisms that mediate these cell state changes, and how they relate to risk for coronary artery disease (CAD), we have investigated the causality and function of transcription factors (TFs) at genome wide associated loci. Employing in vitro CRISPR-Cas 9 genome and epigenome editing we show that complex genetic signals within a gene desert at 2q22.3 lie within novel smooth muscle long-distance enhancers for
ZEB2
, a TF extensively studied in the context of epithelial mesenchymal transition (EMT) in development and cancer. Single-cell epigenetic and transcriptomic profiling demonstrated that Zeb2 regulates SMC phenotypic transition through chromatin remodeling that obviates accessibility and disrupts both Notch and TGFβ signaling, altering the epigenetic trajectory of SMC transitions. These changes resulted in an inability for transition SMC to turn off contractile programing and take on a fibroblast-like phenotype, and accelerated chondromyocyte differentiation, mirroring features of high-risk atherosclerotic plaques in human coronary arteries. Parallel epigenetic alterations are observed in human coronary artery smooth muscle cells, with ZEB binding motifs preferentially enriched for human genetic signals for coronary artery disease, affirming its role as a master epigenetic regulator of atherosclerosis pathology.
Abstract 9566: Quantification of Valve Regurgitation in the Pediatric Population Using 3-Dimensional Echocardiography: Feasibility and Comparison With Cardiac Magnetic Resonance Imaging
Authors: Kuebler Joseph D , Shea Melinda H , Lu Minmin , Sleeper Lynn A , Harrild David M , Prakash Ashwin , Marx Gerald R
Published: April 2022

Introduction:
Valvar regurgitation in pediatric patients is commonly assessed by cardiac magnetic resonance (CMR). This modality is associated with increased cost and need for anesthesia in young patients when compared to echocardiography. 3-dimensional echocardiography (3DE) can measure ventricular volumes and calculate the regurgitation fraction (RF) by comparison of stroke volumes - similar to CMR. Given the potential advantages of 3DE in children, this study sought to compare the quantification of single valvar regurgitation using 3DE versus CMR as the gold standard.

Methods:
Pediatric patients ≤18 years of age were included in the study. Patients were excluded if they had more than mild regurgitation of an additional valve, significant shunt, or suboptimal imaging windows. Full volume data sets were obtained sub-costally using a Philips IE33 or EPIQ CVx machine (X5 or X7 ultrasound probe). 3DE volumes were analyzed using 4D Cardioview (Tomtec Imaging Systems) and compared with ventricular volumes and RF obtained by CMR. Inter- and intra-observer reliability were assessed for 3DE ventricular volumes and RF.

Results:
34 patients had volumes obtained by 3DE and CMR with two patients having pairs of studies performed on different dates. The median age was 8.7 (IQR; 3.9-12.3) years. 12 studies (33%) were obtained under sedation. Primary valve involvement was: mitral-12 (33%), tricuspid-9 (25%), pulmonary-1 (3%), and aortic-14 (39%). Agreement between 3DE and CMR ventricular volumes by intraclass correlation coefficient (ICC) was excellent (ICC>0.90). Agreement for the regurgitant fraction was good (ICC 0.80 (95% CI; 0.68, 0.88)). Ventricular volume ratios obtained by MRI and 3DE were strongly correlated; Spearman r = 0.92 (95% CI; 0.85-0.96). Inter-observer reliability was excellent for ventricular volumes and moderate for RF (ICC 0.63 (95% CI; 0.23, 0.85)). Intra-observer reliability was excellent for ventricular volumes and RF (ICC≥0.97).

Conclusions:
Assessment of single valvar regurgitation using 3DE compares favorably with CMR in pediatric patients. The shorter time for image acquisition and lower cost will allow for standard application of 3DE to measure single valve regurgitation in this population, particularly on a serial basis.
Abstract 9569: Increased Incidence of ECG Abnormalities in General Population during the Covid-19 Pandemic
Authors: Tsuji Hisako , Shiojima Ichiro
Published: April 2022

Background:
To examine influence of COVID-19 pandemic on cardiovascular system in general population, ECG changes during the COVID-19 pandemic period were compared with those before the pandemic period.

Methods:
Incidence of newly appeared ECG abnormalities (T wave abnormalities and ST-segment depression including minor changes, and abnormal Q wave) was evaluated in subjects 40 to 74 years of age who had 12-lead ECG recording in annual health checkup offered to adult citizens of Moriguchi city, Osaka, Japan in 2019 and 2020. The incidence was compared with that of those who received ECG recording in 2018 and 2019 as the control value before the COVID-19 pandemic. Those with history of cardiovascular disease, any T wave abnormality, any ST-segment depression, abnormal Q wave, left bundle brunch block, or pace-maker rhythm at baseline ECG were excluded. Multivariate logistic regression analyses were performed adjusted for age, sex, hypertension, current smoking, diabetes, drinking habit and hypercholesterolemia.

Results:
There were 5,221 (mean age 63±10, men 40%) subjects who received ECG recording in 2018 and 2019 and 4,100 (mean age 63±10, men 41%) subjects who received ECG recording in 2019 and 2020. The incidence of newly appeared T wave abnormalities was 5.2 %, ST-segment depression was 2.8 % and abnormal Q wave was 1.1 % from 2018 to 2019, whereas the incidence of newly appeared T wave abnormalities was 5.8 %, ST-segment depression was 4.3 % and abnormal Q wave was 1.7 % from 2019 to 2020. The incidence of ST-segment depression (odds ratio (OR)=1.59, 95% confidence interval (CI)=1.27 to 1.98, p<0.0001) and that of abnormal Q wave (OR=1.56, 95% CI=1.09 to 2.22, p=0.0149) from 2019 to 2020 was significantly higher compared to that from 2018 to 2019.

Conclusions:
Increased incidence of ST-segment depression and abnormal Q wave was observed during the COVID-19 pandemic period.
Abstract 9571: Major Adverse Cardiac Events in Hypertrophic Cardiomyopathy Among Index Patients and Their Affected Relatives
Authors: Nielsen Soren K , Hansen Frederikke G , Fischer Thomas A , Madsen Trine , Klausen Ib C , Møller Dothe S , Jensen Morten , Lassen Jens F , Rasmussen Torsten Bloch B , Mogensen Jens
Published: April 2022

Introduction:
The incidence of major adverse cardiac events (MACE) is well established among index patients with hypertrophic cardiomyopathy (HCM) carrying pathogenic sequence variants in recognized HCM genes. However, MACE among their affected relatives is unknown. It was the aim to compare the incidence of MACE among index patients with HCM and their affected relatives.

Methods:
Clinical and genetic investigations were performed in consecutive index patients with HCM. Genetic investigations by next-generation sequencing were made in 116 recognized and likely HCM genes, and variants were classified by American College of Medical Genetics and Genomics criteria. Relatives at risk of having HCM were invited for clinical investigations (echocardiography, ECG-recording, and genetic testing when relevant). MACE was defined as a composite endpoint of sudden cardiac death, death due to end-stage heart failure or stroke, and heart transplant.

Results:
A total of 453 HCM families underwent clinical and genetic investigations, of whom 40% (183/453) carried pathogenic variants. Among relatives, 383 carried the same variant as the index-patient, and the penetrance of HCM in those was 42% (160/383). The median age of diagnosis was 47 years (p=0.13) in relatives and index patients. MACE occurred in 18% (33/183) of index patients, 18% (28/160) of relatives with HCM, and 0% (0/223) of healthy variant carriers. The median age of MACE was 43 years for index patients and relatives (p=0.48). During eight years of follow-up, incidence rates of MACE were not significantly different between index patients and relatives (1.2%/year vs. 1.5%/year p=0.2).

Conclusions:
Affected Relatives in HCM families who carried pathogenic sequence variants in recognized HCM genes had the same risk of MACE as index patients. This finding emphasized the importance of family screening, follow-up, and continuous risk stratification to possibly avoid adverse disease complications and sudden death.
Abstract 9579: A History of Multiple Tropical Diseases Increases Risk of Hypertension: A Cross-Sectional Study from the Amazon Basin
Authors: Holm Anna Engell , Gomes L. , Lima K. , Wegener Alma , Matos L. , Vieira I. , Kaagaard Molly D , Souza R. , Marinho C , B-S T , ms o , Brainin Philip
Published: April 2022

Introduction:
Studies have linked infectious diseases to cardiovascular conditions, however, little is known about tropical disease burden and hypertension.

Hypothesis:
We hypothesized that a history of multiple tropical infections was associated with greater risk of hypertension.

Methods:
We examined participants from outpatient clinics in the Amazon Basin, Brazil, who underwent a detailed questionnaire on prior infections with tropical diseases, including dengue, malaria hospitalization and leishmaniasis. Participants were categorized with hypertension if they had a prior diagnosis of hypertension, were treated with anti-hypertensive medication or had systolic/diastolic blood pressure ≥140/≥80mmHg.

Results:
A total of 556 participants (mean age 41 ± 15 years, 61% women) were enrolled, of which 38% (n=214) had hypertension and 354 (n=64%) had a history of tropical infectious disease. The distribution of tropical diseases was the following: Dengue 76% (n=270), malaria hospitalization 49% (n=104) and leishmaniasis 14% (n=48). In logistic regression models, each increase in prior tropical infections was significantly associated with hypertension (OR 1.50 [95%CI 1.15 to 1.96], P=0.003). The association remained significant after adjusting for age, sex, body mass index, education, income, work status, living area (urban/rural), smoking status, vegetable intake and plasma creatinine (Figure A). Persons with a history of ≥2 tropical infections (n=64) had the greatest risk of hypertension (OR 2.04 [95%CI 1.15 to 3.63], P=0.015) (Figure B). In adjusted models, prior infection with dengue was associated with higher risk of hypertension (P<0.05), but no associations were found for malaria hospitalization or leishmaniasis (P>0.05).

Conclusions:
A history of multiple tropical infections was associated with hypertension. This finding supports the idea that infectious diseases may be related to cardiovascular conditions.
Abstract 9585: Impaired Renal Function Pre- and Post- MitraClip Implantation is an Independent Predictor of Late All-Cause Mortality: A Systematic Review and Meta-Analysis
Authors: SAFIRIYU ISRAEL , Nagraj Sanjana , Palaiodimos Leonidas , Faillace Robert
Published: April 2022

Background:
Impaired renal function, a well-recognized complication of severe heart failure, is associated with adverse outcomes following cardiovascular interventions. There are conflicting data reported about its impact on late all-cause mortality following transcatheter mitral valve repair with MitraClip (MC) implantation in patients with grade 3 or 4 mitral regurgitation.

Hypothesis:
We hypothesized that pre- and post- procedural renal dysfunction negatively impacts late (≥ 1 year) all-cause mortality following MitraClip implantation.

Methods:
Electronic databases PubMed, Embase, and Web of Science were systematically reviewed from inception to February 2021 for studies evaluating outcomes after MC implantation, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A random-effects model meta-analysis was performed and heterogeneity of the included studies was assessed by using I-squared test.

Result:
Out of 2606 articles, 16 studies with 19,503 patients were included. Pre-procedural renal dysfunction i.e. chronic kidney disease (CKD) was independently associated with higher late all-cause mortality (Hazard ratio [HR] 1.59, 95% CI 1.25 - 2.02, I
2
= 60%) after MC implantation (fig 1). On subgroup analysis, late all-cause mortality rates were higher with CKD ≥stage 4 compared to CKD stage 3 (HR 2.86, 95% CI 1.87 - 4.39, I
2
= 26% VS HR 1.55 95% CI 1.19 - 2.01, I
2
= 0%). Development of post procedural acute kidney injury was also independently associated with higher late all-cause mortality (HR= 2.32, 95% CI 1.71 - 3.15, I
2
= 42%) after MC implantation (fig 2).

Conclusion:
Impaired renal function pre- and post-MC implantation is a strong independent predictor of late all-cause mortality. This should be considered during the clinical decision-making process of patients undergoing the MC procedure.
Abstract 9591: Minority Stress and Incident Hypertension in Sexual Minority Women
Authors: Caceres Billy A , Sharma Yashika , Levine Alina , Wall Melanie M , Hughes Tonda
Published: April 2022

Introduction:
Sexual minority women (SMW; e.g., lesbian, bisexual) are at higher risk of hypertension than heterosexual women. Minority stressors (defined as unique psychosocial stressors attributed to sexual minority identity) are hypothesized to contribute to hypertension risk in SMW. However, research has yet to formally test the association of minority stressors with hypertension. We sought to examine the association between several key minority stressors and self-reported incident hypertension among SMW.

Hypothesis:
Minority stressors will be positively associated with incident hypertension in SMW.

Methods:
We conducted a secondary analysis of data from Chicago Health and Life Experiences of Women study, a 21-year longitudinal study of SMW’s health. Using two waves of data we examined the associations of minority stressors (i.e., experiences of discrimination, stigma consciousness, and internalized homophobia) with incident hypertension. We ran mutually adjusted logistic regression models to estimate the odds ratios of the associations between minority stressors and incident hypertension, after adjusting for demographics, insurance status, body mass index, and smoking status.

Results:
The analytic sample included 348 SMW; mean age 38.4 (±12.8) years. More than half were women of color (56.6%). Approximately 60% had completed a bachelor’s degree and most had healthcare insurance (73.6%). Mean follow-up was 7.0 (±0.6) years; during which 12.6% were diagnosed with hypertension. After covariate adjustment, we found that a 1-standard deviation increase in internalized homophobia scores was associated with higher odds of incident hypertension (AOR 1.50, 95% Cl = 1.05-2.10). Stigma consciousness (AOR 0.80, 95% CI = 0.52-1.23) and experiences of discrimination (AOR 1.13, 95% CI = 0.76-1.61) were not associated with incident hypertension.

Conclusions:
This is the first study to document that internalized homophobia is associated with incident hypertension in SMW. Future research is needed that examines the associations of minority stressors with objective measures of hypertension. Findings highlight there is a need for psychosocial interventions to reduce internalized homophobia and hypertension risk in SMW across the lifespan.