bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 16974: Gender Differences in Patients Undergoing Transcatheter Aortic Valve Replacement: a Single Center Experience
Authors: Warren Josephine L , Baber Usman , Yu Jennifer , Aquino Melissa , Bhat Arjun , Basnet Sandeep , Dangas George , Mehran Roxana , Pyo Robert , Kovacic Jason , Sharma Samin K , Kini Annapoorna S
Published: July 2021

Background:
Current data suggest that women experience different outcomes to men following transcatheter aortic valve replacement (TAVR). We reviewed the Mount Sinai valve database to compare men and women undergoing TAVR according to procedural characteristics and outcomes.

Methods:
124 patients underwent TAVR at Mount Sinai from May 2012-2014. All patients received Edwards Sapien valves. Follow-up was conducted at 30-days.

Results:
Women accounted for 61% (n=76) of the TAVR cohort. The mean age of women was 80.7, and 82.2 for men (p=0.30). Men were more likely to have undergone previous cardiac bypass surgery and were more likely to be on dialysis and have a pacemaker or intra-cardiac defibrillator in-situ (27.1% vs. 7.9%, p=0.004). Women had lower baseline hemoglobin. These disparities did not translate to differences in STS Risk Score or EuroScore. In women, the aortic annulus (21.2mm vs. 23.4mm, p<0.0001), left atrial (24.6mm vs. 27.2mm, p = 0.02) and left ventricular (3.09mm vs. 4.11mm, p<0.001) areas were smaller, as was the ilio-femoral artery diameter (7.4mm vs. 8.03mm, p=0.02). In contrast, men had a lower left ventricular ejection fraction (49.9% vs. 57.6%, p=0.004) and mean aortic valve gradient (43.5mmHg vs. 48.8mmHg, p=0.004). Procedural length did not differ between genders, nor did the method of approach. Women were less likely to experience conduction complications requiring pacemaker insertion both intra-procedurally (2.6% vs. 12.5%, p=0.03) and 30-days post-discharge (2.7% vs. 13.2%, p = 0.03). Women were more likely to receive in-hospital transfusion (51.3% vs. 18.8%, p=0.0003), but mortality rates did not differ between genders (7.0% vs. 6.7%, p=0.5).

Conclusion:
Despite discrepancies in some important pre-procedural parameters, as well as rates of post-procedural conduction abnormalities and in-hospital transfusion, these did not translate into differences in mortality rates between genders in patients undergoing TAVR.
Abstract 16977: MicroRNA-mediated Regulation of SUMO1 Expression in Heart
Authors: Oh Jae Gyun , Lee Ahyoung , Jeong Dongtak , Baccarini Alessia , Brown Brian D , Kho Changwon , Hajjar Roger J
Published: July 2021

Background:
Cardiac sarcoplasmic reticulum calcium ATPase pump (SERCA2a) is a key regulator in cardiac cells and its function and expression are decreased in heart failure (HF). Our group has shown that SERCA2a gene transfer induces beneficial effects in HF models and in patients with severe HF. Recently, our group determined that SERCA2a is SUMOylated by small ubiquitin related modifier type 1 (SUMO1), ultimately impacting cardiac function. The expression of SUMO1 in the myocardium is significantly decreased in failing hearts and its knockdown results in severe HF. However, the mechanisms by which SUMO1 is regulated remain unknown.

Methods/Results:
To identify potential miRNAs targeting SUMO1, we first generated 19 candidates by sequence based prediction. Among 19 candidates, miR-146a was upregulated concurrently with SUMO1 expression in murine models of HF and in human HF ventricular tissues. Using a luciferase reporter assay, we confirmed that miR-146a targets the SUMO1 3’-untranslated region. Overexpression of miR-146a suppressed the expression of SUMO1 in mRNA and adversely affected the calcium transient in cardiomyocytes. Conversely, transfection of ‘decoy’ genes which has tandem complementary sequences of miR-146a increased both mRNA and protein of SUMO1. Introduction of miR-146a ‘decoy’ increased sumoylation of SERCA2a in cardiomyocytes.

Conclusion:
These findings provide new insight into the regulation of SUMO1 in cardiomyocytes. It implies modulation of miR-146a is a potential target in HF therapy.

Key Words: heart failure, microRNA, SUMO, SERCA2a
Abstract 17001: Is There Cytomegalovirus Disease After Prophylaxis?
Authors: Huang Helen C , Patel Jignesh , Chang David H , Yu Zhe , Liou Frank , Yabuno Jamie , Kittleson Michelle , Azarbal Babak , Czer Lawrence , Zakowski Phillip , Kobashigawa Jon
Published: July 2021

Purpose:
Cytomegalovirus (CMV) disease (specific organ involvement) is a significant cause of morbidity and mortality in orthotopic heart transplantation (OHT). CMV disease is reported to increase the development of cardiac allograft vasculopathy (CAV). The duration of CMV prophylaxis in recipients is dependent on their CMV serostatus in relation to the donors. However, the effective duration of CMV prophylaxis post-transplant remains unclear.

Methods:
Between 2007 and 2012, 267 OHT patients were divided into four groups based on the CMV serostatus of the donors (D) and recipients (R): D+/R-, D+/R+, D-/R+, D-/R-. CMV prophylaxis was given for up to one year in D+/R- patients, up to six months in D+/R+ and D-/R+ patients, and three months in D-/R-. Endpoints included two-year overall survival and freedom from development of CMV disease, CAV, and NF-MACE (defined as myocardial infarction¼..) after the end of CMV prophylaxis in the four study groups, respectively.

Results:
After the end of respective CMV prophylaxis in the four study groups, there was no significant difference in two-year overall survival and freedom from development of CMV disease, CAV, and NF-MACE among the four groups. Of the D+/R- group, one patient developed CMV gastritis, one patient CMV pneumonia, and one patient CMV colitis. Two patients developed CMV colitis in the D+/R+ group.

Conclusions:
The current recommendations for the duration of CMV prophylaxis appear to be satisfactory in preventing CMV disease and complications after the end of prophylaxis.
Abstract 17050: Association of Kidney Dysfunction with Chronotropic Incompetence in Heart Failure with Preserved Ejection Fraction
Authors: Klein David A , Katz Daniel H , Beussink-Nelson Lauren , Strzelczyk Theresa A , Shah Sanjiv J
Published: July 2021

Introduction:
Chronotropic incompetence (CI) is an important pathophysiologic factor underlying reduced exercise capacity in heart failure with preserved ejection fraction (HFpEF), but clinical factors associated with CI in HFpEF are unknown. Based on anecdotal clinical experience, we hypothesized that coronary artery disease (CAD) and chronic kidney disease (CKD) are associated with CI in HFpEF.

Methods:
We studied 157 consecutive HFpEF patients undergoing cardiopulmonary exercise testing, and defined CI as maximal heart rate (HR) < 80% of estimated HR reserve (< 65% if using beta-blockers). Participants who achieved inadequate exercise effort (respiratory exchange ratio [RER] ≤ 1.05) were excluded. Unadjusted and multivariable-adjusted regression models were used to determine correlates of CI. Results were re-assessed using alternative formulations of chronotropic response.

Results:
Of 157 participants, 73% were women, 64% used beta-blockers, 32% had CKD, and 40% had CAD. RER > 1.05 was achieved by 108 (69%) participants, including 79/108 (76%) with CI. Lower estimated GFR, higher B-type natriuretic peptide, and higher pulmonary artery systolic pressure (but not CAD) were each associated with CI. A 1-SD decrease in GFR was independently associated with CI (adjusted odds ratio = 2.4, 95% confidence interval = [1.3, 4.6]) after adjustment for smoking status, log BNP, and beta blocker usage. Linear regression models demonstrated that GFR was independently and linearly associated with %HR reserve (β=0.31, SE=0.10; P=0.002; Figure). Findings were unchanged after re-calculation of %HR reserve and CI based on alternative formulations used in the literature.

Conclusions:
CI is common and strongly associated with GFR in HFpEF. Our results indicate that kidney function may mark or contribute to the development of CI in HFpEF. HFpEF patients with CKD may need to be screened for CI prior to starting medications (e.g., beta blockers) that could exacerbate CI.
Abstract 17083: Assessment of Both Coronary Microvascular Damage and Left Ventricular Chamber Stiffness after Successful Percutaneous Coronary Intervention Predicts In-Hospital Cardiac Complications and Left Ventricular Remodeling in ST-Segment Elevation Myocardial Infarction
Authors: Yamamuro Atsushi , Tamita Koichi , Kaji Shuichiro , Kitai Takeshi , Furukawa Yutaka , Yoshikawa Junichi
Published: July 2021

Background:
In ST-segment elevation myocardial infarction (STEMI), the short deceleration time of left ventricular (LV) early filling by Doppler is a powerful independent predictor of clinical cardiac events. It has also been reported that the coronary flow velocity pattern in patients with microvascular obstruction is characterized by the presence of early systolic retrograde flow and a rapid diastolic deceleration time (DDT). The purpose of this study was to examine the effects of both microvascular damage and LV chamber stiffness on cardiac complications and LV remodeling after successful percutaneous coronary intervention (PCI) in STEMI patients.

Methods:
Two hundred and one consecutive patients with first anterior STEMI were studied following successful PCI. Microvascular damage was evaluated on the basis of coronary flow velocity patterns using Doppler guidewires. We defined the presence of microvascular obstruction as DDT ≤600 ms and the presence of systolic flow reversal. LV filling patterns were determined by LV inflow pulsed-wave Doppler examination on day 3 after STEMI. Deceleration time ≤130 ms was defined as restrictive. We classified patients into three categories: without restrictive and microvascular obstruction (group 1, n=116), with restrictive or microvascular obstruction (group 2, n= 38), and with restrictive and microvascular obstruction (group 3, n=47). Left ventriculograms were obtained immediately and 6 months after PCI. LV remodeling was defined as an increase in end-diastolic volume index ≥20%. The clinical event rate was compared among the 3 groups.

Results:
The in-hospital event rates for LV thrombus (2/116 [2%], 5/38 [13%] and 14/47 [30%], respectively; P < 0.01) and congestive heart failure (5/116 [4%], 10/38 [26%], and 22/47 [47%]; P < 0.01) were highest in group 3 and lowest in group 1. Group 3 was at the highest risk of LV remodeling, while group 1 was at the lowest (7/116 [6%], 14/38 [37%], and 39/47 [83%]; P < 0.01).

Conclusions:
Assessment of both microvascular damage and LV chamber stiffness can accurately predict in-hospital complications and LV remodeling in STEMI patients who underwent successful reperfusion of the infarct-related coronary artery, identifying a subset of high risk patients.
Abstract 17153: Increased Atherosclerotic Plaque Instability in Advanced Atherosclerosis with Aging: the Role of Calpain 2 in SOD2-deficient ApoE-/- Mice
Authors: Vendrov Aleksandr E , Madamanchi Nageswara R , Stevenson Mark D , Runge Marschall S
Published: July 2021

The prevalence of atherosclerosis and incidence of cardiovascular events increase with advancing age. Increased generation and/or decreased scavenging of reactive oxygen species (ROS) in the vascular wall are major determinants of vascular disease progression. We previously showed that SOD2 deficiency in aging increases vascular oxidative stress and reduces aortic compliance, while young ApoE-/-/SOD2+/- mice show increased mitochondrial DNA damage and accelerated atherogenesis. Here we investigated the effects of aging and SOD2 deficiency on atherosclerosis and vascular wall morphology in ApoE-/- mice.

Compared with the control ApoE-/-, aged ApoE-/-/SOD2+/- mice had increased total vascular wall (P < 0.001) and mitochondrial ROS levels (P < 0.05) and 70% higher atherosclerotic lesion area (P < 0.001). Pulse wave velocity (P < 0.001) and aortic wall collagen content (P < 0.05) were significantly increased, while atherosclerotic plaque fibrous cap thickness (P < 0.01) and vascular smooth muscle cell (VSMC)-positive area (P < 0.01) were decreased in aged ApoE-/-/SOD2+/- mice. Immunofluorescence analysis of atherosclerotic lesions revealed higher levels of calpain 2, a cysteine protease implicated in apoptosis and cleaved caspase-3 localized in smooth muscle-positive areas of the plaque in aged ApoE-/-/SOD2+/- mice. VSMC isolated from aged SOD2+/- had higher levels of mitochondrial oxidative stress and dysfunction compared with VSMC from wild-type mice, as determined by increased superoxide generation and mitochondrial protein carbonylation and lower complex I and III activity. The calpain 2 protein levels were significantly higher in the SOD2+/- VSMCs compared with the wild-type cells and its expression and activity increased after TNF-α treatment, causing apoptosis. TNF-α increased MMP2 activity in SOD2+/- VSMC in Calpain 2-dependent manner.

In conclusion, enhanced mitochondrial oxidative stress in aging increases aortic stiffening, atherosclerotic burden and plaque instability in advanced atherosclerosis, in part, via the activation of calpain 2 and MMP2. Targeting mitochondrial oxidative stress and calpain 2 activity may be a viable strategy to prevent aging-associated atherosclerosis complications.
Abstract 17184: CMR Derived Myocardial Mechanics in Patients With Systemic Sarcoidosis
Authors: Rolim S. Fernandes Veronica , Jauregui Garrido Beatriz , Siqueira Maria E , Katz Jonathan , Jacobi Adam , Fuster Valentin , Narula Jagat , Sanz Javier
Published: July 2021

Objective:
To assess myocardial mechanics by cardiac magnetic resonance (CMR)-derived strain in patients with biopsy-proven systemic sarcoidosis.

Methods:
We included 50 consecutive patients (age 51 ± 11 years old, 30 males) with biopsy-proven systemic sarcoidosis who underwent gadolinium-enhanced CMR for suspected cardiac sarcoid involvement. Late gadolinium enhancement (LGE) was considered positive if showing an intramyocardial/subepicardial location with a nonischemic pattern. From cine images and using dedicated software (TomTec©), we quantified mean left ventricular (LV) longitudinal, radial, and circumferential peak strains as the average of 16 standard myocardial segments. We also randomly selected from our database 15 control subjects without structural heart disease (age 41 ± 11 years old, 5 males).

Results:
Both mean longitudinal strain (LS) and LV ejection fraction (LVEF) were lower in sarcoid patients than controls (-11.8 ± 7.3% vs. -18.1 ± 3.9%, p55%, n=32) mean LS was reduced compared to controls (-12.2 ± 7.8% vs. -18.1 ± 3.9% respectively, p=0.01; Fig 1B). There was no correlation between LVEF and mean LS (r=-0.11, p=0.65). We found no significant differences in circumferential or radial strains.

LGE was present in 16 patients (32%). Sarcoid patients with LGE showed significantly less mean LS than those without (-8.5 ± 8.4% vs. -13.6 ± 6.4%, p<0.001; Fig 1A) although LVEF did not differ significantly (52% vs. 59%, p=0.35). No significant differences in circumferential or radial strains were found.

Conclusions:
In patients with systemic sarcoidosis, evaluation of cardiac mechanics with CMR detects myocardial dysfunction even in the presence of preserved LVEF. This is more pronounced in patients with positive LGE. The potential diagnostic and prognostic significance of CMR-derived myocardial strain in sarcoidosis deserves further investigation.
Abstract 17227: Transplantation of Cardiac Cell Sheet Including Human Ips Cell-derived Cardiomyocytes and Vascular Cells to Infarcted Porcine Heart Restores Impaired Left Ventricular Global Function and Dyssynchrony
Authors: Ishigami Masanosuke , Masumoto Hidetoshi , Aoki Takayuki , Takai Fumie , Ikuno Takeshi , Marui Akira , Minakata Kenji , Ikeda Tadashi , Sakata Ryuzo , Yamashita Jun K
Published: July 2021

BACKGROUNDS:
Previously we reported beneficial effects of transplantation of all mouse ES cell-derived cardiac cell sheets composed of CMs and vascular cells (endothelial cells [ECs]/ vascular mural cells [MCs]) in a rat myocardial infarction (MI) model and importance of co-existence of vascular cells in the cell sheets (Stem Cells, 2012). Here we report a transplantation of human induced pluripotent stem cell (hiPSC)-derived cardiac cells to a porcine MI model.

METHODS & RESULTS:
We induced a mixture of CMs and vascular cells from hiPSCs with a 2-D serum-free method (modified from Uosaki, PLoS One, 2011). We generated cell sheets using 10cm-sized temperature-responsive culture dishes (UpCell; CellSeed, Tokyo, Japan). Self-pulsating cardiac cell sheets were approximately 3.5cm in diameter with 6.8х106±0.8 (n=5) of cells containing cTnT+-CMs (19.4±5.9%), VE-cadherin+-ECs (3.8±4.4%) and PDGFRβ+-MCs (67.2±7.8%). We induced MI in micromini-pigs (12-45 month old) by ameroid constriction of coronary artery and transplanted cell sheets (Tx) 2 weeks after MI induction (4 sheets / recipient) under immunosuppression. In Tx group, echocardiogram showed a significant improvement of systolic function of left ventricle (fractional shortening: 22.6±5.0 vs 39.7±8.7%, p<0.01, n=5). Ejection fraction evaluated by left ventriculogram improved significantly in Tx group (25.3±6.2% vs 39.8±4.2%, p<0.01, n=5). Speckle tracking echocardiogram showed significant increase of attenuated circumference strain in infarcted and border regions leading to restored dyssynchrony (anterior: 10.8±4.1 vs 20.6±3.5%, p<0.01, antero-lateral: 13±6.5% vs 24.8±7.6%, p<0.05, n=5, 2 weeks after Tx). Capillary density in the border region significantly elevated indicating angiogenic effect of the sheet transplantation (75.9±42.6/mm2 vs 137.4±44.8/mm2, p<0.001, n=5).

CONCLUTION:
HiPSC-derived cardiac cell sheets potentially ameliorate cardiac dysfunction of human-size infarct heart.
Abstract 17259: Differential Changes in Plaque Behind the Stent After Bare-Metal and Drug-Eluting Stent Implantation in Humans: Implications for In-Stent Restenosis?
Authors: Andreou Ioannis , Shishido Koki , Antoniadis Antonios P , Takahashi Saeko , Tsuda Masaya , Papafaklis Michail I , Saito Shigeru , Coscun Ahmet U , Feldman Charles L , Stone Peter H
Published: July 2021

Background:
The natural history and the role of the atherosclerotic plaque located behind the stent (PBS) are still poorly understood. We evaluated the serial changes in PBS following bare-metal (BMS) compared with first-generation drug-eluting stent (DES) implantation and the impact of these changes on in-stent neointimal hyperplasia (NIH).

Methods:
3D coronary reconstruction by angiography and intravascular ultrasound were serially performed after intervention and at 6- to 10-month follow-up in 157 Japanese patients treated with BMS (n=90) and DES (n=98; 68 sirolimus-eluting and 30 paclitaxel-eluting stents) included in the PREDICTION Study. Each reconstructed stented coronary artery was divided into consecutive 1.5-mm segments. External elastic lamina, lumen, stent, and PBS area were measured for each segment at both baseline and follow-up. At follow-up NIH area was assessed. Due to the very low rate of events in our population we used significant NIH (defined as NIH area >50% of stent area) as a binary anatomic outcome.

Results:
Patient, lesion, and stent characteristics were comparable between BMS and DES. There was a significant decrease in PBS area after BMS (median relative change: -7.2%, IQR -19.3 to 5.2%, p<0.001) and a significant increase after DES implantation (median relative change: 6.1%, IQR -5.7 to 20.5%, p<0.001). The decrease in PBS area significantly predicted NIH area at follow-up after controlling for baseline lumen area and baseline PBS area in both BMS (β 0.15, 95% CI 0.1 to 0.2, p<0.001) and DES (β 0.09, 95% CI 0.07 to 0.11, p<0.001). The decrease in PBS area was the most powerful predictor of significant NIH in both BMS (OR 1.13, 95% CI 1.02 to 1.26, p=0.017) and DES (OR 1.65, 95% CI 1.16 to 2.36, p=0.005).

Conclusions:
The PBS significantly decreased 6 to 10 months after BMS implantation, whereas after DES it increased. The decrease in PBS area was significantly associated with the development of NIH at follow-up in both stent types. These findings raise the possibility of a communication between the lesion within the stent and the underlying native atherosclerotic plaque, and may have important implications regarding the pathobiology of in-stent restenosis.
Abstract 17285: A Selective Transforming Growth Factor-β and Growth Differentiation Factor-15 Ligand Trap Attenuates Pulmonary Hypertension
Authors: Yung Lai-Ming , Paskin-Flerlage Samuel D , Nikolic Ivana , Pearsall Scott , Kumar Ravindra , Yu Paul B
Published: July 2021

Introduction:
Excessive Transforming Growth Factor-β (TGF-β) signaling has been implicated in pulmonary arterial hypertension (PAH), based on activation of TGF-β effectors and transcriptional targets in affected lungs and the ability of TGF-β type I receptor (ALK5) inhibitors to improve experimental PAH. However, clinical use of ALK5 inhibitors has been limited by cardiovascular toxicity.

Hypothesis:
We tested whether or not selective blockade of TGF-β and Growth Differentiation Factor (GDF) ligands using a recombinant TGFβ type II receptor extracellular domain Fc fusion protein (TGFBRII-Fc) could impact experimental PAH.

Methods:
Male SD rats were injected with monocrotaline (MCT) and received vehicle or TGFBRII-Fc (15 mg/kg, twice per week, i.p.). C57BL/6 mice were treated with SU-5416 and hypoxia (SUGEN-HX) and received vehicle or TGFBRII-Fc. RNA-Seq was used to profile transcriptional changes in lungs of MCT rats. Circulating levels of GDF-15 were measured in 241 PAH patients and 41 healthy controls. Human pulmonary artery smooth muscle cells were used to examine signaling
in vitro
.

Results:
TGFBRII-Fc is a selective ligand trap, inhibiting the ability of GDF-15, TGF-β1, TGF-β3, but not TGF-β2 to activate SMAD2/3
in vitro
. In MCT rats, prophylactic treatment with TGFBRII-Fc normalized expression of TGF-β transcriptional target PAI-1, attenuated PAH and vascular remodeling. Delayed administration of TGFBRII-Fc in rats with established PAH at 2.5 weeks led to improved survival, decreased PAH and remodeling at 5 weeks. Similar findings were observed in SUGEN-HX mice. No valvular abnormalities were found with TGFBRII-Fc treatment. RNA-Seq revealed GDF-15 to be the most highly upregulated TGF-β ligand in the lungs of MCT rats, with only modest increases in TGF-β1 and no change in TGF-β2/3 observed, suggesting a dominant role of GDF-15 in the pathophysiology of this model. Plasma levels of GDF-15 were significantly increased in patients with diverse etiologies of WHO Group I PAH.

Conclusions:
These findings demonstrate that a selective TGF-β/GDF-15 trap attenuates experimental PAH, remodeling and mortality, without causing valvulopathy. These data highlight the potential role of GDF-15 as a pathogenic molecule and therapeutic target in PAH.
Abstract 17306: The Most Expensive Patients in the Hospital
Authors: Joynt Karen E , Makar Maggie , Gawande Atul , Cutler David , Obermeyer Ziad
Published: July 2021

Introduction:
In the Medicare population, 1% of the patients is responsible for 15% of spending. There are two patterns typical of highest-cost patients: those who cycle in and out of the hospital with preventable conditions, and those who have a single catastrophic event. While a great deal of focus has been placed on the former, much less is known about the latter. We do know that a large proportion of these most-expensive patients receive prolonged mechanical ventilation (PMV).

Methods/Results:
We used national Medicare data to explore diagnoses, procedures, and costs associated with these most-expensive patients. There were 91,054 hospitalizations for Medicare patients with a DRG containing PMV in 2010. The majority of PMV patients were admitted emergently (71.9%); an additional 16.7% were admitted urgently. Elective admissions represented 9.5%, and trauma accounted for 1.8%. Median length of stay was 16 days, and the median stay in the intensive care unit was 11 days. Procedures were performed in the majority of these patients, and clinical outcomes were exceedingly poor (table). The financial costs associated with this group of patients were high. The average total hospitalization charge was $227,917; the maximum charge was over $9 million. The mean Medicare payment for PMV patients in 2010 was $61,995, with a maximum of $1.3 million. This was largely through the set DRG price (mean $59,491), though outlier payments (mean $5,957, maximum $1.2 million) and patient-paid coinsurance (mean $835, maximum $88,644) played a significant role as well.

Conclusions:
A small group of Medicare beneficiaries undergoing PMV have extremely high costs and poor outcomes. This shared clinical pathway suggests that there is room for improvement, both in terms of identifying these patients early during hospitalization to prevent progression to PMV, as well as in terms of clinical innovation to improve care within the intensive care unit for those who are already ventilated.
Abstract 17443: Inhibition of the Calcineurin Interaction Site on TRPV1 Reduces Myocardial Infarct Size in Rats
Authors: Gross Eric R , Qvit Nir , Gross Garrett J , Mochly-Rosen Daria
Published: July 2021

Introduction:
With recent public concerns of opioid overuse, misuse and addiction along with the heightened FDA restrictions on opioid prescribing, non-opioid cardiac-safe pain therapeutics for those with cardiovascular disease is needed. The transient receptor potential vanilloid 1 (TRPV1), a mediator of heat, pain and noxious stimuli, mediates nociception. While blocking TRPV1 reduces pain, the finding preconditioning-induced cardioprotection is lost in TRPV1 knockout mice or by TRPV1 inhibition indicates a dual role for TRPV1 both in protection from cardiac injury and in pain signaling.

Hypothesis:
We tested whether a peptide corresponding to a calcineurin interaction site on TRPV1 could separate the functions of TRPV1 by reducing myocardial injury while providing pain control.

Methods:
The peptide was synthesized using a Liberty peptide synthesizer and conjugated to TAT for intracellular entry. Male Sprague-Dawley rats 8 weeks of age were used for both isolated heart and in vivo studies consisting of 30 minutes of ischemia followed by reperfusion. Infarct size was assessed by triphenyltetrazolium staining.

Results:
Testing the peptide using a calcineurin activity assay kit in vitro showed the peptide inhibited calcineurin activity vs. TAT control (0.46±0.03* vs. 0.77±0.02, nmol phosphate, n=3/group, *P<0.05). Further, peptide treatment of isolated hearts (1μM, infused over 10 minutes prior to ischemia) reduced infarct size and creatine phosphokinase (CPK) release when compared to TAT-treated hearts (Infarct size: 19±3%* vs. 53±4%, %infarct/left ventricle; CPK: 69±22* vs. 459±132, n=6/group, *P<0.01). In an in vivo myocardial ischemia-reperfusion model, the peptide (1mg/kg), given subcutaneously to the abdominal skin prior to ischemia, reduced infarct size compared to control (50±2*% vs. 66±1%, *P<0.001). Initial evidence also suggests that the peptide provides analgesia in pain models.

Conclusions:
Our results suggest a peptide blocking the calcineurin interaction site of TRPV1 reduces myocardial infarct size. Therefore, disrupting specific protein-protein interactions between calcineurin and TRPV1 may provide a novel strategy to design non-opioid therapeutics for cardioprotection, while also providing pain relief.
Abstract 17541: An Education Intervention Focused on Self-monitoring for Symptom and Sodium Intake Improves Adherence to the Low Sodium Diet and Health Outcome in Patients with Heart Failure
Authors: Song Eun Kyeung , Moser Debra K , Kang Seok-Min , Lennie Terry A
Published: July 2021

Background:
Despite the clinical emphasis on recommending a low sodium diet (LSD), adherence to a LSD remains poor in patients with heart failure (HF). Additional research is needed to determine successful interventions to improve adherence to a LSD and health outcomes.

Purpose:
To determine the effect of an education intervention on adherence to a LSD and health outcomes.

Method:
A total of 109 HF patients (age 64±9 years, 29% female) who were non-adherent to LSD, indicating > 3g of 24-hour urinary sodium excretion (24hr UNa) at baseline, were randomly assigned to one of 3 groups: 1) symptom monitoring and restricted 3 gram sodium diet (SMART) group, 2) the telephone monitoring (TM) group, or 3) usual care control group. The SMART group received individualized teaching and guidance of self-monitoring for worsening symptom and sodium intake using symptom and food diary for 4 sessions over 8 weeks. Patients assigned to either of the 2 intervention groups (SMART or TM) received phone calls every 2 weeks over 8 weeks. At 6 months follow-up, adherence to a LSD was assessed using 24hr UNa. Patients were followed for 1 year to determine time to first event of hospitalization or death due to cardiac problems. Repeated measures ANOVA and Cox regression were used to determine the effect of intervention.

Results:
The SMART group (n=37) showed a significant reduction in sodium intake across time compared to the TM group (n=35) and control group (n=37) (p= .022). In the Cox regression, patients in the SMART group had longer cardiac event-free survival compared to the control group after controlling for age, gender, ejection fraction, angiotensin-converting enzyme inhibitor use, and better blocker use (p=.008).

Conclusion:
An education intervention focused on self-monitoring for symptom and sodium intake improved adherence to LSD and health outcomes in patients with HF. Helping patients engage in self-monitoring for symptom and sodium intake by themselves can promote better health outcome.
Abstract 17559: Ultra-Early Endothelialization of Biolimus A9 With Bioresorbable Polymer Stent (Nobori
®
) in Porcine Coronary Model: Possible Mechanism for Low Frequency of In-stent Thrombosis and Restenosis
Authors: Mori Masayuki , Nakahashi Takuya , Takabatake Shu , Nakanishi Chiaki , Sakata Kenji , Okada Hirofumi , Yoshida Shohei , Hayashi Kenshi , Yoshimuta Tsuyoshi , Kawashiri Masa-aki , Matsuda Takehisa , Yamagishi Masakazu
Published: July 2021

Background:
The stent with biolimus A9 coated by a bioresorbable polymer (Nobori
®
) has the potential to reduce thrombosis by degradation of polymer over the period. However, few data exist regarding the vessel response and endothelialization at ultra-early phase after its implantation. Therefore, we examined ultra-early endothelialization of Nobori
®
in porcine model.

Methods and Results:
Fifteen Nobori
®
and 14 control bare-metal stents (S-Stent
TM
) were implanted in 12 swine (mean weight 31.9 kg). Histopathological evaluation of stented segments were performed at 2 and 14 days after implantation. Morphometric analysis of the inflammation (graded as score 0 to 3) and the intimal fibrin content (graded as score 1 to 3) was also assessed. At 14 days, neointimal thickness and % neointimal area, defined as 100 х neointimal area / stent area, were significantly lower in Nobori
®
than in S-Stent
TM
(51.4 ± 5.9 μm vs 76.4 ± 9.6 μm, p < 0.05 and 11.2 ± 1.1 % vs 15.7 ± 1.3 %, p < 0.01, respectively). Importantly, there were no significant differences in these parameters between 2 groups at 2 days (17.3 ± 6.1 μm vs 26.7 ± 6.1 μm, p = NS and 3.8 ± 1.3% vs 6.9 ± 1.7%, p = NS, respectively). Under these conditions, stent surface endothelialization evaluated by scanning electron microscope at 2 days showed similar appearance of endothelial coverage above the struts in Nobori
®
compared with S-Stent
TM
(Figure). Furthermore, there were no significant differences in inflammatory (1.3 ± 0.1 vs 1.3 ± 0.1, p = NS) and intimal fibrin content (2.5 ± 0.1 vs 2.3 ± 0.1, p = NS) scores.

Conclusion:
These results demonstrated that endothelialization could occur at ultra-early phase after Nobori
®
implantation with similar inflammatory reaction to bare-metal stent, probably contributing to low frequency of in-stent thrombosis and restenosis. The use of Nobori
®
may have a potential benefit even at early phase before the degradation of polymer as well as long-term benefit.
Abstract 17696: Pulmonary Vein Obstruction: a European Congenital Heart Surgeons Association (ECHSA) Multicentric Study
Authors: Kalfa David , Belli Emre , Bacha Emile , Lambert Virginie , di Carlo Duccio , Sairanen Heikki , Rubay Jean , Kostolny Martin , Schreiber Christian , Nosal Matej , Hazekamp Mark , Berggren Hakan , Yemets Illya , Maruszewski Bohdan , Sarris George , Pozzi Marco , Ebels Tjark , Lacour-Gayet François ,   European Congenital Heart Surgeons Association (ECHSA)
Published: July 2021

Pulmonary vein obstruction (PVO) still has a poor prognosis and its optimal management and risk factors for pejorative outcomes remain controversial in the absence of large multicentric studies. We assessed the hypothesis that diffuse PVO and postoperative pulmonary hypertension are associated with worse outcomes while the sutureless surgical technique is associated with better outcomes.

Methods:
One hundred and seven patients treated for native or acquired PVO in 16 European or North-American centers (2000-2012) were included retrospectively. A specific PVO severity score (range:0-16) was developed. Endpoints were 1) PVO-related death, 2) persistence or recurrence of PVO, and 3) PV reintervention or PVO-related death. A univariate and multivariate risk analysis (logistic regression and Cox model) was performed. Mean follow-up was 34±41 months.

Results:
Patient characteristics, outcomes and risk analyses are summarized in Tables 1, 2 and 3 respectively. In conclusion, both native and acquired PVO still have a poor prognosis. Sutureless repair is significantly associated with lower risks of PVO recurrence and PV reoperation/PVO-related mortality in the univariate analysis. A postoperative pulmonary hypertension and a high degree of severity of the disease evaluated by a new severity score are independent risk factors for pejorative outcomes.
Abstract 17710: Phrenic Nerve Injury Despite High-Output Pacing in Patients Undergoing Radiofrequency Catheter Ablation of Atrial Fibrillation
Authors: Izzo Brett , Yokokawa Miki , Jongnarangsin Krit , Ghanbari Hamid , Latchamsetty Rakesh , Crawford Thomas , Good Eric , Bogun Frank , Pelosi Frank , Oral Hakan , Morady Fred , Chugh Aman
Published: July 2021

Introduction:
High-output pacing has been advocated as a strategy to avoid injury to the phrenic nerve (PN) during antral pulmonary vein (PV) isolation. We assessed the hypothesis that pacing does not prevent PN injury in patients undergoing radiofrequency (RF) ablation of atrial fibrillation (AF).

Methods:
The medical records of 198 consecutive patients (age=63±12 years, 129 men, ejection fraction=57±10%, LA=44±6mm, paroxysmal=49%) undergoing their first ablation procedure for AF were reviewed. All patients underwent antral PV isolation using a 3D mapping system (CARTO XP or CARTO 3) and a 3.5 mm irrigated-tip ablation catheter (maximum power, 25 W). Prior to RF energy delivery, high-output pacing (20 mA @ 10 ms, maximum output) was performed to asses for PN capture. Sites that afforded PN capture were avoided and RF energy was delivered at adjacent sites without PN capture. The 3-D maps were reviewed to identify the prevalence and sites of PN capture.

Results:
High-output pacing along the anterior right antrum resulted in PN capture in 35 patients (18%). The most common site with a positive response was the crux between the upper and lower PVs (60%), followed by the right superior PV (43%), and the right inferior PV (20%). Of the patients with PN capture, 49% had only one site of capture, 20% with two sites, and 31% had 3 or more sites. All PVs were isolated at the end of the procedure. Two patients (1%) developed PN injury (symptom onset on the day after the procedure), which was confirmed on radiography. In neither case was there evidence of PN capture during the procedure. Symptoms resolved in both patients within 3 months, with normalization of radiographic findings.

Conclusions:
High-output pacing along the anterior right PV antrum yields PN capture in roughly one-fifth of the patients undergoing PV isolation. Despite a negative response to pacing and alteration of the lesion set, PN injury may occur. The reason for this discordance is unknown, but may include the possibility that the capture threshold of the PN exceeds the maximum output of the stimulator, or that RF energy may injure the pericardiophrenic artery, which accompanies the PN. Avoiding high-power or long-duration lesions and high contact force in this region may minimize the risk of PN injury.
Abstract 17729: Ideal Cardiovascular Health is Associated With a Lower Prevalence of Adverse Left Ventricular Remodeling Patterns in the Framingham Offspring Study
Authors: Nayor Matthew , Enserro Danielle , Vasan Ramachandran S , Xanthakis Vanessa
Published: July 2021

Introduction:
The American Heart Association Heart Healthy score (AHA score or Life’s Simple 7™) is inversely associated with atherosclerotic vascular disease including heart failure (HF), but its relationship to adverse left ventricle (LV) geometric patterns (known precursors of HF) is unknown. LV geometry can be categorized into 4 distinct patterns: normal (normal LV mass [LVM] and relative wall thickness [RWT]), concentric remodeling (normal LVM with increased RWT), eccentric hypertrophy (increased LVM with normal RWT) and concentric hypertrophy (increased LVM and RWT).

Hypothesis:
We hypothesized that ideal cardiovascular health is inversely associated with adverse LV geometric patterns.

Methods:
We evaluated the cross-sectional relations between the AHA score (range 1-7, based on lifestyle and risk factor profile, 7 being healthiest) and the prevalence of echocardiographic LV geometric patterns in 2392 Framingham Offspring Study participants (mean age 58 years, 56% women). Using generalized logits models, we calculated odds ratios (OR) for each pattern of LV remodeling as compared to the normal pattern (that served as referent) for every unit-increase in AHA score, adjusting for age and sex.

Results:
Normal geometry was present in 1283 participants (54%), concentric remodeling in 486 (20%), eccentric hypertrophy in 352 (15%) and concentric hypertrophy in 271 (11%). Each unit- increase in the AHA score was associated with lower odds of concentric remodeling and hypertrophy, Table. We did not observe a significant association between the AHA score and the odds of eccentric hypertrophy.

Conclusions:
Our findings support the association between ideal cardiovascular health and a lower prevalence of adverse cardiac remodeling, consistent with the favorable impact of both a healthy lifestyle and optimal risk factor profile on HF risk.
Abstract 17744: In Vivo Platelet Activation and Aspirin Responsiveness in Type 1 Diabetes Mellitus
Authors: Zaccardi Francesco , Pagliaccia Francesca , Rizzi Alessandro , Petrucci Giovanna , Habib Aida , Tanese Luigi , Rizzo Paola , Martini Francesca , Pitocco Dario , Rocca Bianca , Patrono Carlo
Published: July 2021

Introduction:
While reduced responsiveness to low-dose aspirin has been associated with type 2 diabetes mellitus (T2DM), aspirin responsiveness remains unexplored in T1DM.

Hypothesis:
We investigated in vivo platelet activation, as reflected by the urinary excretion of 11-dehydro-TXB2 (TXM) and platelet COX-1 inhibition, as assessed by serum TXB2 (sTXB2), in uncomplicated, normotensive, normolipidemic T1DM subjects on insulin therapy.

Methods:
Upon informed consent, we enrolled 40 T1DM patients (26M, age 35±11yr, disease duration 16±11yr, BMI 24±2 kg/m2) and 10 healthy controls (6M, age 33±7yr). In 9 patients we assessed the stability of TXM excretion on 3 different visits. Thirty-one patients and all controls were given 100 mg daily aspirin for 21 days, and urinary TXM and sTXB2 were measured before and 24h after stopping aspirin. To assess the influence of glycemic variability on aspirin response, 26 patients underwent continuous glucose monitoring (CGM) for the first 24h after drug withdrawal.

Results:
TXM excretion in T1DM was significantly higher than in controls (930 [659-1358] vs 568 [385-619] pg/mg creatinine; p<0.001) and quite stable across repeated sampling (p for linear trend = 0.755). By multivariate analysis, urinary TXM was associated with microalbuminuria (β=0.23; p=0.042) at baseline. The degree of inhibition at 24h after aspirin dosing was similar in T1DM and controls for both sTXB2 (98.2% vs 98.6%, p=0.607) and urinary TXM (68.8% vs 68.4%, p=0.962). CGM-derived mean and standard deviation glucose were not associated with sTXB2 or TXM inhibition at 24h.

Conclusions:
We conclude that enhanced platelet activation in T1DM is independent of glycemic control and associated with kidney/endothelial damage. Moreover, in contrast to T2DM, the response to aspirin is unchanged, suggesting that the metabolic disturbance per se is not responsible for altered pharmacodynamics.
Abstract 17755: Cardiac Myosin Binding Protein C Contributes to the Protection of the Heart During Immune Response to Infection
Authors: Dusio Giuseppina , Liu Yang , Tobin Richard P , Mukherjee Sanjib , Mukhopadhyay Dhriti , Rosas Paola C , Newell Rogers Martha K , Tong Carl W
Published: July 2021

Infections can exacerbate heart failure and contribute to heart transplant rejection. We hypothesize that cardiac myosin binding protein C (MyBPC3), a thick filament protein, contributes to protection of the heart during an immune response to infection. We tested our hypothesis by comparing wild type (WT) vs. MyBPC3(-/-) mice for their immunologic response to non-pathogenic doses of Eschericia coli lipopolysaccharide (LPS). LPS caused increased hypertrophy, worsening of diastolic dysfunction, and increased apoptosis in MyBP3(-/-) hearts. We then performed flow cytometric analyses on immune cells isolated from the myocardium, the spleen, and the bone marrow. Prior to LPS challenge, MyBPC3(-/-) hearts have relatively fewer myeloid cells characterized by CD11b+GR1High in comparison to WT hearts. LPS challenge dramatically increased myeloid cell population in WT, but not in MyBPC3(-/-) hearts. Thus, myeloid population demonstrated inverse relationship with cardiac dysfunction and apoptosis. LPS increased B cells(CD19+) infiltration into MyBPC3(-/-) hearts only, suggesting that increases in B cells correlate with increased cardiac myocyte cell death. In spleen, LPS increased total number of immune cells of all types (CD45+) only in WT. MyBPC3(-/-) showed depressed myeloid cell populations in spleen and bone marrow. Thus, loss of MyBPC3 may have contributed to overall decreased myeloid population. These results suggest that CD11b+GR1High cells are myeloid derived suppressor cells (MDSC) which protect cardiac myocytes during an immune response, and B cells are associated with cardiac myocyte cell death. Furthermore, MyBPC3 may be necessary to recruit MDSCs to maintain protection of the heart during infection. Finally, these results imply that modulating recruitment of MDSCs and preservation of MyBPC3 may provide the basis for new treatments to prevent infection-associated exacerbation of heart failure and heart transplant rejection.
Abstract 17814: Prenatal Diagnosis is Associated with a Lower Rate of Pre-Operative Brain Injury in Newborns with Transposition of the Great Arteries
Authors: Peyvandi Shabnam , de Santiago Veronica , McQuillen Patrick
Published: July 2021

Objective:
Literature suggests that prenatal diagnosis of critical congenital heart disease does not lead to improved mortality. However, it has been associated with better pre-operative conditions in single ventricle lesions and better neurodevelopmental outcome in transposition of the great arteries (TGA). We sought to describe the frequency of pre-operative brain injury in neonates with prenatal and postnatal diagnosis of TGA. We hypothesize that prenatally diagnosed neonates with TGA have a lower prevalence of pre-operative brain injury.

Methods:
Term newborns with TGA were studied with brain magnetic resonance imaging preoperatively to determine brain injury severity based on the presence of white matter injury and/or stroke. Comparisons were made between prenatal and postnatal diagnosis. Other variables compared included estimated gestational age at birth (EGA), birth weight (BW), lowest oxygen saturation, balloon atrial septostomy (BAS), age at surgery, and hospital mortality. Analysis was performed with Fisher’s exact test or Student t-test. Further analysis will be performed including data from other centers and cardiac diagnoses.

Results:
The presence of brain injury was significantly higher in postnatally diagnosed neonates than those prenatally diagnosed (Table). There were trends toward lower EGA, lower BW, higher oxygen saturation and younger age at surgery in the prenatal group. BAS did not differ by prenatal diagnosis. Mortality was low and the only two deaths were in the postnatal group.

Conclusions:
Prenatally diagnosed neonates with TGA have a lower prevalence of preoperative brain injury as compared to those diagnosed postnatally. This finding is significant even when other known risk factors for brain injury did not differ between groups. Our data is consistent with prior literature demonstrating lower EGA and BW in prenatally diagnosed patients. The impact of these findings on neurodevelopmental outcomes will be studied.
Abstract 17840: Progression of Cardiovascular Risk Factors Across the Menopausal Transition - Results from Study of Women’s Health Across the Nation
Authors: Khan Zubair A , Janssen Imke , Powell Lynda H , Dumasius Andrius , Everson-Rose Susan A , Barinas-Mitchell Emma J , Weinstock Perry J , Hollenberg Steven M
Published: July 2021

Objectives:
To correlate arterial compliance and measures of subclinical atherosclerosis with menopausal status during menopausal transition.

Background:
Cardiovascular risk increases in women after the menopausal transition. To assess factors that might explain this increased risk, we used radial tonometry to measure arterial compliance in SWAN (Study of Women’s Health Across the Nation), a longitudinal study of women in the menopausal transition.

Methods:
Raw waveforms were digitized and a generalized transfer function was utilized to calculate central Augmentation Pressure (cAP) & aortic Augmentation index (AIx) adjusted for heart rate of 75bpm. Carotid intima-media thickness (cIMT) was calculated using B-mode ultrasound. Coronary artery calcium (CAC) and thoracic aortic calcium (TAC) scores were obtained by computed tomography. Pulse wave velocity (PWV) was recorded as time taken for the arterial pulse to propagate from the carotid to the femoral artery.

Results:
Mean age was 52±9, BMI 28±6; 7% of women were premenopausal, 48% perimenopausal, and 45% were postmenopausal. PWV, cAP, cIMT, CAC and TAC were higher in post-menopause than peri-menopause and lowest in the premenopausal group with a similar trend for AIx (see Table). Higher PWV correlated significantly with higher cIMT (r=0.32), cAP (r=0.34), AIx (0.17), CAC (r=0.13) & TAC (r=0.19).

Conclusion:
Physiologic measures of arterial stiffness were higher through the menopausal transition along with morphologic measures of subclinical atherosclerosis, with a correlation between the two. Such changes may help to explain the increased risk of cardiovascular disease in women after menopause and may be assessed using a combination of physiologic and morphologic parameters.

Supported by NIH/DHHS (grants U01AG012505, U01AG012546, R01HL065581, R01HL065591, R01HL089862).