bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12265: Normalization of Renal AT1 Receptor Expression is Observed With Enalapril But Not Diltiazem in a Rat Model of Chronic Kidney Disease
Authors: Ismail Basma , deKemp Rob A , Croteau Etienne , Hadizad Tayebeh , Burns Kevin , Beanlands Rob S , DaSilva Jean N
Published: April 2024

Introduction:
Use of ACE inhibitors (ACEi) improves outcomes in patients with proteinuric chronic kidney disease (CKD) and is considered first line of treatment in recent guidelines. In addition to renin angiotensin (Ang) system blockers, other antihypertensive agents such as calcium channel blockers (CCBs) achieve similar therapeutic effectiveness in renoprotection. Our objective was to determine the impact of antihypertensive therapy on renal Ang type 1 receptor (AT
1
R) in 5/6 subtotal nephrectomy (Nx) rat model of CKD using PET imaging.

Methods:
Ten weeks after Nx, Sprague-Dawley rats (n=6-8/group) were administered 10mg/kg/d enalapril (NxE), 30 mg/kg/d diltiazem (NxD) or left untreated (Nx) for an additional ∼10 weeks. Systolic blood pressure (SBP), plasma creatinine, urine albumin, plasma and tissue Ang II were measured at the end. AT
1
R was assessed using
in vivo
[
18
F]FPyKYNE-losartan PET and
in vitro
autoradiography. Heart function was evaluated with echocardiography.

Results:
Compared to shams, Nx rats exhibited higher SBP that was reduced by both enalapril and diltiazem (142.7±2, 188.8±17.3, 152±8.7 and 145.8±5.8 mm Hg in sham, Nx, NxE and NxD, respectively,
p
<0.05). At ∼20 weeks, plasma creatinine and albuminuria were significantly increased in Nx rats, while no changes occurred in NxE rats compared to shams. By contrast, NxD rats demonstrated further increases in these parameters, compared to Nx alone (
p
<0.05). Plasma and kidney Ang II were raised in Nx rats, lowered by enalapril and increased significantly in NxD rats (
p
<0.05). PET kidney AT
1
R level decreased in Nx rats compared to shams and only enalapril treatment normalized AT
1
R expression (2.8±0.5, 2±0.3, 2.9±0.6, 1.9±0.5 ml/cm
3
in sham, Nx, NxE and NxD respectively,
p
<0.05) and was confirmed by
in vitro
results. Enhanced echo LV mass in Nx rats was not reversed by enalapril but was further increased with diltiazem (
p
<0.001).

Conclusions:
In rats with CKD, delayed treatment with the ACEi enalapril normalized AT
1
R expression and reduced progression of the disease, whereas the CCB diltiazem exacerbated renal and cardiac dysfunctions. [
18
F]FPyKYNE-Losartan PET allows longitudinal determination of AT
1
R abnormalities with progression of cardiorenal failure and monitoring of therapy.
Abstract 12314: β-2-Hydroxyglutarate Inhibits Glycolysis in Pulmonary Vascular Cells
Authors: Oldham William , Loscalzo Joseph
Published: April 2024

β-2-hydroxyglutarate (L2HG) is a metabolite of unknown function that we have found to increase in pulmonary arterial endothelial cells, smooth muscle cells, and lung fibroblasts (PAEC, PASMC, LF) in response to hypoxia. L2HG is produced from the reduction of mitochondrial 2-oxoglutarate (2OG) and is oxidized back to 2OG by L2HG dehydrogenase (L2HGDH) in a redox cycle coupled to the oxidation of NADH and reduction of FAD, respectively. As these are the only known reactions in which L2HG participates, we hypothesized that L2HG metabolism plays an important role in cellular redox homeostasis. To test this hypothesis, we measured the effect of L2HGDH levels on cellular NADH/NAD
+
in LF using an enzymatic cycling assay. L2HGDH knockdown potentiated hypoxia-mediated increases in cellular NADH/NAD
+
(138 ± 10% v. 169 ± 14%, siCTL v. siL2HGDH, p = 0.08) while L2HGDH overexpression had the opposite effect (139 ± 10% v. 127 ± 7%, Vector v. L2HGDH, p = 0.08). Given these results, we next examined the effect of L2HGDH knockdown on mitochondrial electron transport and glycolysis using the Seahorse Extracellular Flux Analyzer. We found that siL2HGDH decreased maximal, FCCP-stimulated oxygen consumption rate in LF (10.8 ± 1.0 v. 9.8 ± 0.9 nmol O2/min/10
6
cells, p < 0.001) and inhibited maximal, oligomycin-stimulated glycolytic flux (790 ± 42 v. 519 ± 61 mpH/min/10
6
cells, p = 0.02). The effects of siL2HGDH on glycolysis were confirmed in PAEC and PASMC, where the knockdown decreased oligomycin-stimulated extracellular acidification rate (ECAR) by 24% and 16%, respectively. Cell-permeable L2HG inhibited ECAR to a similar degree. Metabolomic profiling of LF treated with siL2HGDH identified increases in the pentose phosphate pathway intermediates 6-phosphogluconate and pentose monophosphate, suggesting phosphofructokinase as a potential target of L2HG. Together, these data indicate that L2HG accumulation in hypoxia reduces mitochondrial reductant stress.
Abstract 12422: Influence of Polypharmacy on the Efficacy And Safety Of Dabigatran Versus Warfarin for the Treatment of Acute Venous Thromboembolism: A Pooled Analysis of RE-COVER
®
and RE-COVER II
™
Authors: Goldhaber Samuel Z , Eriksson Henry , Kakkar Ajay , Schellong Sebastian M , Feuring Martin , Fraessdorf Mandy , Kreuzer Joerg , Schulman Sam
Published: April 2024

Background:
Polypharmacy in patients treated for acute venous thromboembolism (VTE) has been associated with increased bleeding risk during warfarin (W) treatment. Polypharmacy is common in patients with VTE, who are likely to carry a greater burden of comorbidity, and may itself indicate increased VTE risk. In RE-COVER
®
and RE-COVER II
™
, dabigatran etexilate (DE) showed similar efficacy and lower bleeding vs W.

Objective:
To evaluate the impact of polypharmacy on the efficacy/safety of DE vs W, we conducted a pooled post-hoc analysis of RE-COVER
®
/RE-COVER II
™
subgroups taking ≤3 or >3 concomitant medications (con-meds) at baseline.

Methods:
Patients with acute VTE, initially on parenteral anticoagulation, were randomized to W (parallel initiation; target INR range 2.0–3.0) or DE 150 mg bid for 6 months. The efficacy endpoint was recurrent, symptomatic VTE/VTE-related death at the end of post-treatment follow-up (6 months + 30 days). Safety endpoints were centrally adjudicated major bleeding events (MBEs), composite of MBEs or clinically relevant non-major bleeding (MBEs/CRBEs), and any bleeds during the 6-month oral-only treatment period (DE or W alone, double-dummy).

Results:
2553 patients received DE and 2554 W; both groups had similar proportions taking con-meds: ≤3, 47.5% and 48.3%; >3, 52.5% and 51.7% for DE and W, respectively. VTE/VTE-related deaths occurred at low rates (Graph), with no statistically significant differences between treatments. Irrespective of number of con-meds, rates of MBEs, MBE/CRBEs, and any bleeds were lower with DE vs W, and statistically significant for MBE/CRBEs and any bleeds. With both treatments, more con-meds generally corresponded with greater risks of bleeds and a slightly greater risk of VTE/VTE-related deaths.

Conclusion:
Polypharmacy was an indicator of increased bleeding risk with both anticoagulants; however, irrespective of number of con-meds, safety outcomes were better with DE and efficacy was similar to W.
Abstract 12444: Toll-like Receptor 3 is Required for Neonatal Heart Repair and Regeneration Following Myocardial Infarction via Glycolysis Dependent Yap/taz Activation
Authors: Wang Xiaohui , Hu Yuanping , Ha Tuanzhu , Ma He , Liu Li , Kalbfleisch John , Kao Race , Williams David , Li Chuanfu
Published: April 2024

Regenerative therapies for repair of the damaged heart could benefit millions of patients annually. The neonatal heart has the capability of repairing/regenerating damaged myocardium. However, this capability is lost when cardiomyocyte metabolism changes from glycolysis to oxidative phosphorylation, within 7 days after birth. Interestingly, Toll-like receptors (TLRs) are required for somatic cell nuclear reprogramming, which is important for tissue regeneration. The Hippo pathway effector YAP promotes cardiac regeneration. We have reported that TLR ligands can induce protection against myocardial ischemic injury. We hypothesized that TLRs are required for cardiac regeneration in neonatal heart via glycolysis dependent YAP/TAZ activation. To evaluate our hypothesis, myocardial infarction (MI) was induced in one day of wild type (WT) and TLR3 deficient (TLR3
-/-
) neonatal mice (n=5/group). Cardiac function was examined by echocardiography 3 weeks after MI. Cardiomyocyte regeneration and proliferation were examined by histone3 phosphorylation (p-histone3) and EdU incorporation into the cardiomyocytes. In WT neonatal MI mice, cardiac function completely recovered, infarct size was smaller, more p-histone3, EdU was incorporated into the cardiomyocytes, and YAP/TAZ activation was significantly increased following MI. In contrast, TLR3
-/-
neonatal hearts showed impaired cardiac function, larger infarct size, less p-histone3 and EdU incorporation and inactivation of YAP/TAZ after MI. To examine whether stimulation of TLR3 will promote glycolysis, cardiomyocytes were isolated from one day old WT neonatal mice and treated with Poly I:C, the TLR3 ligand. Poly I:C treatment significantly increases lactate production, NAD
+
/NADH ratio, extracellular acidification (ECAR) and YAP/TAZ activation. However, inhibition of glycolysis with 2-Deoxyglucose (2DG) prevented Poly I:C-induced neonatal cardiomyocyte proliferation and regeneration as well as YAP/TAZ activation.
In vivo
treatment of WT neonatal mice with 2DG (n=6/group) abolished cardiac functional recovery 3 weeks after MI. We conclude that TLR3 is required for neonatal heart regeneration and repair after MI. The mechanisms involve glycolysis dependent activation of YAP/TAZ.
Abstract 12454: Mitochondrial Transcription Factor 2B as a Mediator of Mitochondrial Retrograde Signaling and Endothelial Cell Shape
Authors: Forrester Steven J , Kawai Tatsuo , Elliot Katherine J , Eguchi Kunie , Park Joon-Young , Rizzo Victor , Eguchi Satoru
Published: April 2024

Mitochondrial dysfunction, such as observed in endothelial cells, has been implicated in various cardiovascular diseases including, hypertension and atherosclerosis. Mitochondrial transcription factor 2B (TFB2M) is an essential component to maintain proper transcriptional and functional control of mitochondrial DNA. As well, elongation of endothelial cells is a characteristic of atheroprotective regions within the vasculature, and the relationship between the mitochondria and EC shape is currently unknown. Additionally, recent interest has been focused on mechanisms by which the mitochondria may signal to the nucleus to affect cell function. The aim of our study is to investigate the hypothesis that TFB2M has a novel role in enhancing endothelial function. Human umbilical vein endothelial cells (HUVECs) were harvested 72 hours after adenoviral transduction with TFB2M (100 moi). HUVECs transduced with TFB2M showed an elongated cell morphology when compared to GFP control. To further investigate the effect of TFB2M on regulating mitochondrial function and cell shape, immunoblotting was carried out for markers involved in mitochondrial function/dynamics and markers indicative of cytoskeleton reorganization. TFB2M transduction resulted in increased expression of mitochondrial biogenesis marker VDAC (2.6 fold increase), mitochondrial fusion protein MFN2 (2.1 fold increase), and phosphorylated myosin phosphatase targeting protein MYPT1 at Thr850 (2.2 fold increase,
p
< 0.05 for all proteins). Additionally, fluorescence microscopy showed enhanced mitochondrial fluorescence in TFB2M transduced cells using mitotracker red staining (3.5 fold increase,
p <
0.001). These data indicate that TFB2M has a previously undiscovered function contributing to altered EC function and shape, potentially through a novel mitochondrial retrograde signaling mechanism. Further research will focus on distinguishing the exact mechanisms culminating in a protective EC phenotype and the beneficial role of endothelial TFB2M-mediated enhanced mitochondrial function in the treatment of EC dysfunction associated with various cardiovascular diseases.
Abstract 12490: Class I Indications for Statin Therapy in Primary Prevention by Three Cholesterol Guidelines and Risk of Incident Cardiovascular Outcomes: Multi-ethnic Study of Atherosclerosis (MESA)
Authors: Flueckiger Peter , Qureshi Waqas , Blaha Michael , Burke Gregory , Sandfort Veit , Michos Erin D , Herrington David , Yeboah Joseph
Published: April 2024

Introduction:
The major societal guidelines on cholesterol treatment (2013 ACC/AHA, 2004 NCEP/ATP III, and the 2011 ESC/EAS) differ in identifying patients with a class 1 recommendation for statin therapy for atherosclerotic cardiovascular disease (ASCVD). ACC/AHA emphasizes a need for clinician-patient dialogue on the risks/benefits of statins in primary prevention of ASCVD. Limited data exist on the accuracy of statin-eligibility (Class I) for ASCVD events to inform this dialogue. We assessed the accuracy of class I statin eligibility with incident ASCVD events by ACC/AHA compared with NCEP/ATP III and ESC/EAS guidelines.

Methods:
We evaluated the sensitivity (SN), specificity (SP), positive predictive value (PPV), negative predictive value (NPV) of class I recommendation for statin therapy by each guideline for respective 10 yr. adjudicated incident ASCVD outcomes [NCEP/ATP III- MI, CHD death; ACC/AHA- MI, CHD death, fatal/non-fatal strokes; ESC/EAS: ASCVD death] in participants of the Multi Ethnic Study of Atherosclerosis. We stratified analysis by age, sex, and race. 4723 out of 6814 persons, not on statins at baseline, had complete data.

Results:
Mean age was 59±9 yrs., 47% male, 37% white, 28% African American (AA), 23% Hispanic, and 12% Asian, 7.5% T2DM, 15%/35% current/former smokers, and mean BMI of 28±6 kg/m2. 7.3% had ASCVD, 5.2% ASCVD death and 5.1% had a CHD event after 10 yrs. See Table 1 for results. Subgroup analysis shows AHA/ACC had a higher SN and lower SP in men vs. women (SN = 76% vs. 46%, SP = 54% vs. 77%) and in those >60 vs. <60 yrs (SN = 79% vs. 40%, SP = 41% vs. 85%). For AHA/ACC, SN was highest in Asians (75%) followed by AA (74%), Hispanics (56%), whites (56%). SP in whites (70%), Hispanics (68%), Asians (68%), AA (60%)

Conclusions:
Class I statin indication by all 3 guidelines have relatively low sensitivities for a good screening tool. ACC/AHA has higher SN, lower SP, similar NPV and higher PPV compared with NCEP/ATP III and ESC/EAS for primary ASCVD events.
Abstract 12548: Expression of Let-7 Family microRNAs in Skin Correlates Negatively With Severity of Pulmonary Hypertension in Patients With Systemic Scleroderma
Authors: Izumiya Yasuhiro , Kimura Yuichi , Yamamura Satoru , Onoue Yoshiro , Hanatani Shinsuke , Araki Satoshi , Ogawa Hisao
Published: April 2024

Introduction:
Pulmonary hypertension (PH) is a serious complication in patients with systemic scleroderma (SSc), therefore it is important to identify the factors that could predict the presence and progression of PH. Skin biopsy is performed in patients with SSc to examine the type and severity of the disease. MicroRNAs (miRNAs) are potential biomarkers for various cardiovascular diseases including PH.

Hypothesis:
In patents with systemic scleroderma (SSc), skin miRNAs expression profiles varies depending on the presence or absence of PH.

Methods and Results:
We determined the skin miRNA expression profile in 15 female SSc patients with (n=6) and without PH (n=9). Plasma BNP level was significantly higher in the PH group than non-PH group, but left ventricular function and dimension were not different between the two groups. A mixture of equal amounts of miRNAs from PH and non-PH patients were prepared and used for miRNA PCR array analysis. The analysis identified 591 upregulated miRNAs and 57 downregulated miRNAs in the PH group. Of these, only miRNAs with a Ct value of less than 35 were subjected to further analysis. When a 1.5-fold difference was considered meaningful, 32 miRNAs were upregulated and 14 miRNAs were downregulated in the PH group. Interestingly, 5 out of 14 downregulated miRNAs belonged to the let-7 family. The results were validated by quantitative real-time PCR with specific primer for each miRNA, which showed significant downregulation of five let-7 family members (let-7a, -7d, -7e, -7f, -7g) in 6 PH compared with 9 non-PH skin samples. Circulating these miRNA levels were trended to decrease in PH group, but it did not reach statistically significant. The expression of let-7b and -7d correlated significantly and negatively with the estimated pulmonary arterial pressure. The expression of let-7a, -7e, -7g, -7f tended to correlate negatively with the estimated pulmonary arterial pressure, albeit insignificantly.

Conclusions:
The expression level of let-7 family microRNAs in skin are lower in patients with SSc with PH than those without PH. Skin miRNA is a potentially useful marker for evaluation of PH in patients with SSc. Skin biopsy can be considered in patients with collagen diseases to identify the presence and severity of PH.
Abstract 12554: Association of Left Ventricular Diffuse Fibrosis and Scar Assessed by Cardiac Magnetic Resonance Imaging With Depolarization and Repolarization on 12-Lead Electrocardiography: MESA (Multi-Ethnic Study of Atherosclerosis)
Authors: Inoue Yuko Y , Ashikaga Hiroshi , Ambale-Venkatesh Bharath , Volpe Gustavo J , Mewton Nathan , Ohyama Yoshiaki , Sharma Ravi K , Wu Colin O , Liu Chia-Ying , Bluemke David A , Soliman Elsayed Z , Lima João A
Published: April 2024

Introduction:
Left ventricular (LV) interstitial diffuse fibrosis and scar (replacement fibrosis) affect ventricular depolarization and repolarization parameters on an electrocardiogram (ECG) through local electrophysiology as well as LV global structure. The aim of this study is to examine the association between the two different types of fibrosis and ECG indices.

Methods:
A total of 1,669 participants (aged 54 to 94 years, 50% women) free of prior myocardial infarction or conduction delay underwent cardiac magnetic resonance with late gadolinium enhancement (LGE), and 1,136 participants without an LGE-defined scar were analyzed using T1 mapping. The associations of LV diffuse fibrosis or scar with ECG parameters [QRS Sokolow-Lyon and Cornell voltage, QRS duration, and corrected QT (QTcorr) interval] were evaluated using multivariable regression analyses adjusted for cardiovascular risk factors, LV end-diastolic volume, and LV mass.

Results:
Lower post-contrast T1 time at 12 min and 25 min, indicating greater diffuse fibrosis, was significantly associated with lower QRS Sokolow-Lyon voltage, lower QRS Cornell voltage, and shorter QRS duration (all P<0.05). Greater extracellular volume fraction (ECV) was also significantly associated with lower QRS Sokolow-Lyon voltage (β=-38.9, P<0.001) and Cornell voltage (β=-23.5, P<0.001). By contrast, the presence of LV scar (n=106) was associated with longer QTcorr interval (β=4.2, P=0.034).

Conclusions:
In middle-aged multi-ethnic population, LV diffuse fibrosis assessed by T1 mapping was significantly associated with lower QRS voltage and shorter QRS duration, whereas LV scar was associated with longer QT interval; independent of cardiovascular risk factors and LV structure. Our results reveal the potential of 12-lead ECG of evaluating two different type of fibrosis.
Abstract 12587: Telomere Length Regulates Cellular Fate of Cardiac Progenitor Cells
Authors: Emathinger Jacqueline , Nguyen Nathalie , Quijada Pearl , Bers Donald , Sussman Mark , Hariharan Nirmala
Published: April 2024

Myocardial regeneration following injury is severely limited by aging. Understanding the impact of age-associated factors such as telomere shortening is critical to enhance the regenerative potential of cardiac progenitor cells (CPCs), which are currently used in clinical trials. Telomere length (TL) determines the proliferation potential such that short telomeres cause senescence of CPCs, however the impact of TL on regulating the balance between quiescence and differentiation of adult stem cells remains undetermined. We hypothesize that TL regulates the equilibrium between quiescence, proliferation, commitment and senescence, thus determining cellular fate of CPCs. CPCs were isolated from 3 mouse strains with varying TLs- common laboratory mouse strains FVB (TL:70Kb) and C57 (TL:50Kb), as well as a naturally occurring wild mouse strain,
Mus musculus castaneus
(CAST) possessing critically short telomeres (TL:18Kb) comparable to humans (TL:5-10Kb). CAST CPCs with short TLs have slower proliferation rate (-80% vs FVB, p<0.01), increased population doubling time and exhibit characteristics of senescence such as flattened cell morphology, increased beta-galactosidase activity (p<0.05) and p53 expression (1.7 fold, p<0.05). Interestingly, CAST CPCs also undergo basal differentiation in the absence of commitment cues, as evidenced by increased expression of lineage markers smooth muscle actin (SMA; 16.6 fold, p<0.01), Tie2 (1.7 fold, p<0.05), and sarcomeric actinin (1.75 fold). Acquisition of differentiation and senescence is accompanied by reduced expression of quiescence marker p21 (-33%). Consistent findings of senescence, increased basal differentiation (11.3 and 1.6 fold increase in SMA and Tie2 levels) and loss of quiescence (-26% decrease in p21 levels) are evidenced in CPCs isolated from old FVB mice with short TLs relative to young CPCs. Corroborative findings in adult human failing heart CPCs with short TLs suggests that telomere shortening tips the equilibrium away from quiescence and proliferation into differentiation and senescence leading to exhaustion of CPCs. Understanding mechanistically how TL regulates CPC fate will enable identification of molecular strategies to enhance the therapeutic effects of CPCs.
Abstract 12648: Severe Aortic Stenosis With Preserved Left Ventricular Ejection Fraction: Impact of Transaortic Flow, Transaortic Gradient and Age on Outcomes
Authors: Fanari Zaher , Barmpouletos Dimitrios , Reddy Vivek K , Hammami Sumaya , Zhang Zugui , Weintraub William S , Marshall Erik S
Published: April 2024

Background:
Combining transaortic flow and gradient defined four different aortic stenosis (AS) subgroups. The impact of transaortic flow and gradient and age on predicting the outcomes of severe AS with preserved ejection fraction (EF) is not well defined.

Methods:
We identified consecutive patients presenting to our echo lab with an aortic valve area (AVA) < 1.0cm
2
and EF≥ 50%. We stratify patients depending on gradient (≥ 40 vs. < 40 mmHg) and stroke volume index (SVI < 35 vs. ≥35 ml/m
2
). 4 groups were identified (, normal flow, high gradient [NF/HG]; normal flow, low gradient [NF/LG]; low flow, high gradient [LF/HG] and low flow, low gradient [LF/LG]. These 4 groups were also stratified depending on age (Age < 75 vs. ≥75 years). All patients were retrospectively followed for the occurrence of death.

Results:
A total of 954 patients were included in analysis. Mean follow up was 2.45 ± 1.9 years. The mean age was 75.4 ± 5.6 years. Patients with LF had significant higher mortality than those with NF [32.6% vs. 25.8%; HR=1.39 (1.04-1.86); P=0.03]. Similarly, patients with HG had significant higher mortality than those LG [34.9% vs. 25.7%; HR=1.55 (1.17-2.06); P<0.01]. Comparing all 4 AS subgroups, the mortality was higher in LF/HG followed by LF/LG, NF/HG and NF/LG (LF/HG 37.1% vs. LF/LG 33.9% vs. NF/HG 30.3%vs. NF/LG 20.2%; Log Rank Test, P=0.003). Older patients have a higher mortality rate than younger patients. [31.1% vs. 22.5%; HR= 1.55 (1.1-2.19); P= 0.01]. In Patients older than 75, comparing all 4 AS subgroups, the mortality was higher in LF/HG followed by LF/LG, NF/HG and NF/LG (LF/HG 37.9% vs. LF/LG 37.8% vs. NF/HG 35.0% vs. NF/LG 19.6%; %; Log Rank Test, P=0.003). Comparing the 4 flow-gradient groups in patients younger than 75 shows a similar, but not significant trend with the mortality is higher in LF/HG followed by LF/LG, NF/HG and NF/LG (LF/HG 32.4% vs. LF/LG 30.7% vs. NF/HG 25.8% vs. NF/LG 9.6%; Log Rank Test, P=0.058).

Conclusion:
Combining transaortic flow and gradient is essential in in predicting prognosis in severe aortic stenosis with preserved EF. Age add an incremental value to transaortic gradient and flow in predicting prognosis.
Abstract 12685: Hospital Variation in Adherence to Secondary Prevention Medications After Acute Myocardial Infarction
Authors: Wang William T , Mathews Robin , McCoy Lisa A , Thomas Laine , Shah Rashmee , Ali Murtuza J , Peterson Eric D , Wang Tracy Y
Published: April 2024

Background:
Hospital transition of care practices may influence patient adherence to secondary prevention medications post-discharge. We assessed inter-hospital variation in 90-day post-MI medication adherence and its association with downstream patient outcomes.

Methods:
We linked 19,704 post-acute MI patients >65 years discharged alive from 459 hospitals in ACTION Registry-GWTG to Medicare data. Adherence was defined as ≥80% proportion of days covered using Part D prescription fill data. Based on the distribution of odds ratios, hospitals were divided into high (>75
th
percentile), medium, or low (<25% percentile) adherence. We used Cox regression to compare 2-year MACE outcomes (death, MI, stroke, or non-staged revascularization) after adjusting for hospital case mix differences.

Results:
By 90 days post-MI, 68% of patients were adherent to discharge-prescribed beta-blocker therapy, 63% to statins, 64% to ACEI/ARBs, and 72% to thienopyridines. There was significant inter-hospital variation in 90-day adherence (p<0.001), the probability of which varied the least for ACE-I/ARBs, and most for beta-blockers (Figure). Hospitals with medium medication adherence had lower unadjusted 2-year MACE risk than hospitals with low adherence, but this did not reach statistical significance after adjusting for differences in patient case mix (unadjusted 33.4% vs. 37.3%, adjusted HR 0.94, 95% CI 0.86-1.02); however, high medication adherence hospitals had significantly lower unadjusted (29.9%) and adjusted risk of MACE (HR 0.90, 95% CI 0.82-0.98).

Conclusion:
Patient adherence to secondary prevention medications varied markedly across U.S. hospitals. Discharge from hospitals with higher adherence rates was associated with lower risks of MACE. Our results suggest that the development of collaborative initiatives between healthcare providers and patients to improve post-discharge medication adherence may enhance longitudinal patient outcomes.
Abstract 12708: Similar Risk of Heart Failure Hospitalization in MADIT-RIT Programming Arms
Authors: Goldstein Robert E , Haigney Mark C , Dwyer Edward M , Greenberg Henry , McNitt Scott , Zareba Wojciech , Kutyifa Valentina , Moss Arthur J
Published: April 2024

Background:
In MADIT-RIT (Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy), we reported a significant reduction in inappropriate ICD therapy and mortality with novel ICD programming, either a high-rate cut-off (VT zone ≥ 200 bpm, Arm B) or 60-sec delayed therapy in the VT zone 170-199 bpm (Arm C), as compared to conventional programming (VT zone>170 bpm, Arm A). However, the effect of novel ICD programming on heart failure (HF) events has not been investigated.

Methods:
In MADIT-RIT patients (n=1500), we assessed risk of hospitalization with heart failure (HF) in the three programming arms. Brief summaries of each hospitalization were independently reviewed by three experienced cardiologists and HF events identified according to pre-specified criteria. Discrepancies were resolved by a fourth cardiologist. Kaplan-Meier cumulative probabilities and multivariable Cox hazards regression analyses were performed.

Results:
There was a similar probability of HF hospitalization (p=0.341) and HF hospitalization or death (p=0.207) in all three programming arms in MADIT-RIT (Figure). There were no differences in HF hospitalization in Arm B vs. A (HR=0.91, 95%CI: 0.63-1.33, p=0.629) or Arm C vs. A (HR=1.20, 95%CI: 0.84-1.72, p=0.310) after multivariable adjustments for age, NYHA class, diabetes, ICD vs. CRT-D, ejection fraction, and ischemic vs. non-ischemic cardiomyopathy. Similarly, there were no differences in HF or death in Arm B vs. A (HR=0.78, 95%CI: 0.56-1.10, p=0.154), or in Arm C vs. A (HR=1.06, 95%CI: 0.77-1.45, p=0.723) after multivariable adjustments. Risk of multiple hospitalizations was also the similar in the three programming arms.

Conclusions:
In MADIT-RIT, the mortality benefit seen with novel ICD programming was not accompanied by reduction in heart failure events. Conversely, greater mortality risk with conventional ICD programming was not associated with increased risk of heart failure hospitalization.
Abstract 12813: Orphan Nuclear Receptor Nur77 Inhibits Angiotensin Ii-induced Vascular Remodeling via Downregulation of β-catenin Activity
Authors: Cui Mingli , Cai Zhaohua , Chu Shichun , Yu Ying , Sun Zhe , Nie Peng , Sun Shiqun , Wang Xiaolei , Hu Liuhua , Yi Jing , Shen Linghong , He Ben
Published: April 2024

Background:
Angiotensin II (Ang II) is the predominant effector peptide of the renin-angiotensin system (RAS). Ang II contributes to vascular remodeling in many cardiovascular diseases (e.g., hypertension, atherosclerosis, restenosis, and aneurysm). Orphan nuclear receptor Nur77 has a crucial role in the functional regulation of vascular cells. The objective of this study was to define the specific role of Nur77 in Ang II-induced vascular remodeling.

Methods and Results:
Male Nur77

-/-

and wildtype (WT) littermate control mice (12-16 weeks of age) were continuously infused with Ang II using a mini-osmotic pump. Nur77 expression was increased in medial vascular smooth muscle cells (VSMCs) of thoracic aorta from WT mice after 2 weeks of exogenous Ang II administration. Loss of Nur77 resulted in enhanced outward vascular remodeling as reflected by increased medial area (197000±7091 μm
2
vs
. 174000±5927 μm
2
,
p
<0.05) and luminal diameter (880.7±24.13 μm
vs
. 825.2±10.38 μm,
p
<0.05), and more severe elastin disruption and collagen deposition. In situ immunofluorescence analysis indicated that there were increases in VSMC proliferation and matrix metalloproteinases (MMPs) production, and decreases in the expression of VSMC-specific contractile genes, accompanied by elevated β-catenin expression in remodeling aortas from Nur77

-/-

mice compared with WT mice. We also isolated rat VSMCs from Sprague-Dawley rats and mouse VSMCs from WT and Nur77

-/-

mice, and stimulated them with Ang II
in vitro
. Ang II increased Nur77 expression via the MAPK/PKA-CREB signaling pathway in rat VSMCs. Under both basal and Ang II-induced conditions, Nur77
-/-
mouse VSMCs exhibited increased proliferation and migration, and reduced expression of VSMC-specific genes. The results of additional experiments suggested that Nur77 suppressed Ang II-induced β-catenin signaling pathway activation by promoting β-catenin degradation and inhibiting its transcriptional activity.

Conclusions:
These results indicated that Nur77 is a critical negative regulator of Ang II-induced VSMC proliferation, migration, and phenotypic switching via the downregulation of β-catenin activity. Nur77 may reduce the Ang II-induced vascular remodeling that occurs in many cardiovascular diseases.
Abstract 12894: The Relations of Central Hemodynamics and Aortic Stiffness With Cardiac Structure and Function: The Framingham Heart Study
Authors: Kaess Bernhard , Rong Jian , Larson Martin G , Hamburg Naomi M , Vita Joseph A , Cheng Susan , Aragam Jayashree , Levy Daniel , Benjamin Emelia J , Vasan Ramachandran S , Mitchell Gary F
Published: April 2024

Introduction:
Relations of steady and pulsatile components of central hemodynamics and aortic stiffness with cardiac dimensions and function have not been fully elucidated.

Methods:
We measured mean arterial pressure (MAP, steady component of blood pressure), central pulse pressure (CPP, pulsatile component of central blood pressure), and carotid-femoral pulse wave velocity (CFPWV, a measure of aortic stiffness) by arterial tonometry in 5799 Framingham Heart Study participants (mean age 51 years, 54% women). We related these to echocardiographic left ventricular (LV) dimensions and systolic and diastolic function using multivariable-adjusted partial Pearson correlations.

Results:
MAP was associated positively with LV wall thickness (r=0.168; p<0.0001) and LV diastolic dimension (r=0.035, p=0.006). Adjusting for MAP, CPP was positively associated with LV wall thickness and LV diastolic dimension (r=0.044 and r=0.080, both p<0.0001). CFPWV was not associated significantly with LV structure (all p≥0.27) in MAP-adjusted models. MAP and CFPWV were associated negatively with LV diastolic function (E’; r=-0.140 and r=-0.153, respectively; both p<0.0001). The MAP relation persisted after adjustment for LV mass and CPP (r=-0.142) and the CFPWV relation persisted after adjustment for LV mass and MAP (r=-0.108, both p<0.0001). MAP and CFPWV were not associated significantly with LV fractional shortening (p≥0.10), whereas CPP was positively related (r=0.064, p<0.0001). The figure shows adjusted LV diastolic dimension (Panel A) and LV wall thickness (Panel B) partioned by tertiles of MAP and CPP, and E’ partitioned by CFPWV tertiles (Panel C).

Conclusions:
Steady and pulsatile components of central pressure are jointly yet differentially related to LV structure and function. Higher CFPWV is related to reduced LV diastolic function, but not systolic function.
Abstract 12912: Impact of Graft Configuration of The Right Internal Mammary Artery in Coronary Artery Bypass Grafting: In-situ Versus Y Composite versus Aorto-coronary Bypass
Authors: Sakai Jiro , Komiya Tatsuhiko , Tsuneyoshi Hiroshi , Shimamoto Takeshi
Published: April 2024

Background:
Right internal mammary artery (RIMA) has been used as second graft with various configurations. The aim of this study was to compare the patency of RIMA with using either aorto-coronary bypass (AC) or Y composite grafting proximally anastomosing to left internal mammary artery (LIMA) or in-situ grafting.

Methods:
Between January 1996 and June 2013, 324 patients underwent isolated coronary artery bypass grafting (CABG) using RIMA in addition to LIMA-left anterior descending artery (LAD) bypass. Target vessel of RIMA was either diagonal or circumflex branch with significant stenosis. Those patients were divided into 3 groups according to the proximal anastomosis site of RIMA. Group I contained 247 cases with in-situ RIMA grafting. Group A contained 33 cases with AC bypass with proximal anastomosis of RIMA to ascending aorta. Group Y contained 43 cases with Y composite grafting with proximal anastomosis to LIMA. Patients were evaluated by coronary angiography or CT scan postoperatively at discharge and during follow up. Graft patency and risk factors influencing IMA patency were statistically investigated.

Results:
RIMA patency at discharge were 97.6% in group I and 97.0% in group A, 93.0% in group Y, respectively (p=0.695). RIMA patency in 5 years were 90.5% in Group I, 100% in group A, 88.4% in group Y, respectively (Logrank P=0.309). LIMA patency at discharge were 99.2% in group I and 97.0% in group A, 97.7% in group Y, respectively (p=0.438). LIMA patency in 5 years were 100% in group A, 96.0% in group I, 76.2% in group Y (Logrank P= 0.009). Survival rate in 5 years were 89.7% in group I, 86.6% in group A, 60.7% in group Y (Logrank P= 0.011).

Multivariate analysis showed Y composite grafting as risk factor in late LIMA occlusion (p=0.024, Hazard ratio (HR) 6.867, 95% Confidence Interval (CI) 1.29-36.5) and late death (p<0.001 HR 2.99, 95% CI 1.70-5.27).

Conclusion:
In our study, the patency of RIMA was not significantly different between the groups, but LIMA patency was inferior when used as the inflow of Y composite grafting with RIMA. Y composite grafting may impact on the patency of LIMA and furthermore late survival.
Abstract 12921: Role of Transesophageal Echocardiogram in Affecting Treatment in Older Adults Undergoing Evaluation for Transient Ischemic Attack or Stroke
Authors: Van Woerkom Ryan C , Davis Megan L , LaBanc Austin J , Coakley Maria F , Lester Stephen J , Temkit M'hamed , Demaerschalk Bart M , Wilansky Susan
Published: April 2024

Background:
As the United States medical system transitions to value-based reimbursement, interested parties will increase scrutiny in testing that may not alter management or outcomes. We investigated whether transesophageal echocardiography (TEE) provokes treatment alteration across age strata in hospitalized patients undergoing a TIA/stroke work-up.

Methods:
Consecutive patients admitted to the Mayo Clinic Arizona healthcare system between 1/1/2010 and 2/9/2015 were evaluated. A total of 832 patients were identified of which 314 were excluded primarily due to the fact that the TEE was performed as an outpatient. Therefore, 518 subjects (mean age = 68.2 +/- 14.1 y, 42.5% female) were included. A change in treatment was defined a priori as: anticoagulation (AC) initiated for atrial fibrillation found on TEE only (i.e. not identified on telemetry), complex proximal aortic arch plaque, left atrial or left atrial appendage thrombus, intracardiac mass, intracardiac shunt (atrial septal defect (ASD)/ patent foramen ovale (PFO)) ; PFO closure; cardiac mass removal; valve replacement for endocarditis; antibiotics for endocarditis.

Results:
See Tables A & B

Conclusion:
TEE in the evaluation of hospitalized patients with TIA/stroke resulted in a change in treatment in approximately 7% of patients regardless of age. Many of the decisions to change treatment were judgment-based and therefore adoption of the routine use of TEE in all patients with TIA/stroke is dependent on institutional practice standards.
Abstract 12954: A Novel-Particle Image Velocimetry (PIV) Assay to Measure the Maturity and Functional Cardiomyocytes Contractility
Authors: Rajasingh Johnson , Rajasingh Sheeja , Czirok Andras , Samanta Saheli , Isai Dona G , Kosa Edina , Dawn Buddhadeb
Published: April 2024

Introduction:
The most important functional property of cardiomyocytes (CMCs) from a therapeutic standpoint is the ability to produce contractile force. Current methods of assessing the same, such as patch clamping and confocal calcium imaging, are labor-intensive, invasive or require fluo-dye in culture medium, which can affect the cells’ contractility. No optimal method is currently available to assess CMC functionality.

Hypothesis:
We hypothesized that a novel particle image velocimetry (PIV) method would provide accurate assessment of CMC contractility and maturity.

Methods:
We generated induced pluripotent stem cells (iPSCs) from adult human cells using a highly efficient viral-free transfection of DNA and mRNA combination. iPSCs were further differentiated into functional CMCs with defined culture conditions.

Results:
To analyze the contractility of iPSC-derived CMCs (iCMCs), we recorded the same areas of culture plate at various time-points using high frame-rate video microscopy (Fig. A, n=11). A novel image analysis technique provided beat patterns time series data of cell displacement, measured relative to a resting reference state (Fig. B, C). As beat patterns of recordings in video microscopic images revealed, the contractility of early CMC nodes was asynchronous in space and irregular in time (Fig. D1-D2, three beating fields are marked as red, green and blue). During subsequent days after the onset of beating, however, the spatially distinct contractile centers became synchronous even as their frequency remained unstable (Fig. D3-D6). The transmission electron microscopic images confirmed a well-developed pattern of sarcomeres in late-stage (day 30) CMCs.

Conclusions:
This PIV image analysis is a novel method that enables assessment of CMC contractility multiple times, if necessary, without jeopardizing the biology of cells. This method may also prove beneficial for drug screening and detection of cardiotoxicity in iPSC-derived CMCs.
Abstract 13007: Prognostic Significance of Persistent D-dimer Elevation in Patients With Acute Decompensated Heart Failure
Authors: Hamatani Yasuhiro , Nagai Toshiyuki , Sugano Yasuo , Honda Satoshi , Okada Atsushi , Asaumi Yasuhide , Aiba Takeshi , Noguchi Teruo , Kusano Kengo , Ogawa Hisao , Yasuda Satoshi , Anzai Toshihisa
Published: April 2024

Backgrounds:
Heart failure is associated with a prothrombotic state. D-dimer (DD) is a marker of fibrin turn over, and increased DD levels predict poor outcomes in patients with chronic heart failure. However, data regarding the DD level in patients with acute heart failure (AHF) are limited.

Methods:
Of 651 consecutive AHF patients who admitted to our institution between January 2013 and March 2015 from prospective registry, patients with acute coronary syndrome, oral anticoagulant therapy, and venous thromboembolism were excluded. Finally, 296 patients were divided into two groups according to the higher DD (above 2.7 μg/ml, the median), or lower DD (below 2.7 μg/ml) on admission. DD level was measured within 24 hours from admission and at discharge.

Results:
Although patients with higher DD were older (77±11 vs. 73±14 years; P<0.01), other baseline characteristics in terms of sex, NYHA classification, prevalence of co-morbidities including atrial fibrillation, and echocardiographic parameters including left ventricular ejection fraction were comparable between the two groups. During the median follow-up of 281 days, 4 patients died during hospitalization and 19 patients died after discharge. Kaplan-Meier curves for all-cause mortality are shown in the figure. Higher DD level on admission was associated with higher mortality (HR: 2.78, 95% CI: 1.19-7.25, P=0.02), even after adjustment by age. At discharge, DD level was persistently elevated (above 2.7 μg/ml) in 62% of patients with higher DD on admission. Among patients with higher DD on admission, persistent elevation of DD level during hospitalization was associated with higher mortality after discharge (HR: 7.00, 95% CI: 1.33-128.52, P=0.02).

Conclusions:
In patients with AHF, higher DD level on admission, especially persistently higher DD level during hospitalization, was associated with higher all-cause mortality, suggesting an importance of DD level as a prognostic surrogate marker of AHF.
Abstract 13085: Isolated Tricuspid Valve Surgery: Failure of Its Principle? Long-Term Outcome Analysis
Authors: Lucchese Gianluca , Cummings Ian , Oo Lionel , Roxburgh James , Avlonitis Vassilios
Published: April 2024

Introduction:
Isolated tricuspid valve (TV) surgery for acquired TV disease is high-risk surgery and the decision to operate is still controversial. We describe a single-centre experience with isolated TV surgery and our long-term analysis for adverse outcome.

Methods:
A retrospective analysis of 62 consecutive patients who underwent isolated TV surgery for acquired TV disease between 2002 and 2014 has been performed. Associated cardiac procedures and congenital TV disease were exclusion criteria. The Kaplan-Meier, Univariate and Cox regression analysis were respectively used to evaluate mortality and identify risk factors at long-term follow-up. The Duke Activity Status Index (DASI) questionnaire, to measure the functional status related to daily living, has been used to assess the survivors’ quality of life.

Results:
Mean patient age was 60.2±18.9 years, 38% were male and the average log EuroSCORE was 16.8%±15.9%. TV repair was performed in 38 cases (61%), replacement in the remainder and 38% were reoperations. 30-day mortality was 15% (n=9) , similar for repair and replacement. Follow-up (median=35.7 months, range=0.1-150) was 100% complete. Survival at 1, 5 and 10 years was 79.5%±5%, 69.8%±6% and 53.5%±9.7% respectively. Sinus rhythm, NYHA class < III, age < 60 years were identified as independent predictors of survival at long-term follow-up. Furthermore, we found that survivors with a lower pre-operative NYHA functional class were also those with the best quality of life at follow-up (DASI score 20.5 ± 8.6 vs 12.7 ± 7, p=0.028).

Conclusions:
Patients who undergo isolated TV surgery continue to be a high-risk group in with high early and late mortality. There is no difference in mortality between TV repair and replacement at long-term follow-up. Our experience suggests that a shift towards earlier surgery may be proven to confer an advantage, as surgery before the onset of NYHA class 3 symptoms is associated with improved outcome and better quality of life.
Abstract 13143: The Relationship Between Coronary Microvascular Dysfunction and Preclinical Left Ventricular Diastolic Dysfunction: Invasive Physiologic and Echocardiographic Study
Authors: Kobayashi Yuhei , Kobayashi Yukari , Haddad Francois , Pargaonkar Vedant , Lee David P , Fearon William F , Yeung Alan C , Tremmel Jennifer A
Published: April 2024

Background:
Microvascular dysfunction has been associated with the development of diastolic heart failure. We hypothesized that invasively assessed microvasculature is related to diastolic function as assessed by echocardiography, even before the development of diastolic heart failure.

Methods:
We prospectively enrolled 63 subjects with preserved ejection fraction (≥55%) and no heart failure symptoms. Coronary physiologic assessment, including fractional flow reserve (FFR), coronary flow reserve (CFR), and the index of microcirculatory resistance (IMR), was performed in the LAD. Coronary flow was assessed with a thermodilution method by obtaining a mean transit time (Tmn: an inverse correlate to absolute flow) at rest and hyperemia. IMR was measured as distal coronary pressure x hyperemic Tmn. Left ventricular diastolic function was evaluated by an echocardiographic parameter (E/e’) using the following criteria; normal E/e’<8, intermediate 8<E/e’<15, and high E/e’>15, where a higher value was correlated with diastolic dysfunction.

Results:
Mean age was 54.5±12.3 years. All subjects had no significant stenosis in the LAD (FFR: 0.87±0.05). Mean CFR and IMR were 4.4±1.9 and 18.2±8.3, respectively. CFR and IMR were not significantly different among the 3 E/e’ groups (ANOVA p=0.60 for CFR and p=0.14 for IMR). Conversely, both resting and hyperemic Tmn were significantly shorter in patients with a high E/e’ value than with a normal value (p=0.04 for resting Tmn and p=0.03 for hyperemic Tmn, Figure), suggesting that coronary flow both at rest and hyperemia increases along with the progression of diastolic dysfunction.

Conclusions:
In this preclinical population, invasively assessed microvascular function (CFR/IMR) is not associated with diastolic dysfunction, whereas both resting and hyperemic flow are increased in subjects with diastolic dysfunction. Future studies are warranted to test the prognostic value of increased coronary flow.