bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 17080: The Anesthetized Rat Model of Exercise Faithfully Simulates Respiratory Abnormalities in Chronic Heart Failure
Authors: Nishizaki Akiko , Saku Keita , Miyamoto Tadayoshi , Kishi Takuya , Sunagawa Kenji
Published: March 2022

Background:
Abnormal respiration during exercise is one of the major manifestations and a powerful predictor of survival in chronic heart failure (CHF). There have not been proposed the appropriate animal model to investigate the mechanism of respiratory abnormalities in CHF during exercise. In this study, we developed an experimental model using anesthetized CHF rats to evaluate exercise-induced abnormal respiration and central chemoreflex control function during exercise in CHF.

Methods:
We used anesthetized 16 weeks old rats with/without myocardial infarction induced CHF. To mimic exercise, we induced muscle contraction by stimulating bilateral distal sciatic nerves. We recorded the respiratory change in response to sciatic nerve stimulation (SNS) with ramp (5 Hz, 0.01 Volts/sec) and step (5 Hz, 0.5 Volts) protocols. We also evaluated the change of the central chemosensitivity (ventilatory response to partial pressure of carbon dioxide in arterial blood; PaCO2) by CO2 gas inhalation (0, 3 and 5%) during exercise in normal and CHF.

Results:
In ramp protocol, SNS significantly increased minute ventilation (VE) in CHF to a greater extent than in that of normal (normal 155.2±27.9, CHF 211.2±48.6 mL/min, p<0.01). CHF markedly steepened the VE-carbon dioxide production relationship (VE/VCO2 slope) (normal 26.8±12.7, CHF 38.5±5.9, p<0.05) (Fig. 1). CHF shifted the relationship of tidal volume (TV) to respiratory rate (RR) rightward reflecting the rapid and shallow breathing during exercise (Fig. 2). The SNS-induced upward shift of the VE-PaCO2 line observed in CHF indicated that exercise-related respiratory abnormalities arise from pathophysiological change in the central chemoreflex control (Fig. 3).

Conclusion:
Anesthetized rat exercise model simulated respiratory abnormalities in CHF reasonably well. It will provide us an opportunity to clarify the physiological mechanisms of exercise-induced abnormal respiration in CHF.
Abstract 17081: Long-term Administration of Eicosapentaenoic Acid Ameliorates Vascular Endothelial Dysfunction Through the Renin-angiotensin-aldosterone System Inhibition Resulting in the Improvement of Muscle Oxygen Metabolism in Patients With Lifestyle Related Disease
Authors: Nakamura Takeshi , Masuda Takashi , N Ogura Misao , Shimizu Ryosuke , Kamekawa Daisuke , Akiyama Ayako , Kamada Yumi , Tanaka Shinya , Hamazaki Nobuaki , Aoyama Akihiro , Yabu Kanae , Maekawa Emi , Ako Junya
Published: March 2022

Background:
Elevated activity of renin-angiotensin-aldosterone system (RAAS) is known to induce vascular endothelial dysfunction in patients with lifestyle related disease such as diabetes mellitus (DM), hypertension (HT) and dyslipidemia (DL). Because the vascular endothelial dysfunction disturbs an appropriate blood flow to skeletal muscles, it is considered that the oxygen metabolism is impaired in them. Although eicosapentaenoic acid (EPA) has been reported to inhibit the RAAS, it is unclear whether EPA ameliorates vascular endothelial dysfunction via the RAAS inhibition resulting in the improvement of muscle oxygen metabolism. This study investigated the effects of EPA on vascular endothelial function and muscle oxygen metabolism during exercise in patients with lifestyle related disease.

Methods:
Ninety-two patients (68±8 years, 50 males) were divided into two groups based on the EPA administration in crossover method, after their DM, HT and/or DL were optimally treated. When patients took 1,800 mg of EPA daily for 8 months or not, they were in the EPA(+) group or in the EPA(-) group. In the end of each treatment period, cardiopulmonary exercise test was performed to measure oxygen uptake (VO
2
) at anaerobic threshold (VO
2 AT
), peak VO
2
and the time from the start of the test to the AT (Time
AT
) and endpoint (Time
EP
). We measured serum EPA, plasma renin activity (PRA), aldosterone (ALD), adrenalin (ADRN) and noradrenalin (NORA), and reactive hyperemia index (RHI). We used the changes in PRA, ALD, ADRN and NORA before and after a cycle ergometer exercise test (ΔPRA, ΔALD, ΔADRN and ΔNORA) as neurohumoral factors, RHI as a parameter of vascular endothelial function and Time
EP
as an exercise capacity.

Results:
There were no significant differences in ΔPRA, ΔALD, ΔNORA, peak VO
2
and Time
EP
between the two groups. The PRA, ALD and ΔADRN were significantly lower in the EPA(+) group than in the EPA(-) group (P<0.05, respectively). The RHI, VO
2 AT
and Time
AT
were significantly higher in the EPA(+) group than in the EPA(-) group (P<0.05, respectively).

Conclusion:
Long-term administration of EPA ameliorated vascular endothelial dysfunction via the RAAS inhibition resulting in the improvement of muscle oxygen metabolism in lifestyle related disease patients.
Abstract 17095: Clinical Characteristics and Short-term Outcomes of Aortic Disease Patients With Cardiovascular Shock: Results From the Shock Registry of the Japanese Circulation Society
Authors: Tsujita Yasuyuki , Doi Yasuji , Kadokami Toshiaki , Matsuura Hirohide , Imai Ryuichirou , Miyamoto Takamichi , Tachibana Eizo , Yonemoto Naohiro , Nagao Ken
Published: March 2022

Background:
The mortality rate of aortic disease patients with cardiovascular shock (CVS) is still high. We examined the factors related to short-term outcomes of aortic disease patients with CVS.

Methods:
The Japanese Circulation Society Shock Registry was a prospective, observational, multi-center (83 institutions), cohort study that enrolled 980 patients presenting with CVS when transported to the emergency room between May 2012 and June 2014. Of those, 82 aortic dissection (AD) and 63 aortic aneurysm (AA) patients were enrolled in this study. Because each institution used a different D-dimer kit, adjusted D-dimer levels were calculated by dividing the measured D-dimer value by the upper limit of the normal range of the kit.

Results:
The mean age was 76 years and 52% were male. The 30-day mortality rate was 46% (AD, 39%; AA, 56%). In AD, Stanford type A accounted for 95% and surgical intervention was performed in 68%. In AA, 24% were thoracic; 6%, thoracoabdominal; 69%, abdominal AA, and surgical intervention was performed in 57%. In AD, adjusted D-dimer levels on admission of non-survivors were significantly higher than those of survivors [median (interquartile range): 75.6 (19.5-229.4) vs. 25.8 (8.0-61.3) arbitrary units, respectively; P=0.01]. In AD, surgical intervention, a transferred case, absence of aortic rupture, and low D-dimer levels (adjusted D-dimer < 33.2 arbitrary units, which was the median value) were associated with the 30-day survival. In AA, surgical intervention, a transferred case, higher consciousness level, higher systolic blood pressure, and abdominal AA were associated with 30-day survival. Cox proportional hazards analysis indicated that surgical intervention (hazard ratio 0.14; 95%CI, 0.049-0.40; P<0.001) and low D-dimer level (hazard ratio 0.21; 95%CI, 0.067-0.57; P<0.001) were independent predictors of 30-day survival in AD, and surgical intervention (hazard ratio 0.087; 95%CI, 0.023-0.28; P<0.001) was an independent predictor of 30-days survival in AA.

Conclusions:
Surgical intervention was the only method to improve short-term outcomes of aortic disease patients with CVS. In AD, lower D-dimer level was associated with more favorable short-term outcomes regardless of surgical intervention.
Abstract 17109: Input Impedance Analysis of Pulmonary Hypertension Models Indicates That Monocrotaline and Sugen/hypoxia Induce Mechanically Different Vascular Remodeling
Authors: Nishikawa Takuya , Saku Keita , Sakamoto Takafumi , Murayama Yoshinori , Kishi Takuya , Sunagawa Kenji
Published: March 2022

Introduction:
Although complex pulmonary arterial remolding characterizes pulmonary hypertension (PH), the vascular mechanics has been evaluated by the static pressure-flow relationship (resistance, R) ignoring dynamic mechanical properties (compliance, C). We therefore evaluated pulmonary arterial input impedance (Z) capable of identifying not only resistance but also compliance in monocrotaline (MCT) and Sugen/Hypoxia (SuHx) PH models.

Methods:
In 6 weeks Sprague-Dawley rats, we induced PH by the subcutaneous injection of MCT (60 mg/kg) or Sugen5416 (20 mg/kg) with 3 weeks hypoxia. In anesthetized PH rats, we measured pulmonary artery flow (PAF) and pressure (PAP) at 1000 Hz for 107.52 seconds under irregular pacing. We Fourier transformed both PAF and PAP to derive ensembled power spectra and crosspower spectra and taking their ratio yielded Z. We fitted the 2-element Windkessel model to Z and estimated R and C.

Results:
MCT and SuHx significantly increased mean PAP (Control: 19.4±2.0, MCT: 31.3±4.0, SuHx: 39.4±6.5 mmHg,
p
<0.01) and shifted Z upward indicating the increased R (Control: 17.8±3.3, MCT: 71.4±16.3, SuHx: 81.8±18.4 mmHg/ml/sec,
p
<0.01). MCT and SuHx both decreased C (Control: 2.6±0.4, MCT: 1.5±0.6, SuHx: 0.9±0.2 х10
-3
ml/mmHg,
p
<0.01). However, the time constant was higher in MCT than in SuHx (Control: 90.7±8.6, MCT: 130.0±21.5, SuHx: 92.6±2.0 msec,
p
<0.05) (Figure). MCT predominantly remodeled resistance vessels while SuHx remodeled both resistance and compliance vessels.

Conclusions:
We conclude that the impedance analysis is capable of characterizing how remodeling affects vascular mechanical properties, which are not identifiable if we analyze resistance alone. Hence the impedance analysis is applicable in patients, it may serve as a new tool in functionally analyzing vascular remodeling in PH patients.
Abstract 17179: Combined Doxycycline and Tauroursodeoxycholic Acid Slows Progression of Transthyretin Cardiac Amyloidosis
Authors: Sadegh Marjan , Trota Danielle L , Falk Rodney H
Published: March 2022

Introduction:
Transthyretin (TTR) cardiac amyloidosis (CA) is a progressive infiltrative cardiomyopathy with no specific therapy. In animals, doxycycline disrupts existing amyloid fibrils and may prevent fibrillogenesis. Tauroursodeoxycholic acid (TUDCA), a bile acid, prevents extracellular TTR monomer deposits, and the 2 drugs work synergistically in a mouse model of amyloidosis to decrease tissue amyloid. We sought to determine whether a combination of TUDCA and doxycycline could slow the progression of amyloid-associated LV dysfunction in patients with TTR cardiac amyloidosis.

Methods:
17 patients with biopsy-proven TTR cardiac amyloidosis, mean age 71.3 yr (all men: 16 wild-type and 1 mutant TTR), received doxycycline 100 bid and TUDCA 250 mg tid for 12 months. The primary endpoint was change in longitudinal strain (LS) at 12 months, when compared to a group of 14 patients studied serially without therapy (mean age 72.4 yr, all men). All patients had echocardiograms performed on a GE Vivid machine, and analyzed by the same investigator. LS was measured from the apical 4-chamber view.

Results:
Doxycycline/TUDCA was well-tolerated. Mean baseline LS was no different between treatment group and untreated patients, and both groups showed deterioration of LS at 12 months. However, deterioration of LS was less in the treated group than controls (table). NTproBNP, a marker of disease was measured in the treatment group only, and rose slightly from a mean of 3108 pg/ml to 3669 pg/ml,(p<0.05) consistent with the change in LS.

Conclusion:
1. TTR cardiac amyloidosis is characterized by a consistent decrease in LV strain over a 1 year period, associated with a rise in NTproBNP. 2. Although doxycycline/TUDCA combination does not entirely halt progression of LV dysfunction, it appears to significantly slow the progression of disease and offers a well-tolerated therapy for disease modification.
Abstract 17189: Prevalence and Relevance of Recurrent Premature Ventricular Complexes in the Pre-discharge Period Following Pvc Ablation
Authors: Mohanty Sanghamitra , Burkhardt John David , Trivedi Chintan , Gianni Carola , Gunes Mahmut F , Gokoglan Yalcin , Al-Ahmad Amin , Sanchez Javier , Hranitzky Patrick , Gallinghouse G. J , Horton Rodney , Di Biase Luigi , Natale Andrea
Published: March 2022

Background:
Radiofrequency catheter ablation is widely-used to target frequent premature ventricular complexes (PVCs) in patients with and without structural heart disease, with reported ablation-success rate being in the 80% range. However the risk-factors that correlate with ablation-failure have not been defined yet. We aimed to assess the prevalence of recurrent PVCs in the immediate post-ablation period and their relevance in relation to the clinical outcome of catheter ablation of PVCs.

Methods:
A consecutive series of 104 patients (age: 58±15 years, male 57%, LVEF 54±10.8) with frequent PVCs and without structural heart disease referred for catheter ablation at our center, were included in this prospective analysis. Successful ablation was defined as the absence of spontaneous or induced clinical PVC, both with or without isoproterenol at the end of the procedure. Arrhythmia burden was assessed at baseline and follow-up using 24-hour Holter recording. Telemetry was performed for at least 12 hours in the immediate post-ablation period. Ablation success was defined as ≥ 90% reduction of the initial PVC burden at 3-month follow-up.

Results:
At baseline, the mean number of PVC morphologies was 1.4± 2.2 and the predominant PVCs commonly originated from right ventricular outflow tract [34 (32.6%)], coronary cusps [28 (27%)], interventricular septum [16 (15.3%)] and left ventricular outflow tract [13 (12.5%)]. Elimination of predominant PVCs was achieved in all patients. In the 12-hour post-ablation period, recurrence of PVCs was observed in 16 (15%) patients, which were transitory and never documented at follow-up monitoring. The most common sites of origin of these early PVCs were anterior cardiac veins, papillary muscles and mitral valve annulus. At follow-up, recurrence was reported in 5 of the 104 patients (4.8%) of which only one had early PVCs during the 12-hour post-ablation period.

Conclusions:
Recurrence of PVCs in the immediate post-ablation period is transient and not indicative of the failure of the index procedure. Furthermore, pre-discharge PVCs do not demonstrate any definite correlation with the risk of late recurrence. This is most likely the result of myocardial irritation secondary to the trauma of the ablation procedure.
Abstract 17215: Exercise Training Restores Dimeric nNOS by Regulating PIN Expression in the Paraventricular Nucleus of Chronic Heart Failure Rats
Authors: Sharma Neeru M , Liu Xuefei , Zheng Hong , Patel Kaushik P
Published: March 2022

Introduction and Hypothesis:
Exercise training (ExT) is an established non-pharmacological therapy that improves the health and quality of life in patients with chronic heart failure (CHF). CHF is characterized by exaggerated sympathetic drive due to an imbalance of the autonomic nervous system. Neuronal nitric oxide synthases (nNOS) in the paraventricular nucleus (PVN) produce nitric oxide (NO), which is known to regulate the sympathetic tone. Previously we have shown that during CHF, catalytically active dimeric form of nNOS is significantly decreased (~40% decrease in dimer/monomer ratio) with a concurrent increase in PIN expression (~50%), a protein that uncouples dimeric nNOS to monomers and facilitate its degradation. Dimerization of nNOS also requires tetrahydrobiopterin (BH4) for stability and activity. Previously, we have shown that ExT improve NO-mediated sympathetic inhibition in the PVN, however, the molecular mechanism remains elusive. We hypothesized; ExT restores the sympathetic drive by reinstating the levels and catalytically active form of nNOS by abrogating changes in PIN in the PVN of CHF rats.

Methods and Results:
CHF was induced in adult male Sprague-Dawley rats by coronary artery ligation, which reliably mimics CHF in patients with myocardial infarction. After 4-weeks, Sham and CHF rats were subjected to 3-4 weeks of progressive treadmill exercise. ExT significantly (p < 0.05) restored PIN expression (0.68±0.05 CHF vs 0.40±0.06* ExT-CHF), and reinstated dimer/monomer ratio (0.67±0.04 CHF vs 0.90±0.07* ExT-CHF), in the PVN of rats with CHF. Moreover, we found decreased GTP cyclohydrolase 1(GCH1) expression: a rate-limiting enzyme for BH4 biosynthesis in the PVN of CHF rats (0.74±0.03 Sham vs 0.48±0.02* CHF), suggesting that perhaps reduced BH4 availability may also contribute to decreased nNOS dimers. Interestingly, CHF induced decrease in GCH1 expression was ameliorated with ExT (0.48±0.02 CHF vs 0.70±0.07* ExT-CHF).

Conclusions:
Our findings revealed that ExT- rectified, decreased PIN and GCH1 expression and improved dimer/monomer ratio of nNOS in the PVN, which may lead to increase NO resulting in amelioration of activated sympathetic drive during CHF.

Acknowledgements:
AHA- 14SDG19980007 and NIH-HL62222 grants.
Abstract 17225: Therapeutic Strategies Following Major Bleeding in Atrial Fibrillation: Findings From ORBIT-AF
Authors: O'Brien Emily C , Simon DaJuanicia N , Fonarow Gregg C , Ansell Jack E , Kowey Peter R , Gersh Bernard J , Mahaffey Kenneth , Peterson Eric D , Piccini Jonathan P , Hylek Elaine M
Published: March 2022

Background:
Little information exists on clinical characteristics and treatment patterns of patients with atrial fibrillation (AF) following a major bleeding event in clinical practice.

Methods:
We used data from a large, national outpatient registry, ORBIT-AF (2010 – 2011), to evaluate event characteristics and oral anticoagulation (OAC) management following a major bleeding event. Major bleeds were defined according to ISTH criteria. We compared baseline characteristics among patients who persisted on OAC therapy at the first clinic visit following a major bleed and those in whom OAC was discontinued using chi-squared tests.

Results:
Of 10135 patients enrolled in ORBIT-AF, n=791 (7.8%) bleeding events occurred during 2 years of follow-up. Among patients who were receiving OA, n=632 (3.5 per 100 person years) experienced a major bleed. Of these, 67.3% experienced a fall in hemoglobin and 46.8% required transfusion of 2 of more units of red blood cells. Critical site bleeding occurred in 150 OAC patients, with the majority of these classified as intracranial bleeding (n= 89), followed by retroperitoneal (n=25) and intraocular (n=17). Fatal bleeds occurred in 37 patients (5.9% of all major bleeds). Nearly one-third of patients (31.0%) discontinued OAC therapy following the major bleeding event. Compared with those who persisted on OAC, patients who discontinued OAC were more likely to have hypertension and CKD. Those who discontinued OAC were more likely to have gastrointestinal or CNS site bleeding compared with those who persisted (Table).

Conclusions:
One in three patients who experienced a major bleed were no longer optimally anticoagulated after the event. Those who discontinued OAC had a greater comorbidity burden and more likely to have bleeding in a critical site those who persisted on OAC.
Abstract 17261: Comparing SF-36 Scores versus Traditional and Novel Biomarkers to Predict Mortality in Primary Cardiac Prevention Patients
Authors: Lahoud Rony , Chongthammakun Vasutakarn , Brennan Danielle , Cho Leslie
Published: March 2022

Background:
Risk stratification plays an important role in evaluating patients with no known cardiovascular disease (CVD). Few studies have investigated health-related quality of life questionnaires such as the Medical Outcomes Study Short Form-36 (SF-36
®
) as predictive tools for mortality, particularly in direct comparison with biomarkers. Our objective is to measure the relative effectiveness of SF-36
®
scores in predicting mortality when compared to traditional and novel biomarkers in a primary prevention population.

Methods:
The study analyzed patient characteristics and all-cause mortality among 7056 consecutive patients evaluated for primary cardiac prevention in a cardiology clinic at Cleveland Clinic between January 1996 and April 2011. Patient characteristics included history and physical examination, SF-36
®
questionnaire and a laboratory panel consisting of total cholesterol, triglycerides, HDL, LDL, apolipoprotein A, apolipoprotein B, fasting glucose, hemoglobin A1c, creatinine, homocysteine, lipoprotein(a), fibrinogen, high-sensitivity C-reactive protein, uric acid and urine albumin:creatinine ratio. The primary outcome was all-cause mortality.

Results:
A low SF-36
®
physical score independently predicted a 6-fold increase in death at 8 years (above vs. below median Hazard Ratio [95% confidence interval] 5.99 [3.86-9.35], p<0.001). In a univariate analysis, SF-36
®
physical score had a c-index of 0.75, which was superior to that of all the biomarkers. It also carried incremental predictive ability when added to non-laboratory risk factors (Net Reclassification Index = 45.4%), as well as Framingham risk score components (Net Reclassification Index = 59.4%). Biomarkers added no incremental predictive value to a non-laboratory risk factor model when combined to SF-36 physical score.

Conclusions:
The SF-36
®
physical score is a reliable predictor of mortality in patients without CVD, and outperformed most studied traditional and novel biomarkers. In an era of rising healthcare costs, the SF-36
®
questionnaire could be used as a simple and cost-effective predictor of mortality.
Abstract 17279: Have the 2013 AHA/ACC Cholesterol Guidelines Affected Clinicians’ Lipid Management Strategies?
Authors: Navar Ann M , Goldberg Anne C , Robinson Jennifer G , Roger Veronique L , Virani Salim S , Wilson Peter F , Elassal Joseph , Lee L. Veronica , Webb Laura E , Pencina Michael P , Peterson Eric D , Wang Tracy Y
Published: March 2022

Background:
The 2013 ACC/AHA Cholesterol Guidelines departed from prior ATPIII guidelines, recommending statin treatment based on patients’ predicted 10-year ASCVD risk and de-emphasizing LDL-C targets. However, the degree to which these new guidelines have been adopted by clinicians in community practice is unknown.

Methods:
We surveyed 522 clinicians in 133 cardiology, primary care, and endocrinology practices participating in the Patient and Provider Assessment of Lipid Management (PALM) Registry. Clinicians were asked about their likelihood of prescribing statins in 4 hypothetical patient scenarios.

Results:
Among responders, 79% were physicians (60% cardiologists, 38% primary care or general practice, 2% endocrinology), 18% were advanced practice providers, and 3% trainees. When queried, 73% of providers reported primarily using the 2013 ACC/AHA Guidelines to guide lipid management. However, only half reported “often” or “always” calculating 10-year ASCVD risk to aid lipid management decisions for primary prevention.

When presented with a high 10-year ASCVD risk patient (>15%) with a high LDL-C (150 mg/dL), 92% of providers recommended statins. Similarly, 83% of providers would use statins in a diabetic patient with a LDL-C of 140 mg/dL. Yet, only 37% reported they would prescribe a statin to an older adult (age 70) for whom guidelines recommend statin based on high 10-year ASCVD risk alone (10.1%). And up to 40% would prescribe a statin to a younger (age 40) with a low 10-year risk, but a high LDL (165 mg/dL) who would not otherwise meet criteria for statin therapy under the new guidelines. Cardiologists and non-cardiologists were similarly likely prescribe statins in most scenarios with the exception of to the younger patient with elevated LDL-C were cardiologists used statins more commonly (32% vs. 42%. OR 1.5, 95% CI 1.1-2.2, p=0.02).

Conclusion:
Initial survey results show that while most clinicians claim adoption of the 2013 ACC/AHA Guidelines, reported practices are not always adherent to these guidelines. Providers do not always calculate 10-year ASCVD risk to guide lipid management and many do not prescribe statins to patients eligible based on 10-year ASCVD risk.
Abstract 17298: Association of Left Atrial Size and Incident Heart Failure and All-cause Death: The Chronic Renal Insufficiency Cohort (CRIC) Study
Authors: Zamani Payman , Hsu Jesse Y , Keane Martin G , Bansal Nisha , Delafontaine Patrice , Go Alan S , He Jiang , Kawut Steven M , Ky Bonnie , Lora Claudia M , Seliger Stephen L , Sharif Tariq , Shlipak Michael , Tao Kelvin , Townsend Raymond R , Feldman Harold I , Deo Rajat
Published: March 2022

Introduction:
Chronic kidney disease (CKD) increases the risk for adverse cardiovascular events including heart failure (HF) and death. Left atrial size is an easily quantified metric that provides prognostic information in non-CKD populations.

Hypothesis:
We hypothesized that left atrial size would be an independent risk marker for incident HF and death in individuals with CKD.

Methods:
The Chronic Renal Insufficiency Cohort (CRIC) is a large, multicenter, multiracial cohort study established to understand the progression of cardiovascular and renal disease among individuals with CKD. We evaluated echocardiograms among participants without a history of heart failure. The left atrial area was measured in the apical 4-chamber view and indexed to body surface area (LAAI). Cox proportional hazards models were constructed to assess the risk between left atrial size and incident HF and death.

Results:
Among the 2960 CKD participants without known heart failure, higher tertiles of LAAI were associated with older age, Hispanic ethnicity, a history of stroke, myocardial infarction, atrial fibrillation, higher systolic blood pressure, hypertension, diabetes, and lower eGFR (P<0.005 for all). The median left ventricular ejection fraction was 55% across LAAI tertiles. Over a median [IQR] follow-up of 6.6 [5.7-7.6] years, 344 participants developed HF and 472 died. An increase in LAAI was a strong risk marker for the development of heart failure after multivariable adjustment (Table 1). LAAI was modestly associated with all-cause death after controlling for demographics and clinical variables; however, additional adjustment for echocardiographic variables and cardiac biomarkers rendered the association non-significant. There was no significant interaction between LAAI and sex or race for either outcome.

Conclusion:
Among adults with CKD, LAAI is a stronger marker of risk for incident HF than death.
Abstract 17311: Molecular Memory and the Epigenetic Regulation of Cardiac Intracellular Matrix Metalloproteinase-2
Authors: Lovett David H , Luk Stanley , Uttarwar Lalita , Joshi Sunil , RAffai Robert L
Published: March 2022

Introduction:
We have identified an intracellular isoform of MMP-2 generated by oxidative stress activation of a promoter in the first intron of the MMP-2 gene. This generates a N-terminal truncated isoform of MMP-2 (NTT-MMP-2) which is enzymatically active and found in mitochondria. NTT-MMP-2 triggers the mitochondrial permeability transition leading to myocyte regulated necrosis and inflammation. We hypothesized that transient oxidative stress induces durable epigenetic changes in the NTT-MMP-2 alternate promoter resulting in enhanced injury in subsequent episodes of stress (molecular memory).

Methods:
The intronic promoter was mapped using a combination of PCR-based and intronic/luciferase constructs. In vivo studies used the hypomorphic ApoER61h/h SR-B1-/- murine model (HypoE mice) of diet-induced coronary atherogenesis and myocardial infarction. Chromatin immunopreciptation (ChIP) probed the RNA Pol II, H3K4Me1 and H3K27Me3 epigenetic marks. NTT-MMP-2 was measured by qPCR.

Results:
NTT-MMP-2 transcription start sites were mapped to two stress-activated basal promoters along with a stress-activated NF-κB enhancer element. HypoE mice were fed a high fat diet (HFD) for 20 days, followed by gene repair of the hypomorphic ApoE alleles and returned to normal diet for 6-15 weeks. NTT-MMP-2 expression at 20 days of HFD was elevated two-three fold as compared to controls, remained elevated after 6 weeks of normal diet and returned to baseline at 15 weeks. ChIP of the intronic promoter revealed association of RNA Pol II at 6 weeks of normal diet and was not detectable at 15 weeks. In contrast, the pro-transcriptional mark H3K4Me1 remained elevated out to 15 weeks; the inhibitory H3K27Me3 mark returned to baseline at 15 weeks. A brief return to HFD (7 days) at 6 weeks increased NTT-MMP-2 expression resulting in myocyte inflammation and necrosis relative to controls exposed to only 7 days of HFD.

Conclusions:
Transient periods of oxidative stress lead to durable epigenetic changes in the NTT-MMP-2 promoter that facilitate exaggerated responses to otherwise minor levels of oxidative stress. Our findings may provide an explanation for the enhanced injury susceptibility to relatively minor stresses of patients with pre-existing cardiac disease.
Abstract 17326: Clues to Attenuating Plaque Inflammation: Heat Shock Protein-27 Augments Macrophage Histone Deacetylase-6 Activity and Cytoskeletal Migratory Capacity
Authors: Koumbadinga Gérémy A , Alvarez-Omeldo Daiana , O’Brien Edward R
Published: March 2022

Introduction:
We recently demonstrated that elevated serum levels of Heat Shock Protein 27 (HSP27) are associated with reduced 5-year CV events and that extracellular HSP27 attenuates experimental atherogenesis and lesion progression. Indeed, HSP27 therapy reduces plaque macrophage and cholesterol content and enhances histological features associated with resilience to plaque rupture. Cell motility and adhesion involves dynamic microtubule acetylation/deacetylation, a process regulated by the enzyme histone deacetylase 6 (HDAC6), a major cytoplasmic α-tubulin deacetylase. We hypothesize that HSP27 enhances HDAC6 activity to promote favorable plaque remodeling by enhancing macrophage migration.

Methods / Results:
1. The HDAC6 activity of THP-1 macrophages treated with recombinant HSP27 was assessed using a fluorescent plate reader ELISA. In a dose-dependent fashion, rHSP27 treatment resulted in a 100% increase in HDAC-6 activity compared to the control and was independent of HSP27 phosphorylation. Moreover, HDAC-6 activity was enhanced 100% in peritoneal macrophages harvested from rHsp27-treated ApoE-/- vs. control mice. With the addition of cycloheximide HDAC-6 activity was not prolonged, suggesting that HSP27 did not have an effect on the enzymatic half-life.

2. When HSP27 expression was knocked down in THP-1 cells transfected with a lentivirus carrying specific shRNA-HSP27 vector there was a reduction in HDAC6 activity and an increase in tubulin acetylation - and both of these effects were rescued with the addition of rHSP27.

3. Using a Boyden chamber cell migration assay, we found that rHSP27 treatment increased migration of THP-1 cells without and with ox-LDL loading by ~2- and ~1.5-fold; respectively - an effect that was blocked by either Tubacin (a specific inhibitor of HDAC6) or HSP27 knockdown.

Conclusion:
Extracellular HSP27 is capable of up-regulating HDAC6 activity in macrophages, an effect associated with enhanced macrophage migratory capacity. These data suggest that HSP27 may be important for potentially improving macrophage egress from plaques thereby resulting in reduced cholesterol content and more stable lesions - factors that may explain the proven predictive biomarker value of elevated serum HSP27 levels.
Abstract 17338: Development of a TIMI Risk Score for Stable Ischemic Heart Disease
Authors: Bohula Erin A , Bonaca Marc P , Aylward Philip E , De Ferrari Gaetano M , He Ping , Lewis Basil S , Merlini Piera , Murphy Sabina A , Sabatine Marc S , Scirica Benjamin M , Braunwald Eugene , Morrow David A
Published: March 2022

Patients (pts) with stable ischemic heart disease (SIHD) who have had a prior myocardial infarction (MI) demonstrate a range of residual risk for recurrent CV events. A risk prediction tool may be useful to identify high risk pts who have the greatest potential for benefit from intensive treatment.

Methods:
The integer-based TIMI Risk Score for SIHD (Prior MI) was derived in 8,200 placebo-treated pts who were stable with a history of MI (2 wks to 12 mo) in the TRA 2°P-TIMI 50 trial. The score was developed to predict CV death, MI or ischemic stroke (CVD/MI/iCVA; n=676 events, median 2.5y follow-up). The score was validated in 8,274 vorapaxar-treated pts from the trial. Differential efficacy and safety (GUSTO severe bleeding) response to randomized treatment was assessed among pts with prior MI without a history of TIA or stroke for whom there is a clinical indication for vorapaxar.

Results:
The risk score predictors were age, CHF, smoking, diabetes mellitus, hypertension, prior stroke, peripheral arterial disease, family history of CAD, prior CABG, and eGFR (Fig 1a). The TIMI Risk Score showed a strong graded relationship with the rate of CVD/MI/iCVA as well as the individual components (p-trend<0.001 for all), a pattern that was confirmed in the validation cohort (p<0.001). In pts eligible for clinical use, those at intermediate (score 2-3) and high (score ≥4) risk had a 2.4% and 3.6% absolute risk reduction in CVD/MI/iCVA with vorapaxar, translating to a number needed to treat (NNT) of 41 and 28 in the intermediate and high risk groups (Fig 1b). Bleeding increased across risk groups (Fig 1b); however, net clinical outcome was increasingly favorable with vorapaxar with an increasing TIMI Risk Score. ICH was 0.5 vs 0.6% and fatal bleeding was 0.3 vs 0.5% with vorapaxar vs placebo in those with a score ≥4.

Conclusions:
The TIMI Risk Score for SIHD (Prior MI) identifies a strong gradient of increasing risk for recurrent CV events and may be useful as a basis for therapeutic decision-making.
Abstract 17341: Comparing the Kansas City Cardiomyopathy Questionnaire and New York Heart Association in Assessing Functional Capacity and Outcomes
Authors: Hawwa Nael , Vest Amanda , Kumar Rahul , Young James , Wu Yuping , Gorodeski Eiran , Cho Leslie
Published: March 2022

Background:
The Kansas City Cardiomyopathy Questionnaire (KCCQ) has emerged as a patient-centered, heart failure-specific health status measure. This study examined the correlation between KCCQ and cardiopulmonary exercise testing (CPET) parameters and clinical outcomes, in comparison to the physician-derived New York Heart Association (NYHA) functional class.

Methods and Results:
We performed a single-centered, observational prospective analysis of 432 outpatients who presented to the Heart Failure Department, completed the KCCQ, and underwent CPET. Outcomes assessed included 30-day heart failure hospitalization and all-cause mortality. Among the KCCQ scores, the physical limitation domain had similar correlations as NYHA with peak oxygen consumption (r = 0.48 for both, p < 0.001) and ventilatory threshold (r = 0.42 versus r = 0.40, respectively, p < 0.001). The KCCQ overall score predicted 30-day hospitalization (OR 0.77, 95% CI 0.66 to 0.88, p < 0.001) and mortality (HR 0.91, 95% CI 0.88 to 0.95, p < 0.0001). NYHA could not differentially predict mortality between functional class II and III patients who comprised the majority of our cohort, although it did predict 30-day heart failure hospitalization in this group. Using model validation, NYHA was the best predictor of peak VO
2
(r
2
= 0.36), KCCQ total symptom score the best predictor of 30-day heart failure hospitalization (AUC = 0.724), and KCCQ physical limitation score the best predictor of mortality (AUC = 0.671).

Conclusions:
KCCQ and NYHA provide a reasonable assessment of functional capacity, the latter being more predictive. KCCQ is superior to NYHA in its ability to predict clinical outcomes. These findings support its routine use in clinical care, as well as its potential to serve as a measure in clinical trials.
Abstract 17358: Stenting of Atherosclerotic Renal Artery Stenosis Does Not Prevent Congestive Heart Failure, an Analysis of the Coral Trial
Authors: Ren Kaili , Xie Yanmei , Haller Steven , Yu Mark , He Wencan , Mei Jingning , Nguyen Hanh , Cooper Emily , Jamerson Kenneth , Murphy Timothy P , Cutlip Donald E , Dworkin Lance , Jaff Michael R , Steffes Michael , Shapiro Joseph I , Henrich William , Tian Jiang , Brewster Pamela , Cooper Christopher J
Published: March 2022

Introduction:
In current guidelines congestive heart failure (CHF) is an indication for renal artery stenting, however there is no data on the utility of stenting for the prevention of CHF. We sought to determine the effect of renal artery stenting in patients with atherosclerotic renal artery stenosis (ARAS) without a history of CHF.

Hypothesis:
In ARAS renal artery stenting does not prevent incident CHF in patients with no history of CHF.

Design and method:
The Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial is a prospective, international, multicenter clinical trial that randomized participants with ARAS, who received optimal medical therapy plus stenting versus no stenting. Optimal medical therapy included treating blood pressure and diabetes to goal, use of an angiotensin receptor-blocking drug, statin, and anti-platelet therapy. Glomerular filtration (eGFR) was estimated using the MDRD-GFR equation. Patients were followed for a median of 43 months (IQR, 31 to 55).

Results:
At enrollment, there were 795 out of 931 patients without a history of CHF, 395 were in the medical therapy group and 400 were in the medical therapy plus stenting group. In this group 117/795 had global renal ischemia. The rate of CHF admission (7% vs. 6%. p=0.74) and the pulmonary edema rate within those admitted for CHF were not different (82% vs. 64%, p=0.21). The rate of incident CHF was not different in patients with global renal ischemia and renal stenting did not prevent CHF events in this subgroup. Neither the composite event rate (35% vs. 34%, p=0.72), nor the rate of cardiovascular death (8% vs. 8%, p=0.96) differed between the two groups. At 3-year follow-up no differences were observed between medical therapy and medical therapy plus stenting for systolic blood pressure (SBP) (135±19 vs. 134±21 mmHg, p=0.74) or eGFR (56±22 vs. 55±23 ml/min, p=0.50).

Conclusions:
Renal artery stenting and optimal medical therapy, when compared to optimal medical therapy only, did not reduce the risk of CHF, or other cardio-renal events in patients that were enrolled without history of CHF in the CORAL trial.
Abstract 17378: Impact of Mitral Regurgitation on Left Ventricular Remodeling in Ischemic Cardiomyopathy
Authors: Shi Weiwei , Girish Apoorva , Bhushan Shashi , Padala Muralidhar
Published: March 2022

Introduction:
Mitral regurgitation (MR) developing secondary to a myocardial infarction(MI) is a clinical challenge, as its impact on adverse ventricular remodeling and dysfunction, and the role of mitral repair remains unknown. Using a novel rodent model, we sought to investigate the impact of MR on left ventricular remodeling and failure.

Hypothesis:
MR accelerates post-MI remodeling and impairs systolic function.

Methods:
Adult rats (~300g, N =49) were randomized to four groups: MR only(n=15); MR + MI (n=11); MI only(n=11); and sham(n=12). MR was induced by puncturing the mitral valve leaflet with a 23g needle inserted transapically into the beating heart with TEE guidance. MI was induced by permanent ligation of the left coronary artery. After 90-days of follow-up, TTE and invasive pressure-volume loops were obtained and the tissue collected. Data are presented as mean ± 1 standard deviation, and ANOVA was used for group comparison.

Results:
Ejection fraction significantly reduced from 56.6 ± 10.7% in sham to 42.5 ±18.4% in MR, 42.6 ± 15.4% in MR +MI, and 37.5 ± 19.3% in MI groups (p<0.05). ESV and EDV were significantly higher than sham in all the experimental groups, with MR+MI having the highest ventricular volumes. The slope of end systolic pressure-volume relationship (ESPVR) in MR, MI and MR+MI groups were 0.36± 0.19, 0.53±0.37, and 0.44±0.20 mmHg/μl, respectively, all of which were significantly reduced than sham(1.8 ±1.6 mmHg/μl), as shown in Figure 1. MI and MR+MI groups showed elevated left ventricular end-diastolic pressure (11.8± 3.3, 12.0 ±5.6 mmHg, respectively) compared to sham group (8.4 ±2.1mmHg). However, dP/dt min, Tau Weiss and Tau Glantz were unchanged.

Conclusions:
Systolic function is most compromised in MR+MI group compared to MR alone or MI alone at 90-days, whereas diastolic function was moderately impaired. This rat model provides a new platform to study the therapeutic impact of different drugs on ventricular function in this valve lesion.
Abstract 17381: Arousals of Sleep Disorders: The Value of Ambulatory Blood Pressure Monitoring
Authors: Porter Ivan , Haley William , Aslam Nabeel , Chimato Nicolette , Fredrickson Paul
Published: March 2022

Background:
Ambulatory blood pressure monitoring (ABPM) is important for the diagnosis of hypertension (HTN) as well as variants such as nocturnal HTN (NH), masked HTN and a non-dipping pattern. NH and non-dipping, a failure of the normal circadian drop in blood pressure during sleep, have been associated with all-cause mortality and cardiovascular risk. Obstructive sleep apnea is associated with HTN and a growing body of evidence suggests that limb movement disorders of sleep may also influence cardiovascular morbidity. The present study investigates arousals of sleep disorders, limb movement or respiratory, and their relationship to ABPM measurements.

Methods:
A retrospective review (January 1, 2010 to December 31, 2014) was performed on patients that underwent both ABPM and polysomnography within a six months of each other. Socio-demographic data, results of 24 hour ABPM and polysomnography, concurrent medication use by class, comorbid conditions and laboratory data were recorded. Patients with incomplete polysomnography or ABPM measurements were excluded.

Results:
330 individuals met criterion for inclusion; 59% male, 86% white. 211 (64%) were found to have NH, 106 (32%) had uncontrolled HTN and 202 (61%) had a non-dipping pattern. Patients with NH were more likely to have diabetes, hyperlipidemia and chronic kidney disease. Elevated arousal indices were more prevalent in those with NH, uncontrolled HTN and non-dippers. There was an association of NH with the total number of arousals per hour of sleep (p<0.01), whether related to respiratory disturbances or limb movements. Limb movement index (LMI) was related to age (p<0.0001) and was associated with all type arousals (p<0.0001).

Conclusions:
ABPM revealed a high prevalence of NH, non-dipping, masked and uncontrolled HTN in patients with sleep disorders. Arousals of all types, whether accompanying respiratory or limb movements, were associated with NH and also with LMI.
Abstract 17396: Effect of Donor Troponin on Heart Transplant Outcomes: A UNOS Registry Analysis
Authors: Madan Shivank A , Saeed Omar , Sims Daniel , Shin Jooyoung J , Pina Ileana , D'Alessandro David , Goldstein Daniel , Jorde Ulrich , Patel Snehal R
Published: March 2022

Introduction:
Heart transplantation is the treatment of choice for end stage heart failure, but is limited to approximately 4000 globally every year due to donor shortage. Despite this, only one-third of the potential donor hearts are recovered for transplantation. Although elevated donor troponin levels have generally been considered a contraindication, the data supporting this practice is limited.

Hypothesis:
Elevated donor troponins in the presence of normal left ventricular ejection fraction (LVEF) do not impact outcomes after transplantation.

Methods:
All adult heart transplant recipients in the UNOS database between 2007 and 2014, with LVEF≥50%, and reported donor troponin I levels were included. The overall cohort was divided into groups based on clinically meaningful troponin I levels: below 1, 1-10, 10.1-20 and above 20 and compared for recipient survival and coronary allograft vasculopathy (CAV).

Results:
11,640 transplants met the study criteria. On comparison of baseline characteristics, higher troponin groups had younger donors and greater donor CPR. Importantly, the ischemic time and proportion of recipients in the ICU and on temporary circulatory support were similar. As shown, there was no difference in survival (figure 1) or CAV (figure 2) up to 5 years of follow up using Kaplan-Meir analysis and cox-hazards ratio. After adjusting for differences in baseline covariates and clinically relevant factors, the findings remained unchanged.

Conclusions:
In this largest analysis to date, elevated donor troponin levels in the setting of preserved LVEF did not impact recipient survival or CAV up to 5 years of follow up. This finding can help expand the donor pool.
Abstract 17405: Phosphodiesterase-based Vasodilation Improves Oxygen Delivery and Clinical Outcomes Following Stage 1 Palliation
Authors: Mills Kimberly I , Walsh Brian K , Kaza Aditya K , Bond Hilary , Wypij David , DiNardo James A , Thiagarajan Ravi R , Kheir John N
Published: March 2022

Introduction:
The use of systemic vasodilators is known to decrease the incidence of postoperative cardiac arrest in infants with hypoplastic left heart syndrome (HLHS) following stage 1 palliation (S1P) with Blalock-Taussig shunt. Their impact on measured oxygen delivery (DO2) are uncharacterized.

Methods:
In 2013, we implemented a treatment algorithm at our institution to standardize care and lower systemic vascular resistance (SVR) in the postoperative period (A). We measured standard hemodynamic variables in consecutive neonates prior to (n=32) and following (n=24) its implementation. 92% of these infants received a Sano modification. We continuously measured oxygen consumption (E-COVX module™, GE Healthcare) and venous oxyhemoglobin saturation (SvO2, PediaSat, Edwards) for Fick-based calculation of DO2 and SVR in a subset (n=21) of patients. Variables were compared pre and post-implementation using linear mixed effects models.

Results:
Demographic, anatomic and echocardiographic risk factors were similar between groups, although aortic cross-clamp (ACC) time was significantly shorter following protocol implementation (120.9 vs 91.9 mins, P<0.001). When corrected for ACC time, serum lactate (p<0.001, B) and incidence of postoperative cardiac arrest (P=0.04, C) were lower (B), and SvO2 (P<0.001) was higher following protocol implementation. Systemic cardiac output (β[SE], 0.52 [0.32] L/min/m2; P=0.10) and systemic DO2 (β[SE], 86.7 [55.4] mL/min/m2; P=0.12, D) were higher post-implementation. DO2 was most closely correlated with SVR (r2=0.87), and commonly utilized surrogate variables such as arterial saturation (r2=0.01), SvO2 (r2=0.1), and arterial-venous saturation difference (r2=0.35) correlated poorly.

Conclusions:
The implementation of a phosphodiesterase-based treatment algorithm decreased SVR, lactate accumulation and the incidence of cardiac arrest in infants with HLHS following S1P with Sano modification.