bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4185: Low Testosterone Level is an Independent Determinant of Endothelial Dysfunction in Men
Authors: Akishita Masahiro , Hashimoto Masayoshi , Ohike Yumiko , Iijima Katsuya , Eto Masato , Ouchi Yasuyoshi
Published: April 2024

Background: Epidemiological studies have shown that relative hypogonadism is associated with the higher incidence of cardiovascular disease, the mechanism of which remains unknown. We investigated whether relative hypogonadism would be related to endothelial dysfunction in men.

Methods: Consecutive 188 men (mean age ± SD = 47±15 years), who examined flow-mediated vasodilation (FMD) of the brachial artery using ultrasonography, were enrolled. The subjects with cardiovascular disease, malignancy, overt endocrine disease or having steroid hormones were excluded. Plasma hormone levels were determined after 12-hour fast in the morning, and the relationship between hormone levels and FMD was analyzed.

Results: Total and free testosterone and dehydroepiandrosterone-sulfate (DHEA-S) were significantly correlated with %FMD (r=0.262, 0.355 and 0.296, respectively; p<0.001), while estradiol or cortisol was not. %FMD in the highest quartile of free testosterone was 1.7-fold higher than that in the lowest quartile (5.6±2.9 vs. 3.3±2.6 [mean±SD], p<0.05). Multiple regression analysis revealed that total and free testosterone were related to %FMD independent of age, body mass index, hypertension, hypercholesterolemia, diabetes mellitus and smoking (β=0.197 and 0.240, respectively; p<0.01), and independent of age, body mass index, systolic blood pressure, total cholesterol, HDL cholesterol, fasting plasma glucose, smoking and carotid intima-media thickness (β=0.211 and 0.259, respectively; p<0.01). DHEA-S was not significantly related to %FMD on multivariate analysis.

Conclusions: Low plasma testosterone level was associated with endothelial dysfunction in men independent of other risk factors, suggesting a protective effect of testosterone on the endothelium.
Abstract 4187: Glu27 β
2
-Adrenoceptor Polymorphism Enhances Body Weight Loss and 24h-Ambulatory Blood Pressure Reduction in Obese Women
Authors: Rondon Maria U , Rezk Claudio C , Trombetta Ivani C , Forjaz Claudia L , Gowdak Marcia M , Batalha Luciana T , Frazzatto Eliana , Halpern Alfredo , Villares Sandra M , Negrao Carlos E
Published: April 2024

Introduction:
Obesity has been linked to genetic and environmental determinants. Glu27 β
2
-adrenoceptor polymorphism has been associated with obesity and hypertension. In addition, muscle vasodilatation during physiological maneuvers is increased in individuals with Glu27 β
2
-adrenoceptor polymorphism. Not known is the impact of hypocaloric diet and exercise training on body weight and blood pressure (BP) in obese individuals with Glu27 β
2
-adrenoceptor polymorphism.

Methods:
From an initial sampling of 216 volunteers, we studied 42 middle-age normotensive obese women selected to represent two genotypes: 19 with Glu27 β
2
-adrenoceptor polymorphism and 23 wild type Gln27 (883± vs 86±2kg, P30.48, respectively). Hypocaloric diet consisted of a 600kcal/day reduction. Exercise training consisted of three 60-min exercise session/week during 4 months. Twenty-four hour ambulatory BP, cardiac output (CO, carbon dioxide rebreathing), and muscle sympathetic nerve activity (MSNA, microneurography) were evaluated pre and post interventions.

Results:
Hypocaloric diet and exercise training significantly decreased body weight, body mass index (BMI), 24-hour systolic BP, 24-hour pulse pressure, and CO in Glu27 and Gln27 groups. However, the comparisons between groups showed that the reduction in body weight (10.7±1 vs 7.4±1kg,
P
=0.02), BMI (4.1±0.4 vs 2.8±0.2kg/m
2
,
P
=0.01), 24-hour systolic BP (5.1±1 vs 2.2±1mmHg,
P
=0.05), 24-hour pulse pressure (3.6±1 vs 1.5±1mmHg,
P
=0.01), and CO (0.8±0.2 vs 0.4±0.1L/min,
P
=0.04) were significantly greater in Glu27 group than in Gln27group. No significant differences in diastolic BP, mean BP, and MSNA levels between groups were found.

Conclusions:
Obese women with Glu27 of the β
2
-adrenoceptor are more susceptible to body weight loss, and BP and CO reduction after hypocaloric diet and exercise training than wild type Gln27 obese women.
Abstract 4191: Abnormal Cardiac Energetics are Associated with Diastolic Dysfunction in Uncomplicated Obesity
Authors: Robinson Monique , Scheuermann-Freestone Michaela , Blamire Andrew , Styles Peter , Manners David , Watson Gillian C , Clarke Kieran , Neubauer Stefan
Published: April 2024

Background: Abnormal cardiac high energy phosphate metabolism may lead to contractile dysfunction in heart failure. As the incidence of heart failure is increased in obesity, we have determined whether cardiac energy metabolism is abnormal in healthy, obese subjects.

Methods and Results: Cardiac phosphocreatine (PCr) to ATP ratios and function were measured using magnetic resonance spectroscopy and imaging, respectively, in 20 asymptomatic obese adults and 19 age- and sex-matched controls. Fasting plasma leptin, glucose, insulin, C-reactive protein, lipid and free fatty acid (FFA) concentrations were also measured. With a mean body mass index (BMI) of 31 kg/m2, the obese subjects had 16% lower cardiac PCr/ATP ratios and 54% higher fasting plasma FFA concentrations than the control subjects, who had a mean BMI of 24 kg/m2. Multivariate stepwise linear regression analysis demonstrated that plasma FFA concentrations (β −0.5, P = 0.001) and BMI (β −0.3, P = 0.03) were significant independent predictors of the cardiac PCr/ATP ratio (model adjusted R2 = 0.46). The peak filling rate, a measure of diastolic dysfunction, correlated with the cardiac PCr/ATP ratio (r = 0.42, P = 0.013).

Conclusions: Uncomplicated obesity is associated with decreased cardiac PCr/ATP ratios, diastolic dysfunction and increased plasma FFA concentrations, raising the possibility that abnormal cardiac high energy phosphate metabolism may contribute to the increased incidence of heart failure in obesity.
Abstract 4192: Tissue ACE Inhibitors for Secondary Prevention of Adverse Cardiovascular Events in Patients with Preserved Left Ventricular Function: A Pooled Meta-Analysis
Authors: Saha Sandeep A , Molnar Janos , Arora Rohit R
Published: April 2024

Introduction:
Although the role of angiotensin converting enzyme (ACE) inhibitors in patients with depressed left ventricular function is well established, their role in patients with preserved ventricular function is uncertain. We conducted a meta-analysis of recent clinical trials to evaluate the role of tissue ACE inhibitors in secondary prevention of cardiovascular disease in patients with preserved left ventricular function.

Study Selection:
Randomized placebo-controlled clinical trials of at least 12 months duration, conducted in patients who had experienced an acute cardiovascular event or were at high risk for cardiovascular events.

Data Synthesis and Analysis:
A total of 31,555 patients from 4 selected trials were analyzed. Relative risk estimations were made using pooled data from the 4 trials. Statistical significance was determined using the Chi-square test (two-sided alpha error <0.05).

Results:
When compared to placebo, the use of tissue ACE inhibitors was associated with significant relative risk reductions in all-cause mortality (p<0.001), cardiovascular mortality (p<0.001), fatal & non-fatal myocardial infarction (p<0.001) and stroke (p<0.001), as well as hospitalization for congestive heart failure (p=0.001) & occurrence of new-onset diabetes mellitus (p<0.001). The need for invasive coronary revascularization was also reduced (p<0.03), but the risk of hospitalization for angina was not significantly affected.

Conclusion:
Tissue ACE inhibitors decrease mortality and cardiovascular morbidity in high risk patients with cardiovascular disease and preserved left ventricular function in randomized placebo-controlled clinical trials.
Abstract 4193: A Randomized, Double-blind, Double-dummy, Comparison of Efficacy and Tolerability of Fluvastatin XL alone, Ezetimibe alone and the Combination, in Patients with a History of Muscle Related Side Effects with other Statins
Authors: Stein Evan A , Ballantyne Christie M , Gimplewicz Claudio , Seper Claudia , Ghani Sajda
Published: April 2024

Reduction of LDLC is the core of cardiovascular disease (CVD) prevention. Trials showing the lower the LDLC the lower the CVD risk have led to revision of the NCEP guidelines for high risk patients. Statins, the most effective class for achieving LDLC reduction, are generally well tolerated and serious side effects are rare. However in clinical practice muscle related side effects (MRSE), such as pain, cramps and weakness are more common than reported in clinical trials. A recent observational study of nearly 8,000 patients in primary care practice reported 10.5% MRSE with statins. MRSE were the major reason for discontinuation. Inability to use statins leaves physicians and patients minimal ability to achieve LDLC goals at any risk level. Fluvastatin XL (FXL) has a number of unique pharmacological features that suggest it would have a lower propensity for MRSE. The present trial, is the first randomized, double dummy, controlled trial done in patients with statin associated MRSE, to test the hypothesis that in such patients FXL 80 mg would be as well tolerated as a non-statin lipid lowering agent. Ezetimibe (EZE) 10 mg, a cholesterol absorption inhibitor, was selected as a widely used, effective well tolerated agent. The study randomized 199 mostly high-risk subjects with a history of statin related MRSE in 27 centers. After 4 week diet only lead-in patients were randomized to 12 week treatment with FXL + placebo (Pbo) EZE; EZE + Pbo FLX or FLX + EZE. Results are shown below: The present study demonstrates that patients with statins related MRSE tolerate FXL, either alone or as combination therapy with EZE, with MSRE side effects no different from that of EZE alone. Few patients at high risk for CVD reach LDLC goal with EZE alone, one third do with FLX and nearly 4 of 5 do so with FLX + EZE. With 1–2 million patients estimated to have discontinued statins due to MRSE, fluvastatin XL offers a readily available and effective alternative therapy.

Results
Abstract 4196: Effect of 3-Hydroxy-3-Methylglutaryl-CoA Reductase Inhibitors (Statins) on Renal Function
Authors: Sukhija Rishi , Bursac Zoran , Mohandas Bhavna , Sachdeva Rajesh , Garza Luis , Aude Y W , Sinha Anjan K , Mehta Jawahar L
Published: April 2024

Background: 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) reduce serum cholesterol, and cardiovascular morbidity and mortality. The role of lipids in the progression of kidney disease and the potential beneficial effects of statins on renal function is unknown. Oxidative stress and inflammation may be the missing link between CAD and chronic kidney disease. Statins may protect the kidney through both lipid lowering properties and pleiotropic effects.

Methods: We analyzed data in 197, 551 patients (mean age 64.8±13.6 years, 95% males, 29.5% (58,332) statin users, and 70.5% (139, 219) non-statin users), who had baseline creatinine less than 3.5 mg/dl, from the cross-sectional data mined from the Veterans Affairs VISN 16 database. Deterioration of renal function was defined as doubling of the baseline or increase in creatinine of 0.5 mg/dl over at least 90 days.

Results: Based on this definition, 3.4% of patients developed renal deterioration over 5 year of follow-up. After adjustment for demographics, diabetes mellitus, smoking, and other medications (especially use of angiotensin-converting enzyme inhibitors, calcium channel blockers and aspirin, all of which were confounders of the statin-renal deterioration relationship), use of statins reduced the odds of deterioration in renal function by 15% (OR 0.85, 95% CI=0.80 – 0.89, p<0.0001). This effect was independent of cholesterol lowering effect of statins. Impact of other variables was as follows: age (OR=1.04, CI=1.03–1.04, p<0.0001), diabetes (OR=1.76, CI=1.67–1.85, p<0.0001), and smoking (OR=1.76, CI=1.05–1.23, p=0.0014).

Conclusion: Statin use may retard the progression of renal disease. Although the precise mechanism is not known, lowering of LDL-cholesterol and improvement in endothelial function by statins may relate to reno-protective effect.
Abstract 4197: Statins and ACE-Inhibitors Prevent Renal Deterioration in Patients with Peripheral Arterial Disease
Authors: Feringa Harm H , Welten Gijs , Hoeks Sanne , Dunkelgrun Martin , Azizi Fahim , van Gestel Yvette , Vidakovic Radosav , Schouten Olaf , van Domburg Ron , de Liefde Inge , Karagiannis Stefanos , Poldermans Don
Published: April 2024

Background:
Renal dysfunction is an underestimated risk factor in patients with peripheral atherosclerotic disease.

Aim:
To assess the prevalence and prognosis of decreased estimated glomerular filtration rate (eGFR) in patients with peripheral atherosclerotic disease and to evaluate whether statins and angiotensin-convering enzyme (ACE-) inhibitors are associated with reduced renal deterioration and reduced cardiovascular event rate.

Methods
: In a prospective observational cohort study of 1939 consecutive patients with peripheral arterial disease, clinical characteristics, cardiac medication and serial creatinine concentrations were obtained. During follow-up, renal deterioration (>25% decrease in eGFR) was determined and hard cardiac events (cardiac death or non-fatal myocardial infarction) were noted.

Results:
No, mild, moderate and severe renal dysfunction (eGFR of >75, 60.0–74.9, 45.0–59.9, and <45.0 ml/min per 1.73 m
2
, respectively), was assessed in 55%, 19%, 14% and 12% of patients. Renal deterioration occurred in 9%, 8%, 13%, and 20% of patients, respectively. Hard cardiac events during a mean follow-up of 6.4 years occurred in 20%, 27%, 30%, and 32% of patients, respectively. Statins and ACE-inhibitors were significantly associated with reduced renal deterioration (HR: 0.62, 95% CI: 0.49– 0.79, and HR: 0.55, 95% CI: 0.44– 0.70, respectively). In multivariate Cox proportional hazard regression analysis, lower baseline eGFR (per 10 mg/min/1.73 m
2
) and higher decreases in eGFR (per 10%) were significantly associated with a higher hazard of hard cardiac events (HR: 1.16, 95% CI: 1.12–1.21 and HR: 1.07, 95% CI: 1.02–1.11, respectively). In patients with mild, moderate or severe renal dysfunction, statins and ACE-inhibitors were both associated with a reduction in hard cardiac event rate (HR: 0.60, 95% CI: 0.38–0.87 and HR: 0.65 (0.46–0.92), respectively), after adjusment for possible confounding risk factors and propensity scores.

Conclusion:
Abnormal eGFR and deterioration in eGFR are frequently observed in PAD and carry an adverse prognosis. Statins and ACE-inhibitors are associated with a reduction in renal deterioration and both drugs improve cardiovascular outcome in PAD patients with renal dysfunction.
Abstract 4199: Influenza Vaccination in Prevention from Coronary Events in Coronary Artery Disease. FLUCAD Study.
Authors: Ciszewski Andrzej , Bilinska Zofia T , Brydak Lidia B , Machala Magdalena , Piotrowski Walerian , Ksiezycka Ewa , Maczynska Renata , Ruzyllo Witold
Published: April 2024

Background: Influenza vaccination is recommended in patients (p) with cardiovascular disease, however there is few data proving its protective effect on clinical course of coronary artery disease (CAD). We present, to the best of our knowledge, first, randomized, double blind, placebo controlled study in this field. The aim of the study was to evaluate the effect of influenza vaccination on the incidence of coronary events in p with CAD confirmed by coronarography.

Methods: Single center, randomized, prospective, double blind, placebo controlled study. The randomization was 1:1 (placebo : active vaccine). Cox proportional hazards model analysis was performed. Study group: Between October 2004 and February 2005, we included and vaccinated 658 CAD p; 477 men, mean age 59.9+/−10.3 years. There were 287 p enrolled before discharge from the hospital after percutaneous coronary intervention (PCI), and 371 p without recent PCI.

Results: 325 p received the active vaccine, and 333 p received placebo. There were no significant differences between the study groups. No patient was lost to follow-up. Mean follow-up was 296.8+/−35.7 days. Primary end-point: cardiovascular death occurred in 2 p (0.61%) in the vaccine vs in 2 p (0.60%) in the placebo group (NS). First composite end-point: cardiovascular death, or myocardial infarction, or non-planned coronary revascularization (PCI or coronary bypass surgery) tended to occur less frequently in the vaccine group in comparison to the placebo group: 9 p (2.8%) vs 17 p (5.1%), respectively, (HR 0.54; 95% CI, 0.24 to 1.21; p= 0.13). Second composite end-point: cardiovascular death, or myocardial infarction, or non-planned revascularization or hospitalization for ischemia occurred significantly less frequently in the vaccine group: 16 p (4.9%) vs 30 p (9.0%) in the placebo group, (HR 0.54; 95% CI, 0.29 to 0.991; p=0.047). On multivariate analysis : primary PCI (HR 2.93; 95% CI 1.51 − 5.65, p=0.0014), influenza vaccination (HR 0.38; 95% CI 0.19 − 0.78, p=0.009), and female sex (HR 2.15; 95% CI 1.11 − 4.15, p=0.023), emerged as independent predictors of the occurrence of composite point 2.

Conclusion: Influenza vaccination may reduce frequency of coronary events in patients with coronary artery disease.
Abstract 4203: Resting Heart Rate and its Changes Over Years as a Risk Factor for Mortality in the General Population: The Paris Prospective Study I
Authors: Jouven Xavier P , Empana Jean Philippe , Buyck Jean François , Poitrine Florence Canoui , Kane Awa , Mouries Christine , Courbon Dominique , Ducimetiere Pierre
Published: April 2024

Background: Whether resting heart rate (HR) is a risk factor for mortality remains discussed. The aim of the study was to investigate whether HR changes are related to mortality in the population.

Methods: 4320 native Frenchmen aged 42 to 53 years were recruited between 1967 and 1972, and had yearly examinations during the next 5 years in the same standardized conditions. Subjects had electrocardiograms and physical examinations conducted by a physician, provided blood samples for laboratory tests, and answered questionnaires administered by trained interviewers. Resting HR was determined by measurement of the radial pulse during a one-minute recording, after a five-minute rest in supine position.

Results: During the follow-up period (> 20 years) 1018 men died. Subjects were divided into 9 groups according to their baseline HR (≤ 60 bpm , 61–75, and > 75 bpm) and to HR variation between baseline and the 5
th
examination (decrease > 7 bpm, low variation ie between − 7 and +7 bpm, and increase > 7 bpm). Relative risks of mortality were estimated by Cox model after adjustments for age, physical activity, tobacco consumption, body mass index, systolic blood pressure, glycemia, and total cholesterol. Compared to the reference group (baseline HR between 61 and 75 bpm and low variation at the 5
th
examination), baseline HR but also changes over years were both associated with the risk of death (table

).

Conclusion: Our results show that resting HR and its changes are independent risk factors of mortality in the general population.

mortality associated with resting heart rate and its trend
Abstract 571: Triggered Delayed Afterdepolarizations induce Multifocal and Bidirectional Ventricular Tachycardia in a Model of Andersen-Tawil (Long QT 7) syndrome
Authors: Morita Hiroshi , Zipes Douglas P , Morita Shiho T , Lopshire John , Wu Jiashin
Published: April 2024

(
Introduction
) Andersen syndrome (AS) is a rare channelopathy induced by the mutation of KCNJ2, which encodes the inward rectifier potassium current (IK1) Kir2.1. ECG shows prolonged QT interval, large U waves and frequent multifocal ventricular tachycardia (VT), which is often bidirectional VT. Torsades de pointes (tdp) is rare. We investigated the mechanism of VT in AS using cesium chloride (Cs), an IK1 blocker, in canine ventricular tissues.

(
Method and Results
) Using an optical mapping system, we mapped action potentials (APs) at 256 sites on the cut-exposed transmural surfaces of 16 canine left ventricular preparations. Tissues were perfused by Tyrode solution having normal potassium (K = 4.7 mEq, n = 7) or low K concentration (K = 2.5 mEq, n = 9). Pacing (cycle length, CL = 4000 - 400 ms) was performed in control, Cs (5–10 mM) and Cs with isoproterenol (Cs+ISP, 0.15 uM) preparations. Cs prolonged the QT interval and AP duration (APD) at both K concentrations, but more so in low K Tyrode (normal K: endocardial APD control 254 ± 17, Cs 385 ± 16 ms, p<0.01; low K: endocardial APD control 293 ± 19, Cs 459 ± 22 ms, p<0.01). Midmyocardial APDs did not show excessive APD prolongation (i.e., no M cell behavior). Rapid pacing (CL 1000 - 400 ms) induced delayed afterdepolarizations (DAD) at both K concentrations with Cs (occurrence of DAD: low K 100%, Normal K 11%) and ISP increased DAD prevalence in normal K (Normal K 67%). DADs often appeared in mid wall and endocardium sites and resulted in large U waves in 11 tissues. Repetitive triggered activity from DADs induced multifocal VT at both K concentrations with Cs+ISP (VT occurrence: low K 100%, normal K 56%). Migration of DAD-VT foci within transmural tissues from mid to endocardium resulted multifocal VT. Alternating discharge of 2 DAD foci resulted in bidirectional VT in 4 tissues with low K. VT was sustained and had multiple foci in low K Tyrode compared to normal K Tyrode (VT duration: low K 10.9 ± 7.2, normal K 1.3 ± 1.5 min, p<0.01; number of foci: low K 5.2 ± 2.0, normal K 1.9 ± 1.5, p<0.01). Early afterdepolarizations and tdp did not occur in this model. Verapamil abolished DADs in all tissues.

(
Conclusion
) IK1 blockade mimicking AS induced long QT and manifest U waves. Migration of multiple DAD-VT foci induced multifocal and bidirectional VT.
Abstract 575: Both Phosphorylation and Dephosphorylation of Ryanodine Receptor Enhance Sarcoplasmic Reticulum Calcium Leak in Canine Ventricular Myocytes
Authors: Terentyev Dmitry , Terentyeva Radmila , Gyorke Sandor
Published: April 2024

In recent years, there has been an increase of emphasis on the possibility that alterations in phosphorylation of the cardiac ryanodine receptor (RyR2) may contribute to the defective intracellular Ca release in heart failure (HF). However, the specific mechanisms proposed by different laboratories remain controversial. We studied the effects of exogenous and endogenous kinases and phosphatases on sarcoplasmic reticulum (SR) Ca release by measuring [Ca] changes in the cytosolic and SR luminal ([Ca]SR) compartments, using the Ca indicators rhod-2 and fluo-5N, respectively, in permeabilized canine ventricular myocytes. Application of PP1 (10 u/ml) led to an acute increase in the frequency of spontaneous Ca release events (Ca sparks) followed by a decline in intra-SR [Ca] consistent with the possibility that activation of RyR2s contributes to unloading of the SR by releasing Ca. Indeed, PP1 caused a marked acceleration of the RyR2-mediated SR Ca leak directly measured as time-dependent decline of [Ca]SR in the presence of the inhibitor of the SR CaATPase (SERCA2), thapsigargin. Application of cAMP (20 uM) and PKA (10 u/ml) resulted in a significant increase in Ca spark frequency that was paralleled by an increase in [Ca]SR. Direct measurements of the RyR2-mediated leak in the presence of thapsigargin revealed a small but significant acceleration in the leak following cAMP or PKA application, implying that the potentiation of sparks in the absence of thapsigargin may involve direct effects upon RyR2s in addition to effects mediated by SERCA2-dependent increase in [Ca]SR. As determined by a phosphospecific antibody, RyR2 phosphorylation on Ser-2809 was increased by cAMP and reduced by PP1. Collectively, these results suggest that under baseline phosphorylation conditions, both phosphorylation and dephosphorylation stimulate RyR2 activity resulting in an increased SR Ca leak. Considering the multimeric nature of the RyR2 and the presence of multiple sets of phophorylation sites, these results can be rationalized by suggesting that the effects of kinases and phosphotases on RyR2 function are mediated by different degrees of RyR2 phosphorylation at a certain set of sites (e.g. Ser-2809) or by phosphorylation/dephosphorylation of different sets of sites.
Abstract 577: S100A1 Decreases Calcium Spark Frequency and Alters their Spatial Characteristics in Ventricular Cardiomyocytes
Authors: Völkers Mirko , Loughrey Christopher M , MacQuaide Nial , de George Brent , Koch Walter J , Smith Godfrey L , Most Patrick
Published: April 2024

Background:
S100A1, a Ca
2+
-sensor protein of the EF-hand type, exerts positive inotropic effects in the heart via enhanced cardiac ryanodine receptor (RyR2) activity. Although we have shown that S100A1 enhances excitation-contraction coupling gain in cardiomyocytes, the effect of S100A1 on diastolic RyR2 activity and SR Ca
2+
-leak has not been investigated yet.

Methods and Results
: Confocal imaging and coimmunoprecipitation studies show that S100A1 protein (0.1μM) interacts with the RyR2 in resting permeabilized cardiomyocytes at free Ca
2+
-levels comparable to diastolic Ca
2+
-concentrations (~150nM). Preincubation with the S100A1 C-terminus (S100A1-ct, aa 75–94, 10μM) inhibited both S100A1 protein colocalization and coimmunoprecipitation with the RyR2. Alterations of RyR2 function due to S100A1 binding was assessed via analysis of Ca
2+
-spark characteristics. Ca
2+
-spark frequency, amplitude and duration were all significantly reduced upon perfusion with 0.1μM S100A1 protein (n=350 sparks, n=12 myocytes) by 38%, 14% and 18%, respectively, compared to control (n=336 sparks, n=10 myocytes, p<0.05). Most likely, these effects were conveyed through the S100A1 C-terminus (S100A1-ct; amino acids 75–94) as the corresponding S100A1-ct peptide (0.1μM, n=374 sparks, n=12 myocytes) that inhibited S100A1 protein binding to the RyR2 similarly attenuated frequency, amplitude and duration of Ca
2+
-sparks by 52%, 8% and 26%, respectively, compared to control (n=368 sparks, n=10 myocytes, p<0.05). Accordingly, S100A1 (n=15) significantly increased sarcoplasmic reticulum Ca
2+
-content (+15%, p<0.05) but did not alter the stoichiometry of other accessory RyR2 modulators such as sorcin or FKBP12.6 as assessed by Western blotting.

Conclusion:
Hence, we propose S100A1 as a novel inhibitory modulator of RyR2 function at diastolic Ca
2+
-concentrations in cardiomyocytes that might contribute to prevention of diastolic SR calcium leak through inhibition of RyR2 activity at rest but enhances the calcium-activated state of the channel in systole.
Abstract 586: Hydroxycholesterol or Cyclic AMP Upregulates the Expression of Renin in Human Mesenchymal Stem Cells
Authors: Matsushita Kenichi , Morello Fulvio , Pratt Richard E , Dzau Victor J
Published: April 2024

Renin is a key enzyme in the renin-angiotensin system which plays a vital role in the regulation of cardiovascular homeostasis. Metanephric mesenchymal cells are assumed to be the origin of vascular smooth muscle cells and of renin precursor cells. It is also suggested that renin precursor cells are metaplastically modified smooth muscle cells and/or precursor of smooth muscle cells during ontogeny. However, there is no direct evidence that mesenchymal stem cells (MSCs) can be induced to become renin expressing cells. Previously we have reported that the nuclear hormone receptor liver X receptor (LXR) is a major transcriptional regulator of renin gene expression. In this study we examined the effect of LXR agonists on renin gene expression in human mesenchymal stem cells.

Methods: Human mesencymal stem cells were subjected to serum starvation for 16 hours. We then added the LXR natural ligand 22-hydroxycholesterol (10
-7
M) and investigated mRNA expression of renin and ATP-binding cassette transporter A1 (ABCA1) which is well known upregulated by LXR activation after 6 hours of pharmacological treatment by using real-time RT-PCR. We further examined the renin and ABCA1 mRNA expression by adding cyclic AMP (10
-3
M).

Results: Human MSCs treated with 22-hydroxycholesterol exhibited an increase in expression of renin (1.7 ± 0.3 fold change for MSCs without treatment, P < 0.05). There was an increase in ABCA1 expression (1.6 ± 0.1 fold change, P < 0.05), suggesting that 22-hydroxycholesterol effectively acted as a LXR ligand. Furthermore, cyclic AMP showed also upregulated renin and ABCA1 mRNA expression (2.2 ± 0.3 and 1.9 ± 0.1 fold changes for MSCs without treatment, respectively, P < 0.05).

Conclusion: Our results suggest that the activation of liver X receptor upregulates renin mRNA expression in human mesenchymal stem cells and suggest that these cells may be the origin of renin cells during embryonic development. Our observations provide insight into possible novel understanding of the renin-angiotensin system (RAS) and RAS related cardiovascular disease.
Abstract 596: Cardiac Autophagy is a Maladaptive Response to Hemodynamic Stress
Authors: Zhu Hongxin , Tannous Paul , Johnstone Janet L , Kong Yongli , Shelton John M , Richardson James A , Levine Beth , Rothermel Beverly A , Hill Joseph A , Reynolds Donald W
Published: April 2024

Background:
Autophagy is a highly conserved mechanism of protein and organelle degradation linked to several neurodegenerative diseases. Nothing is known about the possible role of autophagy in heart failure.

Methods and Results:
Short-term nutrient deprivation, an established trigger of autophagy, induced dramatic increases in the ratio of LC3-II:LC3-I in ventricular lysates, indicative of increased autophagic activity. To determine the specific contribution of cardiomyocyte autophagy, we generated αMHC-GFP-LC3 transgenic mice. Short-term starvation induced a robust increase in the punctate localization of GFP-LC3 in myocytes, demonstrating cardiomyocyte autophagy and confirming the validity of our “autophagy reporter” mice. To test for autophagy in failing heart, we induced pressure overload by severe constriction of the thoracic aorta (sTAB). Fluorescence microscopy demonstrated autophagosome-localized GFP-LC3 in left ventricular myocytes 24h after banding which peaked at 48h and subsequently declined (though remaining elevated relative to control, p<0.05). EM revealed double-membrane autophagosomes in cardiomyocytes in failing heart. Lysosome activity was increased in failing LV as demonstrated by immunostaining for cathepsin D and LAMP-1, suggesting that diminished activity of distal lysosomal pathways was not responsible for autophagosome accumulation. To explore whether cardiomyocyte autophagy is beneficial or maladaptive, we studied mice with targeted disruption of
beclin 1
, a gene required for autophagosome formation. Heterozygous disruption of
beclin 1
led to decreased autophagy in pressure-stressed cardiomyocytes. Heart failure-associated declines in LV systolic function were significantly attenuated in
beclin 1
mutants.
Beclin 1
over-expressing transgenic mice manifested an amplified pathological response to sTAB. Compared with WT,
beclin 1
transgenic mice subjected to standard TAB manifested increased autophagic activity, impaired systolic performance, increased load-induced fibrosis, but similar levels of apoptosis.

Conclusions:
These findings implicate autophagy in the pathogenesis of load-induced heart failure and suggest it may be a target for novel therapeutic intervention.
Abstract 597: Targeted Deletion of Thioredoxin-Interacting Protein Prevents Cardiac Dysfunction in Response to Pressure Overload
Authors: Yoshioka Jun , Imahashi Kenichi , Chutkow William A , Burds Aurora A , Gannon Joseph , MacGillivray Catherine , Schulze P. C , Murphy Elizabeth , Lee Richard T
Published: April 2024

Biomechanical overload induces left ventricular (LV) hypertrophy and failure, and reactive oxygen species (ROS) play a role in both processes. We previously identified Thioredoxin-Interacting Protein (Txnip) as a mechanically regulated gene that controls cell growth and apoptosis in part through the inhibition of the endogenous dithiol antioxidant thioredoxin. Here we show in mice that Txnip is a critical regulator of the cardiac response to pressure overload, potentially through regulation of myocardium glucose utilization. We generated cardiac-specific and systemic Txnip null mice (Txnip-KO) using Flp/frt and Cre/lox technology. Epitope-mapped monoclonal antibodies demonstrated complete absence of Txnip protein in targeted tissues. Compared with wild-type littermates (WT), Txnip-KO hearts had reduced LV mass (Δ%LV mass/ tibial length from baseline to TAC −50±20%, n=14), myocyte cross-sectional area (−16±6%, n=11, P<0.05), and percent fibrosis area (−54±19%, n=11, P< 0.05) in response to pressure overload by transverse aortic constriction. Echocardiography and catheterization revealed that Txnip-KO hearts had preserved fractional shortening (Δ%FS +41±18% from baseline to TAC, n=17, P<0.05), stroke volume (+43±20%, n=4, P<0.05), and LV developed pressure (dP/dt max: +19±10%; dP/dt min: +64±22%, n=6, P<0.05) after TAC compared with wild-type littermates. Surprisingly, the beneficial effects of Txnip deletion on cardiac performance were not associated with increased myocardial thioredoxin activity or reduced levels of ROS. Since the systemic Txnip-KO mice were hypoglycemic, we measured myocardial 2-deoxyglucose uptake (2-DG) using
31
P NMR spectroscopy. Txnip-KO hearts showed a robust increase in 2-DG uptake in an insulin-independent manner (3.2±0.5-fold over WT, n=6, P<0.01). LV developed pressure was preserved during 2-DG uptake in Txnip-KO hearts (2.3±0.3-fold over WT; n=6, P<0.01). These data demonstrate that deletion of Txnip prevents cardiac dysfunction in response to pressure overload in vivo, but the benefits of Txnip deletion may be due to an unanticipated role in myocardial glucose metabolism rather than inhibition of thioredoxin activity.
Abstract 599: RV Protection Conferred by Chronic Effects of Percutaneous Transluminal Septal Myocardial Ablation During High Level LV Unloading in Sheep
Authors: Mau James , Menzie Stuart , Ward Michael , Hunyor Stephen N
Published: April 2024

Background:
Severe RV failure is common (~25%) following acute LVAD unloading. The role of IVS dysfunction in this response remains uncertain, so we studied chronic ventricular interactions with incremental LV unloading following IVS damage.

Methods:
Percutaneous transluminal septal myocardial ablation (PTSMA) with ethanol caused irreversible IVS damage in 6 sheep. Main septal artery catheterization was performed in 6 other sham animals, and both groups underwent hemodynamic assessment 4w later. RV volume was derived from a 3-axis ellipsoidal subtraction model using sonomicrometer dimensions. RV- ejection fraction (EF), pressure recruitable stroke work (PRSW), end-systolic elastance (Ees), 1
st
derivative of maximum RV pressure (dP/dt), and Tau were derived from P/V loops during IVC occlusion and LV unloading (25/50/75/100%) using a Bio-Medicus pump. Flow-probes measured % steady-state pulmonary, aortic, and mechanical bypass flow.

Results:
Response to varying LV assist levels is shown in the Figure

(
*
=P<0.05). RV- EF, PRSW and Ees decreased in shams, but remained stable in PTSMA during high level LV unloading. DP/dt decreased in shams at 75% LV unloading and trended down at 100%. In contrast, high baseline Tau after PTSMA normalized with moderate ≥50% LV assist.

Conclusions:
Institution of LV unloading in a chronic IVS damaged but otherwise healthy heart protects against compromised RV function, whereas sham animals respond adversely. Chronic IVS fibrosis may confer protection by limiting changes in RV chamber geometry.
Abstract 602: Repetitive Coronary Stenosis Induces a Third Window of Ischemic Preconditioning
Authors: Shen You-Tang , Yan Lin , Depre Christophe , Kudej Raymond K , Xi ZhouZhou , Zhang Yan , Vatner Dorothy E , Vatner Stephen F
Published: April 2024

The mechanisms responsible for the 1
st
and 2
nd
window of protection following ischemic preconditioning (IPC) have been studied in detail. We tested the hypothesis that chronic myocardial ischemia (repetitive bouts of coronary stenosis, CS) may induce IPC mediated by different mechanisms. To study this, 6 episodes of 90 min chronic CS (reduction in coronary blood flow, >35% from baseline), followed by reperfusion every 12 hrs were examined in conscious pigs chronically instrumented to measure left ventricular (LV) pressure and regional wall thickness. Infarct size/area at risk (IF/AAR) was assessed in all groups after 60 min of coronary artery occlusion (CAO) followed by 4 days of reperfusion. This resulted in IF/AAR of 42±5% in control pigs without IPC (n=5). Following repetitive CS, IF/AAR was markedly decreased (p<0.05) (4±6%, n=4). The 2
nd
window of IPC was induced in 5 pigs by two 10 min periods of CAO. 24 hrs later, the 60 min of CAO also resulted in reduced IF/AAR of 16±4%. In 6 pigs, 24 hrs after IPC without 60 min of CAO, the IPC myocardium was found to have significant, p<0.05, 2– 4-fold increases in iNOS, Cox-2, phosphorylated PKC and AMPK. None of these proteins was elevated in myocardium subjected to repetitive CS. Pretreatment with an NO synthase inhibitor, L-NNA, prevented the 2
nd
window of IPC as expected, since iNOS was elevated, but failed to prevent the ischemic protection following repetitive CS, where iNOS was not elevated. Following repetitive CS, genomic microarray analysis revealed upregulation of cytoprotective genes, e.g., IAP, H11 kinase, αB-crystallin, Akt 1, Bcl-2. These cytoprotective genes were also found to be upregulated in samples from patients with chronic coronary artery disease and hibernating myocardium. Thus, repetitive CS induces powerful protection against lethal myocardial ischemia, with mechanisms radically different from that observed in the 2
nd
window of IPC, suggesting a novel “third window” of IPC, which could also be involved in the protection inherent to hibernating myocardium.
Abstract 607: Degradation of Metabolic Post-translational Modification Sensitizes Cardiac Myocytes to Hypoxia
Authors: Ngoh Gladys A , Watson Lewis J , Harrison Linda T , Jones Steven P
Published: April 2024

We have recently discovered an endogenous mechanism of cytoprotection in the heart that involves the post-translational modification of proteins with a metabolic signal. Although this stress-responsive modification (beta-O linkage of N-acetylglucosamine, i.e. O-GlcNAc) exerts profound salubrious effects on the myocardium in vivo, the details regarding the pathobiology of this modification in the cardiac myocyte remain unexplored. We hypothesized that O-GlcNAc levels decrease following hypoxia and that manipulation of these levels would affect cardiac myocyte survival. We subjected isolated cardiac myocyte cultures (n >/= 4/ all groups) to hypoxia (3 hours) and reoxygenation (up to 1 hour). We measured O-GlcNAc levels and determined that they begin decreasing within 15 minutes, and continue to decrease through one hour, of reoxygenation in cardiac myocytes. Such a significant decrement (p < 0.05 vs. baseline) in O-GlcNAc levels was associated with a reduction in mitochondrial membrane potential (according to TMRM via fluorescence microscopy) and release of LDH (via spectrophotometric assay) into the media. To further investigate the regulation of O-GlcNAc levels following hypoxia, we targeted the enzymes controlling the presence of O-GlcNAc on proteins. Blocking the addition of O-GlcNAc (with TT04) profoundly sensitized myocytes to cell death while blocking the removal of O-GlcNAc (with PUGNAc) preserved myocyte survival (according to TMRM microscopy and LDH assay). We conclude that augmentation of O-GlcNAc levels attenuates, while diminution of O-GlcNAc levels exacerbates post-hypoxic injury in cardiac myocytes.
2006 Distinguished Scientist Lecture—Insights Provided by Framingham Population Research
Authors: Kannel William B.
Published: April 2024

The Framingham Study established the utility of population-based research for seeking out correctable predisposing conditions for cardiovascular disease (CVD), putting prevention at the forefront of cardiology. It established the risk factor concept of CVD evolution, recognizing that there is no single cause that is essential or sufficient by itself for CVD occurrence. It demonstrated the importance of distinguishing between usual (average) and optimal risk factor levels. It corrected clinical misconceptions about vascular disease, including: the hazard of atrial fibrillation; the relevance of diabetes as a macrovascular threat; the significance of left ventricular hypertrophy and small amounts of proteinuria; and the role of obesity, weight gain, and physical activity. Framingham investigation dispelled the concept of “benign essential hypertension” and the greater importance of diastolic blood pressure. It determined the full clinical spectrum of CVD, including sudden death, and silent coronary, stroke, and peripheral artery disease. The study determined CVD population incidence at a time when only mortality statistics were available, and now the lifetime risk. It quantified the hazard of a family history of CVD based on observations on parents and their offspring. The study provided insights on mechanisms of atherogenesis, including: LDL and HDL dyslipidemia, obesity-induced clustering of CVD risk factors, and smoking as a trigger for coronary attacks. It warned in 1985 of the lack of efficacy and danger of estrogen replacement for preventing CVD. The Framingham Study devised CVD risk profiles enabling physicians to pull together risk factor information to assess the global risk of heart attacks, failure, strokes, and peripheral artery disease. Findings of the study stimulated pharmaceutical industry development of agents for reducing blood pressure, lipids, glucose, and smoking, as well as trials demonstrating the efficacy of correcting risk factors. It also stimulated national campaigns against smoking, hypertension, hypercholesterolemia, and obesity.
2009 James B. Herrick Award and Lecture—Clinical Research at the Crossroads
Authors: Bonow Robert O.
Published: April 2024

Cardiovascular clinical research is experiencing unprecedented pressures in funding and manpower at a time when there are also unprecedented needs to expand the cardiovascular portfolio in translational research, outcomes research, and comparative effectiveness research. The clinical cardiovascular investigator is literally experiencing the best of times and the worst of times. Funding for the NIH, which increased at an annual rate of 15% during the years of doubling of the NIH budget from 1998 to 2003, has been essentially flat since 2003. NHLBI pay-lines for RO1 applications, which peaked at 35% in 2001, have steadily declined to 15%. The average age at which investigators receive their first NIH grant is 43 years, and in 2004, 44% of NIH awardees were over the age of 50 years. The deceleration of research funding, along with the real or perceived challenges facing young investigators in obtaining mentorship and funding, has had a chilling effect on attracting the brightest aspirants to pursue careers in clinical investigation. Simultaneously, junior cardiology faculty face increasing demands for clinical RVU productivity by their institutions because of shrinking reimbursement for clinical care, which often pushes them into private practice. These pressures are mounting at a time when there are pressing needs for clinical investigators to confront the continuing global epidemic of cardiovascular disease, which can only be overcome by innovative advances in translational, outcomes, and comparative-effectiveness research. The two highest priorities for comparative-effectiveness research in the 2009 Institute of Medicine report were studies in healthcare delivery systems and cardiovascular disease. Through the collective scientific and advocacy efforts of all of us in the community of science and medicine, these remarkable challenges can be overcome.
2009 Stroke Council Award and Lecture—Stroke: A Chronic Disease
Authors: Duncan Pamela
Published: April 2024

Stroke is managed as an acute illness, with mean lengths of stay of less than 5 days in acute-care hospitals. Recovery has been reported to be most dramatic in the first month and to plateau by 3 to 6 months. However, stroke is a chronic condition with multiple risk factors (diabetes, heart disease, hypertension, vascular cognitive impairments, depression, limited physical activity, and falls) for continued decline in health functional status and quality of life. Fewer than 50% of individuals with stroke have their stroke risk factors assessed, treated, or controlled; only 75% of individuals persist with secondary-prevention medications described at discharge; poststroke depression is underdiagnosed and undertreated; the level of physical activity in individuals with mild impairment after stroke is less than half that of healthy older individuals; and the risk of falls and fracture is 2 to 7 times higher in stroke survivors. Among individuals who receive inpatient rehabilitation services, recovery of walking speed is not sufficient to sustain physical activity and participation. Even among those among those with a high degree of early functional recovery, there are modest annual declines in function. Care management after acute stroke is highly variable and fragmented, and major quality-improvement initiatives to improve stroke outcomes (Paul Coverdale Registry and AHA Get With the Guidelines) do not extend beyond the acute-care hospital stay. There is an immediate need to develop more integrated and innovative poststroke management programs. The efforts to develop quality-improvement programs and quality indicators of care for acute care should be paralleled in chronic management after acute stroke.
Absence of SOCS3 Regulation on gp130 Signaling in the Cardiac Myocyte Results in Increased Voltage-gated Sodium Channel (SCN5A) Current, Arrhythmogenicity and Cardiomyopathy
Authors: Yajima Toshitaka
Published: April 2024

Abstract #3059

Toshitaka Yajima, Hanbing Zhou, Stanley Park, Jonathan Housman, Zhao-Hua Zhong, Byung-Kwan Lim, Platoshyn Oleksandr, Yusu Gu, Nancy Dalton, Tomoko Yajima, Jason X.-j. Yuan, Kirk U. Knowlton, Univ of California San Diego, La Jolla, CA

Toshitaka Yajima, 2009 Finalist and Presenting Author
Myocardial Infarction Repair With iPS Induced by Human Stemness Factors
Authors: Nelson Timothy
Published: April 2024

Abstract #3088

Timothy Nelson, Almudena Martinez-Fernandez, Satsuki Yamada, Carmen Perez-Terzic, Yasuhiro Ikeda, Andre Terzic, Mayo, Rochester, MN

Timothy Nelson, 2009 Finalist and Presenting Author
Heart Failure Causes Cholinergic Transdifferentiation of Cardiac Sympathetic Nerves via Gp130-Mediated Cytokines
Authors: Kanazawa Hideaki
Published: April 2024

Abstract #3089

Hideaki Kanazawa, Satoshi Ogawa, Keiichi Fukuda, Keio Univ Sch of Med, Tokyo, Japan

Hideaki Kanazawa, 2009 Finalist and Presenting Author
Radiation Dose From Single Heartbeat Coronary CT Angiography Performed Using a 320 Detector-Row Volume Scanner
Authors: Einstein Andrew J.
Published: April 2024

Abstract #251

Andrew J. Einstein, Carl D. Elliston, Columbia Univ Medical Ctr, New York, NY; Andrew E. Arai, Marcus Y. Chen, Natl Heart Lung and Blood Inst, Bethesda, MD; Richard Mather, Toshiba America Medical Systems, Tustin, CA; Gregory D. Pearson, Robert L. DeLaPaz, Edward L. Nickoloff, Ajoy Dutta, David J. Brenner, Columbia Univ Medical Ctr, New York, NY

Andrew J. Einstein, 2009 Finalist and Presenting Author
A 22-Year-Old Female With Non-Hypertrophic Hypertrophic Cardiomyopathy
Authors: Sakhuja Rahul
Published: April 2024

Abstract #3080

Rahul Sakhuja, Massachusetts General Hosp, Boston, MA; J. Eduardo Rame, Colleen Brown, Univ of California, San Francisco, San Francisco, CA; Karen Ordovas, Univ of Californa, San Francisco, San Francisco, CA; Philip Ursell, Univ of California, San Francisco, San Francisco, CA; Teresa De Marco, Univ of San Francisco, California, San Francisco, CA

Rahul Sakhuja, 2009 Finalist and Presenting Author