bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3356: Does Severe Obesity Cause Progressive Impairment of Left Ventricular Systolic Function?
Authors: Owan Theophilus , Morley Kimberly , Ault Travis G , Jiji Ronny , Hall Nathaniel , Preece Kevin , Williams Zachary , Adams Ted , Hunt Steve , Litwin Sheldon
Published: July 2021

Background:
Obesity is associated with an increased risk of developing heart failure. Based on cross sectional studies, it has been hypothesized that the duration of obesity is the key factor leading to impaired cardiac function. However, longitudinal data to confirm this hypothesis are not available.

Methods:
We prospectively studied 62 severely obese patients at baseline, 2 and 5 years after randomization to nonsurgical therapy (NonSurg, n = 25) or Rouxen-Y gastric bypass surgery (GBS, n = 37). Echocardiography was used to measure left ventricular (LV) size and ejection fraction (EF).

Results:
At enrollment, the mean BMI was 46±9 and the mean age was 47±11 years (range 25– 66). GBS subjects lost 96± 26 vs. 6±18 lbs at 2 years and 78±42 vs. 17±42 lbs at 5 years compared to NonSurg (p<0.0001 for both). At baseline LVEF was not different between GBS and nonsurg (67±9 vs. 64±8%) and it did not change at 2 years (64±9 vs. 63±9%) or 5 years (63±9 vs. 63±10%). LV diastolic dimension did not change over time in control (4.3±1.0 vs. 4.2±0.6 vs. 4.5±0.3) or GBS patients (4.4±0.6 vs. 4.3±0.7 vs. 4.4±0.4). Stratifying the entire group by quartiles of age or duration of obesity (quartile 1 avg duration = 16 years, quartile 4 average duration = 56 years), we found no evidence of time-dependent changes in LV size or function.

Conclusion:
In this, prospective study of severely obese patients we found no evidence of progressive changes in LV size or EF over a period of 5 years. Moreover, we find no relationship between age or duration of obesity and LV size or LVEF. These data argue strongly that other factors such as the development of coronary disease are the most likely causes of heart failure in obese patients.
Abstract 3360: Depressed Left Atrial Function and its Relation to Left Ventricular Filling Pressure in Systolic Heart Failure Patients.
Authors: Carluccio Erberto , Chinali Macello , Biagioli Paolo , Girfoglio Daniela , De Marco Marina , Alunni Gianfranco , de Simone Giovanni , Ambrosio Giuseppe
Published: July 2021

Background
: In uncomplicated hypertensive patients with preserved left ventricular (LV) function, enhanced left atrial systolic force (LASF) is associated with LV hypertrophy. In contrast, in patients with prevalent cardiovascular disease, reduced LASF has been shown to be associated with incident atrial fibrillation and poor cardiovascular prognosis. To date the relation between LASF and LV filling pressures in patients with systolic heart failure (HF) has not been adequately investigated.

Methods
: Doppler echocardiographic measurements of LV systolic, diastolic, and Tissue-Doppler longitudinal function, were obtained in 108 patients (66±12 years; 20% women) with systolic HF [NYHA class III; ejection fraction <40% (mean EF%=27.7±7.7%)]. LASF was calculated from mitral orifice area and transmitral peak A velocity. Population study was dichotomized according to the presence or absence of restrictive filling pattern (RF), defined as DT <150 ms. LV end-diastolic pressure (LVEDP) was derived combining transmitral peak E velocity and tissue Doppler E’ (E/E’ ratio).

Results
: In the overall population, LASF averaged 10.7±5.8 kdynes. LASF was significantly reduced in patients showing RF (n = 43; 39.8% of study population) compared to non-RF patients (8.1±4.8 vs 12.5±5.8 kdynes, p<0.0001). Consistent with this finding, LVEDP was significantly higher in RF patients (p<0.001). In RF patients, LASF was correlated positively with EF% (r=0.23, p<0.05) and TD systolic peak velocity (r=0.39, p<0.0001), and negatively with isovolumic relaxation time (r=0.68, p<0.0001). In additional analysis comparing quartiles of LV end-diastolic pressure, LASF decreased with increasing quartiles of LV end-diastolic pressure (13.7±7 kdynes vs 12±7 kdynes vs 10.6±5 kdynes vs 8±4 kdynes; p for trend <0.01).

Conclusions
: In systolic HF patients in class NYHA III, left atrial systolic force is reduced in the presence of restrictive filling pattern due in part to increased LV end-diastolic pressure, also associated with reduced LV systolic performance. In CHF patients, increased LVEDP partially blunts LA atrial function, and might be considered as an index of atrial afterload.
Abstract 3369: Association Between Bi-directional Mitral Isthmus Block and Atypical Flutter Following Left Atrial Linear Ablation in Patients with Symptomatic Atrial Fibrillation
Authors: Anousheh Ramtin , Sawhney Navinder , Tate Charles , Panutich Michael , Whitwam Wayne , Feld Gregory
Published: July 2021

Background:
Incomplete or unidirectional mitral isthmus block (MIB) during left atrial linear ablation (LALA) for atrial fibrillation (AF) may be proarrhythmic, and is the most common target for repeat ablation in patients with atypical atrial flutter (AAFL) after LALA.

Objective:
To determine if achieving bidirectional MIB during LALA will reduce occurrence post-ablation AAFL and/or recurrence of AF.

Methods and Results:
Fifty-six consecutive patients (pts), 49 males and 7 females, mean age 59±8 years, who underwent LALA for symptomatic, persistent (61%) or paroxysmal (39%) AF were evaluated. Thirty-four pts had been previously ablated, none had MIB from the first ablation. All pts underwent LALA including two encircling lesions around the right and left pulmonary veins, a line at the roof of the left atrium between the two circles, and a line from the lateral mitral valve annulus (MVA) to the left circle with adjunctive coronary sinus ablation as needed to achieve MIB. Thirty pts had an additional line from the septal MVA to the right circle. Bi-directional MIB was documented by pacing from the left atrial appendage and proximal coronary sinus. Bi-directional MIB was achieved in 38 pts (68%), with ablation in the coronary sinus required in 87.5% of pts. Thirty-seven pts underwent LALA with a standard 8 mm tip (Blazer™ or Navistar™) catheter and 19 pts with saline-irrigated catheters (ThermoCool™, Chili™). Patients were followed for 6±2 months. AAFL occurred in 15 pts (27%), and 17 pts (30%) had recurrence of AF. In pts with AAFL, 8 had documented bi-directional MIB during ablation and 7 did not. The odds of AAFL was 7.6 times higher in pts without MIB compared those with MIB (p=0.02); adjusting for age, gender, diagnosis, type of catheter, coronary sinus ablation and history of previous ablation. This study did not show similar association between recurrence of AF and MIB (p=0.5).

Conclusions:

Achieving bi-directional MIB will reduce incidence of post-ablation AAFL significantly.

Recurrence of AF is not reduced by achieving bi-directional MIB.
Abstract 3380: Levosimendan Improves Right Ventricular Function In Cardiogenic Shock Following Myocardial Infarction
Authors: Russ Martin A , Christoph Arnd , Carter Justin , Prondzinsky Roland , Schlitt Axel , Lemm Henning , Winkler Matthias , Buerke Michael
Published: July 2021

Background: Levosimendan, a novel inodilator, has been shown to improve hemodynamic function in acute heart failure and cardiogenic shock following acute myocardial infarction. Limited data are available on its use in patients with impaired right ventricular function. We hypothesised that levosimendan, due to its vasodilating and positiv inotropic profile, could ameliorate right ventricular hemodynamic function in critically ill patients with cardiogenic shock following myocardial infarction.

Methods: Patients (n=25) with cardiogenic shock received initial conventional inotropic therapy after reperfusion of infarct related artery. After insufficient hemodynamic improvement patients received levosimendan (2μg/kgbw/h) over 24 hours. Hemodynamic measurements were routinely performed initially i.e., − 24 hours, at baseline (prior to levosimendan infusion) at 3 hours, 24 and 48 hours after start of levosimendan infusion using a Swan-Ganz thermodilution catheter.

Results: With conventional catecholamine therapy (i.e., norepinephrine and/or dobutamine) we observed only marginal change of right ventricular perfomance parameters. In contrast, upon levosimendan infusion there was a significant decrease in pulmonary vascular resistance, while right ventricular Cardiac Power Index, a new measure of right ventricular performance similar to left ventricular CPI, significantly increased. Central venous pressure did not change which makes a significant dependency on preload unlikely.

Conclusion: Levosimendan infusion in patients with cardiogenic shock following acute MI and PCI seems to improves substantially and persistently right ventricular hemodynamic parameters, superior to conventional catecholamine therapy. Further studies addressing the benefit of levosimendan in right ventricular failure like in cardiogenic shock due to right myocardial infarction or acute pulmonary embolism are warranted.

Hemodynamic Parameters With Catecholamine Teatment and Additional Levosimendan
Abstract 3382: Three-Dimensional Color Doppler Echocardiography for Direct Measurement of Mitral Regurgitation Vena Contracta Area: A Clinical Experience
Authors: Little Stephen H , Kumar Rahul , Pirat Bahar , McCulloch Marti L , Zoghbi William A
Published: July 2021

Introduction:
3D color Doppler allows a direct measurement of Vena Contracta (VC) area in patients with mitral regurgitation (MR), without the need for geometric assumptions.

Hypothesis:
3D color Doppler VC area provides a more accurate assessment of MR severity than the conventional 2D color Doppler VC diameter.

Methods:
Patients with ≥ mild MR underwent 2D and 3D color Doppler and a quantitative echo-Doppler study. 2D VC diameter was measured from a zoomed parasternal long-axis view. 3D VC area was acquired using real-time 3D (Philips) and measured off-line (TomTec). MR severity was assessed both quantitatively, as effective regurgitant orifice area from pulsed Doppler [EROA = (mitral stroke volume - aortic stroke volume)/MR time velocity integral], and semi-quantitatively as recommended by the American Society of Echocardiography.

Results:
61 patients (65 ± 15 years) were studied. MR severity was mild in 25%, moderate in 36%, and moderate to severe or severe in 39%. Mitral valve pathology was prolapse in 33%, restricted closure in 44% and annular calcification in 7%. Regurgitant MR jet was eccentric in 49% of patients. For all patients, 3D VC area correlated significantly with EROA, better than 2D VC diameter (figure

). The advantage of 3D VC area over 2D VC diameter was more pronounced in eccentric jets (r=0.76, p< 0.001 vs. r=0.5, p =0.006, respectively) and in moderate to severe or severe MR (r=0.65, p<0.001 vs. r =0.13, p=0.54, respectively).

Conclusions
: Measurement of VC area is feasible with real-time 3D and provides a simple parameter that accurately reflects MR severity, particularly in eccentric and clinically significant MR where geometric assumptions may be challenging.
Abstract 3395: Potassium Supplement Use May Increase Hospitalization without Affecting Mortality in Chronic Heart Failure: Implications for Use of Aldosterone Antagonists to Maintain Potassium Balance in Chronic Heart Failure
Authors: Ahmed Ali , Adamopoulos Chris , Sui Xuemei , Love Thomas E
Published: July 2021

Background:
Hypokalemia is common in heart failure (HF). Aldosterone antagonists can raise serum potassium (K) and also improve survival. Yet, K-supplements are often used to correct hypokalemia; although little is known about the effects of K-supplements in HF.

Methods:
Of the 7788 ambulatory chronic HF patients in the Digitalis Investigation Group trial, 2199 (28%) were receiving K-supplements. Propensity scores for K-supplement use was calculated for each patient and were used to match 2131 patients receiving K-supplements with 2131 no-K-supplements patients (absolute standardized differences <10% for all measured covariates). Matched Cox regression models were used to estimate effects of K-supplements on outcomes during 40 months of median follow-up.

Results:
Compared with 68% (rate, 4120/10000 person-years) of no-K-supplement patients, 71% (rate, 4777/10000 person-years) of patients receiving K-supplements were hospitalized from all causes (hazard ratio, 1.15; 95% CI, 1.05–1.26; P=0.004). Compared with 38% (rate, 1313/10000 person-years) of no-K-supplement patients, 38% (rate, 1327/10000 person-years) of patients receiving K-supplements died from all causes (hazard ratio, 1.05; 95% CI, 0.94–1.18; P=0.390).

Conclusion:
K-supplement use was associated with no mortality reduction but increased hospitalization. This first report on the effect of K-supplement in HF raises question about the wisdom of K-supplement use to correct hypokalemia and maintain normokalemia in HF. Given the proven mortality benefits of aldosterone antagonists and their ability to raise serum K, spironolactone may be preferable to maintain normokalemia in chronic HF.

Figure 1.

Association of potassium supplement use and all-cause hospitalization
Abstract 3401: Cell Therapy For Idiophatic Dilated Cardiomyopathy
Authors: de Carvalho Antonio C Campos , Martino Helena F , Oliveira Paulo S , Assunção Edmilson , Vilela Rita , Gaze Miriam , Souza Fernando C , Costa Patricia C , Muccillo Fabiana , Weitzel Luis H , Arvello Sophie , Oliveira Amarino
Published: July 2021

Given the limited therapeutic options for refractory dilated cardiomyopathy we decided to perform a phase I clinical trial using bone marrow derived mononuclear cells in patients with functional classes II and IV of the NYHA. Inclusion criteria required EF% (Simpson) <35%, VO2 max < 16 kg.ml /min and signed informed consent. After enrollment patients were subject to the following exams at baseline, 2 and 6 months after cell therapy: 12 lead ECG and 24hs holter, echocardiography, chest X-ray, blood biochemistry, BNP, ergoespirometry, MRI and Minnesota Questionnaire. Patients were subject to bone marrow aspiration (80–100 mL) under sedation and local anesthesia and mononuclear cells were obtained after Ficoll gradient centrifugation. A mean of 198 million cells diluted in 20 ml of saline were slowly delivered through catheterization in the coronary arteries (10 ml in LAD, 5 ml in RC, 5 ml in CX). After the procedure patients remained hospitalized for 48hs. We report the results of the first 22 patients that completed the follow-up period. No adverse effects related to the procedure were observed, nor were arrhythmias detected after cell delivery. Four patients died during follow up. For the 18 patients that completed follow up, there was a significant improvement in NYHA functional class and quality of life at 2 and 6 months (p<0.03 and p< 0.007, respectively). There were no statistically significant changes in EF% (18.6%, 18.6% and 19%), EDV (360, 371, 386 ml) or ESV (295, 308, 314 ml) at baseline, 2 and 6 months respectively as measured by MRI. Maximal oxygen consumption showed as significant increase after cell therapy (12.5, 15.3, 16.8 ml/kg.min), and the number of patients with oxygen consumption below the threshold for cardiac transplantation decrease from 75% at baseline to 25% six months after cell therapy. BNP levels were not significantly altered (650, 475, 530 pg/ml). When observed individually, 4 of the 17 patients examined showed an increase in EF% by MRI ≥5%, 7 did not change EF% and 3 decreased EF% by ≥5%. In conclusion, the procedure is safe and feasible but further studies are necessary to test for efficacy.
Abstract 3409: Monitoring of Changes in Atheroma Volume by 64-Slice Computed Tomography.
Authors: Ibanez Borja , Cimmino Giovanni , Sanz Javier , Speidl Walter S , Santos-Gallego Carlos G , Prat-Gonzalez Susanna , Pinero Antonio , Benezet-Mazuecos Juan , Zafar M Urooj , Fuster Valentin , Garcia Mario J , Badimon Juan J
Published: July 2021

Non-invasive assessment of plaque burden by Multislice Computed Tomography (MDCT) has been recently shown to be feasible. However, to date, there is no data on its accuracy to assess changes in atheroma burden We and others have previously shown that apoA-IMilano (apoA-IM) infusion induces a large plaque regression in a very short period of time The aim of our study was to assess the feasibility of MDCT to accurately quantify the changes in atheroma volume induced by apoA-IM infusion

Methods
Aortic atherosclerotic lesions were induced in New-Zealand-White Rabbits (n=7) by 9-month atherogenic diet and aortic denudation, as previously reported. Animals were then randomized to receive 2 infusions, 4 days apart, of apoA-IM (ETC-216, Pfizer. n=4) or equal volume of placebo (n=3). All animals underwent 2 imaging studies in a 64-Slice MDCT scanner (Sensation 64, Siemens), pre- and post-treatment (Rx). After last MDCT study, animals were sacrificed and the aorta processed for histological atherosclerotic lesions characterization and volume quantification . Axial MDCT images were reconstructed (3 mm thick, no overlap). Display settings were manipulated according to previous validated studies. For lumen delineation: window width (WW) 1 and level (WL) 65% of lumen attenuation . For outer vessel boundaries: WW 155% and WL 65%.

Results
MDCT showed that plaque burden regressed by 29% in apoA-IM group (418mm
3
pre-Rx vs. 302mm
3
post-Rx, p=0.031). Conversely, no significant change was observed by MDCT studies done pre- and post-placebo administration. MDCT performed post-Rx showed that mean plaque volume in apoA-IM animals was 11.5% smaller than that of placebo animals (p=0.018). Mean plaque volume in histology showed similar results:plaque volume was 10.6% smaller in the apoA-IM group (p=0.005 vs. placebo). The interobserver variability for plaque volume quantification in MDCT was 10±4%.

Conclusion
MDCT detects the changes in atherosclerotic plaque volume induced by apoA-IM infusion. Furthermore, an excellent correlation was found between MDCT and histological plaque volumes. These results, combined to the short time of scan and the accessibility to the coronary territory suggest that MDCT could be applied in human studies testing changes in coronary plaque volume.
Abstract 3420: Effects on Myocardial Perfusion at 3 and 15 Months in Recanalized Chronic Total Occlusions - Randomized Comparison of Blood-Derived Progenitor Cells and Inactive Serum
Authors: Thiele Holger , Schuster Andreas , Erbs Sandra , Adams Volker , Lenk Karsten , Linke Axel , Hambrecht Rainer , Schuler Gerhard
Published: July 2021

Background:
MRI is an excellent diagnostic tool for serial assessment of changes in myocardial perfusion, left ventricular function, and infarct size. In chronic total occlusions (CTO) the effects of recanalization on perfusion and function are contradictory and might depend primarily on viability. Circulating progenitor cells (CPC) injected intracoronarily after successful CTO recanalization might improve perfusion and function.

Methods and results:
Twenty-eight patients with reperfused CTO were randomized to either CPC’s or inactive serum (control), which were infused into the target vessel. First-pass myocardial perfusion MRI at rest and stress using adenosine at standard dose revealed a significant improvement of the myocardial perfusion reserve index (MPRI) in the affected segments. The baseline MPRI in affected segments was 1.50±0.17 in CPC versus 1.46±0.16 in control (p=0.62). In CPC the MPRI improved to 1.76±0.16 (p<0.001) at 3 and 1.82±0.20 (p<0.001) at 15 months; in control the change was 1.58±0.10 (p=0.01) at 3 and 1.61±0.08 (p=0.004) at 15 months follow-up. However, the MPRI recovery was significantly better in CPC as compared to control at 3 (p=0.004) and 15 months (p=0.005). In remote myocardium the MPRI was 1.70±0.30 and 1.69±0.25 (p<0.01 versus affected segments), respectively. At follow-up there was no significant improvement for both groups. The change in MPRI at 3 and 15 months was correlated with a change in overall infarct size for CPC (3 months: r=−0.68, p<0.02; 15 months: r=−0.81, p=0.001), whereas in control there was no correlation (r=−0.38, p=0.26; 15 months: r=−0.21, p=0.56). Infarct transmurality influenced MPRI improvement at follow-up. CPC patients had a trend towards more improved segments in particular those with higher transmurality (p=0.06).

Conclusions:
Analysis of serial contrast-enhanced MRI suggests that intracoronary application of CPC post recanalization of CTO is associated with improved myocardial perfusion and subsequent improved recovery of left ventricular function as compared to a control group at mid- and long-term follow-up. Further investigations of the pathophysiological CPC effects on macro- and microvascular function are required.
Abstract 3426: The Generation Of Biosynthetic Small Caliber Grafts With Improved Patency Using Autologous Genetically Modified Endothelial Cells.
Authors: Preis Meir , Schneiderman Jacob , Koren Belly , Cohen Tzafra , Ashkenazi Dana Levin , Shofti Rona , Lewis Basil S , Shaul Yosef , Flugelman Moshe Y
Published: July 2021

Introduction:
Seeding polymer-based synthetic vascular grafts with endothelial cells (EC) improves grafts biocompatibility and consequently grafts patency. EC adhesion and survival on the synthetic polymer remains a considerable challenge. We used pseudo-typed retroviral vectors to modify EC to co-express fibulin-5 and VEGF
165
and created a unique EC phenotype with increased adhesion and enhanced proliferation and used these cells to seed vascular grafts.

Methods:
Polymer-based grafts seeded with autologous venous EC transduced to co-express fibulin-5 and VEGF
165
were implanted in the carotid arteries of the donor sheep. 18 grafts (8 seeded grafts with EC co-expressing fibulin-5 and VEGF, 6 seeded with control EC and 4 bare grafts) were implanted for two week in nine sheep. Six months studies were performed on 18 grafts (6 study, 6 seeded with control EC and 6 bare) implanted in 18 sheep. Histological studies for cell adhesion, intra-luminal thrombosis and transgene expression were tested in implanted grafts after angiography.

Results:
At two weeks all 8 grafts seeded with EC co-expressing fibulin-5 and VEGF were patent with no significant thrombosis and 73% coverage by seeded EC, while 3/10 control grafts were thrombosed and only 30% of seeded unmodified EC remained on grafts luminal surface. At 6 months, 5/6 grafts seeded with EC co-expressing fibulin-5 and VEGF were patent while 9/12 control grafts (6 bare, 6 seeded with unmodified EC, p<0.04) were occluded. At 6 months, the genetically modified cells were identified on the graft surface and these grafts had improved EC coverage and reduced intra-luminal neo-intima and thrombosis. No local or systemic side effects were attributed to the implanted grafts.

Conclusion
: Polymer-based vascular grafts seeded with EC transduced to co-express fibulin-5 and VEGF have lower propensity to thrombosis and improved patency. Use of grafts seeded with EC co-expressing fibulin-5 and VEGF provides a potentially clinically relevant method for small caliber blood vessel engineering.
Abstract 3427: Uncoupling of Skeletal Muscle Perfusion and Metabolism in Peripheral Arterial Disease
Authors: Anderson Justin D , Epstein Frederick H , Meyer Craig H , Hagspiel Klaus D , Wang Hongkun , Berr Stuart S , Harthun Nancy L , Weltman Arthur L , Isbell David C , Norton Patrick T , Kramer Christopher M
Published: July 2021

Introduction
Studies suggests that limb hemodynamics do not correlate with functional capacity in patients with peripheral arterial disease (PAD). Alterations in microcirculatory function and muscle metabolism are postulated to account for part of this inconsistency. We sought to further characterize the relationship between macrovascular obstruction, tissue perfusion and cellular metabolism in patients with PAD.

Methods
Sixty-two patients with mild-to-moderate PAD (35 males, mean age±S.D. 65±11 years) had their most symptomatic leg studied (resting ankle-brachial index (ABI) 0.68±0.13). To assess macrovascular disease, a runoff magnetic resonance angiogram was segmentally scored (MRAi) according to the number and degree of arterial stenoses distal to the aorta. A calf muscle perfusion index (PI) was measured at peak exercise with a magnetic resonance imaging (MRI) compatible pedal ergometer using first pass gadolinium-enhanced MRI. PI was defined as the ratio of slopes of calf muscle tissue perfusion to arterial input.
31
Phosphorus MR spectroscopy measured calf muscle phosphocreatine recovery time constant (PCr) immediately after peak exercise. Correlations between ABI, MRAi, PI, and PCr were examined by Pearson’s correlation coefficient.

Results
Mean MRAi was 0.97±0.74, PI was 0.45±0.15, and PCr was 73.1±30.0 sec. For reference, values in normal subjects are 0, 0.69±0.17 and 34.7±16.6 sec, respectively. The ABI correlated with PI (r=0.46, p<0.001), inversely with MRAi (r=−0.39, p<0.005) and modestly inversely with PCr (r=−0.27, p = 0.05). The MRAi showed a trend towards an inverse correlation with PI (r=−0.27, p<0.06), but did not correlate with PCr (p = 0.29). PCr likewise did not correlate with PI (p=0.85).

Conclusions
In mild to moderate PAD, lower limb blood pressure relates to macrovascular obstruction and both calf muscle perfusion and metabolism at peak exercise. However, calf muscle perfusion does not correlate with cellular metabolism as determined by PCr recovery at peak exercise. Thus, there is uncoupling between calf muscle perfusion and metabolism, supporting the concept that factors independent of blood flow and intrinsic to skeletal muscle are critical in PAD.
Abstract 3432: Patients with Upper Extremity Arterial Disease Have Similar Major Adverse Clinical Events as Those with Lower Extremity Arterial Disease
Authors: Chi Yung-Wei , Woods T. Cooper
Published: July 2021

Introduction: Upper extremity arterial disease, although it occurs less frequently compared to lower extremity arterial disease, negatively impacts one’s lifestyle. Most studies on peripheral arterial disease have been focused on the lower extremities and the clinical impact of upper extremity arterial disease remains less well known.

Hypothesis: Patients with upper extremity arterial disease have similar major adverse cardiovascular events (MACE) as those with lower extremity arterial disease.

Methods: Sixty-seven consecutive patients with upper extremity arterial studies and 359 consecutive patients with lower extremity arterial studies performed in 2004 by an accredited vascular laboratory were followed for at least 2 years. MACE including death, stroke, transient ischemic attack (TIA), myocardial infarction (MI) and unstable angina (USA) were tabulated and compared between the 2 groups. Final results were adjusted for diabetes mellitus, hypertension, hyperlipidemia, smoking status, and renal insufficiency. One-tailed t test was used.

Results: Eight events (28%) occurred in 29 patients with abnormal upper extremity arterial study compared to 24 events (21%) in 112 patients with abnormal lower extremity arterial study, p=NS. Five events (13%) occurred in 38 patients with normal upper extremity arterial study compared to 8 events (28%) in those with abnormal upper extremity arterial study, p=0.02. Twenty events (8%) occurred in 247 patients with normal lower extremity arterial study compared to 24 events (21%) in those with abnormal lower extremity arterial study, p<0.0001.

Conclusion: Patients with upper extremity arterial disease defined by abnormal upper extremity arterial study have similar MACE to those with lower extremity arterial disease (28% versus 21%, p=NS). In addition, those with either upper or lower extremity arterial disease have statistically more MACE than those without disease.

Major Adverse Clinical Events
Abstract 466: Valproic Acid Enhances Human Cord Blood CD34
+
Cell Differentiation Toward The Endothelial Phenotype
Authors: Avitabile Daniele , Burba Ilaria , Biondi Andrea , Pompilio Giulio , Capogrossi Maurizio C. , Pesce Maurizio
Published: July 2021

Background
. Human umbilical cord blood (UCB) CD34
+
cells are bi-potential progenitors that differentiate into hematopoietic and endothelial cells. Epigenetic control of gene expression by histone deacetylase (HDAC) activity is linked to lineage-decisions in uncommitted stem cells. Here we tested whether HDAC inhibitor valproic acid (VPA) modifies the balance between hematopoietic and endothelial commitment of CD34
+
cells.

Methods and results.
UCB CD34
+
cells selected by magnetic sorting were cultured in serum-free medium containing IL-3 and IL-6 (20 ng/ml), Stem Cell Factor and Flt3L (100 ng/ml) cytokines ±VPA (2.5mM) for 7 days. At day 0 CD34
+
cells were 84.2±5.2%. After 1 week in culture CD34 expression exhibited a marked decrease and this effect was inhibited by VPA (CD34
+
cells; 90.0±0.8% vs. 30.0±2.0%; n=4; P<0.01). In contrast, VPA had a negative effect on CD34
+
cell proliferation, as it induced G0/G1 arrest (cells in G0/G1; 93.0±0.9% vs. 74.1±4.3%; n=3; P<0.05) and decreased the stem cell proliferation index (16.2±2.8% vs. 44.0±8.8%; n=3; P<0.05) as well as total cell number. The negative effect of VPA on cell proliferation was associated with upregulation of p16 and p21 genes. VPA enhanced CD34
+
cells stemness; it increased Rhodamine123 dye extrusion by CD34
+
cells (Rhodamine 123
low
; 24.6 ± 6.8% vs 4.7 ± 1.1%; n=3; p<0.05) and enhanced CD34 and GATA-2 genes expression. To assess the effects of VPA on CD34
+
cells endothelial vs. hematopoietic commitment it was determined the expression of endothelial and hematopoietic markers at day 7. VPA enhanced CD146
+
(76.7±5.7 vs 1.4±0.8; n=3; P<0.05) and Ac-LDL-DiI
+
(88.3±6.7 vs 59.3±3.2; n=3; P<0.05) cells. In contrast, CD14
+
expressing cells were reduced (1.8±2.6% vs 7.7±4.0%; n=4; P<0.05) and CD31
+
, CD105
+
, CD144
+
and KDR
+
cells were unchanged. Finally, CD34
+
cells cultured with VPA for 7 days and plated in endothelial differentiation medium for additional 7 days in fibronectin-coated dishes, formed adherent spindle-shaped cells resembling late EPCs outgrowths while control cells remained unattached and round resembling hematopoietic cells.

Conclusions.
VPA modulates UCB CD34
+
cells stemness and cell cycle distribution; further, it enhances their commitment toward the endothelial phenotype.
Abstract 3479: Emerging Cardiovascular Risk Factors That Account For A Significant Portion Of Attributable Mortality Risk In Chronic Kidney Disease: A Precis Study.
Authors: Shishehbor Mehdi , Oliveira Leonardo P. J. , Lauer Michael , Sprecher Dennis , Wolski Kathy , Cho Leslie , Hoogwerf Byron , Hazen Stanley
Published: July 2021

Background:
Chronic kidney disease (CKD) increases cardiovascular risk and mortality. However, traditional cardiovascular risk factors do not adequately account for the substantial increase in mortality observed in CKD.

Methods and Results:
Prospective cohort study of 4,680 consecutive new patients from a tertiary care preventive cardiology program from 1996 to 2005. Estimated glomerular filtration rate (eGFR) was calculated by the Modification of Diet in Renal Disease (MDRD) method. Baseline levels of traditional (LDL-C, HDL-C, triglycerides, total cholesterol, fasting glucose) and emerging risk factors (apolipoprotein (apo) A1 and apoB, lipoprotein(a), fibrinogen, homocysteine, and CRP) were examined. All-cause mortality was obtained by social security death index. There were 278 deaths for a median follow up of 22 months. CKD (eGFR ≤ 60ml/min) was strongly associated with mortality after adjusting for traditional cardiovascular risk factors (Hazard ratio (HR), 2.31, 95% CI=1.77–3.11, p<0.001) and with addition of propensity score (HR = 2.33, 95% CI=1.75–3.10, p<0.001). Of all the traditional and emerging risk factors monitored, only addition of homocysteine and fibrinogen significantly attenuated the association between CKD and mortality (adjusted HR = 1.73, 95% CI=1.23–2.34, p<0.001), explaining 38% of the attributable mortality risk from CKD. A significant interaction (p = 0.004) between homocysteine and eGFR was observed whereby annual mortality rate in CKD subjects with homocysteine < 10 μmol/L (bottom tertile) was similar to those with normal renal function (1% per year), while homocysteine levels ≥ 12.5 μ mol/L (top tertile) were associated with a 7 fold higher mortality risk.

Conclusion:
Homocystiene and fibrinogen levels explain 38% of the attributable mortality risk from CKD.
Abstract 3489: Presence of Thoracic Aorta Calcification Predicts All Cause Mortality Independent of Traditional Cardiovascular Risk Factors and Coronary Artery Calcification
Authors: Nasir Khurram , Budoff Matthew J , Shaw Leslee J , Callister Tracy Q , Rumberger John , Sarwar Orakzai , Raggi Poalo , Berman Daniel , Blumenthal Roger S
Published: July 2021

Background: Recent guidelines have suggested that presence of coronary artery calcium (CAC) is an independent marker of adverse cardiovascular disease (CVD) events and mortality. However the predictive value of thoracic aorta calcification (TAC) that can be additionally identified without further scanning during assessment of CAC is unknown.

Method: We followed a cohort of 8418 asymptomatic individuals (mean age: 53 ± 10 years, 69% men) undergoing cardiac risk factor evaluation and coronary calcium testing with electron-beam CT for median period of 5.0 years. Multivariable Cox proportional hazards models were developed to predict all-cause mortality obtained from the National Death Index with presence of TAC.

Results: 141 (2%) all cause deaths were recorded. Overall survival was 96.7% and 98.8% for subjects with and without detectable TAC (p < 0.0001). As compared to those with absent TAC (reference group) the hazard ratio for mortality for subjects with TAC was 3.07 (95% CI: 2.20 – 4.38) in unadjusted analyses (table

). After taking into account age, gender and CVD risk factors the association was reduced to 1.77 (95% CI: 1.11–2.29). The association of TAC with mortality remained statistically significant even after taking into account CAC (table

), although TAC appeared to predict events more strongly in the absence of CAC (HR: 2.81; 95% CI: 1.17– 6.79, p = 0.02) than with CAC > 0 (HR: 1.39; 95% CI: 0.93–2.08, p = 0.10). However the interaction term between TAC and CAC for mortality was not significant (p = 0.23).

Conclusions: Presence of TAC was associated with all-cause mortality in our study. This relationship was independent of conventional CVD risk factors and CAC.

Hazard Ratio for All Cause Mortality with Presence of Thoracic Aorta Calcification
Abstract 3490: Formal Comparison between absolute and relative cut points for Coronary Artery Calcification in At Intermediate Risk Community-Based Men and Women: The Framingham Heart Study
Authors: Hoffmann Udo , Massaro Joseph M , Fox Caroline S , Manders Emily , O’Donnell Christopher J
Published: July 2021

Background:
Coronary artery calcification (CAC) may improve risk stratification of individuals at intermediate Framingham Risk. We determined the agreement between absolute and relative cut points to identify subjects with elevated CAC in individuals at intermediate Framingham Risk.

Methods
: The amount of CAC was quantified in 3238 participants from the Framingham Heart Study (FHS) Offspring and Third Generation cohorts (48% women, mean age 53 years) free of cardiovascular disease who underwent ECG triggered cardiac MDCT. We included subjects at intermediate Framingham risk, defined as 6 –20% ten year event risk, (n = 1177) and subjects free of cardiovascular risk factors (n = 1586). Distribution of CAC according to absolute (Agatston Score [AS] > 400) and relative (90
th
percentile stratified by age as derived from the healthy reference subset) cut-points were determined for men and women

Results:
Among men with intermediate FRS, 17.7% had CAC above the 90
th
percentile of the healthy referent sample, whereas 14% had CAC > 400. Similar findings were observed in women: 11.5% had CAC above the 90
th
percentile of the healthy referent sample, whereas 2% had CAC > 400. Among all individuals at intermediate FRS Only 10.8% of subjects above the 90
th
percentile had an AS < 400.

Conclusions:
The fraction of subjects with elevated CAC as determined by an AS > 400 is lower than subjects above the 90
th
percentile especially among women at intermediate FRS in the community-based FHS. Overall, the agreement between absolute and relative cut points to identify subjects with elevated CAC is poor in this population. Prospective outcomes studies are necessary to test the hypothesis that relative rather than absolute cutpoints of CAC should be used to further stratify subjects at intermediate risk.
Abstract 3559: β2-adrenoceptor Protein Expression Is Different Between Buffy Coat And Adipose Tissue
Authors: Masuo Kazuko , Katsuya Tomohiro , Rakugi Hiromi , Sugimoto Ken , Ogihara Toshio , Esler Murray D
Published: July 2021

Background:
Obesity and hypertension are associated with β2-adrenoceptor polymorphisms accompanying with heightened sympathetic nerve activity. In the present study we compared β2-adrenoceptor protein expression between buffy coats (white blood cells as a representive for whole-body) and abdominal subcutaneous fat to further evaluate the contributions of sympathetic nerve activity and β2-adrenoceptor to obesity and hypertension.

Methods:
In 17 obese normotensive Caucasian men (BMI≥30.0 kg/m2) and 8 age-matched lean Caucasian men (BMI<25 kg/m2), we measured BMI, blood pressure (BP), whole-body plasma norepinephrine (NE) spillover, NE clearance, plasma leptin, and β2-adrenoceptor protein concentration and leptin receptor protein concentration in buffy coats and in abdominal subcutaneous adipose tissue. The β2-adrenoceptor protein expression and leptin receptor protein expression were analysed by Western blotting.

Results:
Obese subjects had significantly higher whole-body NE spillover (673±245 ng/mL vs. 431±156, P<0.05), plasma leptin (15.2±4.3 ng/mL vs. 4.8±2.4, P<0.01), and BP levels (P<0.05) compared to lean subjects, but the whole-body NE clearance rate was similar. Obese subjects had significantly greater expression of β2-adrenoceptor protein in buffy coats (P<0.05) compared to lean subjects, while they had significantly less β2-adrenoceptor protein expression in abdominal fat (P<0.05). Leptin receptor protein expression in both buffy coats and abdominal fat were greater in obese subjects compared to lean subjects.

Conclusions:
Obese subjects had greater β2-adrenoceptor protein expression in buffy coats, but less β2-adrenoceptor protein expression in fat. This may suggest that blunted sympathetic nerve activity in adipose tissue (observed by less β2-adrenoceptor protein expression in fat) might relate to obesity and heightened sympathetic nerve activity in whole-body (observed by greater β2-adrenoceptor protein expression in buffy coats and higher NE spillover) may be linked to hypertension. The findings support the concept of selective leptin resistance. Sympathetic nerve activity and β2-adrenoceptor, not leptin, plays an important role is mechanisms of obesity and obesity-related hypertension.
Abstract 3574: Unsuspected Left Ventricular Wall Motion Abnormalities Identified by Cardiovascular Magnetic Resonance in a Free-Living Population: Lessons from the Framingham Heart Study
Authors: Tsao Connie W , Gona Philimon , Salton Carol J , Danias Peter G , Blease Susan , Albert Mark G , Levy Daniel , O’Donnell Christopher J , Manning Warren J , Yeon Susan B
Published: July 2021

INTRODUCTION: Resting left ventricular (LV) wall motion abnormalities (WMAs) are associated with significant morbidity and mortality. We hypothesized that unsuspected resting WMAs would be present in a healthy population and applied cardiovascular magnetic resonance (CMR) to characterize the prevalence of these in a free-living population.

METHODS: 1794 subjects in the Framingham Heart Study Offspring Cohort (844M, 65±9 yrs) underwent cine CMR in short-axis, 2-ch, and 4-ch planes. Wall motion was scored using a standard 17-segment model with a 5-point scale. Global and regional (Ant, Sept, Inf, Lat) wall motion score indices (WMSI=wall motion score/# segments) were calculated with a WMSI>1 considered abnormal. LV ejection fraction (EF) and mass index (LVMI) were measured from the short axis stack. Adjudicated clinical events [CE; a history of coronary heart disease (CHD) or congestive heart failure (CHF)] were assessed.

RESULTS: WMAs were present in 143 subjects. Compared to subjects with no prior CE, those with CE (n=157) had greater prevalence of WMA (Global, 34% vs 6%; Ant, 16% vs 2%; Sept, 18% vs 3%; Inf, 28% vs 4%; Lat, 27% vs 3%; all p<0.0001) and higher Framingham Risk Score (FRS) (11±3 vs 7±4, p<0.0001). In subjects with CE, WMA was associated with higher LVMI (70±14 g/m
2
vs 59±14 g/m
2
, p<0.0001) and lower EF (53±11% vs 69±6%, p<0.0001), but not age, blood pressure (BP), or FRS. Among 1637 subjects with no CE, 90 (5.5%) had a WMA. In these subjects, WMA was associated with greater age, BP, FRS, and LVMI, and lower EF (TABLE

). In the entire (n=1794) cohort, WMAs were more prevalent in men than in women (40% vs 19% with CE; 9% vs 3% without CE, respectively, both p<0.0001).

CONCLUSIONS: In this closely followed free-living population, 5.5% of subjects have WMAs despite the absence of CE. WMAs were associated with other parameters of cardiovascular risk. The presence of WMAs among subjects without history of CHD or CHF may identify those at risk for adverse cardiovascular events.
Abstract 3588: Treatment of Diabetes and Outcome After Myocardial Infarction: A Community Study
Authors: Patch Richard K , Arruda-Olson Adelaide M , Leibson Cynthia L , Vella Adrian , Weston Susan A , Killian Jill M , Frye Robert L , Roger Veronique L
Published: July 2021

BACKGROUND
Epidemiological cohorts can assist with post-marketing surveillance as they provide community-based outcomes data. Concern was raised about the adverse impact of sulfonylureas (SU) drugs on the outcome of diabetes after myocardial infarction (MI). We evaluated the outcome of MI according to treatment among diabetic persons compared to non-diabetic counterparts in a community-based cohort.

METHODS
All MIs that occurred in Olmsted County, MN between 1979 and 2002 were validated by standardized epidemiological including cardiac pain, biomarkers and ECG Minnesota coding. Diabetes mellitus (DM) was defined by the National Diabetes Data Group criteria.

RESULTS
Among 2732 persons with MI (mean age 70 ± 12 years, 44% men), 486 (18%) had DM. Subjects with DM were treated with second generation SU (SU2) (24%), insulin (47%) or diet alone (22%) Diabetic subjects were more likely to be overweight, hyperlipidemic and to receive reperfusion therapy during hospitalization than non-diabetic subjects. One year after the MI, 518 subjects died. Diabetic subjects taking SU2 experienced better survival than subjects without diabetes, while subjects treated with diet alone or insulin experienced worse survival. (Figure

). After adjusting for age, sex, reperfusion and duration of DM, an excess risk of death was detected among persons with insulin-treated DM, particularly those with long-standing DM. No association was found for DM patients treated with SU2 or diet.

CONCLUSION
These data do not support the concern for an adverse impact of SU2 on survival and underscore the potential role of community studies for population surveillance.
Abstract 3594: Serotonin in Adipose Tissue Acts as an Autocrine Factor Required for Adipocyte Differentiation and Lipolysis
Authors: Ono Koh , Horie Takahiro , Abe Yukiko , Kawamura Teruhisa , Kinoshita Minako , Nishi Hitoo , Nagao Kazuya , Satoh Noriko , Shimatsu Akira , Kita Toru , Hasegawa Koji
Published: July 2021

The differentiation of preadiopocytes (preAdps) into mature adipocytes (Adps) is closely associated with the expression of adipocyte (Adp)-specific gene products that are deeply involved in insulin resistance; therefore, it is critical to identify genes required for Adp differentiation. We used retrovirus insertion-mediated random mutagenesis to generate 3T3-L1 preAdp cells which lose their ability to differentiate into mature Adps. Using this approach, we discovered that tryptophan hydroxylase-1 (TPH1), a rate-limiting enzyme for the biosynthesis of serotonin (Ser), was required for Adp differentiation. While differentiation was clearly reduced in a mutant 3T3-L1 cell line that lacked expression of the normal TPH1 gene, reconstitution of the TPH1 gene in this cell line restored its differentiation potential. The administration of Ser enhanced differentiation in 3T3-L1 cells and in cells of the stromal vascular fraction from adult mice. On the other hand, differentiation was inhibited by 5-hydroxy tryptophan type 2A (5HT2A) receptor antagonists as well as the Ser synthesis inhibitor. Differentiation into mature Adp was significantly impaired in preAdps prepared from TPH1−/− mice compared to those from wild-type mice. We observed no differences in the histology of adipose tissue between TPH1−/−and wild-type mice at the basal state; however, after obesity was induced by a high-fat diet, increases in body weight and mesenteric fat weight were more prominent in TPH1−/− mice than in wild-type mice. In obese groups, we observed extremely large (140μm∼) Adps without any small Adps in TPH1−/− mice, in contrast to usually hypertrophied (μ80∼m) Adps and small Adps in wild-type mice. Interestingly, Ser treatment of mature cultured Adps enhanced lipolysis, which was blocked by the 5HT7 receptor antagonist but not by the 5HT2A receptor antagonist. Oral administration of 5HT2A receptor antagonist in high fat diet-induced obese mice reduced mesenteric fat weight and the number of small adipocytes; however, it did not increase the number of extremely large adipocytes as seen in TPH1−/−mice. Thus, Ser in adipose tissue acts as an autocrine factor required for Adp differentiation and lipolysis. Distinct receptor subtypes appear to mediate these two processes.
Abstract 3595: Inverse Association of Adiponectin with Insulin Resistance is Attenuated with the Escalation of Insulin Resistance: a Possible Finding of Adiponectin Resistance
Authors: Matsushita Kunihiro , Yatsuya Hiroshi , Tamakoshi Koji , Muramatsu Takashi , Mitsuhashi Hirotsugu , Shibata Rei , Kondo Takahisa , Murohara Toyoaki , Toyoshima Hideaki
Published: July 2021

Introduction:
Adiponectin has been known to play an important role in the glucose and lipid metabolism, and thereby may be considered as a potential treatment target for diabetes mellitus or atherosclerotic diseases. Recently, some basic studies showed that adiponectin might not function in an insulin-resistant condition, a concept called “adiponectin resistance.” However, this concept has not been confirmed in human. Therefore, we assessed the hypothesis that the well-known inverse association between adiponectin and insulin resistance is weakened in the insulin-resistant state.

Methods:
We studied 2,316 middle-aged Japanese men without a medical history of cancer, cardiovascular disease, diabetes, hypertension, or dyslipidemia to determine whether or not the association between serum adiponectin levels and the insulin resistance index (HOMA-IR) differed according to insulin resistant states.

Results:
Mean age and body mass index of study subjects were 48±7 and 23±3, respectively. A multiple linear regression analysis revealed that log-adiponectin was inversely associated with log-HOMA-IR independently of covariates (β= − 0.235,
P
<0.001). Subsequently, we re-analyzed after dividing study subjects according to the tertile of HOMA-IR. As shown in the Table

, the inverse association between adiponectin and HOMA-IR was considerably weakened with the escalation of insulin resistance. Specifically, adiponectin was almost positively associated with HOMA-IR in insulin-resistant subjects (β= 0.114,
P
=0.059). Interestingly, statistically significant associations of adiponectin with triglyceride and HDL-C were uniformly observed in all tertiles.

Conclusion:
The inverse association of adiponectin with insulin resistance weakened with the escalation of insulin resistance, suggesting the existence of “adiponectin resistance” in insulin-resistant individuals. This adiponectin resistance may be restricted in glucose metabolism.

Table.

Coefficients of adiponectin in multiple linear regression analyses with independent variables