bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2852: Cystatin C is an Independent Predictor of Sudden Cardiac Death among Elderly Persons
Authors: Deo Rajat , Katz Ronit , Sotoodehnia Nona , Fried Linda F , Sarnak Mark , Chonchol Michel , Kestenbaum Bryan , Psaty Bruce , Siscovick David , Shlipak Michael G
Published: July 2021

Background
- Cystatin C is a novel measure of kidney function that is superior to estimated glomerular filtration rate in predicting cardiovascular disease.

Objective
- We evaluated whether kidney function was an independent predictor of sudden cardiac death (SCD) risk.

Methods
- Subjects were participants in the Cardiovascular Health Study. Measures of kidney function were cystatin C and creatinine-based estimated glomerular filtration rate (eGFR). SCD was defined as a sudden pulseless condition from a cardiac origin in a previously stable individual occurring out of the hospital or in the emergency room.

Results
- Among the 5157 participants, there were 156 adjudicated SCD events over a median follow-up of 11.2 years. The incidence of SCD events increased across cystatin C quintiles: 0.15% per year in quintile 1, 0.27% per year in quintile 2, 0.32% per year in quintile 3, 0.42% per year in quintile 4, and 0.53% per year in quintile 5. In addition, the rate of SCD events increased as eGFR decreased (0.28% per year among those with eGFR ≥ 60 ml/min/1.73m
2
and 0.49% per year among those with eGFR < 60 ml/min/1.73m
2
. SCD risk increased across cystatin C quintiles after multivariate adjustment with a greater than two fold odds of risk in the highest quintiles compared to the lowest [HR = 1.62, 95% CI (0.86 –3.07) in quintile 2; HR = 1.81, 95% CI (0.96 –3.39) in quintile 3; HR = 2.29, 95% CI (1.24 – 4.22) in quintile 4; HR = 2.28, 95% CI (1.21– 4.30)] in quintile 5]. Low eGFR was predictive of SCD risk in unadjusted analysis [HR = 1.72, 95% CI (1.20 –2.47)] but did not achieve statistical significance after multivariate analysis [1.33, 95% CI (0.91–1.92)]. High cystatin C concentrations remained predictive of SCD risk even among participants without chronic kidney disease after multivariate analysis [HR = 1.84, 95% CI (1.18 –2.86)]. Finally, we noted excess SCD risk occurred in the 1633 participants with prevalent or incident MI or CHF; although, elevated cystatin C concentrations still remained predictive of SCD events in those without prevalent or incident cardiovascular disease (p for interaction = 0.05).

Conclusions
- Cystatin C is a sensitive measure of kidney function that is an independent predictor of SCD risk among elderly persons.
Abstract 2894: Modulation of the Pulsing Interval During Ultrasound-mediated VEGF Plasmid Delivery Can Selectively Target Transfection to Different Vascular Compartments
Authors: Thirugnanam Subarna , Kuliszewski Michael A , Lindner Jonathan R , Kobulnik Jeremy , Lekas Michael , Klibanov Alexander L , Stewart Duncan J , Leong-Poi Howard
Published: July 2021

Ultrasound-mediated (UM) destruction of plasmid-bearing microbubbles targets gene delivery to the vascular endothelium, promoting therapeutic angiogenesis. We hypothesized that modulation of the ultrasound pulsing intervals (PI) would allow targeting of gene delivery to selective vascular compartments based upon blood flow velocities, allowing differential targeting of faster filling vessels (arterioles) versus slower vessels (capillaries).

Methods:
Unilateral hindlimb ischemia was produced by iliac artery ligation in 60 rats. At day 14 post-ligation, microvascular blood volume (MBV) and blood flow (MBF) in the proximal hindlimb muscles were assessed by contrast-enhanced ultrasound (CEU). UM-delivery of VEGF
165
/GFP plasmid (500 μg cDNA)-bearing microbubbles (1x10
9
), was performed, at PIs of 2, 5 and 10 s (n=20 for each). Perfusion was re-assessed by CEU at days 17 and 28 (n=10 for each). Fluorescent microangiography (FMA) was performed at day 28 to assess vessel density. Transfection was localized using immunohistochemistry. PCR was used to quantify transgene expression.

Results:
VEGF
165
/GFP mRNA expression was greatest at day 17, and was similar for PI 5 and 10 s, however reduced for PI 2 s. Fluorescent microscopy demonstrated GFP transfection predominantly within arterioles for shorter PIs (PI 5 s >> PI 2 s), and more capillary expression with PI 10 s. Prior to delivery, normalized MBV and MBF in ischemic muscle were similarly reduced in all groups. By day 28, for PI 5 and 10 s, there was a significant increase in normalized MBV (1.4±0.2
vs
0.9±0.2, p<0.001, and 1.3±0.3
vs
0.9±0.2, p<0.001 respectively) and MBF (0.9±0.3
vs
0.3±0.1, p<0.001, and 0.5±0.2
vs
0.3±0.1, p<0.001 respectively), with increases in MBF significantly (p<0.001) higher for PI 5 s. There were no significant changes in MBV or MBF with delivery at PI 2 s. Changes in vascular density by FMA paralleled changes in MBV, increasing at day 28 for both PI 5 and 10 s, and remaining unchanged for PI 2 s.

Conclusions:
Altering the PI during UM-gene delivery can result in targeted delivery to selective vascular compartments. For the purposes of gene therapy for angiogenesis in chronic ischemia, a strategy that selectively targets arterioles is more effective than one that targets capillaries.
Abstract 2896: Quantitative Left Ventricular Flow Vortex Analysis is Superior to Conventional Echo-Doppler to Predict Hemodynamics and Symptoms in Patients with Systolic Heart Failure:
A Novel Quantitative Vorticity Imaging Study Using Contrast Echocardiography and Particle Image Velocitimetry
Authors: Hong Geu-Ru , Li Peng , Nguyen Huy , Zhao Wei , Liu Shizhen , Jin Shannon , Pedrizzetti Gianni , Tonti Giovanni , Houle Helene , Vannan Mani A , Narula Jagat
Published: July 2021

Background:
We have previously shown that the morphology and location of LV flow vortex is a critical determinant of directed blood flow during ejection. We evaluated whether quantitative LV flow vortex analysis by contrast echocardiography (CE) was superior to conventional echo-Doppler parameters to predict hemodynamics and symptomatic status in patients with
systolic heart failure
(HF).

Methods:
27 patients had 2-D CE with iv Definity in the apical views. Velocity vector and vorticity of LV flow was measured by Particle Image Velocitimetry (PIV) combined with a Feature Tracking Algorithm (Siemens, CA). Relative and vortex relative strength (RS, VRS), and vortex pulsation correlation (VPC) were measured. LVEDP was measured
invasively
, and LA volume index (LAVI), E/E’ were measured by echo-Doppler.

Results:
RS, VRS, and VPC showed strong correlation with LVEDP (r=-0.927, p<0.001, r=-0.913, p<0.001, r=-0.870, p<0.001), but LAVI and E/E’ showed only modest correlation to LVEDP ( r=0.639, p=0.01, r=0.503, p=0.03 ). Furthermore, RS (1.65 ± 0.3 vs 1.25 ± 0.2, p=0.04), VRS (0.79 ± 0.1 vs 0.59 ± 0.2, p=0.03), and VPC (0.83 ± 0.1 vs 0.67 ± 0.1, p=0.04) were significantly decreased in
symptomatic
versus
asymptomatic
HF, respectively. LAVI and E/E’ did not differentiate between symptomatic and asymtomatic HF. Figures A and B

show LV flow vortex in asymptomatic and symptomatic HF respectively: pulsatility is stronger in asymptomatic HF although steady streaming flow is comparable.

Conclusion
: The data from this study shows that quantitative LV flow vortex parameters are superior to echo-Doppler measures to predict hemodymics and symptomatic status in patients with systolic HF.
Abstract 2899: Ultrasound Exposed Microbubbles Cause Local Hyperpolarization of the Cell Membrane.
Authors: Juffermans Lynda J , Kamp Otto , Visser Cees , Musters Rene J
Published: July 2021

Background
Ultrasound (US) and microbubbles have gained wide interest as a tool for local delivery of drugs and genes. However, the exact mechanisms underlying increased cellular uptake of drugs and genes are still not clear. Recently, we showed an increase in cell membrane permeability for Ca
2+
in rat cardiomyoblast (H9c2) cells exposed to US and microbubbles. In this study, we hypothesized that the Ca
2+
influx will have an effect on the membrane potential, and investigated whether Ca
2+
dependent potassium channels (BK
Ca
) are involved. We particularly focused on local events where the microbubble was in contact with the cell membrane.

Material and Methods
H9c2 cells were cultured on US transparent membranes. US exposure consisted of bursts of 1 MHz with a peak negative pressure of 50 or 250 kPa. Pulse repetition frequency was 20 Hz, duty cycle 0.2%. Cells were exposed during 30s in the presence of Sonovue microbubbles. The membrane potential was monitored during US exposure using the fluorescent dye di-4-ANEPPS. The experiments were repeated in the presence of iberiotoxin (100 nM), a specific inhibitor of BK
Ca
channels.

Results
Surprisingly, despite the previously reported Ca
2+
influx, we found patches of hyperpolarization of the cell membrane, as reflected by local increases in di-4-ANEPPS mean fluorescent intensity (MIF), shown in table I

as percentage of control (%MIF/control). This hyperpolarization was caused by the activation of BK
Ca
channels, as iberiotoxin completely prevented hyperpolarization.

Conclusion
US and microbubbles elicit a Ca
2+
influx, which leads to activation of BK
Ca
channels and a subsequent, local hyperpolarization of the cell membrane. This local hyperpolarization of the cell membrane may facilitate uptake of macromolecules through endocytosis and macropinocytosis.

Table I
Abstract 2913: Persistently Increased Serum Concentrations Of Heart-type Fatty Acid-binding Protein Predict Adverse Outcomes In Patients With Chronic Heart Failure
Authors: Niizeki Takeshi , Takeishi Yasuchika , Koyama Yo , Kitahara Tatsuro , Suzuki Satoshi , Kubota Isao
Published: July 2021

Background:
H-FABP is a small cytosolic protein and released into the circulation when the myocardium is injured. We previously demonstrated that H-FABP level at admission was a novel marker for myocardial cell injury and prognosis in CHF patients. In this study we examined whether serial measurements of H-FABP levels provide additional prognostic information.

Methods:
We measured serum H-FABP levels at both admission and discharge in 112 CHF patients, and patients were followed up (mean 686 days) to register cardiac events. Cut off value for H-FABP was determined from ROC curve in previous studies.

Results:
The median H-FABP level was 7.4 ng/ml at admission and 4.9 ng/ml at discharge. The following 3 patterns of changes in H-FABP levels were identified. In 41 patients, H-FABP levels (< 4.3 ng/ml) at both admission and discharge were normal (Group 1). The remaining 71 patients had high initial H-FABP levels (≥ 4.3 ng/ml) at admission. In 20 of these 71 patients (28%), H-FABP decreased to normal range at discharge (Group 2), whereas 51 had persistently high H-FABP levels despite improvement in symptoms and signs of CHF (Group 3). There were 32 cardiac events (29%) during a follow-up period. Kaplan-Meier analysis demonstrated that Group 3 had significantly higher cardiac event rates than Groups 1 and 2 (Figure A

). A stepwise Cox regression analysis also demonstrated that Group 3 was associated with the highest cardiac event risk among 3 groups (hazard ratio 5.68, P = 0.012) (Figure B

).

Conclusion:
These results suggest that serial measurements of H-FABP levels are a new monitoring tool, which provides helpful information to guide optimal therapy and manage CHF patients.

[A]
Comparison of cardiac event rates among 3 groups

[B]
Hazard ratio of cardiac events among 3 groups
Abstract 2919: Medical And Economic Long-term Effects Of B-type Natriuretic Peptide Testing In Patients With Acute Dyspnea
Authors: Mueller Christian , Breidthardt Tobias , Strohmeyer Anne-Henny , Schindler Christian , Meier Sophie , Fischer Michael , Scholer Andre , Noveanu Markus , Christ Michael , Perruchoud André P
Published: July 2021

Background: The objective of this prospective study was to assess the medical and economic long-term effects of using B-type natriuretic peptide (BNP) levels in the management of patients with acute dyspnea.

Methods: We performed follow-up analysis of BASEL, a randomized study including 452 patients who presented to the emergency department with acute dyspnea. Participants were randomly assigned to a diagnostic strategy involving the rapid measurement of BNP levels (n=225) or assessment in a standard manner (n=227). Mortality was assessed at 720 days, morbidity and economic data at 360 days.

Results: BNP testing induced several important changes in initial patient management including a reduction in the initial hospital admission rate, the use of intensive care, as well as initial time to discharge. At 720 days, 172 deaths had occurred. Cumulative all-cause 720-day mortality was not different between the BNP group (37%) and the control group (36%, P =0.6). Morbidity as reflected by days spent in-hospital at 360 days was significantly lower in the BNP group (median 12 days [IQR 2–28]) as compared to the control group (median 16 days [IQR 7–32], P =0.025). Functional status was similar in both groups. Economic outcome as quantified by total treatment cost at 360 days was significantly improved in the BNP group (mean $10,144 versus $12,748 in the control group, P =0.008).

Conclusions: Rapid BNP testing in patients with acute dyspnea has no effect on long-term mortality. However, morbidity as quantified by days spent in-hospital and economic outcome are still improved at 360 days.
Abstract 2925: An inherited mutation of AKAP9 (Yotiao) causes Long QT Syndrome (LQTS)
Authors: Chen Lei , Marquardt Michelle L , Tester David J , Sampson Kevin , Ackerman Michael J , Kass Robert S
Published: July 2021

A-Kinase Anchoring Protein 9 (AKAP9), or Yotiao, binds to the carboxy-terminus (C-T) of the IKs channel alpha subunit KCNQ1 and recruits cAMP-dependent protein kinase A (PKA) and protein phosphatase 1 (PP1) to the channel to control its phosphorylation state. Previously, an inherited LQT1-causing mutation in the KCNQ1 C-T/Yotiao binding domain was shown to disrupt the complex and render the channel functionally insensitive to cAMP-dependent regulation. Despite the critical role of Yotiao in mediating this fundamental physiological response, the large size of the Yotiao protein (over 200 kD) has hindered patient screens and, to date, no disease-linked mutations have been found in this adaptor protein. The objectives of the present study were

first to locate reciprocal binding site(s) for KCNQ1 on Yotiao and

to test whether mutation(s) in the binding module(s) might cause LQTS.

Using GST fusion protein pull down and immunoprecipitation (IP) techniques, we identified two regions in Yotiao necessary for binding to KCNQ1: one within the Yotiao N-terminus (residues 29 – 46), and a second within its C-terminus (1574 –1643). Targeted sequence analysis was then carried out in fifty clinically diagnosed but genotype negative LQTS patients in the coding regions for these two KCNQ1 binding domains in AKAP9-encoded Yotiao. This analysis identified a novel missense mutation, S1570L-Yotiao, present in two siblings diagnosed with LQTS but absent in the normal population. We found that the S1570L mutation, located close to the Yotiao C-T binding motif for KCNQ1, disrupted the interaction between the two proteins and significantly reduced both basal and exogenous cAMP-induced KCNQ1 phosphorylation. Perforated patch experiments in CHO cells revealed that expression of S1570L-Yotiao significantly reduced basal IKS channel activity and completely ablated the response of the IKs channel to cAMP plus the phosphatase inhibitor okadaic acid. These reconstituted cellular consequences of the inherited S1570L-Yotiao mutation are consistent with delayed repolarization of the ventricular action potential observed in the affected siblings. Thus, we have demonstrated for the first time a link between an inherited AKAP mutation and human disease, LQTS.
Abstract 2954: In Vivo Molecular Imaging of Myocardial Angiogenesis Using
99m
Tc-RAFT-RGD, a Novel α
v
β
3
Integrin-Specific Tracer
Authors: Dimastromatteo Julien , Pons Guillaume , Riou Laurent , Pellegrini Eric , Gavrilina Tatiana , Ahmadi Mitra , Boturyn Didier , Dumy Pascal , Fagret Daniel , Ghezzi Catherine
Published: July 2021

Introduction
- Myocardial angiogenesis following reperfusion of an infarcted area affects postinfarct remodelling and may therefore impact on patient prognosis. The non-invasive molecular imaging of angiogenesis is thus of potential clinical relevance in this setting. Angiogenic vessels overexpress the α
v
β
3
integrin. Tc-RAFT-RGD is a novel
99m
Tc-labelled tracer composed of four α
v
β
3
integrin-specific cyclo(RGDfK) sequences tethered on a cyclodecapeptide platform.

Hypothesis
- We hypothesized that Tc-RAFT-RGD binding to the α
v
β
3
integrin would allow the molecular imaging of myocardial angiogenesis in vivo.

Methods
- Myocardial infarction was induced by left anterior descending coronary artery occlusion for 45 min prior to reperfusion in 24 anesthetized male Wistar rats. Fourteen days later, the animals were injected intravenously with Tc-RAFT-RGD (n = 16) or Tc-RAFT-RAD (negative control, n = 8). Tracer uptake was assessed 60 min following injection in 12 and 4 animals injected with Tc-RAFT-RGD and Tc-RAFT-RAD, respectively. In those animals, the hearts were quickly excised for autoradiographic imaging, nitroblue tetrazolium (NBT) infarct staining, CD31 immunostaining of neovessels, and for gamma-well counting of myocardial tracer activity in the infarcted and normal areas. The remaining animals were dedicated to in vivo dual-isotope pinhole SPECT imaging following the simultaneous injection of Tl-201 and Tc-RAFT-RGD (n = 4) or Tc-RAFT-RAD (n = 4).

Results
- Neovessels were observed in the infarcted area using CD31 immunostaining. The Tc-RAFT-RGD infarcted-to-normal zone activity ratios by gamma-well counting and ex vivo imaging (2.6 ± 0.6 and 3.9 ± 1.0, respectively) were significantly higher than those of Tc-RAFT-RAD (1.7 ± 0.5 and 2.1 ± 0.4, respectively,
P<
0.05). Quantification of short-axis images from SPECT acquisitions indicated similar Tl-201 defect magnitudes in animals injected with Tc-RAFT-RGD and Tc-RAFT-RAD (0.3 ± 0.1 and 0.4 ± 0.1,
P
=NS). The infarcted area was readily visible in vivo with Tc-RAFT-RGD but not with Tc-RAFT-RAD (infarct-to-normal zone activity ratio, 2.8 ± 0.6 and 1.6 ± 0.4, respectively,
P<
0.05).

Conclusions
- Tc-RAFT-RGD allowed the experimental in vivo molecular imaging of myocardial angiogenesis.
Abstract 2955: Increased Luminal Diameter With Drug-eluting Versus Bare-metal Stenting Of The Piglet Ductus Arteriosus
Authors: Lee Kyong-Jin , Hinek Aleksander , Almeida Claudia , Chaturvedi Rajiv , Benson Lee
Published: July 2021

Introduction:
Maintaining ductus arteriosus (DA) patency by stent implantation may be advantageous in congenital heart disease management algorithms. Rapamycin, an immuno-suppressant drug, has anti-proliferative properties, inhibits smooth muscle cell (SMC) migration and may deter intimal hyperplasia occurring during spontaneous closure and post stent implantation of the DA.

Methods:
16 Yorkshire piglets (age 7–11 days old, weight 2.2– 4.9 kg) underwent stent implantation of the DA (rapamycin-eluting (n = 8), bare metal (n = 8) stents, (3.5 mm diameter) and were sacrificed at 2, 4 and 6 weeks. Dissected DA were analyzed for SMC and extracellular matrix components (elastin, collagen and glycosaminoglycans). External diameter, wall thickness and lumen diameter were analyzed by morphometric software. DA-derived SMC were isolated and cultured for 7 days in the presence or absence of 100mM of rapamycin. Cellular proliferation rates were assessed by proliferative antigen Ki-67 detection and [
3
H]-thymidine incorporation. Specific antibodies to elastin, collagen type I, and chondroitin sulfate-containing glycosaminoglycans were analyzed.

Results:
Rapamycin-eluting stents significantly inhibited neointimal formation compared with bare metal stents at 4 and 6 weeks resulting in larger luminal diameters (p<0.001). The in vitro studies demonstrated rapamycin-treated cultures of the DA-derived SMC had 50% lower proliferation rates (p<0.001).

Conclusions
: Rapamycin has anti-proliferative actions on the DA. Drug-eluting stents may be a more efficient tool for prolonging patency of the DA in neonates palliated for future correctional surgery.
Abstract 2983: Sex Differences in Quality of Life and Health Status in the COURAGE Trial
Authors: Kolm Paul , Boden William E , Spertus John A , Maron David J , O’Rourke Robert , Dada Marcin , Zhang Wei , Hartigan Pamela M , Weintraub William S
Published: July 2021

Purpose: The Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation (COURAGE) trial randomized 2,287 patients to percutaneous coronary intervention (PCI) plus optimal medical treatment (OMT) or OMT alone. The purpose of this study was to assess sex differences in quality of life (QOL) and health status between randomized initial management strategies over the trial follow-up period.

Methods: Of the 2,287 patients, 979 males and 169 females were randomized to PCI, and 968 males and 169 females were randomized to OMT. Quality of life was assessed with the Seattle Angina Questionnaire (SAQ) and health status with the RAND-36 at baseline, 1, 3, 6, 12 months and annually thereafter. SAQ and RAND-36 scores were assessed by analysis of variance (ANOVA), and linear mixed effects models.

Results: There were no significant sex by treatment group interactions indicating PCI vs. OMT differences were similar for the 1,947 men (85%) and 338 women (15%). Men had significantly higher SAQ Physical Functioning scores at baseline and 1 month post-treatment (p < 0.004) and a trend of higher means thereafter (Figure 1A

) and significantly higher RAND-36 Physical Functioning scores over 3 years of follow-up (p < 0.001, Figure 1B

). Men also had significantly higher RAND-36 Energy/Fatigue means scores (p < 0.05, Figure 1C

). RAND-36 scores for the other domains were similar fbetween the two groups (Figure 1D

).

Conclusions: Men and women in both arms experienced improvement in quality of life and health status over time. Men had significantly higher physical functioning as well as energy/fatigue scores, but were similar to women in other quality of life and health status domains.
Abstract 411: Endogenous miRNA Induced By Ischemic Preconditioning Reduces Myocardial Infarct Size following Ischemia/Reperfusion In Mice
Authors: Yin Chang , Salloum Fadi N , Kukreja Rakesh C
Published: July 2021

BACKGROUND:

Due to its short length (~24 nt) and non-coding nature, microRNA (miRNA) used to be regarded as “evolutionary transcriptional debris”. Recent evidence suggests that miRNA is a novel regulator for transcription and translation. It is known that brief episodes of ischemia during ischemic preconditioning (IPC) trigger complex genetic pro-survival program that results in modulation of several key proteins involved in protection against I/R injury. We hypothesized that miRNA synthesized during IPC is the potential mediator of such protection.

METHODS / RESULTS

: Hearts were isolated from 3 groups (n = 6/group) of adult ICR mice and subjected to the following treatments in Langendorff mode: 120 min of perfusion with Krebs-Henseleit buffer (control); 30 min global ischemia followed by 1 hr reperfusion (I/R); 2 cycles of 30 sec ischemia and 90 sec reperfusion followed by 30 min ischemia and 1 hr reperfusion (IPC). Infarct size (IS) was measured by triphenyl tetrazolium staining. IPC in the Langendorff model reduced IS from 29.7 ± 2.1% in the I/R hearts to 9.1 ± 1.8 % in the IPC group. This protection was associated with a significant induction of miRNA-1 (162 ± 13%), miRNA-21 (118 ± 6%), and miRNA-24 (46 ± 12%). To test its protective role, miRNA was extracted from 6 hearts following the IPC protocol; and then injected
in vivo
into the left ventricle wall in another group of 6 mice. Forty-eight hrs later, these mice were subjected to I/R injury
in vivo
by left coronary artery ligation for 30 min followed by reperfusion for 24 hr. In addition, a subset of mice was treated with miRNA inhibitors (methylated antisense miRNA) in conjunction with miRNA from IPC hearts. The results show that miRNA extracted from the IPC hearts reproduced a protective phenotype with significantly lower infarction (18.8 ± 2.5 %)
in vivo
as compared to saline-treated control (37.5 ± 2.2%). This protective effect was totally abolished by specific inhibitors of miRNA-1 and miRNA-21 (IS: 43.7 ± 2.1%).

CONCLUSION

: miRNA extracted from preconditioned hearts shows a protective role against I/R injury. The detection of miRNA in preconditioned hearts offers a novel strategy in cardioprotection. Further studies are needed to identify the gene targets by which miRNA generate protective phenotype.
Abstract 412: Cardiac-Specific Overexpression of Caveolin-3 Induces Endogenous Cardiac Protection
Authors: Patel Hemal H , Tsutsumi Yasuo M , Yokoyama Utako , Insel Paul A , Roth David M
Published: July 2021

Caveolae are lipid-rich microdomains of the plasma membrane that localize and enrich cardiac protective signaling molecules. Caveolin-3 (Cav3), the dominant caveolin isoform found in cardiac myocytes, is a determinant of caveolae formation. We hypothesized that cardiac-directed overexpression of Cav3 would enhance the formation of caveolae and augment protective signaling of the heart
in vivo
. Full-length cDNA for mouse Cav3 was cloned into a vector containing the α-myosin heavy chain promoter to allow for cardiac myocyte-specific expression of Cav3. A transgenic (Tg) mouse line was derived with a 5.5-fold increase in Cav3 mRNA and a 2.4-fold increase in Cav3 protein that localized to the sarcolemma. No significant increase in Cav3 expression was observed in lung, liver, brain, or skeletal muscle from Tg-positive mice. Electron microscopy revealed enhanced formation of caveolae on the sarcolemmal membranes of Tg-positive mice compared to Tg-negative littermate controls and no apparent structural defects in the heart. Echocardiography of 7–9 month old Tg-positive and Tg-negative mice showed no significant differences in cardiac function. Tg-positive mice subjected to ischemia/reperfusion injury had a significantly reduced infarct size relative to Tg-negative mice (23.9 ± 3.3 vs. 44.4 ± 5.9 % risk area, p<0.01). The endogenous protection induced in Cav-3 Tg-positive mice was similar to that produced in wild-type mice undergoing ischemic preconditioning (27.2 ± 2.5 % risk area). Hearts excised from Tg-positive mice had a 1.5-fold increase in basal phosphorylation of Akt (p<0.05, n = 6 Tg positive, 4 Tg-negative). Cardiac protection in Cav3 Tg-positive mice was blocked by treatment prior to ischemia reperfusion with 5-hydroxydecanoate, a mitochondrial KATP channel blocker. These results reveal that cardiac-specific overexpression of Cav3 produces an endogenous protected phenotype in mice in association with greater basal Akt activation and a phenotype that is sensitive to antagonism via mitochondrial KATP channel inhibition. The findings suggest that approaches to increase Cav3 expression may provide a novel means to augment cardiac protection independent of ischemic preconditioning.
Abstract 2997: Post-Operative Statin Use and Lower LDL Cholesterol Concentration Are Associated with Reduced Incidence of Stroke
Authors: Becker Matthew C , Galla John M , Daly Ryan P , Philip Femi , Zimbwa Peter , Chen Stephen O , Chow Chen H , Hu Tingfei , Krasuski Richard A , Askari Arman T
Published: July 2021

Background
: Post operative stroke remains a catastrophic and costly complication of coronary artery bypass grafting (CABG). Prior work has demonstrated a significant reduction in the rate of stroke associated with statin use in the non-operative setting. We evaluated the effect of post-operative statin use and LDL cholesterol concentration (LDL-C) on the incidence of stroke following CABG.

Methods
: The Cleveland Clinic Cardiothoracic Surgery Database was used to identify 5,205 consecutive patients who underwent first time, isolated CABG from 1/1993–12/2005. Patients with a prior history of atrial fibrillation, known clotting disorder, or requirement for anticoagulation were excluded from analysis. Discharge medications, including statins, were prospectively collected. Patients were divided into groups based upon serum LDL-C: <70mg/dl, 70 –100, 101–130, or >130.

Results
: The overall incidence of postoperative stroke at 1 year was 3.3% (181 events). Patients discharged on statin therapy were more likely to have a lower LDL-C and were significantly less likely to suffer a post operative stroke at 1 year (see table

). Multivariate logistic regression identified age (HR 1.05 [1.024, 1.075]; p<0.001), peripheral vascular disease(1.89[1.233, 2.891]; p<0.004), and renal disease (2.79 [1.654, 4.709]; p<0.001) as independent predictors of the combination of stroke, MI, or death. Use of both statin (0.366 [0.177, 0.757]; p<0.007) and ACE inhibitor (0.545 [0.36, 0.82]; p<0.003) therapies significantly reduced this risk.

Conclusions:
In patients undergoing first time, isolated CABG, post-operative statin therapy was associated with lower LDL-C concentration which significantly reduced risk of stroke as well as the composite endpoint of death, MI, or stroke. These data suggest that a discharge regimen including statin therapy may reduce post-operative morbidity and warrants prospective validation.
Abstract 3003: Programmed Ventricular Stimulation Does Not Predict the Outcome of Patients with Arrhythmogenic Right Ventricular Cardiomyopathy (from DARVIN study)
Authors: Corrado Domenico , Leoni Loira , Link Mark S , Calkins Hugh , Wichter Thomas , Bevilacqua Michela , Basso Cristina , McKenna William J , Estes Mark N , Favale Stefano , Santini Massimo , Buja Gianfranco , Thiene Gaetano , Iliceto Sabino
Published: July 2021

Background: The Defibrillator in Arrhythmogenic Right Ventricular Cardiomyopathy International (DARVIN) study was a multicenter investigation that enrolled patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) who received an implantable defibrillator (ICD) for either secondary or primary prevention of sudden death.

Methods: In this DARVIN substudy, we examined whether programmed ventricular stimulation (PVS) is able to predict the arrhythmic risk in a large cohort of 201 ARVC patients (133 males, 68 females, aged 36 ± 12 years) who received an ICD. Implant indications were a history of cardiac arrest in 13 (6%) patients; sustained ventricular tachycardia (VT) in 82 (41%); syncope in 42 (21%); asymptomatic nonsustained VT in 40 (20%); and a family history of sudden death in 24 (12%). PVS prior to ICD implantation was carried out in 143 of 201 patients (71%). All antiarrhythmic drugs were discontinued ≥ 5 half-lives (≥ 6 weeks for amiodarone) before the study. PVS included a minimum of 2 drive cycles length and up to 3 ventricular extrastimuli while pacing from two right ventricular sites.

Results: One hundred-nine patients (76%) were inducible to either sustained VT (patients 70; 64%), with a mean cycle length of 287 ± 66ms (range 220 to 410 ms), or ventricular fibrillation/flutter (VF) (patients 39; 36%). Of 109 patients who were inducible at PVS, 56 (52%) did not experience ICD therapy during a mean follow-up of 47 ± 22 months, whereas 11 of 34 (33%) noninducible patients had appropriate ICD interventions. Overall, the positive predictive value of PVS was 48%, the negative predictive value 67%, and the test accuracy 53%. The incidence of ICD discharges on VF, which in all likelihood would have been fatal in the absence of ICD therapy, did not differ between patients who were and were not inducible at PVS (26 of 109, 24% vs 7 of 34, 21%; p=0.87), regardless of clinical presentation. The type of ventricular arrhythmia inducible at PVS did not predict VF during the follow-up.

Conclusions: The presence (or absence) of an inducible arrhythmia on PVS did not correlate with subsequent appropriate ICD interventions, suggesting a limited role for PVS in arrhythmic risk stratification of ARVC patient population. A negative PVS may not indicate better prognosis.
Abstract 3010: Thrombin Receptor Antagonist (TRA;SCH530348) is a Selective, Potent Inhibitor of PAR1 Activity with Predictable Pharmacokinetics
Authors: Jennings Lisa K , Earhart Angela , Becker Richard C , Reyderman Larissa , Veltri Enrico , Harrington Robert A
Published: July 2021

Background:
TRA-PCI was a multicenter, randomized, double-blind, placebo-controlled study demonstrating the safety of SCH 530348, a potent thrombin receptor antagonist (TRA), in patients undergoing non-urgent percutaneous coronary intervention (PCI). A secondary endpoint in a sub-study within the primary evaluable patient cohort was inhibition of platelet aggregation (IPA) induced by appropriate agonists relative to baseline. We hypothesized that TRA therapy would selectively inhibit platelet aggregation induced by the thrombin receptor agonist peptide (TRAP) and that sustained inhibition would be observed. Pharmacokinetic (PK) studies were also carried out.

Methods:
Platelet aggregation responses to TRAP, adenosine diphosphate (ADP), collagen and arachidonic acid (AA) were measured using light transmission aggregometry (LTA) at baseline, 30, 60, 90, 120 min following a loading dose (10, 20 or 40 mg vs placebo) and after a maintenance dose (0.5, 1.0 or 2.5 mg/day) at 30 and 60 days. PK was assessed at 30 and 60 min and 2 hr after loading dose administration.

Results:
TRA was active in inhibiting 15 μM TRAP-induced platelet aggregation with onset of inhibition directly related to dose. Loading doses of 10, 20 or 40 mg achieved >90% inhibition of platelet aggregation (IPA) 60 –120 min post dose with the 40 mg dose achieving >90% inhibition between 60 and 90 min. Patients receiving maintenance doses of 0.5, 1.0 or 2.5 mg exhibited >90% IPA at 30 and 60 days. Placebo treated patients had on average ≥10% IPA to TRAP. TRA had no significant effects on ADP, collagen or AA -induced platelet aggregation compared with placebo controls. TRA PK was characterized by fast distribution and slow elimination (t1/2 = 165–311 hr) with clear evidence of hysteresis.

Conclusion:
Among PCI patients treated with TRA, there was a specific, dose-related, sustained inhibition of TRAP-induced platelet aggregation, without an impact on other aggregation related pathways. These data suggest that TRA is a potent, selective inhibitor of PAR-1 activity induced by thrombin activation of platelets, and, in view of this, is a promising therapeutic utility for treatment of thrombosis.
Abstract 3017: Physiological Factors Associated with Fatigue in Older Adults after Myocardial Infarction
Authors: Crane Patricia B , Allen Jerilyn
Published: July 2021

Fatigue after myocardial infarction (MI) is a barrier to secondary prevention behaviors such as engaging in recommended levels of physical activity. However, little is known about physiologic factors that may contribute to fatigue. The purpose of this study was to describe the prevalence of fatigue in older adults after MI and to examine the associations of physiological factors of cardiac function (b-natriuretic peptide [BNP], mean arterial pressure, heart rate), inflammation (IL-6), BMI, and hemoglobin (Hgb) with self-reported fatigue.

Methods:
A convenience sample of women (
n
=49) and men (
n
=49) ages ≤65 completed questionnaires and underwent physiologic measures 6 – 8 months after discharge post MI. Subjects completed a demographic health form and fatigue measures (Revised Piper Fatigue Scale and the Multidimensional Assessment of Fatigue Scale functional items), and had height, weight, pulse, and blood pressure measured. Fatigue was measured as a total score (range 0 –310) and as 5 subscales (behavior/severity, affective, sensory, cognitive/mood, and function). Blood samples were also taken, and Hgb, IL-6, and BNP were measured in the same laboratory using standardized procedures.

Results:
Patients were an average of 75.69 ± 6.45 years of age. Fatigue was reported by 75 (77%) with a mean score of 102.46 (SD=57.7; range 8 –235). More women (84%) reported fatigue than men (69%), though this difference was not statistically significant. Patients reported higher fatigue scores on the behavior/severity and sensory subscales compared to the other fatigue subscales. Bivariate correlations of physiological factors and the total fatigue score revealed one significant physiological correlate, IL-6 (
r
=.29). Controlling for age and gender, a multiple linear regression model explained 8.7% of the variance in fatigue (
F
= 2.769
; p
<.05) with IL-6 as the only significant independent variable (
p
=.010). An unexpected finding was that BNP did not correlate with fatigue.

Discussion:
Fatigue is prevalent in the majority of older adults after MI. Results indicate that inflammation may play a stronger role in fatigue than other physiological factors. Further research is needed to examine how inflammation and other physiologic factors may influence fatigue post MI.
Abstract 3021: Fatigue as a symptom of Acute Myocardial Infarction
Authors: Eckhardt Ann , Fennessy Michelle , Fink Anne , Jones Jessica , Szigetvari Kathryn , Kruse Donna , Tucco Laura , Ryan Cathy , Zerwic Julie J
Published: July 2021

Purpose: Fatigue may be a commonly experienced symptom of acute myocardial infarction (AMI); however, there is a disturbing lack of data about the fatigue that occurs among men and women at the time of AMI. The purpose of this study was to characterize the fatigue experienced among men and women during AMI using three validated fatigue questionnaires.

Method: Ninety AMI patients were recruited from six Midwestern hospitals. The Profile of Mood States (POMS), Fatigue Severity Index (FSI), and the Short Form 36 Health Survey (SF-36) were completed by each hemodynamically stable subject.

Results: The sample included 76% men (mean age = 61, SD = 10), 24% women (mean age = 59, SD = 13); 78% non-Hispanic white. Subjects scored 1.7 on the POMS fatigue subscale (0 = none, 4 = extremely), 47.3 on the SF-36 vitality subscale (0 = most, 100 = least), and 6.4 on the “most fatigued” item of the FSI (0 = not fatigued at all, 10 = as fatigued as I could be). Scores from AMI subjects were compared to published scores in other populations. Compared to older adult male subjects, AMI subjects had higher levels of fatigue on the POMS fatigue subscale (M = 0.71, t = 7.2, p < 0.001) and the SF-36 vitality subscale (M = 51.0, t = 2.85, p < 0.01). In addition, AMI patients were more fatigued on the “most fatigued” item of the FSI compared to cancer patients in active treatment (M = 5.5, t = 2.28, p = 0.05). Men and women reported similar levels of fatigue across all three measures; however, women reported that fatigue caused more disruption of activities of daily living (p < 0.001), more difficulty with physical activities (p < 0.01), poorer rating of general health (p < 0.05), and more interference with social activities (p < 0.05).

Conclusion: To date, fatigue as a symptom of AMI has focused on using qualitative methods in women. This study used three well-established measures of fatigue to demonstrate that fatigue is commonly experienced by both men and women and at levels that are higher than a healthy older adult sample and cancer patients. Interestingly, fatigue had a greater negative impact on women’s lives.
Abstract 3040: Coronary Artery Bypass Surgery In 14,956 Patients With Cardiogenic Shock: The Society Of Thoracic Surgeons National Database Experience
Authors: Mehta Rajendra H , Grab Joshua D , O’Brien Sean M , Glower Donald D , Jacobs Jeffrey P , Puskas John D , Gammie James S , Peterson Eric D
Published: July 2021

Background

. While only a small minority of patients undergo coronary artery bypass surgery (CABG) in the setting of cardiogenic shock (CS), these patients face a high risk for mortality and morbidity. There exist few studies that characterize clinical features and outcomes in CS patients undergoing CABG in contemporary community practice.

Methods

. We evaluated data of 14,956 patients with CS in comparison with 693637 without CS undergoing CABG between 2002 and 2005 at hospitals participating in the Society of Thoracic Surgeons National Database. Clinical, angiographic and operative features and in-hospital outcomes were studied in patients with and without CS.

Results

. Patients with preoperative CS constituted 2.1% of patients undergoing CABG yet accounted for 16% of all CABG deaths. These patients had greater comorbid conditions and left main disease and lower left ventricular ejection fraction. In-hospital events and length of hospital stay (median 96 vs. 36 days) were significantly higher in CS patients. Operative mortality was high (rising from 20% for isolated CABG, to 33% for CABG+ valve surgery, to 58% for CABG+ ventricular septal repair). While mortality for CABG surgery overall has declined significantly overtime (p for trend< .0001), mortality for CS patients have not changed significantly over the 4 year study period (p= .07, Figure

).

Conclusions

. Patients with CS represents minority of patients undergoing CABG, yet with persistently high operative risks. These patients in fact account for 1 of every 7 deaths in patients undergoing CABG. Ongoing efforts are warranted to continuously develop and evaluate new strategies to improve outcomes of these patients.
Abstract 3047: What Are the Effects of Nonsteroidal Anti-Inflammatory Drugs on Post-Cardiothoracic Surgery Outcomes?
Authors: Ruffin Richard T , Kluger Jeffrey , Wills Stephanie M , White C M , Coleman Craig I
Published: July 2021

Background:
Two previous studies evaluating nonsteroidal anti-inflammatory drug (NSAID) use following cardiothoracic surgery (CTS) demonstrated conflicting evidence regarding their ability to reduce the incidence of postoperative atrial fibrillation (POAF). Moreover, neither study examined negative cardiovascular outcomes such as stroke and myocardial infarction (MI). Since a recent study evaluating paracoxib/valdecoxib following CTS demonstrated an increased risk of cardiovascular events, we sought to evaluate whether NSAIDs could reduce the incidence of POAF without increasing patients’ risk of stroke or MI.

Methods:
Patients (n=555) undergoing CTS from the randomized, controlled Atrial Fibrillation Suppression Trials (AFISTs) I, II and III were evaluated in this nested study. Demographic, surgical and medication use characteristics were prospectively collected as part of the AFIST trials. Endpoints included POAF, stroke, MI and the need for red blood cell transfusion. Multivariable logistic regression was used to calculate odds ratios with 95% confidence intervals.

Results:
The population was 67.8 ± 8.6 years old, 77.1% male, 14.6% underwent valve surgery, 6.1% had prior AF, 12.6% had heart failure and 84.0% and 44.1% received postoperative beta-blockade and prophylactic amiodarone. In total, 127 (22.9%) patients received a NSAID postoperatively. NSAID use was associated with reductions in the odds of POAF and the need for RBC transfusions. (Table

) No elevation in the odds of developing stroke or MI was observed.

Conclusions:
NSAIDs decreased the odds of developing POAF and the need for RBC transfusions without significantly increasing MI or stroke.

Table.

Effect of Nonsteroidal Anti-Inflammatory Drugs on Postoperative Outcomes
Abstract 3050: Assessment of Genetic Risk for Thoracic Aortic Aneurysm Among Hypertensive Patients
Authors: Kato Kimihiko , Oguri Mitsutoshi , Yoshida Tetsuro , Hibino Takeshi , Yajima Kazuhiro , Fujimaki Tetsuo , Yoko Kiyoshi , Matsuo Hitoshi , Warita Shunichiro , Segawa Tomonori , Watanabe Sachiro , Metoki Norifumi , Yoshida Hidemi , Satoh Kei , Nozawa Yoshinori , Ichihara Sahoko , Yamada Yoshiji
Published: July 2021

Introduction:
Aneurysms and dissections at the thoracic aorta (TAA) are the leading causes of mortality and morbidity in the United States and Japan. Although hypertension is a major risk for TAA, several studies have indicated that genetic factors also influence the structural formation of TAA. The purpose of the present study was to identify gene polymorphisms associated with TAA among hypertensive patients for assessment of the genetic risk for this condition.

Methods:
This case-control study comprised 1351 hypertensive individuals, including 88 subjects with TAA and 1263 without any cardiovascular complications. The genotypes for 142 polymorphisms of 121 candidate genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology.

Results:
Evaluation of genotype distributions by the chi-square test and subsequent multivariable logistic regression analysis with adjustment for age, sex, body mass index, and prevalence of smoking, diabetes mellitus, hypercholesterolemia, and metabolic syndrome revealed that the T→G (3′ UTR) polymorphism of the thrombospondin 2 gene (
THBS2
; odds ratio, 4.7) is significantly (P < 0.05) associated with TAA in hypertensive subjects, with the variant
G
allele representing a risk factor for this condition. Furthermore, the -110A→C polymorphism of heat-shock 70-kD protein 8 gene (
HSPA8
; odd ratio, 0.3), the C→T (Pro198Leu) polymorphism of the glutathione peroxidase gene (
GPX1
; odds ratio, 0.3), the -6G→A polymorphism of angiotensin 1 gene (
AGT
; odds ratio, 0.3), and the -850C→T polymorphism of tumor necrosis factor gene (
TNF
; odds ratio, 0.5) were significantly associated with this condition, with the variant allele of each polymorphism being protective against this condition. A stepwise forward selection procedure revealed that polymorphisms of
THBS2
,
HSPA8
,
GPX1
,
AGT
, and
TNF
significantly affected the prevalence of TAA.

Conclusions:
Genetic variant of
THBS2
may be a risk factor for TAA in hypertensive patients, whereas variants of
HSPA8
,
GPX1
,
AGT
, and
TNF
may be protective against this condition. Determination of genotypes for these polymorphisms may prove informative for assessment of the genetic risk for TAA.
Abstract 3074: Success Rate Safety of CRT Devices Implantation : Results from the CARE-HF Trial.
Authors: Gras Daniel , Böcker Dietrick , Lunati Maurizzio , Wellens Hein J , Calvert Melanie , Freemantle Nick , Gervais Renaud , Kappenberger Lukas , Tavazzi Luigi , Erdmann Erland , Cleland John G , Daubert Claude
Published: July 2021

Objectives:
To assess procedural characteristics and adjudicated procedure-related (≤30 days) major adverse events among patients who underwent cardiac resynchronization therapy (CRT) implantation in the CARE-HF study.

Background:
The CARE-HF study shows that CRT improves symptoms and reduces morbidity and mortality in New York Heart Association (NYHA) class III/IV chronic heart failure (CHF) patients. However, safe and proper implantation of pacing systems remains key to effective CRT delivery.

Methods:
Generalized linear modeling was used to examine the relationships between 1
st
implant success/failure and: NYHA class; beta-adrenergic blocker use; underlying ischemic versus non-ischemic heart disease; history of coronary artery bypass graft or valve surgery; left ventricular (LV) end-diastolic volume ≤ versus >300 cm
3
; and, influence of the participating study-centers.

Results:
Implantation was attempted in 404/409 patients assigned to CRT, and in 65/404 patients assigned to medical therapy. Among these 469 patients, 450 (95.9%) received a successfully implanted and activated device. Complications occurred within 24 h in 47 patients (10.0%), mainly lead dislodgments (n=10, 2.1%) and coronary sinus dissection/perforation (n=10, 2.1%), and between 24 h and 30 days in 26 patients (5.5%), mainly lead dislodgment (n=13, 2.8%). Mean LV lead stimulation threshold was significantly higher than at the right atrium or right ventricle, though remained stable, delivering effective and reliable CRT. Implanting experience was the only predictor of procedural outcome.

Conclusions:
Transvenous CRT system implantation, using a CS lead designed for long-term LV pacing, was safe and reliable. As implanting centers become more experienced, this success rate is expected to increase further.