bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 16968: Troponin I Is an Independent Predictor of Long-Term Coronary Events Following Myocardial Infarction or Unstable Angina: Results from the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Trial
Authors: White Harvey D , Tonkin Andrew , Mann Kristy , Simes John , West Malcolm , Blankenberg Stefan ,   LIPID study investigators
Published: April 2024

Background
The role of higher-sensitivity troponins in predicting long-term outcomes in patients with stable CHD is not clearly defined.

Objective:
To assess the value of a higher sensitivity troponin I (TnI) assay to predict outcomes during median follow-up of 6 years and to assess the effect of pravastatin on TnI levels and outcomes.

Methods
Among 9014 patients in LIPID with cholesterol levels 4.0-7.0 mmol/L randomized to placebo or pravastatin after MI or unstable angina 3-36 months previously, TnI levels (Siemens ultra, level of detection 0.006 ng/mL, 99th percentile with CV 10% 0.04 ng/mL) were measured at randomization and at 1 year. Baseline TnI levels (ng/ml) were assessed in 3 groups: not detectable (38%), 0.006-0.018 (31%), and ≥0.018 (31%), and change over 1 year defined as a change in group.

Results
Patients with the highest TnI levels were older, more likely to have previous MI, and to be on ACE inhibitors but less likely to be on beta-blockers. Levels of TnI at 1 year had decreased in 25%, were unchanged (51%) or increased (23%), but pravastatin had no effect on TnI levels. In a multivariable Cox regression for CHD death or nonfatal MI, HR was 2.02 (95% CI 1.66-2.45),
P
<0.001, for levels of TnI above the reference 99th percentile (0.04 ng/mL), vs undetectable levels, adjusted for baseline risk factors. In multivariable landmark analysis of 6544 patients event-free at 12 months, baseline TnI levels and changes in TnI were both independent predictors of subsequent CHD events (
P
<0.001), even after adjustment for 23 traditional risk factors, including treatment. The effect of pravastatin in reducing CHD events remained highly significant in each model (
P
<0.02) and was independent of TnI levels.

Conclusions
Baseline and change to 1 year in TnI levels, additional to traditional risk factors, were independent predictors of CHD death and MI. TnI was more powerful for predicting fatal than nonfatal events (table), and the benefits of pravastatin were independent of TnI levels.
Abstract 16999: Supraventricular Tachycardia Radiofrequency Catheter Ablation is Associated with a Decrease in Hospitalizations and Emergency Department Visits Post-Procedure
Authors: Doris Jonathan , Turner Jonathan , Gupta Nigel , Brar Somjot S
Published: April 2024

BACKGROUND:
Ablation of supraventricular tachycardia (SVT) is commonly performed in patients symptomatic on medical therapy. The impact of SVT ablation on resource utilization, rehospitalization and emergency department (ED) visit rates, remains unknown.

METHODS:
Consecutive patients undergoing supraventricular tachycardia (SVT) radiofrequency catheter ablation were identified (excluding atrial fibrillation). All patients were members of an integrated pre-paid health plan in Southern California. Subjects were required to have at least 12 months of health plan membership prior to and after the procedure date. The number of all-cause hospitalizations and ED visits 12-months before and after the procedure date were ascertained for each subject. Logistic regression was used to model the probability of a decrease in hospitalizations and ED visits post-SVT ablation.

RESULTS:
There were 1928 patients meeting study criteria who underwent SVT ablation between 1999 and 2010. The mean age was 52 ± 17 years and 58% were female. In the 12-months preceding the ablation procedure, 75% of the patients had at least one hospitalization or ED visit; in contrast, only 35% had one hospitalization or ED visit in the 12-months post-ablation. The incidence rate ratio was 0.47 (0.43 - 0.51; p<0.001), corresponding to a 53% reduction in hospitalizations or ED visits post-ablation. This reduction in events post-ablation was observed for all age groups; however, the reduction was greatest in younger patients (see figure).

CONCLUSIONS:
Ablation of supraventricular tachycardia was associated with a statistically significant reduction in all-cause hospitalizations and ED visits post-procedure. These data suggest SVT ablation is highly efficacious and cost-effective in appropriate patients.
Abstract 17003: Post-Operative Expansion of the Red Cell Distribution Width Powerfully Predicts Poor Outcomes After Aortic Valve Surgery
Authors: Connell Alistair , Aggarwal Suneil , Papalia Francesco , Flint Julia , Weissert Susanne , Aung Nay , Richards Toby , Okonko Darlington O
Published: April 2024

Red cell distribution width (RDW), an index of the variation in red cell volume, is a surrogate of many aberrations (iron deficiency, inflammation, malnutrition and oxidative stress) that could impair early and late outcomes after aortic valve replacement (AVR). Whilst an increase In RDW powerfully predicts morbidity and mortality in heart failure and PCI patients, its prognostic relevance in AVR cohorts is unknown.

Methods:
We analysed the relation of changes in RDW over time to outcomes in 1177 AVR patients (mean [±SD] age 68±13 years, RDW 14.1±1.6%, hemoglobin 12.9±1.8g/dL, EuroSCORE 6±3, 63% male, 24% with ejection fractions [EF]<50%, 60% aortic stenosis, 17% aortic regurgitation, 17% mixed aortic disease).

Results:
Pre-operatively, 19% of patients had an RDW≥15%. This group were more likely to be female (43% vs 36%), non-elective cases (47% vs 26%) with poorer LVEFs (35% vs 21% with LVEF<50%), have greater congestive symptoms (17 vs 7), and spend more days ventilated (1.7 vs 1.2) and hospitalized (17 vs 14) (all P<0.05). Over a median (±IQR) stay of 8±5 days, 906 (77%) patients had an increase in RDW and 39 (3.3%) died in hospital. Early mortality was related to an increase in RDW over time (HR 1.4, CI:1.2-1.5, P1.6% optimally predicting death (HR 4.0, CI:2.0-8.0, P<0.0001, Figure
A
). This was independent of age, LVEF, EuroSCORE, Parsonnet score, hemoglobin and creatinine. Of the 1138 patients who survived to discharge, 88(8%) died over a median follow-up of 4 years. Late mortality was also related to a rise in RDW (HR 1.3, CI: 1.2-1.4, P0.9% optimally predicting death (HR 3, CI:2-5, P<0.0001, Figure
B
), independently of all covariates.

Conclusions:
An Increase in the RDW post-AVR is associated with an amplified risk of early and late surgical mortality. Understanding and ameliorating the drivers of RDW expansion in this cohort may increment survival.
Abstract 17013: Transverse (T)-tubules Are Widespread in the Human Atrium
Authors: Richards Mark A , Clarke Jessica D , Saravanan Palaniappan , Voigt Niels A , Dobrev Dobromir , Eisner David A , Trafford Andrew , Dibb Katharine M
Published: April 2024

Background:
T-tubules are invaginations of the sarcolemma, present in mammalian ventricular myocytes. T-tubules bring the cell interior close to sarcolemmal membrane, allowing a rapid rise in intracellular Ca upon stimulation. The atria was generally assumed to lack t-tubules due to their virtual absence in the atria of small mammals; therefore Ca release occurs only slowly from the cell centre. Recent work has however shown t-tubules in sheep atria resulting in rapid Ca release in the cell interior, fundamentally altering our view of atrial function. Furthermore atrial t-tubules are lost in disease, dramatically slowing intracellular Ca. The purpose of this study was to determine if the human atrium possesses t-tubules.

Methods:
Samples of right atrial appendage from 9 patients in sinus rhythm were frozen in OCT, sectioned, fixed and incubated with wheat germ agglutinin (WGA)-, Alexa Fluor® 488 conjugate to stain t-tubules and surface membrane. Image stacks were captured confocally, deconvolved and analyzed in Image J.

Results:
T-tubules were present in each sample. The figure shows a transverse, 2 μ m thick human atrium section following staining. T-tubules are clearly present in 3 cells to varying degrees. T-tubules were present in 59 from 86 cells (51 tissue sections) i.e. 69% of human atrial cells. To quantitatively assess the importance of t-tubules in bringing the cell interior close to sarcolemmal membrane we have calculated the distance that points in the cell lie from the surface sarcolemma and surface and t-tubular sarcolemma together. Excluding t-tubules, half the points lie within 2.2 ± 0.2 μ m of sarcolemma and this distance is approximately halved by considering surface and t-tubule sarcolemma together (1.0 ± 0.2 μ m;
p
<0.001, n=9 cells from 4 patients).

Conclusion:
We have shown, for the first time, the presence of t-tubules in human atrium. The role of human atrial t-tubules during excitation contraction coupling and disease remains to be determined.
Abstract 17019: Age-Specific Trends in Acute Myocardial Infarction Hospitalization in Minneapolis/St. Paul
Authors: Smith Lindsay G , Berger Alan K , Jacobs David R , Luepker Russell V
Published: April 2024

Background:
Hospitalizations for acute myocardial infarction (AMI) declined during the past 40 years. However, some studies suggest rising rates of AMI in young adults associated with the increasing prevalence of obesity and diabetes, but there are few data in this group. We hypothesized an increase in the rate of AMI hospitalizations among young and middle-aged adults (<50 years) and a decline among older adults.

Methods:
Data from the Minnesota Hospital Association (MHA) were utilized to identify patients hospitalized with a primary discharge diagnosis of AMI (ICD-9 410) at the 20 acute care hospitals within the Minneapolis-St. Paul metropolitan area (2.85 million) between 1999-2008.

Results:
From 1999 to 2008, there were 42,850 AMI hospitalizations (4507 in 1999, 3904 in 2008; 13.4% decline) among those aged ≥ 30 years. Among women, the age-standardized rate of AMI hospitalization declined from 239 in 1999 to 169 in 2008, representing an annual proportionate decline of 3.2% (p=0.01) [Table]. Despite the overall decline, the rates of hospitalization among women 30-39 and 40-49 increased during this period (by 1.9% and 2.3%, respectively). In 1999, women aged 30-49 accounted for 5.5% of AMI hospitalizations in all women. By 2008, this age group accounted for 9.2% of hospitalizations. Among men, the age-standardized rate of AMI hospitalizations declined from 506 to 351 during this period (annual proportionate decline of 4.8%, p=0.003). The proportionate decline was lowest among men aged 30-39 (2.7%).

Conclusion:
In an era of decreasing hospitalization for AMI, differences in trends exist by sex and age. AMI hospitalizations rates increased among young and middle-aged women between 1999 and 2008, potentially due to increased attention paid to heart disease among women, the use of more sensitive biomarkers or actual increase in risk. Despite the aging population, the overall AMI hospitalization case burden decreased by 13% between 1999 and 2008.
Abstract 17085: MicroRNA-24 Prevents Apoptosis and Preserves Cardiac Function after Myocardial Infarction Through Cell-Autonomous Effects in Cardiomyocytes
Authors: Qian Li , Van Laake Linda W , Huang Yu , Srivastava Deepak
Published: April 2024

Background
Apoptosis due to myocardial infarction (MI) leads to an irreversible loss of cardiomyocytes. MicroRNAs may influence this process by post-transcriptionally regulating the expression of proteins involved in apoptotic pathways. We have previously shown that exogenous application of miR-24 after coronary artery ligation in mice preserves cardiac function by repressing the pro-apoptotic protein Bim. Here, we investigate whether miR-24 delivered by local injection exerts its effects primarily within cardiomyocytes or non-cell autonomously through neighboring cells.

Methods
We genetically targeted miR-24 under control of the cardiac-specific Myh6 promoter, and selected a line of transgenic mice (αMHC-miR-24 mice) with six fold greater expression of miR-24 than control littermates. MI was induced by coronary artery ligation. Apoptosis and infarct size were quantified with TUNEL assays (n=16) and AZAN staining (n=15) 24 hours and 4 weeks post-MI, respectively. Cardiac function was measured by high-resolution echocardiography at baseline and 3 days and 4 weeks post-MI (n=42). QRT-PCR and Western blotting were performed on cardiac tissue 24 hours post-MI (n=6).

Results
αMHC-miR-24 mice were protected against apoptosis after MI compared to wildtype littermates as indicated by reduced numbers of TUNEL-positive cardiomyocytes in the ischemic zone and border zone compared to wildtype littermates. Cardiac function was preserved (Ejection fraction 55.0 ± 0.9 vs. 56.9 ± 0.9 % at baseline, p=NS, 32.8 ± 1.7 vs. 28.1 ± 1.6% at 3 days, p<0.05, 26.7 ± 1.9 vs. 21.9 ± 1.4% at 4 weeks, p<0.05; Fractional shortening 32.9 ± 1.1 vs. 32.5 ± 1.1% at baseline, 15.1 ± 0.5 vs 12.6 ± 0.08% at 3 days, p<0.05, 15.0 ± 0.9 vs. 12.0 ± 0.7% at 4 weeks, p<0.05). Hearts of αMHC-miR-24 mice exhibited lower levels of Bim protein, lower levels of stress markers such as ANF and BNP and partially restored levels of dysregulated miRNAs 19a, 195 and 208, similar to miR-24 mimic injection in the heart.

Conclusion
The similarity between the effects of local delivery and cardiomyocyte-specific overexpression of miR-24 provides evidence that miR-24 improves left ventricular function after myocardial infarction by cell autonomously inhibiting cardiomyocyte death.
Abstract 17103: VEGF-Mimicking Nanostructures for Ischemic Tissue Repair
Authors: Tongers Jörn , Webber Matthew J , Newcomb Christina J , Bauersachs Johann , Stupp Samuel I , Losordo Douglas W
Published: April 2024

Purpose:
Repair of ischemic tissue remains an unsolved goal. Current strategies aim to enhance perfusion and, thereby, overcome dysfunction of ischemic tissue. Neovascularization can be achieved via pro-angiogenic agents that enhance sprouting from preexisting vessels (angiogenesis). Due to practical limitations, therapeutic angiogenesis has not shown convincing results in patients. Advances in bionanotechnology, however, enable the development of specific biomaterials to therapeutically improve recovery.

Methods/Results:
We chose the self-assembling peptide amphiphile (PA) nanofiber platform to design a pro-angiogenic nanofiber that mimics the activity of a pro-angiogenic factor VEGF (VEGF-PA) to enhance angiogenesis. Incubation of human umbilical vein endothelial cells (HUVECs) with VEGF-PA induced cellular functions important for angiogenesis: Compared to untreated control cells, HUVECs treated with VEGF-PA were more resistant to serum-starvation (Annexin staining: VEGF-PA 10±3%, control 32±3, n=6, P<0.001), more mitogenic (CyQuant proliferation assay: VEGF-PA 137±2%, control 100±1%, n=8, P<0.001), and migrated better (scratch assay, reduction of denuded area: VEGF-PA 69±4, control 25±13%, n=6, P<0.05). In a chicken embryo angiogenesis assay, VEGF-PA showed a substantial pro-angiogenic activity (VEGF-PA 229±19%, saline 132±5%, n=16, P<0.001). Local injection of VEGF-PA enhanced limb recovery after surgical hind-limb ischemia in 8-week-old, male FVB/N mice. At day 28, VEGF-PA treated animals showed better perfusion (laser Doppler, ischemic/non-ischemic limb ratio: VEGF-PA 0.7±0.1, saline 0.5±0.1, P<0.05), less tissue damage (score: VEGF-PA 4.2±0.2, saline 3.5±0.2, P<0.05), and better motor function (score: VEGF-PA 4.2±0.2, saline 3.4±0.2, P<0.01) of the ischemic limb. Better recovery after VEGF-PA treatment is associated with more CD31+ capillaries in the ischemic muscle (VEGF-PA 1582±76/mm2, saline 93±53/mm2, P<0.001).

Conclusion:
Self-assembling, pro-angiogenic PA nanofibers mimicking VEGF enhance ischemic tissue repair and thereby constitute a novel therapeutic alternate to overcome practical limitations in therapeutic angiogenesis.
Abstract 17112: Impact of Hyperparathyroidism on Left Ventricular Structure: A Meta Analysis of 367 Patients
Authors: Hachamovitch Rory , Seicean Sinziana , Cook Thomas , Marwick Thomas
Published: April 2024

Background.
Primary hyperparathyroidism (PHPT) is associated with an increased risk of cardiovascular mortality. To date, studies comparing left ventricular (LV) structure in patients (pts) with untreated PHPT to controls have reported mixed results. To this end, we performed a meta-analysis of studies comparing LV structure in untreated PHPT pts versus controls using echocardiographic techniques.

Methods.
The published literature was scanned using searches of electronic databases (PubMed, MEDLINE) and references of relevant articles. The primary echocardiographic metrics included LV mass index (LVMI), LV posterior wall thickness (PWT), and interventricular septal thickness (IVST). PHPT pts were compared to controls with respect to pooled estimates of difference in means and 95% confidence intervals (95%CI) using a weighted random effects model.

Results.
We identified 12 studies that including 367 PHPT pts and 404 controls (76% female, 74 years, parathyroid hormone 4.0 times normal). In these studies, LVMI was greater in PHPT pts versus controls (9 studies; p=0.045; difference in means 9.4 gram/m2, 95%CI 0.2-18.6). This difference was related to increases in both IVST (p=0.002; difference in means 0.47mm, 95%CI 0.17-0.77) and PWT (p=0.047; difference in means 0.47mm, 95%CI 0.01-0.94). No differences in systolic or diastolic LV volumes were noted, or in fractional shortening (all p=NS). Diastolic function, as measured by E/A and interventricular relaxation time was also unchanged (all p=NS).

Conclusions.
Compared to controls, pts with untreated PHPT have greater LV mass index and LV wall thickness without alteration in LV volumes or function. These findings may contribute to the increased cardiovascular risk found in these pts.
Abstract 17118: Isolated Diastolic Hypotension Without Systolic Hypotension or Hypertension is an Independent Risk Factor for Incident Heart Failure Among Community-Dwelling Older Adults
Authors: Guichard Jason L , Zhang Yan , Pepine Carl J , Aban Inmaculada B , Love Thomas E , Calhoun David A , Aronow Wilbert S , Deedwania Prakash C , Ahmed Ali
Published: April 2024

Background:
We have previously demonstrated that isolated diastolic hypotension (IDH), as defined by diastolic blood pressure (DBP) <60 mm Hg with systolic blood pressure (SBP) >100 mm Hg, is a significant independent risk factor for incident heart failure (HF) in older adults with and without hypertension (
2010 ACC Abstract 1241-109
). However, confounding by systolic hypertension was a concern and whether this association would persist in those without hypertension remained unclear.

Methods:
Of the 5795 community-dwelling older adults, age ≥65 years, in the public-use copy of the Cardiovascular Health Study data obtained from the National Heart, Lung and Blood Institute, 3298 had SBP between 100 and 139 mm Hg, of whom 594 (19%) had IDH (DBP <60 mm Hg). Propensity scores for IDH, calculated for each of the 3298 participants, were used to assemble a matched cohort of 548 pairs of individuals with and without IDH who were balanced on 40 baseline characteristics.

Results:
Matched participants had a mean (±SD) age of 73 (±5) years, 62% were women, and 7% were African American. Matched participants with and without IDH had a mean SBP of 120.0 and 120.3 mm Hg respectively (p=0.618). Centrally-adjudicated incident HF occurred in 23% and 16% of matched participants with and without IDH respectively (matched HR, 1.47; 95% CI, 1.12-1.93; p=0.005;
Figure
). IDH had no significant association with all-cause mortality among matched participants (matched HR, 1.18; 95% CI, 0.99-1.42; p=0.067).

Conclusion:
Among community dwelling older adults, isolated diastolic hypotension, in the absence of systolic hypotension or hypertension, was associated with a significant increased risk of new-onset HF but had no significant association with all-cause mortality.
Abstract 17136: Irx3 and Irx5 Cooperatively Regulate Mouse Heart Development and Adult Cardiac Function
Authors: Gaborit Nathalie , Zhang Shan-Shan , Wylie John , Sakuma Rui , Hui Chi-Chung , Bruneau Benoit G
Published: April 2024

Transcriptional regulation of heart development takes place via spatio-temporal and coordinated expression of multimeric complexes of transcription factors. Members of the Iroquois homeobox (Irx) family of transcription factors are expressed in highly cell type-specific and often overlapping patterns in the developing heart, suggesting that these genes may interact in important pathways during cardiogenesis. Single deletions of Irx genes showed subtle but significant defects in several aspects of cardiac function, including cardiac repolarization for Irx5, and ventricular conduction for Irx3. Additionally, Irx3 and Irx5 expression overlap in the cardiac ventricular chambers. Our study suggests that their overlapping expression may mask additional roles of these genes in cardiac development and adult function. Supporting a combinatorial role in pre-natal cardiac development, mice lacking both Irx3 and Irx5 are embryonically lethal due to major structural heart defects that model human congenital heart disease, including a common atrio-ventricular canal and a double outlet right ventricle. We show that the cardiac phenotype originates from the loss of function of Irx3 and Irx5 in endocardial cells. In the adult heart, our data suggest that Irx3 and Irx5 double knockout mice have a prolonged QRS complex and PR interval that is worse than the Irx3 single knockout mice. Moreover, the T wave absent in the Irx5 single knockout mice reappears with the additional deletion of Irx3. These results strongly suggest a role for Irx3 and Irx5 in the ventricular conduction of the electrical influx. All together, our data suggest that Irx3 and Irx5 cooperatively regulate heart development and adult cardiac function.
Abstract 17139: Cathepsin S Deficiency Attenuates AngiotensinII-induced Abdominal Aortic Aneurysm Without Altering Hypertension in ApoE Knockout Mice
Authors: Kim Chanwoo , Son Dongju , Albert-Grill Noah , Kumar Sandeep , Jo Hanjoong
Published: April 2024

Abdominal aortic aneurysm (AAA) formation is characterized by weakening of the vessel wall, followed by progressive expansion and eventual rupture of the diseased aortic segment. Extracellular matrix remodeling contributes importantly to the pathogenesis of cardiovascular diseases such as atherosclerosis and abdominal aortic aneurysms. The cysteine protease, cathepsin is one of the most potent mammalian elastases and collagenases, which were highly expressed in the AAA wall compared to that in healthy arteries. Here, we examined the hypothesis that Cat S and Cat K plays a key role in AAA formation. When infused with Angiotensin II (Ang II; 1 μg/kg/min) using osmotic pumps for 28 days, 69% of ApoE KO mice (9 of 13 mice), 75% of Cat K_ApoE DKO (6 of 8 mice) and only 7% of Cat S_ApoE DKO (1 of 13 mice) developed AAA as determined by increases in abdominal aorta diameter by more than two-fold above control. In mice infused with angiotensin II, mortality due to aortic rupture occurred more frequently in ApoE KO mice (4 of 13 mice; 30%) compared to Cat K_ApoE DKO mice (1 of 8mice; 12.5%) and Cat S_ApoE DKO mice (1 of 13 mice; 7%). AngII infusion also significantly increased systemic blood pressure (155-165 mmHg) in ApoE KO mice (n=13), Cat K_ApoE DKO (n=8) and Cat S_ApoE DKO (n=13) mice but, there are no significant difference between the groups. Our results showed that Cat K gene deficiency does not affect AAA development while Cat S gene deficiency dramatically prevented Ang II-induced AAA formation without altering hypertension. These data suggest that Cat S plays a central role in AAA development. Targeting the Cat S may lead to an important therapeutic intervention for preventing AAA formation
Abstract 17176: Adiponectin, Metabolic Factors and CRP Changes with a Lifestyle Intervention for Weight Loss in Men and Women with Diabetes: Insights From the Look Ahead (Action for Health in Diabetes) Study
Authors: Belalcazar L. Maria , Lang Wei , Haffner Steven M , Hoogeveen Ron C , Tracy Russell P , Balasubramanyam Ashok , Schwenke Dawn C , Pi-Sunyer F. Xavier , Ballantyne Christie M ,   The Look AHEAD Rsch Group
Published: April 2024

Adiponectin (ADN) has anti-inflammatory effects. In obese diabetic persons, ADN levels are low and CRP levels are high. The associations of changes in total (T) ADN and its high molecular-weight oligomer (HMW-ADN) with CRP change (Δ) in response to an intensive lifestyle intervention for weight loss (ILI) have not been examined within a clinical trial. Little is known about the effects of metabolic changes by sex on these associations in diabetes.

Methods:
Using regression analyses, we examined whether T-ADN and HMW-ADN changes with a 1-year ILI would be associated with CRP Δ in a subset of 1,397 Look AHEAD participants with biomarker data, when compared to usual care, after accounting for weight, HbA1c, HDL-C and fitness changes. Look AHEAD is a randomized trial examining whether ILI, when compared to usual care, will reduce CV events in obese type 2 diabetic persons.

Results:
ILI resulted in greater CRP reductions and increases in T-ADN and HMW-ADN, when compared to usual care (p≤ 0.0001 for all). CRP Δ with ILI was similar in men and women (≈ -40%). The increases in T-ADN and HMW-ADN were greater in men (23.6 and 13.5%) than in women (6.2% and 14.8%), respectively. Change in T-ADN and HMW-ADN in men and in T-ADN in women were significantly associated with CRP Δ, independently of weight, HDL-C, fitness and HbA1c changes (See Table). Fitness change in men and weight change in women, but not HbA1c or HDL-C changes, were associated with CRP Δ after adjusting for T-ADN and HMW-ADN change in separate models.

Conclusion:
In obese diabetic subjects, T-ADN and HMW-ADN are associated with changes in CRP with differential effects in male and female participants, with weight playing a greater role in women and fitness a greater role in men.
Abstract 17192: 3T Myocardial Perfusion Imaging with Multitransmit Technology Compared to Coronary Angiography and FFR
Authors: Ebersberger Ullrich , Makowski Marcus R , Platz Ulrich , Rieber Johannes , Antoni Diethmar , Hoffmann Ellen , Leber Alexander W
Published: April 2024

Background:
Due to steady technical development cardiac magnetic resonance imaging has become a powerful tool to determine myocardial vitality, perfusion and function. In particular the new generation of 3T multitransmit MR scanner with higher field strength, better spatial resolution, improved homogeneity and a reduction of dielectric shading has the potential to increase the accuracy of first pass myocardial perfusion imaging. So far cardiac magnetic resonance perfusion imaging (CMRPI) on a 3T multitransmit MR scanner has not been evaluated against coronary angiography (CA) and/or measurements of the fractional flow reserve (FFR).

Objective:
To evaluate the predictive value of first pass perfusion MRI using 3T multitransmit technology in patients with significant and intermediate lesions using CA as well as FFR- measurements.

Materials and Method:
111 patients with suspected coronary artery stenosis were investigated applying CMRPI on a 3T using multitransmission technology within ±5 days of CA. A high dose adenosine stress/rest perfusion protocol was used. After 3 minutes of adenosine infusion (170 µg · kg-1 · min-1 for 3 minutes), perfusion scans were performed (in-plane spatial resolution 2.97x 2.97mm, slice thickness 8mm; Achieva 3T Tx; Philips Healthcare; Netherlands). In patients with intermediate lesions (40-79%), FFR measurements (St. Jude; USA) were performed to assess functional relevance. Perfusion images were assessed visually. Interobserver disagreements were resolved by consensus in a joint session.

Results:
In 52 vessels revealing either a lesion > 80% on CA or a pathological FFR (< 0.75), adenosine induced stress perfusion deficits could be detected in 92 % (Sensitivity 92 %). In 281 vessels without pathological FFR or lesion < 40 % a perfusion defect could be excluded in 98 % (specificity 98 %). Using ROC analysis, CMPRI was found highly accurate up to an FFR threshold of 0.77.

Conclusion:
Using 3T multitransmit technology we could demonstrate that CMPRI is an excellent tool to assess the functional relevance of significant and intermediate coronary stenosis with a high specificity and sensitivity. CMPRI was highly accurate up to an FFR threshold of 0.77.
Abstract 17194: Maintenance of Sinus Rhythm Following AF Ablation May Preclude ICD Implant for Primary Prevention of Sudden Death: a Pilot Study
Authors: Ramachandra Indiresha , Bhimani Ashish , Sadrpour Shervin , Milolajczak Peter , ELSabbagh Firas , Vitebskiy Sergey , Ivan Cakukev , Goldstein Robert , Mackall Judith , Waldo Albert , Arruda Mauricio S
Published: April 2024

Background:
Atrial fibrillation (AF) ablation is safe and efficacious in pts with AF and impaired LV systolic function. Furthermore, maintenance of sinus rhythm (SR) following AF ablation in pts with CHF has favorable impact on LVEF, functional status and quality of life. Current guidelines recommend an implantable cardiac defibrillator (ICD) for primary prevention of sudden death in pts with LVEF ≤ 35% on optimal medical therapy.

Hypothesis:
This pilot study was designed to test the following hypothesis: “SR after AF ablation in pts with AF and LVEF ≤ 35% will improve LV function and preclude an ICD”.

Methods:
Forty-nine consecutive pts with AF and impaired LV function (including pts with LVEF ≤ 35%) and controlled ventricular rates underwent AF ablation (electrogram-guided pulmonary vein isolation + linear and CFAE ablation if needed) before considering an ICD implant. All pts were rate controlled and on optimal medical therapy for CHF prior to AF ablation. All pts had strict clinical and rhythm monitoring until repeat LV function assessment post ablation.

Results:
Twenty-three pts had LVEF ≤ 35% (Group 1) and 26 pts had LVEF 36-50% (Group 2). Similar to other studies, 18 of 26 (69%) pts in Group 2 had an improved LVEF and no hospitalization post AF ablation. Importantly, 16 pts (70%) in Group 1 had improvement in mean LVEF from 30% to 44% which precluded an ICD implant. Eight of these 16 pts (50%) normalized their EF. Recurrent AF post ablation and myocardial scar due to ischemic cardiomyopathy likely accounted for lack of LVEF improvement in some pts. These pts received an ICD implant if their LVEF remained ≤ 35%. The only significant complication was 1 TIA in 1 pt.

Conclusions:
Maintenance of SR following AF ablation in pts with impaired LV systolic function improves LVEF. This pilot study suggests AF ablation may be considered prior to an ICD implant, particularly in pts with NICM. This pilot study warrants a prospective, multi-center investigation.
Abstract 17199: Platelet ROCK2 is an Important Mediator of Thrombotic Stroke
Authors: Kim Hyung-Hwan , Hwang Seo-Kyoung , Ahn Yong-Joo , Oh Goo Taeg , Beaulieu Lea M. , Freedman Jane E. , Liao James K.
Published: April 2024

Background:
The activation of platelets is the final common pathway for most ischemic strokes. However, the signaling pathways that lead to platelet activation are not well understood. The Rho-associated coiled-coil forming kinases (ROCKs) are important mediators of the actin cytoskeleton. Because changes in the actin cytoskeleton underlie platelet activation and aggregation, we hypothesize that ROCKs in platelets may play an important role in thrombus-mediated ischemic stroke.

Methods and Results:
Platelets from global ROCK2-deficient (ROCK2
-/-
) mice showed decreased thrombin-induced pseudopodia formation, collagen adhesion, and homo- and heterotypic aggregation compared with platelets from wild-type (WT) mice. To determine the role of platelet ROCK2 in thrombosis-mediated ischemic stroke, we generated a mouse strain with platelet-specific ROCK2 deficiency (ROCK2

Plt-/-

) using conditional ROCK2

flox/flox

mice and platelet-specific PF4-Cre mice. ROCK2

Plt-/-

mice were born at expected Mendelian ratios and did not show any obvious developmental or phenotypic abnormalities. One day before ischemic onset, arterial blood was withdrawn from donor mice (WT or ROCK2

Plt-/-

mice), into PE-50 tubing, stored at room temperature for 2 hrs, and then kept at 4 °C for 22 hrs. Middle cerebral artery (MCA) occlusion was induced by injection of the coagulated blood into recipient WT mice. Laser Doppler flowmetry was used to confirm successful MCA occlusion. Following clot injection, an embolus of varying size was found in the proximal MCA of all mice at 24 hrs. Compared to WT→WT mice, ROCK2

Plt-/-

→WT exhibited greater improvement in relative cerebral blood flow (rCBF) (19%
vs.
92% reduction,
p
=0.0026). This correlated with decreased cerebral infarct size (67.6 ± 18.9 mm
3
vs.
126.3 ± 17.0 mm
3
, p<0.05, n=6-9) and improved neurological deficit score (2.3 ± 0.4
vs.
3.5 ± 0.5,
p
=0.037, n=6-9).

Conclusion:
These finding indicate that ROCK2 in platelets is critical for thrombus formation and in mediating MCA occlusion in the clot-embolic model of stroke. These results suggest that inhibition of platelet ROCK2 may have therapeutic benefits in ischemic stroke.
Abstract 17212: T-Cell Compartment Shifts Following Reperfusion After Primary Angioplasty in Patients with Acute Myocardial Infarction
Authors: Hoffmann Jedrzej , Wiley Thomas , Fiser Karel , Dimmick Ian , Stewart Rebecca , Loeher Monika , Pircher Hanspeter , Weaver Jolanta , Keavney Bernard , Martin-Ruiz Carmen , von Zglinicki Thomas , Spyridopoulos Ioakim
Published: April 2024

Background:
Primary PCI (PPCI) has substantially improved clinical outcomes of patients with acute ST elevation myocardial infarction (STEMI). However, myocardial ischemia-reperfusion (I/R) injury still remains an important clinical problem. CD4+ T-lymphocytes have been shown to promote I/R injury in a mouse model. It is unknown though, whether T-cells play any role in I/R inflammatory response in patients with STEMI. The goal of our study was to identify relevant changes in T-cell subsets in reperfused STEMI by using newly established 13-parameter flow cytometry (FACS) and hierarchical cluster analysis (HCA) of surface expression as a screening tool.

Methods and Results:
We analysed 30 patients (pts) with STEMI (12-24h after PCI), 24 stable post-STEMI pts and 18 healthy controls (ctrl) (all male, mean age 60 y). Peripheral blood mononuclear cells were stained for T-cell subset markers (CD3, CD4, CD8, CCR7, CD45RA), co-stimulatory molecules (CD27, CD28) and proliferation-associated markers (CD57, KLRG1, PD1). Following FACS data aquisition, HCA and sequential gating were performed using MATLAB software. While total lymphocyte counts did not differ between STEMI pts, stable post-STEMI pts and ctrl, the analysis of T-cell subsets revealed a significant increase in CD45RA-CCR7+ central memory (CM) populations in both CD4 and CD8 T-cells (see table). HCA revealed strong upregulation of the proliferation marker CD57 on CD4 CM T-cells in STEMI pts. Mean telomere length (mTL) in sorted CD4 T-cells was also reduced in STEMI. A pilot time course study showed a rapid decrease in CD4 T-cells by approx. 30% during the first 60 min following PPCI, possible due to invasion of myocardial tissue by T-cells, which might trigger compensatory proliferation of memory cells.

Conclusion:
Our results identify for the first time expansion of memory T-cells following reperfusion after PPCI in STEMI, which could provide novel insight into the mechanism of myocardial reperfusion injury.
Abstract 17237: The Underlying Necrotic Core is a Determinant of Occlusive Thrombosis
Authors: Nakano Masataka , Otsuka Fumiyuki , Yazdani Saami K , Kutys Robert , Carter-Monroe Naima , Ladich Elena R , Finn Aloke V , Kolodgie Frank D , Narula Jagat , Virmani Renu
Published: April 2024

Background:
It is well known that plaque rupture is not always associated acute coronary syndrome and in fact 10% of asymptomatic individuals dying of other causes have plaque rupture. To identify the underlying mechanisms of high risk plaque that leads to occlusive thrombosis, we examined coronary plaques from our registry of sudden coronary death victims.

Methods and Results:
From our sudden coronary death registry, 102 plaque ruptures (PR) were identified in proximal and middle segments of coronary trees; distal lesions were excluded. Histomorphometric area measurements included EEL, IEL, lumen, necrotic core (NC), calcification, and macrophage positivity (CD68) at the cross-section of rupture site. In addition, thinnest portion of fibrous cap adjacent to rupture site was measured. The lesions with PR were categorized into 2 groups: occlusive (>75% luminal thrombus) or non-occlusive (<75% luminal thrombus). PRs with occlusive thrombosis was associated with larger IEL area, larger NC, thicker fibrous cap as compared to those with non-occlusive thrombosis while EEL, lumen, calcification, and macrophage area were similar in both groups (Table). Multivariate regression analysis revealed that total NC volume is the best predictor of occlusive thrombus with an odds ratio of 1.15 (p=0.019), followed by cap thickness (odds: 1.04, p=0.024). ROC analysis of NC demonstrated the threshold of 2.89 mm
2
with sensitivity 0.61 and specificity 0.67 (AUC 0.67).

Conclusion:
These data suggest that strategies directed at detection of precise necrotic core area are necessary to assess high risk coronary plaques.
Abstract 17256: Hemangiogenic versus Cardiogenic Mesoderm Development Regulated by ER71 Inhibition of WNT Signaling
Authors: Liu Fang , Park Changwon , Kang Inyoung , Chang Li-Wei , Choi Kyunghee
Published: April 2024

Background
Cardiac linage specification is an important area to explore for regenerative medicine. The circulatory system in developing embryo is speculated to develop from two distinct Flk-1
+
mesoderms, hemangiogenic and cardiogenic. However, how Flk-1
+
mesoderm commits to hemangiogenic versus cardiogenic fate has not been addressed. We determined if ER71, an Ets transcription factor critical for hematopoietic and endothelial cell development, could modulate the hemangiogenic or cardiogenic outcome of the Flk-1
+
mesoderm.

Methods and Results
Using chimeric mice or
in vitro
embryonic stem (ES) cell differentiation system, we showed that

Er71
-/-

ES cells failed to generate hematopoietic or endothelial cells. Unexpectedly, ER71 negatively regulated cardiac development.

Er71
-/-

ES cells and
Er71
deficient Flk-1
+
mesoderm generated cardiac and smooth muscle cells more efficiently in culture compared to controls. Enforced
Er71
expression reduced cardiomyocyte and smooth muscle cell generation. We further found that PDGFR alpha expression can segregate Flk-1
+
mesoderm into hemangiogenic (Flk-1
+
PDGFR alpha
-
) and cardiogenic (Flk-1
+
PDGFR alpha
+
) mesoderm. Importantly, ER71 is obligatory for the Flk-1
+
PDGFR alpha
-
hemangiogenic mesoderm development. ER71 deficient embryos and ES cells only produced Flk-1
+
PDGFRalpha
+
cardiogenic mesoderm, which mainly and more efficiently differentiated into smooth muscle cells and cardiomyocytes. Moreover, ER71 could convert committed cardiogenic mesoderm to hemangiogenic mesoderm. Furthermore, ER71 strongly induced VE-cadherin, which formed a complex with beta-catenin and Flk-1. Upon the complex formation, nuclear beta-catenin levels decreased and Wnt signaling reduced. ER71 deficient embryo and Flk-1
+
mesoderm displayed enhanced Wnt signaling, which was reduced by ER71 re-introduction. Enhanced cardiac differentiation from
Er71
deficient Flk-1
+
mesoderm was rescued by Dickkopf-related protein.

Conclusions
Hemangioblast over cardiac lineage specification is achieved by ER71 inhibition of Wnt signaling. Our findings provide strategies for directing pluripotent stem cell differentiation to hematopoietic, vascular and cardiac cells for future regenerative medicine.
Abstract 17281: Programmed Necrosis of Ventricular Myocytes During Ischemic Stress Involves a Mitochondrial Regulated Bnip3- RIP-1- Cyclophilin D Signaling Pathway
Authors: Wang Yan , Gordon Joseph W , Dhingra Rimpy , Hai Yan , Baines Christopher , Kirshenbaum Lorrie A
Published: April 2024

Recent animal studies suggest that programmed necrosis plays a critical role in ischemia/reperfusion induced cardiac cell death and in the progression to heart failure. This caspase-independent form of programmed cell death involves RIP1/RIP3 phosphorylation and activation, as well as the formation of the cyclophilin D (CypD)-dependent mitochondrial permeability transition pore (PTP). Our previous work, along with the work of others, suggests that the hypoxia-inducible death gene, Bnip3, may promote a caspase-independent form of cell demise. Therefore, we hypothesized that Bnip3 was capable of triggering programmed necrosis in ventricular myocytes. We demonstrate for the first time that Bnip3-dependent mitochondrial perturbations involving the inner mitochondrial membrane, and cell death, are blocked by the RIP1 inhibitor, necrostatin-1. Furthermore, forced expression of Bnip3 in post-natal cardiac myocytes increased the mitochondrial localization of phospho-RIP3, which was attenuated by deletion of the mitochondrial-targeting transmembrane domain of Bnip3 or in Bnip3-/- cells. In addition, a physical association between Bnip3, RIP1, and CypD by co-immunoprecipitation, was observed in hypoxic myocytes but not normoxic cells, while inhibition of CypD, by cyclosporine A, was sufficient to block Bnip3-induced necrotic-like death. Furthermore, Bnip3 was incapable of inducing PTP opening or cell death in CypD-/- MEFs, despite its ability to interact with RIP1. Thus, our findings implicate CypD as a critical regulator of Bnip3-induced mitochondrial regulated programmed necrosis, and highlight a novel relationship between RIP1- CypD and Bnip3 for programmed necrosis of ventricular myocytes during ischemic injury.
Abstract 17302: Long-Term Association of Low-Risk Profile and White Blood Cell Count - The Chicago Healthy Aging Study (CHAS)
Authors: Vu Thanh Huyen T , Liu Kiang , Lloyd-Jones Donald M , Pirzada Amber , Garside Daniel B , Stamler Jeremiah , Daviglus Martha L
Published: April 2024

Background:
Low CVD risk factor (RF) burden at younger ages is associated with substantially lower risk of future clinical CVD events. White blood cell (WBC) count, a measure of systemic inflammation, also predicts CVD morbidity and mortality, and is cross-sectionally associated with CVD risk factors. No data exist on long-term associations of risk status at younger ages and WBC at older ages.

Methods:
Using data from CHAS, we assessed the association of baseline low risk (LR) status (1967-73) with follow-up WBC count (2007-10). Participants were classified as baseline LR, 0 RF high, only 1 RF high, and 2+RF high (see table footnote for definitions). WBC counts in the 5th quintile (≥7.5x10
9
cells/L) were classified as "high" compared to all others (<7.5x10
9
cells/L).

Results:
The sample consisted of 1389 participants (28% women, 9% African American, and 20% LR) baseline ages 25-45 (follow-up mean age 71), free of baseline major ECG abnormalities or myocardial infarction. With average follow-up 39 years, multivariate adjusted mean WBC count was higher in a linear fashion across baseline RF categories (P-trend <0.001) (see table footnote for adjustments). Greater number of baseline RFs was also associated with greater likelihood of high WBC count (P-trend= 0.001). Thus, for persons with baseline 0 RF high, 1 only RF high, and ≥2 RFs high, the odds of high WBC count were higher by 57%, 74%, and 81%, respectively, compared to those with baseline LR (see Table). Analyses with individual RFs instead of LR status showed that the above association was mostly due to baseline smoking status and BMI. The association was stronger in women compared to men: coefficient/p-trend was 0.30/<0.001 in women and 0.11/0.049 in men (results not shown).

Conclusion:
Low risk profile at younger ages is associated with lower WBC count in older age. A low risk profile early in life apparently leads to long-term decreased inflammation, as well as reduced risk of CVD events later in life.
Abstract 17329: Myocardial-Specific Overexpression of a Dominant-Negative Mutant of NADPH Oxidase Subunit p67
phox
Attenuates Pressure-Overload-Induced Cardiac Hypertrophy in Adult Transgenic Mice
Authors: Zhao Qiong , Xu Xianyao , Zhao Guiqing , Zhang Chongxu , Deng Jing , Christman John W , Xiao Lei
Published: April 2024

We had reported a transgenic (Tg) mouse model with cardiac-specific overexpression of a dominant-negative (DN) mutant (V204A) of NADPH oxidase (NOX) subunit p67
phox
that inhibits NOX activity. In order to test the role of NOX in pressure-overload-induced cardiac hypertrophy in young adult mice, age and body weight (BW)-matched male homozygous Tg and wild type (WT) C57BL/6 mice (10-12 weeks) were subjected to transverse aortic constriction (TAC) or sham operation. Four-week post TAC, 2-D echocardiography (echo) was performed to determine the following cardiac parameters: left ventricular myocardial area (LVMA); LV wall thickness at end diastole; LV internal dimension at end diastole (IDd), LV end-diastolic volume (EDV), LV ejection fraction (EF), LV mass & aortic pressure gradient. Mice were divided into 4 groups (15-24 mice/group) including WT-sham, WT-TAC, Tg-sham & Tg-TAC. The LVEDV, LVIDd & BW were similar among all groups. The LVEF (mean 48-53%) was not statistically different among all groups. The aortic pressure gradient was between 30-60 mmHg in TAC mice and was statistically similar between the Tg and WT groups (45.3 ±1.7 vs. 50.4 ± 2.1 mmHg,
p
=0.1). Tg-sham showed no significant difference in LVMA, LV mass & wall thickness vs. WT-sham (Table 1). The WT-TAC mice showed significant increase in LVMA, LV mass & wall thickness indicating LV hypertrophy. The Tg-TAC mice also showed mild increase in the above parameters with the LV wall thickness statistically different from Tg-sham. However, these increases in Tg-TAC mice were significantly (
p
<0.05) smaller than those in WT-TAC mice, suggesting TAC-induced LV hypertrophy was attenuated in Tg mice. Our echo finding was also confirmed by our results of heart weight/BW ratio, ANF mRNA expression, and histological study of the LV myocardium. In summary, our results showed that selective inhibition of myocardial NOX subunit p67
phox
attenuated chronic pressure-overload-Induced cardiac hypertrophy in young adult mice.