bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 17327: Ischemic Skeletal Muscle From Patients With Peripheral Arterial Disease Displays Marked Desialylation of Cell Surface Glycans: Implications for Ischemia-Targeted Gene Therapy
Authors: Katwal Arabindra B , Mulkey Eric T , Lye R John , French Brent A , Annex Brian H
Published: July 2021

Introduction:
Ischemic skeletal muscle is preferentially targeted after IV injection of AAV9 in mouse models of hind-limb ischemia (HLI). Ischemia is known to induce desialylation of cell surface glycans, unmasking the cellular receptor for AAV9 and resulting in significantly higher levels of selective gene expression in ischemic vs non-ischemic muscle. To assess clinical relevance, we compared the differential distribution of sialylated and desialylated cell surface glycans in skeletal muscle biopsies from peripheral arterial disease (PAD) patients and normal controls.

Methods:
Gastrocnemius (GA) muscle samples from PAD patients and normals (n=29 each) were biopsied under IRB-approved protocols. Muscle sections were stained using the lectins MAL-I and ECL. MAL-I binds to α2,3-sialylated glycans whereas ECL binds to desialylated galactose residues on cell surface glycans. Lectins were labeled with Streptavidin-Alexa-488 (red) for MAL-I and SA-555 (green) for ECL, and visualized using fluorescence microscopy. Quantification of mean fluorescence signal intensity of lectin staining was performed on each section.

Results:
Visually, MAL-I staining was markedly higher and ECL staining lower in non-ischemic GA from normals when compared to ischemic GA from PAD patients (Figure). The ratio of MAL-I to ECL integrated fluorescence intensity in the ischemic muscles from PAD patients (1.13 ± 0.13) was significantly lower than the same ratio in non-ischemic muscles from normals (1.58 ± 0.14, p<0.02).

Conclusions:
Desialylation of cell surface glycans is significantly higher in ischemic skeletal muscle from PAD patients, consistent with previous work in a mouse model of HLI. This desialylation can potentially be exploited to treat human PAD with gene therapy, since these desialylated cell surface glycans serve as cell surface receptors for AAV9 and provide for efficient and selective gene transfer to ischemic skeletal muscle following systemic or local delivery.
Abstract 17344: Increasing Calcium-activated Potassium Current Shortens and Stabilizes Repolarization in Chronic Heart Failure
Authors: Bonilla Ingrid M , Long Victor , Mowrey Kent , Schober Karsten , Weiss Raul , Gyorke Sandor , Carnes Cynthia
Published: July 2021

Heart failure (HF) is a chronic disease resulting in abnormal prolongation and instability of ventricular repolarization. IKCa has been suggested to stabilize repolarization in HF as IKca blockade has shown pro-arrhythmic effects in the failing ventricle. We tested the hypothesis that an SK channel (IKCa) agonist CyPPA, would shorten and stabilize ventricular repolarization in HF ventricular myocytes.

Methods:
A tachypacing - induced 4 month HF canine model was used (LVFS: 15.9 ± 2.5%), and LV midwall myocytes were isolated and compared to normal controls. Action potential duration at 50 (APD50), and 90% (APD90) repolarization and APD instability (beat to beat variability of repolarization, a measure of arrhythmia risk) were measured before and after the application of CyPPA (0.001nM-20uM) in control ventricular, and in 4 months HF ventricular myocytes (n=10-15 per group).

Results:
In control myocytes, CyPPA shortened action potential APD50 and APD90 in a concentration dependent manner (0.001nM-20uM, p<0.05 vs baseline at 20uM, Figure). In HF myocytes, CyPPA also shortened APD50 and APD90, but at lower concentrations than in controls. Notably, In addition to APD shortening, CyPPA significantly decreased repolarization instability (P<0.05 vs baseline at 1 Hz) in HF. CyPPA did not affect resting membrane potential in either group. Conclusions: HF myocytes are more sensitive to IKCa agonism than control myocytes. An IKCa agonist attenuates electrophysiologic remodeling and stabilizes repolarization in failing ventricular myocytes, suggesting a therapeutic role for this approach in HF.
Abstract 17368: Years of Life Lost Due to Heart Failure in the United States (US)
Authors: Patel Harshali , Kielhorn Adrian , Yurgin Nicole , Hernandez Adrian F
Published: July 2021

Background:
Heart failure (HF) is a complicated syndrome where ~50% of patients die within 5 years of diagnosis. Years of life lost (YLL) is a population-based mortality indicator that takes into account age at death, giving greater weight to deaths occurring at a younger age and thereby providing information on mortality that is relevant to the entire population without the bias of elderly death. A YLL analysis was applied to patients with HF to illustrate the relationship between HF and premature mortality. Further YLL for HF was compared to other common elderly diseases.

Methods:
Data between 1999 and 2012 on the number of deaths attributed to HF and other conditions common in the elderly were from the Centers for Disease Control and Prevention and the National Center for Health Statistics online database; standard life-expectancy data for the US were from the World Health Organization global health observatory data repository. YLL was calculated from the number of deaths multiplied by years of life remaining based on a standard life expectancy at the age at which death occurs. Total YLL over all age groups was then divided by the total number of deaths for the mean YLL per HF patient. The same calculation was made for several other conditions for comparison.

Results:
A total of 804,095 US deaths were attributed to HF. The mean HF YLL was 9.64 years, which was higher than YLL calculated for osteoporosis and Alzheimer’s/other dementias (7.12 and 7.67 years, respectively; Figure) and similar to Parkinson’s disease (9.73 years).

Conclusions:
Analysis of premature mortality by YLL suggests that patients with HF would live on average 9.64 years longer had they not developed HF.
Abstract 17388: Cardiac MRI Derived Forward Stroke Energy is a Better Index of Left Ventricular Pump Function over Ejection Fraction in Mitral Regurgitation
Authors: Kalra Kanika , Padala Muralidhar
Published: July 2021

Introduction:
Mitral regurgitation (MR) into the low impedance left atrium (LA) enables a pop off valve effect and enables a false low end-diastolic volume and increased ejection fraction (EF). EF in these patients seems falsely high even though their ventricular contraction seems impaired, thus better indices that represent ventricular contraction are required in this lesion.

Hypothesis:
In this study we sought to investigate if forward stroke energy (FSE), which represents the forward kinetic energy of the blood through the aortic valve is a better indicator of ventricular contraction than EF.

Methods:
Phase-contrast MRI was performed in patients with MR (n=63; Mild MR =23; Moderate-severe MR=40), at the aortic and mitral valve planes, to compute the transvalvular through-plane flow. EF was measured as ((end-diastolic volume- end systolic volume)/end-diastolic volume), and FSE as (forward aortic stroke volume X mean arterial pressure). LV contractility was computed as the dynamic myocardial wall thickening over the cardiac cycle.

Results:
Regional peak wall thickening was significantly reduced in the moderate-severe MR groups - equatorial sector (5.9±0.6mm vs. 4.3±0.4mm, p=0.02) and apical sector (6.4±0.5mm vs. 4.5±0.3mm, p=0.003), indicating LV dysfunction with higher MR severity. EF did not capture this difference in LV contraction between the groups (50.1±3.7% vs. 48.3±3.2%, p=0.72). However, FSE demonstrated a significant difference between the two groups and a significant negative correlation (6527±483 mmHg.mL vs. 4895±282 mmHg.mL, p=0.002, r(MRfraction)=-0.42, p=0.0007).

Conclusions:
Forward stroke energy may better capture reduced myocardial contractility in the setting of MR, than EF - the current clinical gold standard.
Abstract 17404: Intramolecular Inhibition of Ser473 Phosphorylation by Up-regulated Thr308 Phosphorylation in Akt Contributes to Enlargement of Infarct Size by Chronic Renal Failure
Authors: Tobisawa Toshiyuki , Yano Toshiyuki , Miki Takayuki , Tanno Masaya , Kuno Atushi , Kouzu Hidemichi , Ogasawara Makoto , Muratsubaki Shingo , Ohno Kohei , Nishizawa Keitaro , Mizuno Masashi , Ohwada Wataru , Ishikawa Satoko , Miura Tetsuji
Published: July 2021

Objective:
We previously showed that chronic renal failure (CRF) enlarges infarct size after ischemia/reperfusion (I/R) through impairment of reperfusion-induced Akt activation. Here we examined molecular mechanisms by which CRF impairs Akt activation, focusing on interplay between two phosphorylation sites in Akt, Thr308 and Ser473.

Methods and results:
Rats received 5/6 nephrectomy (SNx) or a sham operation (Sham). Development of CRF in SNx was confirmed by a 2.2-fold increase in serum creatinine level at 4 weeks after the operation. Infarct size after 20-min coronary occlusion/2-hr reperfusion was larger in SNx than in Sham (53.2±5.8 vs. 41.1±2.4% of risk area, p<0.05), indicating impaired tolerance against I/R injury in CRF. Immunoblot analyses revealed that the level of phospho-Akt-Thr308 was higher by 375% in SNx than in Sham under baseline conditions, while the levels of phospho-Akt-Ser473 were similar in the two groups. Upon reperfusion, phosphorylation of Ser473 and that of Thr308 were similarly enhanced in Sham. However, reperfusion-induced phosphorylation of Ser473, but not that of Thr308, was blunted by 32.8% in SNx compared with that in Sham. Reduction in Akt activity after reperfusion in SNx was indicated by lower levels of phospho-p70S6K and phospho-GSK3β compared with those in Sham. The levels of PTEN, a negative regulator of Akt, and PDK1, a promoter of Thr308 phosphorylation, were similar in SNx and Sham. However, the level of PP2A regulatory subunit B55α, which specifically dephosphorylates Thr308, was lower by 23.6% in SNx than in Sham. To determine whether the constitutive phosphorylation of Thr308 mitigates reperfusion-induced phosphorylation of Ser473, HA-tagged wild-type Akt (HA-WT) and phospho-Thr308-mimetic mutant Akt (HA-T308D) were transiently transfected into HEK293 cells. IGF-1 (10 nmol/L)-induced phosphorylation of Ser473 in HA-T308D was lower by 30.5% than that in HA-WT, whereas that in endogenous Akt at Ser473 was comparable between cells overexpressing HA-T308D and HA-WT.

Conclusion:
Insufficient activation of Akt by its intramolecular interplay between Thr308 and Ser473 phosphorylation due to down-regulated B55α contributes to increased myocardial susceptibility to I/R injury in CRF.
Abstract 17410: Catheter-based Radiofrequency Renal Denervation Decreases Renal Norepinephrine Spillover and Improves Cardiac Contractile Function in a Porcine Model of Ischemic Heart Failure
Authors: Tse Hung-Fat , Liao Song-Yan , Zhu Ziyi , Zhen Zhe , DeRama Rita , Hata Cary , Chen Peter
Published: July 2021

Background:
Catheter-based radiofrequency (RF) renal denervation (RD) has been shown to decrease renal norepinephrine (NE) spillover in animal models and humans with hypertension. Nevertheless, the effect of RD on renal NE spillover in systolic heart failure (HF) is unknown.

Methods:
Ischemic HF model was created in 16 porcine by inducing myocardial infarction (MI) via coronary embolization of the left circumflex artery followed by rapid ventricular pacing for 4 weeks (MI+HF). Of these, 8 porcine underwent bilateral RD using the EnligHTN System (St. Jude Medical) and the remaining 8 served as control. All animals were given daily oral metoprolol ZOK (50 mg) plus ramipril (2.5 mg). Serum NE levels at different sites and index of cardiac contractility (dP/dt
max
/IP) were measured at baseline, immediately after MI (post-MI), at MI+HF and at 10 weeks follow-up. Renal arteries were then prepared for histological analysis.

Results:
RD significantly increased the dP/dt
max
/IP as compared with the control group (P<0.05, Figure 1a). RD also decreased the arterial and coronary sinus NE (P<0.05), and renal NE spillover (-54%, P=0.06) at 10 weeks as compared with MI+HF (Figures 1b & 1c). Histological examination showed significant reduction of renal sympathetic efferent nerves (tyrosine hydroxylase+) at proximal, middle and distal portions of the renal artery after RD as compared with the control group (-65%, P<0.05, Figure 1d).

Conclusions:
In a porcine model of ischemic HF, bilateral RD using catheter-based RF effectively destroys renal nerves to decrease renal NE spillover, and improves LV contractile function compared with medical therapy alone.
Abstract 17412: Paracrine Role of B Lymphocytes in Successful Bone Marrow Cell Therapy for Myocardial Infarction
Authors: Wang Xiaoyin , Rodriguez Hilda J , Ruck Melissa A , Aschbacher Kirstin , Hermiston Michelle L , Springer Matthew L
Published: July 2021

Introduction:
Treatment of myocardial infarction (MI) with bone marrow cells (BMCs) or cell-free BMC lysate substantially improves post-MI cardiac function in rodent experiments. However, clinical trials of BMC therapy have been less successful. While most mouse experiments use young healthy BMC donors, MI patients undergoing autologous cell therapy (i.e., receiving their own BMCs) are older and are post-MI. We have previously demonstrated that BMCs from aged and post-MI donor mice are therapeutically impaired, that donor MI induces inflammation leading to changes in BMC composition, and that BMCs from aged or post-MI mice have reduced levels of B cells, which reportedly can be a therapeutic BMC subpopulation. We recently observed that partial depletion of B cells from young healthy donor BMCs reduces the BMCs’ therapeutic effect, mimicking the effects of donor age or MI. Hypothesis: B cells play a crucial role in BMC therapy for MI, and B cell lysate is also therapeutic.

Methods:
We induced permanent coronary artery ligation MI, and implanted purified CD19+ bone marrow B cells from young healthy donors into the recipient infarct border zone 3 days post-MI via ultrasound guidance. CD3ε+ T cells and vehicle (HBSS) were injected as negative controls. A similar experiment was carried out with B cell lysate and T cell lysate.

Results:
In all groups, recipient left ventricular ejection fraction (EF) declined uniformly from baseline to day 2 post-MI, before cell injection. Injection of B cells significantly improved day 28 EF (p<.0005 adjusted for multiple comparisons). In contrast, T cells provided little or no benefit relative to HBSS. Notably, B cell lysate, but not T cell lysate, increased EF comparably to intact B cells. *p<.05 in figure. Conclusions: Bone marrow B cells play a crucial role in BMC therapy for MI via a paracrine mechanism. Reduction of bone marrow B cells by age or MI may explain why autologous BMC therapy in patients has not matched the success of rodent experiments.
Abstract 17442: Effects of Small Conductance Ca2+-activated K+ Channels on Cardiogenesis in Human Induced Pluripotent Stem Cells
Authors: Jeong Imju , Yechikov Sergey , Gluck Jessica , Lieu Deborah K
Published: July 2021

Human induced pluripotent stem cells (hiPSCs) with the ability to form all somatic cells can generate pacemaking cardiomyocytes (CMs) for engineering of biological pacemakers. However, differentiation efficiency of hiPSCs into pacemaking cardiomyocytes is merely at 5% of the total CMs. Membrane potential of a cell can alter cell fate. Activation of small conductance Ca2+-activated K+ channels (SKs) has been shown to induce membrane hyperpolarization. In this study, we demonstrated that SKs are present and functional in hiPSCs and their differentiation progeny. Addition of SK activator (EBIO or CyPPA) hyperpolarized hiPSCs and differentiating hiPSCs 2 and 5 days post-differentiation by -2.5±0.97, -22.7±1.8 and -13.6±3.3 mV, respectively. The magnitude of hyperpolarization exhibited dose-dependency to SK activator in differentiating hiPSCs 2 days post-differentiation. Activation of SK channels by EBIO or CyPPA on day 2-3 from the onset of differentiation significantly upregulated the expression of Islet (Isl)1, a marker for a subset of cardiac progenitor cells that are known to form the sinoatrial node where the pacemaking cardiomyocyte reside. The number of Isl1-positive cells in differentiating hiPSCs with SK activation on day 2-3 has also increased relative to control. Our findings indicate that the activation of SK channels at an appropriate treatment time and length results in a facilitated increase in the differentiation of hiPSCs to pacemaking cardiomyocyte precursors.
Abstract 17539: Conventional vs. Transcatheter Aortic Valve Replacement - Propensity Score Adjusted Comparison of 3,751 Unselected Patients
Authors: Börgermann Jochen , Emmel Eric , Scholtz Smita , Ensminger Stephan , Scholtz Werner , Becker Tobias , Zittermann Armin , Horstkotte Dieter , Kuss Oliver , Gummert Jan F
Published: July 2021

Background and Hypothesis:
Transcatheter aortic valve replacement (TAVR) is an established method in high-risk patients. Two aspects of this procedure are currently under discussion: 1.) Do the data acquired from randomized studies and registers justify expansion of the procedure to include younger and healthier patients? 2.) Is the transfemoral approach superior to the transapical approach with regard to mortality and periprocedural complications? Against this background we examined the mortality and morbidity of all patients who received an isolated conventional, transapical or transfemoral aortic valve replacement in accordance with the criteria of the Valve Academic Research Consortium (VARC)-2.

Methods:
A prospective register was taken from a single center recording all conventional (CONV, n=2,881), transapical (TAVR-TA, n=363) and transfemoral (TAVR-TF, n=570) aortic valve implantations during the period from 07/2009 to 10/2014. Using propensity score (PS) matching, first CONV and TAVRall (TA+TF) and then TAVR-TA and TAVR-TF were paired on the basis of 21 risk variables, creating comparable groups.

Results:
393 pairs CONV vs. TAVRall within a moderate risk could be created (EuroSCORE 18.7 vs. 18.5; STS 5.0 vs. 5.4). Comparison revealed no difference for 30d mortality (4.6% CONV vs. 5.1% TAVRall, p=0.74), stroke (2.8% vs. 2.0%, p=0.48) or myocardial infarction (0.0 vs. 0.3%, p=0.50). Bleeding complications were significantly more frequent in the CONV, SM implantations and vascular complications in the TAVRall group. In the PS-adjusted comparison TAVR-TA vs. TAVR-TF (289 pairs; EuroSCORE 25.1 vs. 22.1; STS 6.8 vs. 6.7) there was also no difference in the hard endpoints (30d mortality 4.9% TA vs. 4.2% TF, p=0.70; stroke 3.1% vs. 2.8%, p=0.81; myocardial infarction 0.4% vs. 0.4%, p=1.00). Here bleeding complications were significantly more frequent in the TA group, SM implantations and vascular complications in the TF group. Subgroup analyses show an advantage of the TAVR procedure in patients with high STS or low LVEF.

Conclusions:
These data show that 1.) conventional aortic valve replacement and TAVR are comparable in the moderate risk group, and 2.) the two approaches, transapical and transfemoral, produce comparable results.
Abstract 17545: Vasoconstriction During Mental Stress Predicts Severity of Mental Stress Induced Myocardial Ischemia
Authors: Isakadze Nino , Alkhoder Ayman , Quyyumi Arshed A , Vaccarino Viola , Bremner J. Douglas , Garcia Ernest , Nye Jonathon , Wilmont Kobina , Mheid Ibhar A , Raggi Paolo , Kutner Michael , Obideen Malik , Abdelhadi Naser , Shah Amit
Published: July 2021

Background:
Evidence supports that peripheral vasoconstriction during mental stress predicts mental stress induced ischemia (MSIMI). However, whether a dose response relationship exists with ischemia severity has not been evaluated; additionally, whether peripheral vascular function during the recovery phase is also related to MSIMI is not known.

Hypothesis:
We hypothesized that increased digital microvascular constriction during both mental stress and recovery are predictive of increased severity of mental stress ischemia.

Methods:
We evaluated 204 patients with stable CAD with high quality vascular data using a standardized mental stress test using a public speaking task. Peripheral artery tonometry (PAT) (Itamar Inc) was used to assess digital microvascular tone. Vasoconstriction was calculated as the ratio of pulse wave amplitude during speech/recovery and the last 3 minutes of baseline, with lower ratio indicating more vasoconstriction. 99mTc sestamibi myocardial perfusion imaging was performed at rest and with mental stress. A summed difference score (SDS) quantifying severity of reversible perfusion defects (inducible ischemia) comparing rest and stress images was computed using a standard 17-segment model. Four categories of increasing severity were based on cut points of 0, 3, and 6.

Results:
The mean (SD) age was 64 (8), 16% were women, and 28% were African American. Each category of increase in ischemia severity was associated with a 10% (p=0.04) decrease in speech PAT ratio (Figure) and 11% (p=0.02) decrease in recovery PAT ratio. After multivariable adjustment for sociodemographics, traditional risk factors, medical history, medication use, and psychological risk factors, the associations persisted, with B=-11%, p=0.02 for speech PAT ratio, and B=-8%, p=0.04 for recovery ratio.

Conclusion:
Peripheral vasoconstriction during mental stress speech as well as recovery predicts MSI severity in a dose-response relationship.
Abstract 17605: Cost-Effectiveness of Contemporary Endovascular Treatment Compared to Open Surgical Revascularization for Cardioembolic Acute Limb Ischemia
Authors: Genovese Elizabeth A , Smith Kenneth J , Barshes Neal R , Makaroun Michel S , Baril Donald T
Published: July 2021

Introduction:
Treatment of acute limb ischemia (ALI) has a high morbidity and mortality given patients’ multiple comorbidities, poor physiologic reserve, and the need for emergent intervention. Traditionally ALI of embolic origin has been treated with open revascularization (OR), however with increasing experience with thrombolytic therapy and adjuvant techniques, endovascular revascularization (ER) for ALI has become a more common treatment due to the lower associated morbidity and mortality.

Hypothesis:
Although associated with higher initial costs and lower technical success rates, ER will be cost effective given the decreased adverse event rate and mortality in a frail patient population.

Methods:
A Markov state-transition model was created to simulate patient oriented outcomes, including technical success, adverse events, limb salvage, discharge facility and quality adjusted life years (QALY) for patients presenting with Rutherford Classification I/IIa/IIb ALI secondary to cardiac embolism. A societal perspective was assumed with a 10-year time horizon. Parameter estimates were derived from published literature and primary data of cardioembolic ALI patients treated at our institution from 2005-2011 with either ER or OR. Costs were adjusted to 2013 U.S. dollars.

Results:
In the model, OR was technically successful in 87% patients, with a $23,881 cost for the initial hospitalization and a 11.5% perioperative mortality rate; ER was technically successful in 71% of patients, with a $39,619 initial cost, and a 4% mortality rate. At 10 years, the ER strategy cost $92,659/QALY gained compared to OR. Sensitivity analyses demonstrated that ER was favorable at a willingness to pay (WTP) threshold of $100,000/QALY when ER technical success was >70%, initial ER hospitalization cost was <$41,052 or if OR mortality was >10%. At a WTP of $50,000/QALY, ER was cost effective if technical success reached 79%, if ER cost was <$31,287 or if OR mortality was >23%.

Conclusions:
Contemporary endovascular treatment of cardioembolic ALI carries a greater cost compared to open revascularization, however it is associated with a decreased mortality rate. ER is potentially cost-effective in patients who are at high risk of post-operative mortality following OR.
Abstract 17662: High-risk Carotid Atherosclerotic Lesions Identified by CT-angiogram Can Predict Acute Coronary Events
Authors: adib keenan , Carmona Rubio Andres , Karki Roshan , Madam Narasa , Gudleski Gregory , Sharma Umesh C
Published: July 2021

Introduction:
Computed Tomography Angiogram (CTA) is increasingly being utilized as an imaging tool for the characterization of atherosclerotic lesions of major arteries. Our recent
ex vivo
study has shown the presence of high-risk necrotic coronary lesions in the subjects who had suffered sudden cardiac death following acute stroke. Although stroke and myocardial infarction (MI) have shared risk factors and outcomes, there are no data available to predict the coronary events based on the high-risk features identified in the carotid arteries by non-invasive CTA of the neck vessels.

Methods:
We examined the carotid CTAs of 485 patients who had presented to our tertiary stroke center with symptoms suggestive of TIA or stroke. Using reformatted CT images, we first characterized the atherosclerotic plaques of the common, internal and external carotid arteries. We then examined the follow up events of these 485 patients for 12-months to evaluate the significance of newly identified carotid lesions for the subsequent development of acute coronary events (ACS). Carotid lesions were defined in terms of the degree of stenosis, calcifications (speckled or eccentric), presence of non-calcified plaques, positive remodeling, and presence of a Napkin-Ring Sign.

Results:
Our data analysis using Mann-Whitney U tests showed that presence of speckled carotid calcifications visualized by CTA was strongly associated with increased risk of obstructive coronary artery disease or ACS within 12-months (p<0.001). Patients who had ACS within a year were more likely to have higher number of calcific speckles (10-speckles in ACS group
vs
4-speckles in non-ACS group; P<0.05) in their carotid arteries. Receiver-Operating Curve analysis showed that presence of more than four calcific speckles in the carotid arteries portends higher likelihood of developing ACS within 12-months (P<0.05).

Conclusions:
This novel study shows that presence of speckled carotid calcifications in patients with symptoms of TIA or stroke can predict the higher risk of developing ACS within 12-months. In fact, Four or more speckles was the optimal cut-off point associated with the higher likelihood of developing ACS within 12-months.
Abstract 17730: The Appropriate Biomarker of a Cardiac Rehabilitation in the Patients With Post Abdominal Aortic Aneurysm Repair
Authors: Nakayama Atsuko , Nagayama Masatoshi , Morita Hiroyuki , Komuro Issei
Published: July 2021

Introduction:
The useful biomarkers of cardiac rehabilitation after post cardiovascular surgery are still unknown. This is the first report describing the markers of the effect of cardiac rehabilitation on prognosis after abdominal aortic aneurysm (AAA) surgery.

Methods:
We conducted an observed cohort study on 1330 patients receiving surgical repair of AAA in the multicenter in Tokyo from January 2003 to December 2014. The patients who had cardiac rehabilitation more than once a week for more than 3 months after surgery were classified into rehabilitation group. The patients in rehabilitation group underwent cardiopulmonary exercise testing (CPX) before and 3 months after surgery. Total 274 inspection items including blood culture, computerized tomography, carotid duplex, ankle-brachial index test, cardiac echography, respiratory function test and CPX were cyclopaedically analyzed. The results of blood culture in rehabilitation group were compared to those in non-rehabilitaion group before surgery, 14 days after and 30days after surgery.

Results:
The average age of patients was 73±8 years and the average follow-up period was 2.5±2.2 years. The 355 patients had cardiac rehabilitation after AAA repair, and the other 975 patients did not. Basal characteristics including age, gender, hypertension, dyslipidemia, diabetes, smoking and drugs were statistically similar in both groups. The predictors of the risk of major adverse cardiac events (MACE) after surgery were co-existence of coronary artery disease, non-intake of beta-blockers, non-intake of ARBs and nonparticipation in cardiac rehabilitation. The ROC curve analysis of the markers demonstrated no remarkable marker for the risk of MACE after surgery. But the level of CRP in rehabilitation group was lower 14 days and 30 days after surgery compared to which in non-rehabilitation group (4.5 ± 4.3 mg/dl vs. 5.9 ± 6.5 mg/dl, p<0.001 and 4.2 ± 4.5 mg/dl vs. 6.5 ± 6.0 mg/dl, p<0.001), although the level of CRP was similar in both groups before surgery.

Conclusions:
Cardiac rehabilitation in patients after AAA surgery improved the risk of MACE, and especially CRP may be useful as a convenient marker of effective rehabilitation for secondary prevention of arteriosclerosis.
Abstract 17805: Gut Microbiota Promote Arterial Hypertension and Vascular Dysfunction by Facilitating Remote Interleukin-17 Signaling
Authors: Karbach Susanne , Hörmann Nives , Jäckel Sven , Schönfelder Tanja , Schüler Rebecca , Finger Stefanie , Knorr Maike , Kossmann Sabine , Brandt Moritz , Münzel Thomas , Bäckhed Fredric , Reinhardt Christoph , Wenzel Philip
Published: July 2021

Background:
The presence of gut microbiota is essential for proper function of the immune cells. Its impact on the blood pressure regulation and systemic vascular function - processes that are described to be immune cell regulated - is unknown.

Methods and Results:
Unchallenged germfree mice (GF) showed no differences in endothelial function or vascular oxidative stress compared to conventionally reared mice (CONV-R), but they provided a dampened systemic T-bet / Interferon gamma (IFNγ) skewing in lymphoid cells. Re-colonization of GF with regular gut microbiota (conventionally-derived, CONV-D) normalized this phenotype. Angiotensin II (1mg/kg/d for 7d)-infused GF mice showed reduced oxidative stress levels in the vasculature, attenuated vascular expression of monocyte chemoattractant protein-1 and iNOS, blocked systemic up-regulation of T-bet / IFNγ and retinoic-acidreceptor-related orphan receptor-γt (ROR-γt) / interleukin-17 (IL-17) signaling in lymphoid cells and protection from endothelial dysfunction compared to CONV-R mice. Flow cytometric analysis showed a reduced infiltration of Ly6G+ neutrophils into the vessel wall and consequently we found an attenuation of arterial hypertension in Angiotensin II infused GF mice compared to Angiotensin II infused CONV-R mice. Protection from Angiotensin II induced vascular injury and the IFNγ / Ly6C+ monocyte axis as well as the IL-17/Ly6G+ axis was reversed in CONV-D mice.

Conclusion:
Gut microbiota seem to facilitate Angiotensin II induced hypertension by supporting a T-bet / IFNγ and ROR-γt / IL-17 driven vascular inflammation with infiltration of Ly6G+ neutrophils.
Abstract 17878: Hospital Admission Rates for Myocardial Infarction and Stroke in New York City Before and After the Ban on Trans Fatty Acids
Authors: Brandt Eric J , Myerson Rebecca , Coca Perraillon Marcelo , Polonsky Tamar
Published: July 2021

Introduction:
Numerous bans on the use of trans fatty acids (TF)s in eateries are in effect across the United States. No studies have examined cardiovascular event rates after the bans were enacted.

Hypothesis:
The July 1, 2007 ban on TFs in restaurants and food trucks in New York City (NYC) was associated with an accelerated decline in MI and stroke.

Methods:
We used the 2002-2013 New York Department of Health Statewide Planning and Research Cooperative System (SPARCS) data to calculate hospital admission rates for incident of MI and stroke in NYC residents (using county of residence). Diagnosis was established using primary discharge ICD-9-CM codes 410.00-410.99 for MI and 430.00-438.99 for stroke. Rates were calculated using Census 2000 and 2010 data and intercensal estimates. Incidence rates of MI and stroke declined between 2002 and 2007. To analyze whether there was additional decline from these prior trends after implementation of the NYC TF ban, we used negative binomial regression to model event trends and compare this to actual trends. We also used publicly available data from the 2004 NYC Health and Nutrition Examination Survey (NYC HANES) to investigate restaurant usage per week among NYC residents. This was reported as never, less than weekly (we estimated as 0.5 uses per week), or 1 to 25 uses per week. All analyses were stratified by decade of age.

Results:
After 2007, younger age groups (25-34 and 35-44) experienced an additional decline in stroke (see table), but not MI, that was greater than would have been expected based on temporal trends. Younger age groups also reported higher mean restaurant use in NYC HANES.

Conclusions:
Stroke rates in NYC among younger adults declined faster than would have been expected after the 2007 TF ban. Additionally, younger age groups were also those that had highest restaurant usage. Further study to compare event trends in NYC counties to other New York counties is warranted to investigate if this trend is related to other secular trends.
Abstract 17891: Impact of Physical Activity and Sedentary Time on Heart Failure Outcomes
Authors: Doukky Rami , Poulin Marie-France , Avery Elizabeth , Mangla Ashvarya , Ibrahim Zeina , Collado Fareed , Richardson DeJuran , Powell Lynda H
Published: July 2021

Introduction:
The impact of physical inactivity and sedentary time on heart failure (HF) outcomes in patients not participating in exercise program is unclear.

Hypothesis:
Physical inactivity and sedentary time are associated with worse HF outcomes.

Methods:
We analyzed data from the multicenter, HF Adherence and Retention Trial (HART) which enrolled 902 NYHA - II/III HF patients with preserved or reduced ejection fraction, followed for 36 months. Based on the mean weekly purposeful physical activity duration, patients were classified into inactive (0 min/wk), partially active (1-90 min/wk), and active (>90min/wk) groups. Patients were also classified according to average daily sedentary television (TV) time into <2 hrs/d, 2-4 hrs/d, and >4 hrs/d groups. Study groups were propensity score matched according to 33 baseline covariates in 1:1:1 ratio. The primary outcome was all-cause death. Secondary outcomes were cardiac death and HF hospitalization.

Results:
There were 196 inactive, 341 partially active and 365 active patients, of whom 492 (164 in each group) were successfully propensity matched. Physical inactivity was associated with higher risk of death and cardiac death than any level of physical activity, Fig 1. There was no significant difference in HF hospitalization. Furthermore, 465 subjects were propensity matched into three sedentary TV time groups (155 in each group). Sedentary TV time >4 hrs/d was independently and incrementally associated with all-cause death (Δ χ
2
= 6.05; P=0.049), beyond physical activity time, Fig 1. There was no significant difference in mortality between <2 and 2-4 hrs/d sedentary TV time groups, after adjusting to physical activity time, Fig 2.

Conclusions:
In symptomatic chronic HF patients, physical inactivity is associated with higher all-cause and cardiac mortality. Modest purposeful physical activity was associated with survival benefit. Extended sedentary time was associated incremental increased mortality.
Abstract 17892: Strain Rate is Affected by Heart Rate in Younger Heart: A Simultaneous Invasive and Noninvasive in vivo Piglet Model
Authors: Fortin-Pellerin Etienne , Hornberger Lisa K , Coe James Y , Mills Lindsay , Serrano-Lomelin Jesus , Cheung Po-Yin , Khoo Nee S
Published: July 2021

Introduction:
In adult human and pig hearts, left ventricular (LV) systolic strain rate (SR) has been shown to be independent of heart rate (HR) in atrial tachycardia. It has been hypothesized that any increase in contractility related to the force-frequency relationship is balanced by a decrease in contractility due to reduced filling time and preload at higher HRs. In this study, we explore the impact of atrial tachycardia on SR of the young infant heart using a simultaneous invasive and noninvasive piglet model to determine whether SR of the immature heart is similarly not influenced by increasing HR.

Methods:
Under general anesthesia (propofol, isoflurane), 1 - 15 day old piglets were instrumented intravascularly with Millar high-fidelity and pacing catheters in the left ventricle and right atrium, respectively. After stabilization, invasive hemodynamic and echocardiography parameters were acquired at baseline, and at 200, 230 and 260bpm. Basal circumferential SR was analyzed off-line by speckle tracking (frame rates 247±7 Hz). Each animal was its own control and repeated measure ANOVA was used for comparison, data is expressed as mean ± SE.

Results:
Fourteen piglets of mean age 8.5±1.8 days, weight 3.6±0.5kg and baseline heart rate of 152±5bpm were assessed. Baseline LV systolic SR was -1.53±0.13 1/s and dP/dt 1656±115mmHg/s. With pacing, LV SR increased significantly (p = 0.002). The increase in SR mirrored the increase in contractility assessed invasively by dP/dt (p<0.001). M-mode LV end diastolic dimension decreased from baseline to 260bpm (73±9.9% of baseline value, p < 0.001) consistent with reduced preload with tachycardia.

Conclusion:
Our study suggests that in the younger heart, SR is augmented by atrial tachycardia itself even in the presence of decreased preload. This is in keeping with preservation of the force frequency relationship. Given our findings, HR should be taken into account when assessing contractility using SR in young patients.
Abstract 17908: Milrinone Lacks Acute Inotropic And Lusitropic Effects Under Constant Afterload Conditions
Authors: DeWitt Elizabeth S , Black Katherine , Mills Kimberly I , Ruoss Lauren , DiNardo James A , Kheir John N
Published: July 2021

Introduction:
Phosphodiesterase III inhibitors are known to improve cardiac output in patients with heart failure. Whether this is due to a reduction in afterload, a positive inotropic effect, or an interaction of these factors is uncertain. We compared the inotropic and lusitropic effects of milrinone to those of commonly used catecholamines in a working Langendorff model under constant loading conditions.

Methods:
Sprague Dawley rats (n=35, 350-400 grams) were anesthetized and heparinized for cardiac explantation. The aorta and left atrium were immediately cannulated by a single experimenter. Left atrial pressure (10 mmHg) and aortic pressure (90 mmHg) were fixed. A conductance catheter (Millar) was inserted into the left ventricle. Following baseline measurements, infusions of milrinone, dopamine, dobutamine, epinephrine, or norephinephrine, alone and in commonly-used combinations, were initiated into the left atrium for 10 minute periods. Changes in cardiac output, contractility (dP/dTmax), diastolic performance (-dP/dT and Tau) relative to baseline were compared between groups by linear regression analysis.

Results:
Cardiac output increased in linear fashion for each of the catecholamines: Dobutamine>>Dopamine>Norepinephrine>Epinephrine (P<0.001 for each). Dobutamine, Norepinephrine, and Dopamine (P<0.05) significantly increased diastolic function, including negative dP/dT (C) and Tau (D), none of which were changed by Milrinone infusion.

Conclusions:
When afterload is fixed using a Starling resistor, milrinone at commonly used doses does not acutely change systolic or diastolic performance or cardiac output. It is possible that clinical improvements are due to milrinone’s vasodilatory properties.
Abstract 17943: Clinical Factors That Determine the Superiority of Femoropopliteal Stenting Compared With Balloon Angioplasty
Authors: Hiramori Seiichi , Soga Yoshimitsu , Kobayashi Yohei , Tomoi Yusuke , Shirai Shinichi , Ando Kenji
Published: July 2021

Background:
It has reported that femoropopliteal stenting is superior to balloon angioplasty. However, it remains unclear that what factors affect the superiority of stent compared with balloon angioplasty.

Purpose:
To investigate the efficacy of stent in femoropopliteal lesions and clinical factors that affect the superiority of femoropopliteal stenting compared with balloon angiography.

Methods:
We analyzed consecutive 1523 de novo femoropopliteal lesions performing endovascular therapy between January 2004 and December 2013 by means of propensity score matching. We assessed the efficacy of stent for femoropopliteal lesion on primary patency and assisted-primary patency, and clinical factors that determine the superiority of stent compared with balloon angioplasty.

Results:
265 lesions in each group were selected by propensity score matching model for comparison. No difference was found in primary patency at 3 year between stent group and non-stent group (58.7% vs 49.3%, p=.06) and in assisted- primary patency at 3 year (63.8% vs 61.6%, p=.89). For the subgroup analysis, hazard ratio for primary patency in non-hemodialytic (hazard ratio [HR], 0.69; 95% confidential interval [CI], 0.50-0.96; p=.03) or ambulatory patients (HR, 0.69; 95% CI, 0.52-0.92; p=.01), or occlusive (HR, 0.58; 95% CI, 0.37-0.91; p=.02), non-calcified (HR, 0.63; 95% CI, 0.39-0.99; p=.04), TASCII non type A (HR, 0.65; 95% CI, 0.46-0.91; adjusted p=.01), or long (>100mm) (HR, 0.57; 95% CI, 0.32-0.98; p=.04) lesions showed the superiority of stent compared with balloon angioplasty.

Conclusions:
Our data suggests that femoropopliteal stenting is not necessarily recommended for all femoropopliteal lesions. However, it seems that femoropopliteal stenting is effective in non-hemodialytic or ambulatory patients, or lesions such as occlusive, non-calcified, TASC II non type A, or lesion length > 100mm compared with balloon angioplasty.
Abstract 17984: No Longer Silent: A Synonymous Coding SNP Modifying a Novel MicroRNA-24:SCN5A Interaction Associates With Non-Arrhythmic Death in Heart Failure
Authors: Boudreau Ryan L , Spengler Ryan M , Skeie Jessica M , Zhang Xiaoming , Cheng Congsheng , Yoon Jin-Young , Gutmann Rebecca A , Bloom Heather L , Dudley Samuel C , Ellinor Patrick T , Shalaby Alaa A , Weiss Raul , Johnson Frances L , Davidson Beverly L , London Barry
Published: July 2021

Mutations that disrupt the coding sequence of Nav1.5, the cardiac Na+ channel encoded by SCN5A, cause inherited arrhythmias and cardiomyopathy. Changes in Nav1.5 splice isoforms, localization and function have also been associated with prognosis in acquired heart disease. However, the role of genetic variants in SCN5A gene regulatory sequences (e.g. those modulating expression) remains poorly understood. MicroRNAs (miRs) have emerged as vital gene regulators in heart, having roles in cardiogenesis, contractile function, and disease. These small non-coding RNAs are loaded into Argonaute proteins to direct post-transcriptional gene suppression by base-pairing with target transcripts, and genetic variants altering miR binding sequences may influence disease. Here, we used high-throughput biochemical means (HITS-CLIP) to generate the first transcriptome-wide map of miR binding events in human heart (4000 sites across >2200 genes). Our query of the data uncovered >500 common SNPs residing in or nearby miR target sites. Among these, we identified a synonymous SNP (rs1805126, T/C) which alters a conserved miR-24 binding site in the terminal coding exon of SCN5A. We hypothesized that this SNP affects Nav1.5 expression and contributes to clinical outcomes in heart failure. In vitro experiments showed that miR-24 suppresses Na+ current on patch clamp analysis (~5-fold; p<0.001) and potently inhibits Nav1.5 expression, with rs1805126 allele C showing a greater decrease relative to T (66% vs. 52%, p<0.01). To assess the clinical relevance of this, we genotyped >1800 subjects with EFs≤30% and implantable cardioverter defibrillators (ICDs) from GRADE, a prospective multicenter study of genetic modulators of heart failure outcomes. We found that CC homozygotes had worse survival rates than T-allele carriers (HR=1.5, p=0.001), but no change in appropriate ICD shocks, a surrogate for sudden death. Together, these data reveal a novel miR-24:SCN5A:SNP regulatory axis that points to a surprising link between cardiac Na+ channel levels and non-arrhythmic death in heart failure. Overall, this work represents a key advance in exploring the interface of cardiac miRs with genetics and disease, perhaps signifying a broader functional relevance for “silent” SNPs.
Abstract 18018: Clinical Predictors of Acute Kidney Injury After Lower Extremity Surgical Bypass in the Society for Vascular Surgery Vascular Quality Initiative
Authors: Flores Erica , Chen Ke , Lewinger Juan Pablo , Clavijo Leonardo , Shavelle David , Rowe Vincent , Woo Karen , Garg Parveen
Published: July 2021

Introduction:
The incidence and factors associated with acute kidney injury (AKI) development after lower extremity bypass (LEB) are not well defined. The objective of this study is to determine the incidence and characteristics associated with the development of AKI in patients undergoing infrainguinal LEB.

Methods:
A retrospective review of all LEB surgeries in the Vascular Quality Initiative (VQI) registry from January 2003 to April 2015 was performed. AKI was defined as post-operative rise in creatinine (Cr) > 0.5 mg/dl or new renal impairment requiring dialysis. Demographic, procedural and clinical variables were collected. Patients on dialysis and those missing pre and post-operative Cr values were excluded. Multivariate logistic regression analysis was performed to identify variables associated with the development of AKI following LEB.

Results:
12,564 patients were included in the analysis; 509 (4%) developed AKI. Comparison of baseline characteristics between patients that developed AKI and those that did not are shown in the Table. In multivariate analysis, diabetes (OR 1.57, p<0.01), history of heart failure (OR 1.60, p<0.01), emergency surgery (OR 1.34, p<0.01), need for blood transfusion (OR 2.41, p<0.01) and chronic kidney disease (CKD) stages 2 (OR 1.39, p<0.01), 3(OR 2.85, p<0.01), and 4(OR 5.46, p<0.01) were all significantly associated with AKI. Factors associated with a lower incidence of AKI included smoking (OR 0.72, p<0.05), female gender (OR 0.69, p<0.01) and higher hemoglobin levels (OR 0.92, p<0.01).

Conclusions:
Overall, the development of AKI in a large contemporary database was 4%. Multiple clinical characteristics are associated with development of AKI, including history of heart failure, diabetes, CKD, emergency surgery and need for blood transfusion, and may help to identify at-risk patients. Further studies are needed to prospectively validate these findings and determine if postoperative AKI increases the mortality risk.