bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 15530: Omega-3 Fatty acids Supplementation Attenuates the Progression of Microalbuminuria in Diabetics With Coronary Artery Disease
Authors: Lakshminarayan Dharshan K , Elajami Tarec K , Soliman Michael , Alfaddagh Abdulhamied , Welty Francine K
Published: July 2021

Introduction:
Microalbuminuria is a marker of generalized endothelial dysfunction, a key step in the pathogenesis of coronary artery disease (CAD). It is also an independent predictor of cardiovascular morbidity and mortality. Angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy is considered a standard of care to attenuate progression of albuminuria in diabetic patients.

Hypothesis:
Omega-3 fatty acids (FAs) supplementation will attenuate progression of microalbuminuria in diabetic subjects with stable CAD.

Method:
In our study, 262 subjects with stable CAD were randomized to 3.6 g of omega-3 FAs (1.86 g of eicosapentaenoic acid + 1.5 g of docosahexaenoic acid) per day or no omega-3 FA (control) for one year. Urine microalbumin to creatinine ratio (urine MCR mg/g) was calculated as a measure of microalbuminuria at baseline and one year follow-up.

Results:
Mean age was 63.3 ± 7.6 yrs, 17% were women, 30% had diabetes, and 74% were on ACEI or ARB therapy. At one year follow-up in non-diabetics, there was no significant difference in the % change in urine MCR between the omega-3 FAs and control groups (see table). In contrast in diabetics, those not receiving omega-3 FAs had a significant 72.3% increase in urine MCR whereas those receiving omega-3 FAs had no change (table). In subgroup analysis, diabetics on an ACEI or ARB receiving omega-3 FAs had no change in urine MCR whereas those not receiving omega-3 FAs had a 64.2% increase at one year follow-up.

Conclusions:
Omega-3 FAs attenuated worsening of urine MCR in diabetics with CAD compared to diabetics not receiving omega-3 FAs over a one year period. Our results suggest that a combination of omega-3 FAs and ACEI or ARB is better in attenuating the progression of microalbuminuria than ACEI or ARB alone in diabetics with CAD. This suggests that omega-3 FAs may provide additional benefit when added to ACEI/ARB in diabetics with CAD.
Abstract 15568: Selective Deletion of Smad4 in Smooth Muscle Cells Causes Thoracic Aortic Aneurysm in Mice
Authors: Carnevale Daniela , Carnevale Raimondo , Da Ros Francesco , Cifelli Giuseppe , Bizzotto Dario , Braghetta Paola , Bressan Giorgio , Lembo Giuseppe
Published: July 2021

TGFβ signaling have been implicated in the onset of thoracic aortic aneurysms (TAAs). Recently, it has been described that mutations in SMAD4, an intracellular transducer required in the TGFβ canonical pathway, present aortic disease in humans. Although transgenic models recapitulating mutations of TGFβ pathway have been studied, the role of Smad4 in the onset of TAA has never been explored.

Smad4 homozygotes mice are embryonically lethal, thus, we postnatally targeted the gene, using a tamoxifen (TAM)-inducible Cre recombinase under the smooth muscle myosin heavy chain promoter. Activation by TAM suppressed Smad4 in aorta SMCs of Smadf/f;Myh11-CreERT2 mice. Most of these mice died 4/6 months later from hemothorax due to rupture of thoracic aorta, while untreated animals survived. Echocardiography showed a progressive dilatation of aorta and TAA formation. Histological analysis revealed progressive fragmentation of elastic lamellae with increased inflammatory infiltrates at sites of disarrangement, rich in macrophages. At the molecular level, we found that lack of Smad4 was followed by increased levels of P-Smad2 and P-Smad1/5/8 early after TAM. This finding suggested an enhancement of TGFβ receptors activity, a condition that could increase non-canonical TGFβ signaling, the canonical one being certainly depressed. We actually found a significant increase in one of the non-canonical TGFβ signaling, i.e. the p65 subunit of NFkB, a protein complex involved in regulating responses to different stress stimuli, including cytokines. Given the particular relevance that the latter molecules may have in TAA, we tested expression of some of them, finding a selective IL-1β upregulation, produced and stored as an inactive precursor and released in its active form by caspase-1 cleavage. In turn, caspase-1 requires the function of NLRP3 inflammasome, a multiprotein platform that assembles in response to infection and tissue damage and is responsible for activation of inflammatory caspases. Therefore, we also tested NLRP3 mRNA levels and found them to be significantly upregulated. Overall, we demonstrated that selective Smad4 deletion in the SMC of adult mice is sufficient to induce ultrastructural damage and immune reaction culminating in the onset of TAA.
Abstract 15583: Serum Vitamin D Deficiency is Independently Associated With Greater Prevalence of Erectile Dysfunction: Results From the National Health and Nutrition Examination Survey (NHANES) 2001-2004
Authors: Farag Youssef M , Guallar Eliseo , Zhao Di , Kalyani Rita R , Martin Seth S , Lutsey Pamela L , Billups Kevin L , Michos Erin D
Published: July 2021

Background:
Erectile dysfunction (ED) and cardiovascular disease (CVD) share common risk factors. Furthermore, up to 80% of ED is from vascular causes, and thus ED may be a marker for subclinical CVD. Low serum 25-hydroxyvitamin D [25(OH)D] levels have been associated with increased CVD risk, perhaps mediated through hypertension and diabetes, but it is unclear if low serum 25(OH)D is associated with ED, independent of CVD risk factors.

Methods:
We performed a cross-sectional analysis of 3,486 men aged ≥20 years free of CVD who participated in NHANES 2001-2004. Serum 25(OH)D was measured by the DiaSorin radioimmunoassay. We defined vitamin D deficiency as a serum level of 25(OH)D <20 ng/mL. Self-reported erectile function was assessed by a single question: “How would you describe your ability to get and keep an erection adequate for satisfactory intercourse?” We defined ED as those who answered “sometimes able” or “never able.” We assessed the relationship between serum 25(OH)D deficiency and prevalence of ED using logistic regression after adjusting for potential confounders.

Results:
The prevalence of vitamin D deficiency and of ED was 30% and 16.4%, respectively. Serum 25(OH)D levels were statistically significantly lower in men with vs those without ED (mean 22.9 vs 24.3 ng/mL, respectively; p=0.0007). Vitamin D deficient men had a significantly higher prevalence of ED compared to those without deficiency (age- and race-adjusted OR 1.53, 95% CI 1.17-2.00). This association was materially unchanged after adjusting for multiple lifestyle variables, comorbidities, and medication use (OR 1.32, 95% CI 1.02-1.74) [
Figure
].

Conclusion:
In this cross-sectional analysis of a representative sample of U.S. men, vitamin D deficiency was associated with an increased prevalence of ED independent of CVD risk factors. Additional research is needed to evaluate if treating vitamin D deficiency results in an improvement of erectile function or prevents vascular events.
Abstract 15592: Role of Electroanatomic Voltage Mapping for Risk Stratification in Patients With Repaired Congenital Heart Disease Involving the Right Ventricle
Authors: Pazzano Vincenzo , Palmieri Rosalinda , Di Mambro Corrado , Russo Mario S , Silvetti Massimo S , Gimigliano Fabrizio , Giannico Salvatore , Leonardi Benedetta , Drago Fabrizio
Published: July 2021

Introduction:
Among adult patients with previous surgical correction for Tetralogy of Fallot or other repaired Congenital Heart Disease (rCHD) involving the RV, ventricular arrhythmias (VA) and sudden cardiac death (SCD) represent a late complication. The imparied haemodynamics that lead to RV dilatation and overload could also alterate its electroanatomic structure.

Hypothesis:
3D electroanatomic mapping (EAM) of the RV could confirm the presence of myocardial electrical abnormalities, allowing to better identify patients at risk for life-threatening arrhythmias.

Methods:
146 patients (age 19.2 ±7.0) with rCHD involving the RV were selected from a population undergoing routine post-surgical follow-up, according to the presence of VA or severe RV dilatation. These patients underwent 3D EAM of the RV. We tested the correlation between size of scar tissue (areas with voltage < 0.5 mV) and several parameters universally accepted by the literature as risk factors for VA in this particular patient population.

Results:
In 125 (85.6%) patients, EAM demonstrated areas of low voltage in the antero-lateral RVOT. In 20 of these (16%, 13.7% of the total) the scar extended to the septum. 72 (49.3%) had a peritricuspid scar, and in 20 (13.7%) other areas of the RV were interested. Total low-voltage area, expressed as % of total endocardial area, was significantly higher in patients with history of PVCs [3.2% (±2.6) vs 2.2% (±1.8), p<0.05], complex PVCs at 24h-Holter ECG (Lown class ≥2) [3.4 (±2.5) vs 2.6 (±2.3), p<0.05], exercise-inducible PVCs [3.8 (±2.4) vs 2.6 (±2.2), p=0.01] and history of previous shunt [4.0 (±2.7) vs 2.6 (±2.2), p=0.01]. Scar size was also positively correlated with age (p=0.01), age at correction (p=0.01) and QRS duration on surface ECG (p<0.05).

Conclusions:
In patients with rCHD involving the RV it is common to observe endocardial low-voltage areas with variable distribution, not always corresponding to the sites of surgical lesion. Morover, the size of the scar tissue area correlates with some of the parameters which have been already identified as risk factors for life-threatening arrhythmias and SCD in adult patients with CHD. We suggest that EAM should become part of the routine tests for the stratification of arrhythmic risk in this population.
Abstract 15645: Carotid Artery Stenting and Endarterectomy in Patients With Stage 5 Chronic Kidney Disease: Insights of the Healthcare Cost and Utilization Project’s National Inpatient Sample
Authors: Lima Fabio V , Yen Tzyy Y , Gruberg Luis
Published: July 2021

Background:
Carotid artery stenting (CAS) has evolved into a viable alternative for the treatment of symptomatic and asymptomatic high-grade carotid artery stenosis, particularly in patients considered to be at a high surgical risk for carotid endarterectomy (CEA).

Hypothesis:
There is limited data on the outcomes of patients with stage 5 chronic kidney disease (CKD) (GFR<15 mL/min/1.73 m
2
or dialysis) undergoing CEA or CAS.

Methods:
The Healthcare Cost and Utilization Project’s National Inpatient Sample was screened for hospital admissions of patients undergoing CAS and CEA from 2003-2012. Baseline clinical characteristics and outcomes were identified in patients with stage 5 CKD. The primary outcome was major adverse cardiac and cerebrovascular events (MACCE), defined as the composite of in-hospital death, acute myocardial infarction and acute cerebrovascular accident (CVA).

Results:
Our study population consisted of 1,723 patients that underwent CEA and 544 patients that underwent CAS. Patients undergoing CAS were younger and had significantly lower rates of coronary artery disease, hypertension and hyperlipidemia. CAS patients experienced significantly higher rates of MACCE compared with patients that underwent CEA, mainly driven by a higher rate of in-hospital strokes (Fig. 1). In a multivariable analysis, CAS (OR 1.53, 95% CI 1.19-1.98) was an independent predictor of MACCE.

Conclusions:
In patients with stage 5 CKD (GFR<15 mL/min/1.73 m
2
or dialysis ) undergoing internal carotid artery revascularization, CAS was associated with higher rates of in-hospital MACCE, driven by higher mortality and stroke rates when compared with CEA.
Abstract 15673: CRISPR-Cas9 Gene Editing in Mice Reveals Novel Thrombotic Function of a Human SNP in STXBP5
Authors: Zhu Qiuyu , Ko Kyung Ae , Ture Sara , Morrell Craig N , Miano Joseph M , Lowenstein Charles J
Published: July 2021

Introduction:
Endothelial cells responds to vascular injury by exocytosis, releasing von Willebrand factor (vWF) into the blood stream. However, the regulation of endothelial vWF release remains poorly understood. Recent genome-wide association studies (GWAS) have identified syntaxin-binding protein 5 (STXBP5) as a candidate gene linked to changes in vWF plasma levels. One top nonsynonymous single nucleotide polymorphism (SNP), rs1039084 (hg19 chr6:g.147635413A>G), encodes p. Asn436Ser substitution (STXBP5-N436S), and is associated with lower plasma vWF, higher bleeding score, and decreased venous thrombosis in humans. We recently discovered that STXBP5 inhibits endothelial vWF exocytosis and regulates thrombosis. However, the role of the STXBP5 genetic variants linked to vWF levels are not completely understood.

Hypothesis:
We hypothesized that STXBP5-N436S further inhibits endothelial exocytosis than wild type (STXBP5-WT).

Methods:
We overexpressed STXBP5-WT and STXBP5-N436S in cultured human endothelial cells and measured VWF release changes. Using CRISPR-Cas9 technique, we generated mice carrying the human rs1039084 SNP in Stxbp5 locus (Stxbp5-N437S mice). We conducted phenotypic analyses including endothelial exocytosis, hemostasis, and thrombosis in wild-type and Stxbp5-N437S mice.

Results:
In human endothelial cells, overexpression of STXBP5-N436S inhibits vWF exocytosis more potently than STXBP5-WT. Germline CRISPR-Cas9 gene editing efficiently and precisely knocked-in the human rs1039084 SNP in murine Stxbp5 locus, without causing detectable off-target genome cleavage. The baseline plasma vWF levels of Stxbp5-N437S mice are similar to WT mice, but Stxbp5-N437S mice showed impaired vWF exocytosis in response to epinephrine challenge. Moreover, Stxbp5-N437S mice have severe hemostasis defects displayed as prolonged bleeding time. Finally, Stxbp5-N437S mice have impaired mesenteric vessel thrombosis and carotid artery thrombosis. We are now studying the effects of the SNP upon STXBP5 structure and function.

Conclusions:
Our study validates the functional relevance of a candidate SNP identified by GWAS, and suggests that genetic variations within STXBP5 is a risk factor for thromboembolic disease.
Abstract 15693: Comorbidities in Heart Failure: A Population-Based Case-control Study
Authors: Chamberlain Alanna M , Boyd Cynthia M , Manemann Sheila M , Dunlay Shannon M , Gerber Yariv , Killian Jill M , Weston Susan A , Roger Veronique L
Published: July 2021

Background:
Whether age alone explains the comorbidity burden in heart failure (HF) is unclear. In particular, differences in the burden of co-morbid conditions in HF patients compared to population controls has not been well documented.

Methods:
The prevalence of 17 chronic conditions defined by the US Department of Health and Human Services were obtained in 1746 incident HF patients from 2000-2010 and controls matched 1:1 on sex and age from Olmsted County, MN. Conditions were ascertained requiring 2 occurrences of a diagnostic code. Logistic regression determined associations of each condition with HF.

Results:
Among the 1746 matched pairs (mean age 76.2 years, 43.5% men), the prevalence was higher in HF cases for all conditions (p<0.05) except dementia and osteoporosis. After adjusting for all conditions, hypertension, coronary artery disease, arrhythmia, asthma, chronic kidney disease, chronic obstructive pulmonary disease, diabetes, hepatitis, and substance abuse were significantly more common in HF (figure). More than a 2-fold increased odds of hepatitis, arrhythmia, and coronary artery disease was observed among HF cases. Arrhythmia (34.2%), hypertension (31.1%), and coronary artery disease (27.8%) had the largest attributable risk of HF; for example, assuming a causal relationship, if arrhythmias were eliminated, 34% of HF would be avoided.

Conclusions:
Compared to age- and sex-matched controls, HF patients have a higher prevalence of many chronic conditions, indicating the excess comorbidity in HF is not due to age alone. Some cardiovascular conditions, including arrhythmia, coronary artery disease, and hypertension were more common in HF. Of the non-cardiovascular conditions, hepatitis had the strongest association with HF and was an unanticipated finding that deserves additional investigation. It is important to understand comorbidities as they play a key role in the excess mortality and healthcare utilization experienced by HF patients.
Abstract 15732: Impact of Bilateral Mammary Artery Grafting for Coronary Revascularization in the Obese Population, a Retrospective Study
Authors: Ruka Emmeline , Dagenais François , Mohammadi Siamak , Chauvette Vincent , Voisine Pierre
Published: July 2021

Context:
The prevalence of obesity has increased over the last decade. Although bilateral internal mammary artery (BIMA) grafting for coronary revascularization is associated with better survival in the general population, it is also a risk factor for deep sternal wound infection (DSWI), a complication more frequently seen in the obese population. The aim of this study is to determine the short and long-term outcomes of the use of BIMA in obese patients undergoing cardiac surgery, assessing the impact on survival and the incidence of DSWI.

Methodology:
This is a single center retrospective cohort study with prospectively collected data. We included obese patients (BMI ≥ 30 kg/m2) undergoing coronary artery bypass grafting (CABG) between April 1991 and April 2014 in our institution. Propensity score matching was conducted for the entire population studied.

Results:
Results showed that 5608 obese patients underwent CABG during the study period. After propensity scoring, 494 patients receiving BIMA revascularization were matched to 5089 patients receiving single internal mammary artery (SIMA) revascularization. All pre-operative characteristics were comparable except for a higher prevalence of heart failure in the SIMA group. In-hospital post-operative mortality in the two groups was comparable (1.0% BIMA vs 1.8% SIMA, p=0.86). In-hospital DSWI was also comparable (1.2% BIMA vs 1.0% SIMA, p=0.63). However total DSWI (including post-discharge DSWI, median time 19 days) was significantly higher in the BIMA group compared to the SIMA group (3.6% vs 2.2%; p<0.0001). Over a median follow-up of 7.2 years (mean follow-up 7.7 ± 4.2 years), there was no observed long-term survival advantage in the BIMA vs the SIMA group (p=0.22).

Conclusion:
Using BIMA instead of SIMA increases the risk of DSWI in obese patients. The use of BIMA is not associated with better survival compared to the use of SIMA in this population. These results suggest that the increased short-term risk of post-operative infection associated with BIMA revascularization is not offset by a long-term survival benefit. Given the increased risk of DSWI and absence of mid- to long-term survival benefit, caution should be exerted when selecting the use of BIMA grafting in the obese population.
Abstract 15758: Relationship Between Physiological Coronary Artery Stenosis Severity Assessed by Fractional Flow Reserve and Optical Coherence Tomography Findings in Stable Angina Pectoris
Authors: Lee Tetsumin , Murai Tadashi , Kanaji Yoshihisa , Usui Eisuke , Araki Makoto , Niida Takayuki , Ichijo Sadamitsu , Kakuta Tsunekazu
Published: July 2021

Backgrounds:
The aim of the present study is to investigate the relationship between physiological coronary artery stenosis severity and lesion instability by Optical Coherence Tomography (OCT) in patients with stable angina pectoris (SAP).

Methods and Results:
We investigated 198 culprit lesions of 180 SAP patients who underwent OCT imaging and fractional flow reserve (FFR) measurement before PCI procedure. Physiological coronary stenosis severity was assessed by FFR analysis, and lesions were divided into two groups on the basis of FFR values; severe stenosis group (group S): FFR <0.75 (n=78, 39%), moderate stenosis group (group M): FFR ≥0.75 (n=120, 61%) according to the previous study. Thin-capped fibroatheroma (TCFA) was defined as lipid-rich plaque (lipid arc ≥90°) with fibrous cap thickness <70μm. The median FFR values in total lesions, group S, and group M were 0.77 (interquartile range [IQR]: 0.69—0.83), 0.65 (0.57—0.72), and 0.81 (0.78—0.87), respectively. There were no significant differences in patient characteristics expect for the frequency of previous myocardial infarction (S: 15%, M: 38%, P <0.01) and previous PCI (S: 29%, M: 60%, P <0.01). In angiographic analysis, there were significant differences in the frequency of culprit lesion location in LAD (S: 72%, M: 49%, P <0.01), minimum lumen diameter (S: 1.07±0.36 mm, M: 1.35±0.32 mm, P <0.01), % diameter stenosis (S: 58.9 % [53.1—70.8], M: 52.8 % [47.7—57.5], P <0.01), and lesion length (S: 13.7 mm [10.6—17.5], M: 11.5 mm [9.2—14.5], P = 0.02) between the two groups. In OCT analysis, there were significant differences in the lipid arc (S: 200° [160—232], M: 168° [143—211], P <0.01), CT (S: 110 μm [63—157], M: 140 μm [93—197], P <0.01), and frequency of TCFA (S: 27%, M: 9%, P <0.01) between the two groups. Subgroup analysis of LAD lesions showed similar results between the two groups.

Conclusions:
Lesions of physiologically severe coronary stenosis in SAP were associated with lesion instability assessed by OCT. These findings may challenge the concept that lesions responsible for acute coronary syndromes are mild in most cases provided that plaque rupture of TCFA evenly results in coronary events in the wide range of stenosis severity in patients with SAP.
Abstract 15775: The Impact of B-type Natriuretic Peptide Activation on the Association of Left Ventricular Longitudinal Strain With All-cause Mortality
Authors: Ye Zi , Enriquez-Sarano Maurice , Malouf Joseph , Michelena Hector I , Jaffe Allan S , Suri Rakesh M , Clavel Marie-Annick
Published: July 2021

Introduction:
Left ventricular longitudinal strain (LV-LS) 1) predicts mortality in patients with aortic stenosis (AS) and 2) is highly correlated to type-B natriuretic peptide (BNP) values. The BNP ratio (measured BNP/maximal expected BNP value specific for age and sex) is a powerful independent predictor of death in patients with AS.

Hypothesis:
we hypothesize that BNP activation (i.e. BNP ratio >1) affects the association between LV-LS and mortality in patients with asymptomatic AS and preserved LV ejection fraction (EF ≥50%).

Methods:
315 patients (age 74±12 years, 56% men and mean aortic valve area = 1.02±0.15cm2) underwent simultaneous Doppler echocardiographic and BNP measurements. LV-LS was calculated as the average of 12 LV segments from apical 2- and 4-chamber views using Velocity Vector Imaging.

Results:
Mean LV-LS was -16.8±3.2%, LV EF 66±7%, median BNP level 121 (interquartile 48-320) pg/ml. 58% of patients had BNP activation. Better LV-LS was associated with lower log BNPratio (regression coefficient 0.10, p<0.001). After a median follow-up of 6.5 yrs (interquartile: 3.6-8.2), 119 deaths occurred. After adjustment for age, sex, Charlson score index, hemoglobin level, aortic valve replacement (as a time dependent variable), LV-LS and log BNPratio were separately associated with increased risk for death (all p<0.01). Further adjustment for predictors of mortality, LV-LS and log-BNP ratio remained associated with increased risk for death (hazard ratio HR [95%CI]: 1.09 [1.03-1.15]; p=0.003 and 1.82 [1.52-2.19]; p<0.0001 respectively). In patients without BNP activation (i.e. normal BNP), LV-LS was associated with mortality (HR: 1.22 [1.04-1.43]; p=0.01) while it was not in patients with BNP activation (p=0.22).

Conclusions:
In patients with asymptomatic AS, without clinically obvious myocardial impairment (i.e. normal LVEF), a notable proportion of patients present with myocardial alterations detected by an elevated BNPratio or reduced LV-LS. These signs of myocardial alterations were predictive of mortality after diagnosis. Thus both BNP and LV-LS should be assessed in the clinical setting to provide complementary information on prognosis in patients with asymptomatic AS and preserved LV EF.
Abstract 15822: Phosphorus Magnetic Resonance Spectroscopy is More Precise at 7 Tesla Field Strength Than 3 Tesla in Patients With Dilated Cardiomyopathy
Authors: Stoll Victoria , Clarke William , Levelt Eylem , Myerson Saul , Robson Matthew , Rodgers Christopher , Neubauer Stefan
Published: July 2021

Introduction:
Phosphorus magnetic resonance spectroscopy (
31
P-MRS) allows insight into cardiac energetics
in vivo
, but is a technique with an intrinsically low signal to noise ratio (SNR). As ultra-high magnetic field MRI scanners become more widely available this limitation will lessen, allowing detection of smaller changes in metabolite concentrations or measurement of changes in smaller patient groups, which will further the understanding of cardiac energetics.

Hypothesis:
We hypothesised that the 2.4x increase in SNR, predicted by theory at 7T compared to 3T, will allow more precise metabolite concentration measurements in dilated cardiomyopathy (DCM) patients.

Methods:
26 idiopathic DCM patients (69% male, mean age 55±2 yr, mean LVEF 35±2%) underwent
31
P-MRS at 3T and 7T field strengths. Patients were NYHA Class I (46%), II (50%) or III (4%).

Results:
The mean SNR increased from 6.5 ± 0.5 to 16.2 ± 1.5 for PCr (p <0.0001, paired t-test) and from 3.4 ± 0.2 to 11.4 ± 0.8 for γATP (p <0.0001) as the field strength increased from 3T to 7T.

The PCr/ATP ratio was consistent between the 2 field strengths; at 3T PCr/ATP was 1.5 ± 0.1 and at 7T 1.5 ± 0.1; there was as expected no statistically significant difference (p=0.67) (fig a).

The Cramér-Rao lower bounds (CRLB) quantify the minimum precision of fitted parameters. A desirable decrease in the PCr/ATP CRLB was seen from 3T to 7T (47 ± 3% vs 25 ± 2% p<0.0001)(fig b), i.e.-metabolites are indeed quantified more precisely at 7T compared to 3T.

Conclusion:
This study represents the first cardiac
31
P-MRS patient data acquired at a 7T field strength. Compared to a 2.8x SNR increase from 3T to 7T previously reported in normal volunteers, we observed a 2.5x increase in this patient population. There is no significant bias at 7T as the PCr/ATP ratios are similar.

In conclusion 7T
31
P-MRS is feasible in DCM patients and more accurate than at 3T, which in future should allow more accurate quantification and understanding of myocardial energetics.
Abstract 15830: ‘Out of Target’ Radiation Therapy Leads to Impaired Cardiac Contractile Reserve in the Mouse
Authors: Mauro Adolfo G , Toldo Stefano , Mikkelsen Ross B , Alam Asim , Weiss Elisabeth , Gewirtz David A , Van Tassell Benjamin W , Abbate Antonio , Mezzaroma Eleonora
Published: July 2021

Introduction:
Radiation therapy (XRT) used for the treatment of cancer, can expose the heart to the radiation beam causing cardiac injury. However, fatigue and exercise intolerance are common symptoms in patients treated with XRT for different types of cancer, in which the XRT field does not involve the heart.

Hypothesis:
We hypothesize that impaired cardiac reserve may occur even when the XRT field is distant from the heart (‘out of target effect’).

Methods:
C57BL/6J female mice underwent two different radiation treatments (20 Gray, single dose) using a Small Animal Radiation Research Platform: a) the isocenter was pointed to the right lung sparing the heart (‘out of target’) and b) the heart was chosen as isocenter, as positive control. An additional group of mice were sham-irradiated, as negative control. Transthoracic echocardiography was used to assess the left ventricular ejection fraction (LVEF) at baseline and the contractile reserve expressed as percentage change in the LVEF measured at rest (LVEFr) and 3 minutes after intraperitoneal administration of the β-adrenergic agonist, isoproterenol (LVEFi)[(LVEFi-LVEFr)/LVEFr]*100].

Results:
Three days after radiation treatment irradiated and sham mice showed normal LVEF at rest. However, the ‘out of target’ irradiation group showed a significant impairment in cardiac contractile reserve compared with sham, and similar to the ‘on target’ group (Figure).

Conclusions:
‘Out of target’ radiation therapy leads to impaired cardiac contractile reserve in the mouse.
Abstract 15856: Left Ventricular Longitudinal Contractility Measured During Routine Cine-cardiac Magnetic Resonance Imaging is an Independent Predictor of Adverse Cardiac Events
Authors: Rangarajan Vibhav , Chacko Satish J , Jariwala Nikhil , Romano Simone , Chung Jaehoon , Farzaneh-Far Afshin
Published: July 2021

Background:
Left ventricular systole involves coordinated contraction of longitudinal, circumferential, and radial myocardial fibers. Longitudinal fiber dysfunction appears to be an early marker for a number of pathological states. We hypothesized that reduced mitral annular plane systolic excursion (MAPSE) measured during cine-Cardiac Magnetic Resonance (CMR) imaging reflects changes in longitudinal fiber function and may be an early marker for adverse cardiovascular outcomes.

Methods:
400 consecutive patients with known or suspected coronary artery disease undergoing CMR were prospectively enrolled. Lateral MAPSE was measured in the 4-chamber cine view by two independent observers. Patients were prospectively followed for major adverse cardiac events (MACE) - death, non-fatal myocardial infarction, hospitalization for heart failure or chest pain, and late revascularization. Cox proportional hazards regression modeling was used to identify factors independently associated with MACE.

Results:
The mean age of the study population was 58(±15) years, with a mean ejection fraction of 59(±14%). 31% of the individuals had known coronary artery disease and 33% were diabetic. 72 MACE occurred during a median follow-up of 14.5 months. By Kaplan-Meier analysis, patients with lateral MAPSE ≤1.11cm (median) experienced significantly higher incidence of MACE than patients with a MAPSE >1.11cm (p = 0.0270) (Figure). After adjustment for established predictors (ejection fraction, age, sex, diabetes, hyperlipidemia, smoking, hypertension, late gadolinium enhancement) lateral MAPSE remained a significant independent predictor of MACE (HR=2.43 per cm decrease; p=0.037).

Conclusions:
Reduced longitudinal fiber function assessed with lateral MAPSE during cine-CMR is an independent predictor of MACE in patients with known or suspected coronary artery disease.

Figure:
Kaplan-Meier curves for MACE in patients with MAPSE above and below the median.
Abstract 15864: Whole Body Periodic Acceleration (pGz); A Novel Therapeutic Approach in Dystrophin
-/-
Utrophin
-/-
(DKO) Cardiomyopathy
Authors: Mijares Alfredo , Kolster Juan , Adams Jose A , Lopez Jose R
Published: July 2021

Duchenne Muscular Dystrophy cardiomyopathy (DMDC) is a progressive lethal disease. The dystrophin and utrophin double knock-out (
DKO
) mice (

dystrophin
–/–
/utrophin
–/–

) share histopathological markers with DMDC.
DKO
is a very severe model of DMDC. pGz is the sinusoidal head to foot motion of the body, inducing pulsatile shear stress to the vascular endothelium activating endothelial nitric oxide synthase (eNOS) to produce small quantities of cardiac eNO. eNO has been shown to reduce ROS production, modulate intracellular Ca
2+
and Na
+
concentrations and inhibit calpain mediated proteolysis. We previously showed that pGz decreases diastolic Ca
2+
and Na
+
overload in cardiomyocytes from mdx mice, and confers cardioprotection.

Hypothesis:
We tested the hypothesis that pGz may also confer cardioprotection in the most severe form of DMDC, the
DKO.

Methods:
DKO
mice were randomized at 3-mo of age to daily pGz (ƒ=480 cpm,Gz ± 3.0 mt/sec
2
,1hr/day for 2 weeks) (DKO+pGz) or none (DKO), a separate age matched non-diseased group of
wt
(CONT) and CONT treated with pGz (CONT+pGz). Cardiomyocytes where isolated from each group and intracellular diastolic Ca
2+
([Ca
2+
]
d
) and Na
+
([Na
+
]
d
) measured with microelectrodes. Calpain activity (Calpain-Glo), ROS production (DCFH-DA), were also measured.

Results:
DKO
mice had a 5X and 4X fold(X) elevation in [Ca
2+
]
d
and [Na
+
]
d,
respectively compared to
CONT
. pGz significantly reduced this elevation. Calpain activity was significantly increased (3X) in DKO compared to CONT and it was reduced by pGz. ROS production which was increased in DKO (3X) was blunted by pGz. pGz did not affect [Ca
2+
]
d,
[Na
+
]
d
, Calpain activity or ROS production in CONT. [(Figure, M±SD )***p< 0.001]

Conclusion:
pGz markedly improves intracellular Ca
2+
and Na
+
as well as decreasing Calpain and ROS production in DKO cardiomyocytes. These finding suggest that pGz has therapeutic potential as a novel therapeutic intervention in DMD cardiomyopathy.
Abstract 15880: Angiopoietin 2, a Pro-inflammatory Protein, is Associated With Major Adverse Cardiovascular Events in Patients With Peripheral Arterial Disease
Authors: Herz Carsten Thilo , Hoebaus Clemens , Obendorf Florian , Pesau Gerfried , Koppensteiner Renate , Schernthaner Gerit
Published: July 2021

Introduction:
Angiopoietin 2 (ANG2) is a pro-inflammatory protein which is elevated in several inflammatory conditions and associated with increased morbidity and mortality.

Hypothesis:
ANG2 is associated with the composite of death, non-fatal myocardial infarction and non-fatal stroke (MACE) in patients with peripheral arterial disease (PAD).

Methods:
We measured serum ANG2 levels at baseline in 363 consecutive PAD patients with using multiplex bead array technology. Follow-up was five years. In Cox regression, confounding was evaluated by examining the relative change in coefficients (delta-beta) for ANG2 after the omission of the respective potential confounder from the fully adjusted model. Significant Confounding was defined as a delta-beta > 10%.

Results:
Using receiver operating characteristics, ANG2 exhibited an area under the curve of 0.6 (95%CI: 0.522 - 0.678) for the proper discrimination between MACE and non-events. A cut-off of 3.74 ng/ml resulted in the highest possible combination of specifity (57.5%) and sensitivity (63.3%) leading to an unadjusted hazard ratio (HR) of 2.17 (95%CI: 1.28 - 3.67) in Cox regression (p=0.004). Adjusting for age, sex, diabetes, systolic blood pressure, smoking status and renal function lead to a HR of 1.89 (95%CI: 1.11 - 3.24) for ANG2 >3.74 ng/ml (p=0.020). The additional adjustment for c-reactive protein (CRP) resulted in a no more significant HR of 1.68 (95%CI: 0.97 - 2.92)for high ANG2 (p=0.067). Diabetes and CRP, both significant predictors of MACE in our cohort, proved to be significant confounders with concomitant delta-betas of 19.7% and 22.9%, respectively.

Conclusions:
We are the first to demonstrate that elevated ANG2 levels are interrelated with MACE in patients with PAD. Inflammation and glucose hemostasis seem to influence this association.
Abstract 15904: Acute Outcomes in Persistent and Long-standing Persistent Atrial Fibrillation Patients Undergoing Rotor Ablation
Authors: Gianni Carola , Metz Tamara , Di Biase Luigi , Mohanty Sanghamitra , Trivedi Chintan , Gökoglan Yalçin , Günes Mahmut F , Bai Rong , Al-Ahmad Amin , Burkhardt J. D , Gallinghouse Joseph G , Horton Rodney , Hranitzky Patrick M , Sanchez Javier E , Tomassoni Gery , Halbfaβ Philipp , Müller Patrick , Schade Anja , Deneke Thomas , Natale Andrea
Published: July 2021

Introduction:
Focal impulse and rotor modulation (FIRM)-guided ablation targets localized sources that are thought to sustain AF. In previous reports, it has been shown that FIRM is effective in terminating or organizing AF. We sought to evaluate the acute success of FIRM in patients with persistent and LSP AF undergoing ablation in our centers.

Methods:
This was a multicenter prospective observational study. FIRM was performed alone or before conventional ablation. Rotors were ablated as confirmed by their absence during remapping and acute success was defined as AF termination, organization or slowing 10%.

Results:
57 patients were enrolled (mean age 63 ± 10; 7% LSP). Rotors-only ablation was performed in 56% of patients, and preceded conventional ablation in 44%. There were no major periprocedural adverse events.

No focal impulses were found, while rotors were present in all patients (3.9 ± 1.2 per patient; 66% in the LA). In the RA, the majority of rotors were in the lateral wall (53%) and in the septum (30%). In the LA, most of the rotors were in proximity of the pulmonary veins (48%), with the second most common locations being around the mitral annulus or in the septum (17% and 13% respectively).

Mean procedural time for FIRM only procedures was 226 ± 52 minutes vs a median of 210 (168-240) minutes for FIRM + conventional ablation procedures (p = NS). Overall acute success was achieved in 35% of patients (3% AF termination, 16% AF organization, 16% AF slowing) with a mean RF time to complete FIRM ablation of 30 ± 15 minutes; no difference in acute success was found when comparing persistent to LSP patients (28% vs 50%; p = NS). Conventional ablation following FIRM did not significantly increase the rate of acute success (1 additional patient converted to sinus rhythm during pulmonary vein isolation).

Conclusion:
Rotors were present in all patients undergoing ablation for non-paroxysmal AF, most commonly the right atrial lateral wall, septum or around the pulmonary veins. Their ablation was not effective in obtaining AF organization/termination during the procedure.
Abstract 15922: Fischer Rats Exhibit High Mortality in the Su5416 Model of Severe Pulmonary Arterial Hypertension Related to Failure of Right Ventricular Adaptation
Authors: Suen Colin , Jiang Baohua , Deng Yupu , Taha Mohamad , Chaudhary Ketul , Stewart Duncan J
Published: July 2021

Introduction:
Inhibition of VEGFR2 with SU5416 (SU) in combination with chronic hypoxia (CH), produces severe pulmonary arterial hypertension (PAH) in rats with complex arterial remodeling that closely resembles plexiform lesions typical of human PAH. Survival in severe PAH is related to the ability of the right ventricle (RV) to adapt to increased afterload. In this study, we explored the effect of genetic background on right ventricular adaptation and survival in the

Methods:
PAH was induced by a single subcutaneous injection of SU5416 (20mg/kg) in 6-week old Sprague-Dawley (SD, Harlan, USA) or Fischer rats (CDF, Charles River), followed by a 3-week exposure to CH (10% O2). RV structure and function was assessed by echocardiography (Vevo 2100, Visual Sonics) and cardiac MRI (Agilent 7.0T). Exercise capacity was evaluated at 4 weeks post-SU by treadmill testing. At end study (4 or 7 weeks post-SU), right ventricular systolic pressure (RVSP) was assessed by right heart catheterization.

Results:
SD and Fischer rats exhibited in similar elevations in RVSP (104± 13 vs 102 ±6 mmHg, respectively), number of occlusive pulmonary vascular lesions and RV hypertrophy (RV/LV+S) in response to SU/CH. However, Fischer rats exhibited markedly higher mortality, with only 27% surviving to 7 weeks compared with 100% survival in SD rats (p<0.01), which was associated with significantly greater RV dilatation (RV/LV end diastolic diameter: 2.16 ± 0.24 vs. 1.19 ± 0.09 mm, p<0.001) at 4 weeks post-SU (Figure 1). Additionally, RV capillary density (516 ± 55 vs 786 ± 38 capillaries/mm2) and exercise capacity (treadmill distance, 59 ± 29 vs 210 ± 52 m, p<0.05) were also significantly reduced in Fischer vs SD SU/CH rats.

Conclusions:
These data suggest that the high mortality in Fischer compared to SD rats in the SU/CH model of severe PAH is related to a strain-dependent abnormality in RV adaptation at least in part due to lack of adequate microvascular angiogenesis in the hypertrophied RV.
Abstract 15934: Higher Midlife Serum Levels of Kidney-injury Molecule-1 (KIM-1) are Associated With Incident Fatal CHD Over Very Long-term Follow-up Among Men
Authors: Mackey Rachel H , Grandits Greg G , Kuller Lewis H , Estis Joel , Todd John A , Yerramilli Malli R , Neaton James
Published: July 2021

Introduction:
Higher levels of kidney-injury molecule-1 (KIM-1) measured in urine are associated with presence and progression of acute renal disease. A recent study reported similar results for KIM-1 measured in blood.

Hypothesis:
We hypothesized that KIM-1 measured in stored serum from middle-aged men who participated in the Multiple Risk Factor Intervention Trial (MRFIT) would differentiate very long-term risk of fatal CHD vs. survival to a mean age of 80 over approximately 30 year follow-up.

Methods:
We conducted a nested case-control study within MRFIT, which in 1973-76 randomized 12,866 high risk but CVD free men ages 35-57 to risk factor intervention vs. usual care. Serum samples were collected at baseline and stored for future use. The trial concluded in 1982 but long-term mortality follow-up was ascertained through 2005 using the National Death Index. From MRFIT participants with stored serum from baseline, we sampled 100 men who died of CHD (mean age 47.3 at baseline and 73.9 at death), and 100 men who survived to 2005 (mean age =48.4 at baseline and 80.1 in 2005.) KIM-1 was assayed from stored serum samples using high sensitivity single-molecule counting technology (Erenna ® Immunoassay System, Singulex), with limit of detection (LoD)=0.5 pg/ml, and lower limit of quantification (LLoQ)=2.0 pg/ml. Results were compared between cases and controls using Wilcoxon rank tests and logistic regression.

Results:
Inter-assay %CVs were 8%. Median KIM-1 was higher for smokers vs. non-smokers and for men with vs. without hypertension, but was not associated with high cholesterol. KIM-1 was significantly higher in cases (183 pg/ml (IQR: 137-239) versus controls, (161 pg/ml (IQR:109-212), p=0.03; OR (95%CI)for Q4 versus Q1 was 2.26 (1.02 - 5.02) Adjusted for age and smoking the OR(95%CI) of fatal CHD for Q4 vs. Q1 was 2.34 (1.02- 5.37), and further adjusted for diastolic BP and serum cholesterol at baseline, was 2.0 (95% CI: 0.8-4.7).

Conclusions:
Higher serum KIM-1 levels at midlife were associated with a ∼2-fold increased risk of fatal CHD vs. survival over ∼30 years of follow-up. This is the first report of a longitudinal association of circulating KIM-1 levels with fatal CHD in long-term follow-up.
Abstract 15943: Left Ventricular Regional Longitudinal Displacement Assessed by Tissue Doppler Imaging is a Powerful Predictor of All-cause Mortality in Patients With Systolic Heart Failure
Authors: Sengeløv Morten , Jørgensen Peter Godsk , Bruun Niels Eske , Olsen Flemming Javier , Hansen Thomas Fritz , Jensen Jan Skov , Biering-Sørensen Tor
Published: July 2021

Objective:
Tissue tracking (TT), obtained by tissue Doppler imaging (TDI), can be utilized to assess the mitral annular longitudinal displacement (LD) during systole. However, the prognostic utility of regional LD in patients with heart failure with reduced ejection fraction (HFrEF) is unknown.

Methods:
Transthoracic echocardiographic examinations from 911 patients with HFrEF were retrieved from a heart failure clinic’s database. The exams were performed from 2005 to 2013. The echocardiographic images were subsequently analyzed obtaining conventional echocardiographic measurements. Regional LD was obtained from the three apical TDI projections with sampling at six mitral annular sites located at the anterior, lateral, posterior, inferior, septal and anteroseptal myocardial walls.

Results:
During a median follow-up period of 40 months 150 (16.4 %) patients died. Patients that died had significantly lower LVEF (23.3% vs 28.3%, p<0.001) and lower regional LD in all six mitral annular sites (Figure).

Many conventional echocardiographic parameters presented as predictors of mortality (LVEF, LVMI, LAVI, E, E/e’, deceleration time and TAPSE). However, only LD at the septal and inferior annular sites remained independent predictors of mortality in cox proportional-hazards models after adjusting for age, gender, BMI, total cholesterol, heart rate, atrial fibrillation, non-independent diabetes mellitus and the aforementioned conventional echocardiographic predictors (Figure). In addition, the septal and the inferior sites had the highest Harrell’s C-statistic of all the echocardiographic predictors (0.70 and 72, respectively).

Conclusion:
In patients with severe heart failure, septal and inferior LD are independent predictors of all-cause mortality. Furthermore, septal and inferior LD proved to be superior prognosticators when compared to all the conventional echocardiographic parameters.
Abstract 15945: Cdc42 is Required for Lymphatic Branching, Maturation and Valve Formation During Development
Authors: Jin Yixin , Liu Yang , Chen Hailin , Wang Rui , Si Hongjiang , Srinivasan Sathish , Zhang Shenyuan , Muthuchamy Mariappan , Zawieja David , Peng Xu
Published: July 2021

Cdc42 is a Ras-related GTPase that plays an important role in regulation of actin cytoskeletal architecture. Blocking the ability of Cdc42 to activate its effectors has been shown to inhibit a range of cellular functions including cell polarization, migration, proliferation and differentiation. Consistent with its critical roles in vitro, the inactivation of Cdc42 in mice resulted in embryonic lethality before E6.5. The early embryonic lethal phenotype of Cdc42-null mice has made it not useful for studies on the interesting questions of the roles and mechanisms of Cdc42 in the vascular development. To overcome this problem, we have generated an endothelial cell (EC) specific Cdc42 knockout mouse line by crossing Cdc42/flox mice with vascular endothelial cadherin Cre mice. Our results have demonstrated that the deletion of Cdc42 in ECs resulted in embryonic lethality with severe edema. Whole mount immunofluorescence staining showed mesentery collecting lymphatic vessel maturation and valve formation defects. Interestingly, lymphangiogenesis in the intestine wall was totally disrupted in Cdc42 EC knockout embryos. Moreover, we analyzed the role of Cdc42 in lymphatic vessel formation in the skin. We found that Cdc42 is required for tip cells filopodia formation and the deletion of Cdc42 in endothelial cells impaired lymphatic vessel sprouting, branching and the mutant lymphatic vessels displayed blunt-ended, bulbous lymphatic. We also noted that the size of lymphatic lumen was significantly increased. Taken together, our data suggested that Cdc42 plays an essential role in lymphatic branching, maturation and valve formation during development.