bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 11589: Comorbidity and Medication Use Are Risk Factors of Non-shockable Rhythm in Patients With Out-of-hospital Cardiac Arrest
Authors: Granfeldt Asger , Wissenberg Mads , Hansen Steen M , Torp-Pedersen Christian , Christensen Erika F , Christiansen Christian F
Published: July 2021

Introduction:
Non-shockable rhythm (NSR) is the most prevalent heart rhythm for both in- and out-of-hospital cardiac arrest (OHCA). While survival from OHCA patients with a shockable rhythm (SR) has increased over time, survival following NSR remains low. Thus, identification of risk factors for NSR is important to reduce mortality.

We hypothesize that patients with NSR and SR are two disparate groups where patients with NSR are characterized by a high non-cardiac disease burden when compared to patients with SR.

Methods:
Using data from the nationwide Danish Cardiac Arrest Registry (2001–2012), we identified 33,617 OHCA patients ≥18 years old. The Danish National Registry of Patients was used to identify comorbidities while the National Prescription Registry was used to identify drug prescriptions (within 180 days). A multivariable logistic regression model was used to estimate odds ratios for risk factors associated with NSR.

Results:
Patients with NSR were characterized by a higher median age 71 years (IQR 60-81) vs. 67 years (IQR 58-77), higher proportion of women (38% vs. 21%), lower proportion of witnessed collapse (50% vs. 79%) and bystander CPR (27% vs. 50%) than patients with SR. A higher proportion of NSR occurred in private homes (77% vs. 58%) and time from recognition of OHCA to first rhythm analysis was longer: 13 min (IQR 7-22) vs. 9 min (IQR 6-14). In a fully adjusted model (patient-related and cardiac arrest-related characteristics included) a higher degree of comorbidity, psychiatric disease, chronic obstructive lung disease and the use of antidepressants, antipsychotics, anxiolytics, analgesics, corticosteroids, and antibiotics (within 14 days) where associated with NSR (Table). In contrast, the use of cardiovascular specific drugs and history of cardiovascular disease was associated with a lower risk of NSR.

Conclusion:
A history of non-cardiac disease and non-cardiac drug use are risk factors of NSR when compared to patients with SR.
Abstract 11598: Is Therapeutic Drug Monitoring of Direct Anticoagulants Really Unnecessary?
Authors: Baldin Bernadette , Warembourg Marion , Bardy Guillaume , Startari Loïc , Rocher Fanny , Spreux Anne , Lavrut Thibaud , Drici Milou-Daniel
Published: July 2021

Introduction:
no routine monitoring is deemed necessary with direct oral anticoagulants dabigatran (D) and rivaroxaban(R). Yet, their misuse may lead to inefficacy or increased risk of bleeding.

Hypothesis:
due to the prevalence of elderly patients in our medical center, the pharmacology department was asked to measure R and D plasma concentrations. Therefore we aimed not only to check their prescription adequacy but also to evaluate whether bleeding or thrombosis adverse events were associated with drug concentrations clearly outside of their expected “normal” range.

Methods:
Patients receiving R or D for either AFib, deep venous thrombosis or its prevention were included and had blood samples drawn for drug measurements, by HPLC-tandem mass spectrometry. Adequacy of the patient prescription was checked by pharmacists according D & R respective SmPCs. A robust and conservative method was applied to evaluate anticoagulant concentrations : D & R concentrations were blindly deemed “normal” when within the [IC]
95
limits (peak and trough, relative to the dose) observed in the respective RE-LY and Rocket-AF pivotal studies, as compared to “out of range” when outside of these limits.

Results:
287 consecutive patients from our center had their concentration of R (n=219 : 76%) or D (n = 68 : 24%) measured. The inadequacy of the prescriptions was 31.4% alltogether. Seventy patients presented with bleeding (n = 48, 17%) or thrombosis (n = 22, 8%), that either led to their admission in emergency, or occurred in the hospital wards. Bleedings and thrombosis were significantly associated with out-of-range concentrations (p<0.01). Patients with hemorrhages had higher concentrations (R: 194 VS 83 μg.l
-1
and D: 128 VS 80 μg.l
-1
) whereas thrombosis were associated with lower ones (R: 75 VS 106 μg.l
-1
D: 29 VS 93 μg.l
-1
). HAS-BLED Score was 2.0 ± 0.9 for bleeding cases as compared to 1.5 ± 0.9 (p<0.01).

Conclusions:
therapeutic drug monitoring of direct oral anticoagulants might not be superfluous, at least for R & D, especially in patients with a higher score HAS-BLED.
Abstract 11614: ASC Methylation and Outcomes in Heart Failure
Authors: Butts Brittany , Dunbar Sandra B , Gary Rebecca A , Butler Javed
Published: July 2021

Background:
Heart failure (HF) is associated with inflammation characterized by the formation of a protein complex, the inflammasome that triggers maturation of inflammatory cytokines. Inflammation in HF is associated with lower quality of life (QOL), depression, and poor outcomes. ASC, a vital component of the inflammasome, is controlled through epigenetic modification via methylation of CpG islands surrounding exon 1, and this methylation is a candidate pathway of worsening HF. The purpose of this study is to examine the relationships between ASC methylation and clinical, psychological, and QOL outcomes in HF.

Methods:
Stored samples from 155 HF outpatients (age 56.9±12.0 years, 64% male, 47% black, and mean LVEF 29.9±14.9) were analyzed for % methylation of seven CpG sites in the intron region preceding exon 1 of the ASC gene using pyrosequencing of bisulfite treated genomic DNA. Clinical, QOL (Kansas City Cardiomyopathy Questionnaire), and psychological (Patient Health Questionnaire [PHQ-9]) outcomes were assessed. Two-year combined clinical endpoint (death, heart transplantation, ventricular assist device implantation, or all-cause hospitalization) was analyzed.

Results:
Mean total ASC methylation was 5.96±0.55%. ASC methylation was inversely related to ASC mRNA (r=-.33, p<0.001) and protein (r=-.464, p<.001). ASC methylation had a positive linear relationship with ejection fraction (r=.81, p<.001) and six-minute walk distance (r=.63, p=.005). ASC methylation had a negative linear relationship with PHQ-9 scores (r=-.65, p<.001) and a positive linear relationship with QOL (r=.83, p<.001). Combined clinical endpoint occurred in 71% (N=110) of participants. Higher levels of ASC methylation were associated with lower odds of clinical endpoint (odd ratio=0.43, 95% CI .187, .997, p=.049), while higher levels of ASC protein expression were associated with higher odds (OR=1.27, 95% CI 1.04,1.54, p=.016).

Conclusion:
Increased methylation of CpG sites in the intron region of ASC is associated with improved clinical, psychological and QOL outcomes in HF. The associated decrease in ASC expression implicates this inflammatory mediator as a possible driver of HF outcomes, and may represent a therapeutic target.
Abstract 11651: Effect of Combination Lipid Therapy on Incident Atrial Fibrillation or its Electrocardiographic Surrogate in the Action to Control Cardiovascular Risk in Diabetes Lipid (ACCORD Lipid) Trial
Authors: Chen Lin Y , Chen Haiying , Bigger Thomas , Hickey Kathleen T , Goff David C , Lochnan Heather , Thomas Abraham , Miller Michael E , Seaquist Elizabeth R , Soliman Elsayed Z
Published: July 2021

Introduction:
Atrial fibrillation (AF) is associated with increased cardiovascular disease (CVD) risk in patients with type 2 diabetes (DM). Observational studies have suggested that higher HDL and lower triglycerides are associated with lower AF risk.

Hypothesis:
We hypothesized that raising HDL and lowering triglycerides will reduce AF incidence in patients with DM. As such, we compared combination lipid therapy with simvastatin and fenofibrate vs. simvastatin alone in relation to incidence of AF or its established ECG surrogate, P-wave indices (PWI), in patients with DM.

Methods:
We analyzed data from the Action to Control Cardiovascular Risk in Diabetes Lipid (ACCORD Lipid) trial (Jan 2001-June 2009), a randomized controlled blinded trial of patients with DM and who were aged 40–79 years with CVD or aged 55–79 years with subclinical CVD or >2 CVD risk factors. Patients were randomized to receive simvastatin plus placebo vs. simvastatin plus fenofibrate. Dosing of simvastatin and fenofibrate was based on trial protocol. The primary outcome was a composite of incident AF (ascertained from study ECGs) or PWI (P wave duration in lead II ≥120 ms, P’ (negative) amplitude in V1 ≥100 μV, or P-terminal force in V1 >-4000 μV.ms).

Results:
Data from 5518 participants (mean age, 62.3 years; women, 30.7%; non-white, 34.5%) were analyzed. The Table shows the results after a mean follow-up of 4.7 years.

Conclusions:
Compared with simvastatin alone, combination lipid therapy with simvastatin and fenofibrate did not reduce the incidence of AF or its ECG surrogate in patients with DM at high CVD risk. Further research is needed to elucidate the role of dyslipidemia in the etiology of AF and to discover effective prevention strategies for AF in patients with DM.
Abstract 11778: Association of Body Mass Index With Corrected QT interval and the Impact of This Association on All-cause Mortality: Results From the National Health and Nutrition Examination Survey (NHANES)
Authors: Waheed Salman , Dawn Buddhadeb , Gupta Kamal
Published: July 2021

Introduction:
Given the high prevalence of obesity, the association of body mass index (BMI) with corrected QT interval (QTc) warrants investigation. Although both BMI and QTc are independently associated with mortality, the influence of BMI on QTc and the specific impact of this association on mortality remain unknown.

Methods:
We analyzed data from 4,579 participants aged 40-65 years from NHANES III for a median of 13.8 years. We divided the weighted sample into 4 categories by BMI as 18.5-25 (reference), >25-30, >30-35 and >35 and 2 categories by Bazette heart rate-corrected QT as normal (<450 ms in males, <460 ms in females) or prolonged. Cox proportional hazards models were used with adjustment for demographic characteristics and traditional cardiovascular risk factors.

Results:
BMI was significantly associated with QTc with a significantly higher QTc among those with higher BMI (Mean QTc: 428, 429, 433 and 439 ms respectively for BMI 18.5-25, >25-30, >30-35 and >35, P for trend: <0.001). Overall, both prolonged QTc or BMI>35 were independently associated with increased mortality compared with those with normal QTc or BMI 18.5-25. When combined, the risk of mortality was higher among those with both prolonged QTc and higher BMI [Hazard ratio (95% CI): 1.92 (1.03-3.56), 1.75 (0.83-3.68) and 2.29 (1.12-4.69)] for categories of prolonged QTc and BMI 25-30, 30-35 and >35, respectively compared with those with BMI 18.5-25 and normal QTc. There was a significant improvement in risk prediction for mortality when QTc was added to the fully adjusted model with BMI (net reclassification index 0.167, P=0.0001).

Conclusions:
Those with higher BMI have a significantly longer QTc. This longer QTc among those with higher BMI translates into a higher risk of mortality. These novel observations suggest that individuals with higher BMI should be screened for the presence of prolonged QTc, especially when treated with medications that may prolong QTc.
Abstract 11791: Blockade of Senescence-associated Microrna-195 in Aged Skeletal Myoblasts Facilitates Reprogramming to Produce Induced Pluripotent Stem Cells
Authors: Kondo Hideyuki , Kim Ha Won , Wang Lei , Okada Motoi , Millard Ronald W , Masuyama Tohru , Wang Yigang
Published: July 2021

Background:
Older age is the major risk factor for heart failure, and reprogramming a patient’s own cells to produce induced pluripotent stem cells (iPSCs) is a promising strategy for autologous cell transplantation therapy. However, low reprogramming efficiency of senescent cells remains as a major pitfall. Recently, our preliminary data suggested that inhibiting senescence-associated miR-195 rejuvenated aged stem cells by reactivating anti-aging defense system. This study investigated the effects of blocking miR-195 expression on the reprogramming efficiency of old skeletal myoblasts (OSkMs).

Methods and Results:
MiR-195 expression was significantly higher in OSkMs isolated from aged mice (24 months) as compared to those from young mice (2 months), as examined by RT-PCR. OSkMs showed impaired expression of anti-aging factors (Tert and Sirt1) and higher expression of pro-aging markers (p53, p21, p16). Intriguingly, blocking miR-195 expression in OSkMs by transfection with anti-miR-195 significantly induced restoration of Tert and Sirt1 as well as telomere re-lengthening as examined by RT-PCR and quantitative fluorescent in situ hybridization. Luciferase assay confirmed that Sirt1 is one of the direct targets of miR-195 relevant to senescence of OSkMs. Importantly, lower reprogramming efficiency of OSkMs was significantly improved by miR-195 abrogation without altering karyotype or expression of pluripotency markers. Furthermore, iPSCs lacking miR-195 successfully differentiated into all three germ layers, indicating that deletion of miR-195 does not affect pluripotency. Notably, contraction rates were markedly higher in beating cells transfected with anti-miR-195 as compared to that with scramble (68.5±5.6 vs 47.3±2.8/min).

Conclusions:
Blocking age-induced miR-195 is a novel promising approach for efficient iPSCs generation from senescent cells, which has beneficial for autologous transplantation of iPSCs in elderly patients.
Abstract 11830: Increased Coronary Perivascular Adipose Tissue Volume on Cardiac Computed Tomography in Patients With Vasospastic Angina -Possible Correlation With Adventitial Vasa Vasorum Formation
Authors: Ohyama Kazuma , Matsumoto Yasuharu , Amamizu Hirokazu , Uzuka Hironori , Nishimiya Kensuke , Hao Kiyotaka , Tsuburaya Ryuji , Takahashi Jun , Ito Kenta , Shimokawa Hiroaki
Published: July 2021

Background:
The adventitial components, such as perivascular adipose tissue (PVAT) and vasa vasorum (VV), play important roles in the pathogenesis of cardiovascular disease. However, the roles of epicardial adipose tissue (EAT) and VV in the pathogenesis of vasospastic angina (VSA) remain to be examined. In this study, we thus examined whether coronary PVAT volume is increased at the spastic coronary segment, and if so, whether the volume is correlated with the extent of VV formation in VSA patients.

Methods and Results:
We measured the volume of EAT and coronary PVAT of the left anterior descending coronary arteries (LAD) on cardiac computed tomography (CT) in 48 consecutive patients with documented spasm in LAD and 18 control subjects without the spasm. We further examined the extent of VV formation of LAD in 26 VSA patients by using optical frequency domain imaging (OFDI). Patient characteristics were comparable between the 2 groups in terms of sex, age, body weight, body mass index and cardiovascular risks. Although the EAT volume was comparable between the 2 groups, the PVAT volume of LAD was significantly increased in VSA group as compared with control group (VSA, 29.8±15.2 vs. control, 18.8±9.2 cm3, P<0.01) (Figure). Furthermore, there was a significant positive correlation between the PVAT volume of LAD and the VV area (R=0.43, P<0.05) (Figure).

Conclusions:
These results indicate that the coronary PVAT volume, but not the EAT volume, is increased at the spastic coronary segments associated with enhanced adventitial VV formation in VSA patients, suggesting the pathophysiological correlation between the 2 changes.
Abstract 11875: Risk of Malignant Cancer Among Women With New-onset Atrial Fibrillation
Authors: Conen David , Wong Jorge A , Sandhu Roopinder K , Cook Nancy R , Lee I-Min , Buring Julie E , Albert Christine M
Published: July 2021

Introduction:
A substantial proportion of patients with atrial fibrillation (AF) die of non-cardiovascular causes, and recent studies suggest a link between AF and cancer. However, this association has not been evaluated in long-term prospective studies.

Methods:
A total of 34691 women ≥45 years and free of AF, cardiovascular disease and cancer at baseline were prospectively followed for incident AF and malignant cancer within the Women’s Health Study. All incident AF and cancer events were validated by medical record review. Cox proportional-hazards models using time-updated covariates were constructed to assess the relationship of new-onset AF with incident cancer and to adjust for potential confounders. We then assessed the risk of incident AF among women with cancer using a similar modelling approach.

Results:
Mean age at baseline was 55±7 years. During 19.1 years of follow-up, we observed 1467 (4.2%) AF and 5130 (14.8%) cancer events. AF was a significant risk factor for incident cancer in age-adjusted (hazard ratio (HR) 1.58, 95% confidence interval (CI), 1.34, 1.87, p<0.0001) and multivariable adjusted (HR 1.49, 95% CI, 1.26, 1.77, p<0.0001) models, and was increased among women with paroxysmal (HR 1.35, 95% CI 1.09, 1.67, p=0.005) and non-paroxysmal AF (HR 1.61, 95% CI 1.23, 2.09, p=0.0004). The risk of cancer was highest in the first 3 months after new-onset AF (HR 3.53, 95% CI 2.05, 6.08, p<0.0001) but remained significant beyond 1 year (adjusted HR 1.44, 95% CI 1.19, 1.73, p=0.0001). New-onset AF was also associated with an increased risk of cancer mortality (adjusted HR 1.37, 95% CI 1.01, 1.85, p=0.04). In contrast, women with new-onset cancer had an increased risk of incident AF within 3 months (HR 4.61, 95% CI 2.81, 7.54, p<0.0001) but not beyond 1 year (HR 1.17, 95% CI 0.97, 1.41, p=0.11).

Conclusions:
In this large cohort of initially healthy women, new-onset AF was a significant risk factor for the short and long term diagnosis of incident cancer. In contrast, cancer was not associated with an increased AF risk over the long term. Our results may suggest that AF could be an early sign of occult cancer or an underlying systemic process conferring an increased cancer risk.
Abstract 11890: S100A8/A9 is Increased in Psoriasis Serum, Relates to Vascular Diseases and Activates Human Endothelial Cells
Authors: Teague Heather , Ng Qimin , Purmalek Monica , Natarajan Balaji , Salahuddin Taufiq , Stansky Elena , Aridi Tarek , Playford Martin P , Kaplan Mariana J , Mehta Nehal N
Published: July 2021

Introduction:
Psoriasis is a chronic inflammatory disorder of the skin affecting 2-4% of the population and is associated with an increased risk of cardiovascular events, specifically myocardial infarction.

Methods:
In a large, ongoing prospective cohort study of psoriasis and cardiovascular diseases (NCT01778569), we studied a consecutive sample (n=100) and aimed to investigate the potential role that S100A8/A9 may have in linking psoriasis to CV disease measured by FDG PET CT and coronary CTA. Furthermore, we conducted in vitro experiments on human aortic endothelial cells (ECs) to examine whether treatement with S100A9 activates these cells. We hypothesized that S100A8/A9 would relate to psoriasis severity, relate to in vivo vascular inflammation by FDG PET CT, non-calcified burden of coronary disease by CCTA and increase endothelial cell activation.

Results:
We observed that the S100A8/A9 heterodimer was elevated in serum (mean psoriasis: 2019 ± 100.1; non-psoriasis: 1634 ± 160.7; p = 0.02), correlating both with psoriasis severity score (adjusted β = 0.53, p = 0.02) and overall aortic vascular inflammation measured by FDG PET CT (adjusted β = 0.48, p = 0.02) beyond the Framingham Risk Score. Additionally, we found that S100A8/A9 was associated with direct coronary atherosclerosis measured by coronary CTA demonstrating an increase in total (β = 0.16, p = 0.04) and non-calcified plaque burden (β = 0.23, p = 0.003) but not dense calcified burden. When EC's were treated with S100A9, ICAM1, E-Selectin and VCAM1 gene expression levels increased 10-fold (p = 0.001), 86-fold (P = 0.007) and 20-fold (p = 0.0002) respectively compared to the untreated human aortic endothelial cells.

Conclusions:
S100A8/A9 related to psoriasis severity, in vivo vascular inflammation, non-calcified plaque in the coronary arteries and EC activation. These findings suggest this protein may play a role in linking psoriasis to CVD and a role in early atherosclerotic plaque formation. Ongoing studies aim to elucidate the source of S100A8/A9 in the blood and to characterize the signaling pathway utilized by S100A8/A9 to understand whether this pathway is broadly applicable to vascular diseases associated with chronic inflammation.
Abstract 11909: Transcoronary Infusion of Cardiac Progenitor Cells in Hypoplastic Left Heart Syndrome: 3-year Results of the TICAP Trial
Authors: Ishigami Shuta , Tarui Suguru , Goto Takuya , Ousaka Daiki , Baba Kenji , Kasahara Shingo , Ohtsuki Shinichi , Sano Shunji , Oh Hidemasa
Published: July 2021

Backgrounds:
Hypoplastic left heart syndrome (HLHS) is still one of the severe congenital heart defects. The first results of the TICAP trial (NCT01273857) conducted in our hospital have shown that intracoronary infusion of cardiosphere-derived cells (CDCs) in children with HLHS was feasible and safe; however, the mid-term safety and efficacy of CDCs infusion in these patients remain unsolved. The aim of this study is to evaluate the safety and efficacy of CDCs injection during mid-term period and to determine the factors that may be related to the beneficial effects of cardiac function after cell injection.

Methods and Design:
This phase 1 trial is a prospective controlled study. Fourteen patients with HLHS undergoing staged-2 or -3 palliations were enrolled between January 2011, and January 2012. Seven patients assigned to receive intracoronary CDCs infusion 1 month after the cardiac surgery followed by 7 patients allocated to a control with standard care alone. The primary endpoint was to assess the safety and the secondary endpoint was to evaluate the cardiac function and heart failure status.

Results:
No complications including tumor formation were reported within 3 years after CDC infusion. Echocardiogram showed a significantly greater improvement in right ventricular ejection fraction (RVEF) in children receiving CDCs than in controls at 3 years (+8.0 ± 4.7% vs. +2.2 ± 4.3%, P=0.03). In cardiac MRI study, improvement of RVEF at 3 years was significantly greater in the CDC-treated group than in controls (+5.7 ± 4.9 vs. -1.0 ± 4.6%, P=0.04). These cardiac function improvements resulted in reduced brain natriuretic peptide levels (P=0.04), lower incidence of unplanned catheter interventions (P=0.04), and higher weight-for-age Z score (WAZ) (P=0.02) at 3 years compared with those of controls. As independent predictors of treatment responsiveness, absolute changes in RVEF at 3 years were negatively correlated with age, WAZ, and RVEF at CDC infusion (age: r=-0.91, P=0.005; WAZ: r=-0.88, P=0.009; EF: r=-0.90, P=0.006).

Conclusions:
Intracoronary CDC infusion in patients with HLHS was safe and improved RVEF during 3 years of follow-up. This therapeutic strategy may merit somatic growth enhancement and reduce the incidence of heart failure.
Abstract 12014: Modified HASBLED Bleeding Risk Score in Dialysis Patients With Atrial Fibrillation
Authors: Murphy Michele , Maddox William , Nahman Stan , Diamond Matthew , Sorrentino Robert , Guha Avirup , Waller Jennifer
Published: July 2021

Introduction:
Hemodialysis patients (HD pts) with atrial fibrillation (AF) have increased risk of stroke. The HASBLED (Hypertension (HTN), Abnl Renal/Liver Function, Stroke, Bleeding Hx, Labile INR, Elderly, Drugs/Alcohol) risk score predicts bleeding in the general AF population. It is unknown whether the HASBLED score can be applied to HD pts who are at additional bleeding risk due to uremic platelet dysfunction and the regular use of heparin.

Hypothesis:
To address this question, we queried the United States Renal Data System (USRDS) for bleeding events in HD pts with AF, and correlated those events with a modified HASBLED (mHASBLED) score.

Methods:
All incident HD pts with AF from the USRDS for 2006-2010 were queried for major bleeding events and mHASBLED parameters using ICD-9 diagnosis codes and data from CMS form 2728. For mHASBLED, the HTN parameter was defined as "HTN as the cause of renal failure", and labile INR as > 16 INRs/yr, but all other parameters could be derived from the dataset. Logistic regression (LR) analysis was used to estimate the odds ratio (OR) for the mHASBLED score to predict major bleeding events.

Results:
74,631 HD pts had AF, and 9.8% had a major bleeding event (GI bleeding and hemorrhagic stroke). By univariate analysis, those who bled were more likely to be elderly, have an underlying cause of renal disease due to HTN, prior bleeding event, hepatitis C, labile INR, and be on oral anticoagulants. By LR, variables with the greatest impact on bleeding were HTN as a cause of underlying renal disease, prior bleeding history, and labile INR (OR of 1.10, 2.20 and 2.24, respectively). The OR for bleeding events increased by 1.28 for each unit increase in mHASBLED. Older age, prior stroke, abnormal renal or liver function, and drug use had the least effect. Note that the lowest possible score in this cohort is 1, given that all patients had renal failure.

Conclusions:
In HD pts with AF, the mHASBLED predicts major bleeding events. The universal presence of renal disease, and the lack of specific clinical data from the USRDS may limit the clinical precision of a given score, however mHASBLED may remain a useful indicator of bleeding risk in this population.
Abstract 12021: Ambulatory Blood Pressure Correlates With Chronic Renal Tubulointerstitial Injury in Patients With IgA Nephropathy
Authors: Haruhara Kotaro , Tsuboi Nobuo , Koike Kentaro , Kanzaki Go , Okabayashi Yusuke , Miyazaki Yoichi , Kawamura Tetsuya , Ogura Makoto , Yokoo Takashi
Published: July 2021

Introduction:
Hypertension is a major prognostic factor in IgA nephropathy (IgAN), the most common form of primary glomerulonephritis and a major cause of ESRD worldwide. However, there are few studies that assessed the ambulatory blood pressure (ABP) in IgAN patients, which could detect the abnormality in circadian BP and predict long-term renal or cardiovascular outcomes.

Hypothesis:
Renal histopathological changes established by chronic exposure to injuries may have effects on the abnormal regulation of circadian BP in IgAN patients.

Methods:
This cross-sectional study included biopsy-proven IgAN patients, in whom both renal biopsy and ABP monitoring were performed during the same hospitalization. The histopathological findings were assessed and analyzed in relation to ABP.

Results:
A total of 111 IgAN patients were included. The score for interstitial fibrosis and tubular atrophy (IF/TA) was significantly associated with the both values of daytime and nighttime ABP. In contrast, the score for global and segmental glomerulosclerosis, arterial, and arteriole lesions did not show significant associations with these ABP values. These results were almost similar in the subgroup analyses of patients without apparent renal function decline (eGFR>30mL/min/1.73m2) or those without antihypertensive medications. In the multiple linear regression analyses, the severity of IF/TA was associated with the both values of daytime and nighttime ABP, independent of age, gender, renal function, severity of proteinuria, and use of antihypertensive medications. On the other hand, the severity of glomerular lesions was not associated with these ABP values after adjustment (Table). The night to day ratio of mean ABP did not display significant trends according to any renal histopathological lesions.

Conclusions:
These results suggest that IF/TA is the most relevant renal histopathological finding associated with abnormal regulation of circadian BP in IgAN patients.
Abstract 12022: Telomere Length, Telomerase Activity and Vascular Aging in Patients With Type 2 Diabetes Mellitus
Authors: Brailova Natalia , Dudinskaya Ekaterina , Pykhtina Valentina , Plochova Ekaterina , Strazhesko Irina , Akasheva Dariga , Tkacheva Olga , Boytsov Sergey , Shestakova Marina
Published: July 2021

Introduction:
Type 2 diabetes mellitus (T2DM) contribute to vascular aging. The telomere length (TL) and telomerase activity (TA) are considered as biomarkers of cellular aging. TL and TA are insufficiently studied in diabetic patients.

Hypothesis:
Telomere biology is associated with vascular aging in diabetic patients.

Methods:
The study group included 50 patients with T2DM (mean age 58.4±7.83 years) and 139 healthy patients (mean age 57.45±8.14 years). All subjects were measured for TL and TA by quantitative polymerase chain reaction; oxidative stress marked by malondialdehyde (MDA); inflammation marked by C-reactive protein (CRP); arterial stiffness evaluated by pulse wave velocity (PWV); carotid intima-media thickness (IMT), plaque presence (PP) and endothelial dysfunction evaluated by flow-mediated endothelium-dependent vasodilation (FMV).

Results:
All patients were divided into 4 groups by the median of TL (9.75): «short» telomeres (T2DM+ (n=15) and T2DM- (n=63) and «long» telomeres (T2DM+ (n=35) and T2DM- (n=76)). Patients with T2DM and «long» TL had the state of vessels, oxidative stress, inflammation, TA as similar as in healthy people: PWV 11.54±3.57 (T2DM+) vs 10.98±1.83 m/s (T2DM-) ((=0.58), IMT 0.83±0.13 vs 0.76±0.16 mm (=0.13), PP 1.36±0.33 vs 1.23±0.20 (=0.79); MDA 2.81±0.78 vs 3.24±0.78 mkmol/l (=0.08); CRP 3.59±0.58 vs 3.66±0.50 mg/l (=0.93); TA 0.51±0.09 vs 0.60±0.05 (p=0.36). FMV was higher in diabetic patients: 11.87±3.36 vs 10.18±2.79 % (=0.049). In contrast patients with «short» TL and T2DM had more pronounced vascular aging, inflammation and lower TA than healthy people: PWV 13.48±3.24 vs 11.59±2.03 m/s (=0.003), IMT 0.95±0.17 vs 0.78±0.14 mm (<0.001), PP 2.23±0.27 vs 1.38±0.17 (=0.006), FMV 8.51±3.20 vs 11.04±3.01% (=0.0002; CRP 7.39±1.47 vs 4.03±0.62 mg/l (=0.046); TA 0.47±0.08 vs 0.62±0.07 (p=0.06).

Conclusion:
In patients with short telomeres and T2DM signs of vascular aging, chronic inflammation and cellular aging were more pronounced than in healthy people. In contrast, in patients with long telomeres and T2DM vascular changes, oxidative stress, chronic inflammation and TA were as similar as in healthy people. Perhaps long telomeres protect patients with T2DM from accelerated vascular aging.
Abstract 12026: Nocturnal Blood Pressure Burden, Diuretics, and Cardiac Load: Determinants of Nocturia in the Japanese at High-Risk of Cardiovascular Disease
Authors: Nagai Michiaki , Niijima Satoshi , Hoshide Satoshi , Takahashi Mami , Shimpo Masahisa , Kario Kazuomi
Published: July 2021

Introduction:
The majority of epidemiologic studies reported a significant relationship between hypertension and nocturia. However, the underlying pathophysiology has not been established.

Hypothesis:
We hypothesized that nocturnal blood pressure (BP) burden, some classes of antihypertensive agents and cardiac load might be associated with severity of noctria. In this study, the relationships of nocturia with self-measured home BP (HBP), the class of antihypertensive agent, B-type natriuretic peptide (BNP) were investigated in the Japanese at high-risk of cardiovascular disease.

Methods:
Among 4310 patients with one or more cardiovascular risks recruited for the Japan Morning Surge-Home Blood Pressure Study, the measurements of HBP at morning, evening, and nighttime as well as BNP were performed in the 2785 patients (63.5 years old, male 48.9%). A self-administered questionnaire included items on nocturia was used.

Results:
According to the number of nocturia (no void: n= 1571; one void: n=557; 2 or more voids per night: n=657), significant associations of systolic BP (SBP) at morning (136 vs 136 vs 140 mmHg, p<0.001), evening (129 vs 129 vs 131 mmHg, p<0.01) and nighttime (120 vs 120 vs 125 mmHg, p<0.001) as well as logBNP (1.15 vs 1.26 vs 1.39, p<0.001) were observed with nocturia severity. In the multinomial logistic regression analysis adjustment for confounders including age, smoking, total cholesterol, fasting blood glucose and HbA1c, the use of diuretics (OR: 1.28, 95%CI: 1.01-1.61, p<0.05) was significantly associated with one nocturnal void, while nighttime SBP (OR: 1.012, 95%CI: 1.01-1.02, p<0.001) and logBNP (1.46, 95%CI: 1.16-1.84, p<0.01) were significantly associated with multiple nocturnal voids. A significant interaction was found between nighttime SBP and logBNP for multiple nocturnal voids (p<0.01). On the other hand, neither morning SBP nor evening SBP had a significant relationship with nocturia.

Conclusions:
In this study, nighttime SBP and BNP were synergetically associated with severe nocturia in the high-risk Japanese population. Antihypertensive treatment to reduce BP burden during sleep as well as cardiac overload might be important to improve sleep quality caused by nocturia.
Abstract 12033: Impact of n-3 Polyunsaturated Fatty Acids on Mortality of Patients With Hospitalized Heart Failure Patients
Authors: Watanabe Shunsuke , Yoshihisa Akiomi , Kanno Yuki , Takiguchi Mai , Miura Shunsuke , Sato Akihiko , Shimizu Takeshi , Nakamura Yuichi , Yamauchi Hiroyuki , Owada Takashi , Abe Satoshi , Suzuki Satoshi , Oikawa Masayoshi , Sakamoto Nobuo , Yamaki Takayoshi , Sugimoto Koichi , Kunii Hiroyuki , Nakazato Kazuhiko , Suzuki Hitoshi , Saitoh Shu-ichi , Takeishi Yasuchika
Published: July 2021

Background:
Intake of n-3 polyunsaturated fatty acids (n-3 PUFA), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), lowers risk of atherosclerotic cardiovascular events, particularly ischemic heart disease. In addition, a ratio of EPA/arachidonic acid (AA) is recently recognized as a risk marker of ischemic heart disease. In contrast, prognostic impact of the EPA, DHA and EPA/AA ratio on patients with heart failure (HF) still remains unclear. Methods and Results: Consecutive 577 patients admitted for HF were divided into 2 groups based on median levels of EPA/AA ratio: low EPA/AA (EPA/AA ≤ 0.32 mg/dl, n=291) and high EPA/AA (0.32 < EPA/AA, n=286) groups. We compared laboratory data, echocardiographic findings and cardio-pulmonary exercise test results, and prospectively followed cardiac and all-cause mortality. The low EPA/AA group, as compared to the high EPA/AA group, had lower levels of EPA and DHA (EPA: 33.9 vs. 86.8 μg/ml, P<0.003; DHA: 107.0 vs. 150.5 μg/ml, P<0.001), and higher levels of AA and dihomosexual linolenic acid (AA: 174.0 vs. 156.5 μg/ml, P<0.001; dihomosexual linolenic acid: 32.4 vs. 29.5 μg/ml, P=0.010). In contrast, body mass index, blood pressure, B-type natriuretic peptide, hemoglobin, estimated GFR, total protein, albumin, sodium, C-reactive protein, left ventricular ejection fraction, peak VO
2
and VE/VCO
2
slope were similar between the two groups. Cardiac mortality (log-rank P=0.004) and all-cause mortality (P<0.001) were higher in the low EPA/AA group than in the high EPA/AA group. In the multivariable Cox proportional hazard analyses, the EPA/AA ratio was an independent predictor of cardiac mortality (HR 0.087, P=0.003) and all-cause mortality (HR 0.233, P=0.009) in HF patients. Conclusions: The EPA/AA ratio was an independent predictor of cardiac and all-cause mortality in HF patients. Thus, taking appropriate management to control EPA/AA balance may improve the prognosis of HF patients.
Abstract 12142: Electrolyte Abnormalities and Risk of Sudden Death in the General Population
Authors: Uy-Evanado Audrey , Teodorescu Carmen , Reinier Kyndaron , Narayanan Kumar , Chugh Harpriya , Gunson Karen , Jui Jonathan , Chugh Sumeet S
Published: July 2021

Introduction:
Electrolyte abnormalities are a substrate for arrhythmogenesis and could be the trigger for sudden cardiac death (SCD). We sought to determine the potential role of electrolyte abnormalities, irrespective of kidney function, in the occurrence of sudden death in the community.

Hypothesis:
Electrolyte abnormalities increases the risk for SCD in the community regardless of kidney function.

Methods:
SCD cases and controls from a large population based study in Northwest US (approx 1 million population, 2002-2014) were included if age ≥18 yrs with creatinine clearance (CrCl) and serum electrolytes available for analysis. For cases, CrCl and electrolytes were required to be measured within 90 days of the SCD event. Demographics and lab results were analyzed using student t-tests and chi-square tests. Multiple logistic regression was used to estimate independent association of risk factors with SCD.

Results:
We evaluated 483 SCD cases (65.8% male) and 886 controls (66.4% male). Cases were more likely to be older (68.8±14.3 vs 67.2±11.3, p=0.03), of black race (9.8 vs 3.2%, p<0.0001) and with worse CrCl (53.4±31.3 vs. 64.0±24.9 ml/min, p<0.0001). Overall, cases had lower levels of mean Na (137.3±4.2 vs 138.3±3.4 mEq/L, p<0.0001), Ca (9.0±0.7 vs 9.2±0.5 mg/dl, p<0.0001) and Mg (2.0±0.5 vs 2.1±0.4 mg/dl, p=0.007); and higher mean K (4.2±0.6 vs 4.1 ±0.5mEq/L, p=0.0008). Prevalence of hyponatremia (<136mEq/L), hyperkalemia (>5.2mEq/L), hypocalcemia (<8.5 mg/dl) and hypomagnesemia (<1.7 mg/dl) were also higher in cases (27.0 vs 16.2%, p<0.0001; 6.1 vs 1.4%, p<0.0001; 19.7 vs 7.9%, p<0.0001 and 20.4 vs 8.3%, p<0.0001, respectively). Adjusting for age, race and kidney function only hyperkalemia [OR 4.65 (95% CI 1.37-15.81), p=0.01], hypocalcemia [2.94 (1.68-5.13), p=0.0001] and hypomagnesemia [2.52 (1.36-4.66), p=0.003] remained significant, conferring a more than two to five-fold increase in SCD risk.

Conclusions:
Electrolyte abnormalities remain independently associated with increased risk of SCD in the community, even after adjusting for renal function.
Abstract 12161: Toll-like Receptor 9 Plays a Pivotal Role in Angiotensin II-induced Atherosclerosis
Authors: Nishimoto Sachiko , Fukuda Daiju , Higashikuni Yasutomi , Tanaka Kimie , Hirata Yoichiro , Yagi Shusuke , Soeki Takeshi , Sakaue Hiroshi , Shimabukuro Michio , Sata Masataka
Published: July 2021

Background:
Chronic vascular inflammation causes atherosclerosis. Toll-like receptor (TLR) 9 recognizes bacterial unmethylated DNA and plays a role in innate defense, whereas it can also provoke inflammation in response to fragmented DNA released from damaged mammalian cells. However, the role of TLR9 in the development of atherosclerosis remains unknown. Here, we investigated whether genetic deletion of TLR9 attenuates atherosclerosis in apolipoprotein E knockout (ApoE KO) mice.

Methods and Results:
We generated TLR9/ApoE double knockout (dKO) mice by crossing ApoE KO mice and TLR9 KO mice, and infused angiotensin II (Ang II) (1000 ng/kg/min) subcutaneously for 28 days using osmotic pump. There were no differences in blood pressure and plasma lipid levels between ApoE KO mice and TLR9/ApoE dKO mice. Ang II infusion significantly increased plasma levels of single-stranded DNA and double-stranded DNA, endogenous ligands of TLR9, in both strains of mice (P<0.001, respectively). TLR9/ApoE dKO mice showed less atherosclerotic lesion progression in the aortic arch and less lipid accumulation in atherosclerotic plaques in the aortic root compared with ApoE KO mice (P<0.05, respectively). TLR9/ApoE dKO mice also showed less gene expression of inflammatory molecules (e.g., ICAM-1, MCP-1) in the abdominal aorta. The result of cell sorting experiment using atherosclerotic aorta obtained from Ang II-infused ApoE KO mice demonstrated that macrophage population mainly expressed TLR9 in this tissue. We, therefore, performed in vitro experiments using thioglycolate-stimulated peritoneal macrophages. CpG ODN, agonistic oligonucleotide for TLR9, markedly promoted the expression of inflammatory molecules (e.g., ICAM-1 and MCP-1) in wild-type macrophages but not in TLR9 KO macrophages. Furthermore, conditioned medium (CM) of human umbilical vein endothelial cells (HUVECs) treated with Ang II promoted gene expression of ICAM-1 and TNF-α in THP-1 macrophages compared with CM of non-treated HUVECs.

Conclusion:
Our results suggested that Ang II infusion activates the TLR9 signaling in macrophages, leading to the promotion of vascular inflammation and atherosclerosis. TLR9 may serve as a potential therapeutic target for atherosclerotic diseases.
Abstract 12178: Non-contrast T1 Mapping Detects Myocardial Edema in Patients With Takotsubo Cardiomyopathy
Authors: Aikawa Yukio , Noguchi Teruo , Morita Yoshiaki , Goto Yoichi , Ogawa Hisao , Yasuda Satoshi
Published: July 2021

Background:
Although early gadolinium enhancement (EGE) and T2-weighted image (T2WI) can detect myocardial edema in patients with Takotsubo cardiomyopathy (TCM), the clinical significance of non-contrast T1 mapping remains unclear.

Methods:
Cardiac magnetic resonance at 3T was performed in consecutive 11 patients with TCM. Non-contrast T1 mapping using T1 relaxation time was evaluated. The EGE phase was defined as 2 minutes after gadolinium administration.

Results:
EGE and high-signal intensity on T2WI were detected at apical ballooning area in all patients (Figure1A, yellow arrows), whereas no late gadolinium enhancement (LGE) was observed. Non-contrast T1 relaxation time in apical region was significantly higher than that in remote myocardium (1510±131 vs. 1291±65 msec, p<0.001) (Figure 1A, green arrows). Non-contrast T1 relaxation time correlated significantly with Extra Cellular Volume (r = 0.793, p = 0.0004) (Figure 1B).

Conclusion:
Non-contrast T1 mapping can detect myocardial edema and may differentiate reversible myocardial damage from normal myocardium in TCM.
Abstract 12236: A Novel Particulate Guanylyl Cyclase B Agonist With Therapeutic Potential Targeting Fibrosis via cGMP Generation for Cardiorenal Disease
Authors: Sangaralingham S. J , Huntley Brenda K , Ichiki Tomoko , Harders Gerald E , Burnett John C
Published: July 2021

Introduction:
Fibrosis is a hallmark of cardiorenal diseases, including heart failure, for which there are few effective therapies. C-type natriuretic peptide (CNP) is a cardiorenal-derived peptide whose mature active form, CNP-22, possesses potent anti-fibrotic actions through the activation of guanylyl cyclase receptor B (GC-B) and its second messenger, cGMP. However, CNP-22’s therapeutic potential is limited due to its short half-life. We recently identified a 53 amino acid (AA) peptide, CNP-53, whose structure consists of CNP-22 with an additional 31 AA on the N-terminus. Herein, we investigated the cGMP generating actions of CNP-53 (compared to CNP-22) in vivo and in vitro, with the goal of advancing a potential anti-fibrotic strategy for cardiorenal disease.

Hypotheses:
We hypothesized that CNP-53 would elevate circulating CNP levels as well as have greater cGMP activating actions compared to CNP-22 in vivo. We also hypothesized that CNP-53 would stimulate GC-B specific cGMP production in vitro.

Methods:
In vivo, two groups of anesthetized normal rats (n=8) received a 75-minute intravenous infusion of an equimolar dose of CNP-53 or CNP-22. Mean arterial pressure (MAP), plasma CNP and plasma and urinary cGMP were assessed. In vitro, HEK 293 cells over-expressing GC-A and GC-B and human fibroblasts (hFs), where GC-B is abundant, were stimulated with CNP-53 or CNP-22 for 10 minutes at a dose of (10-8M). Data are mean ± SE, *p<0.05.

Results:
In vivo, plasma CNP (CNP-53: 311±66, CNP-22: 153±16 pg/ml*) and cGMP (CNP-53: 21±2, CNP-22: 11±1 pmol/ml*) and urinary cGMP excretion (CNP-53: 75±4, CNP-22: 38±1 pmol/min*) were greater with CNP-53 infusion than CNP-22. MAP was similar between the 2 groups (CNP-53: 85±2, CNP-22: 88±4 mmHg). In vitro, both CNP-53 and CNP-22 activated cGMP in GC-B HEK cells and in hFs, with no activation of cGMP in GC-A HEK cells.

Conclusions:
These findings demonstrate that CNP-53 is superior to CNP-22 in activating cGMP in vivo, without inducing hypotension. Additionally, CNP-53 is a GC-B specific cGMP activating peptide that potently increases cGMP in hFs. Thus, CNP-53 may represent a novel first in class GC-B agonist with therapeutic potential targeting fibrosis and preventing the progression of cardiorenal disease.
Abstract 12258: Out-of-hospital Cardiac Arrest With Initially Shockable Rhythm: What Are the Outcomes if No Shock is Given?
Authors: Xiong Yan , Idris Ahamed H
Published: July 2021

Background:
Prompt defibrillation is critical for termination of ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) in out-of-hospital cardiac arrest (OHCA). For ethical reasons, the real impact of not shocking OHCA patients with a shockable rhythm is unlikely to be investigated in clinical trials and thus remains unknown.

Objectives:
To describe demographics, pre-hospital characteristics, interventions, and outcomes in OHCA patients with an initially shockable rhythm who did and did not get shocked in the field in DFW ROC site.

Methods:
We included all non-traumatic OHCA cases ≥18 years old with VF or VT as first known rhythms, who were treated and transported to a hospital within the DFW ROC site between 2006 - 2011. We report return of spontaneous circulation (ROSC) in the field and survival to hospital discharge for victims with and without shock delivered in the field. Multiple variable regression analysis assessed the association between shock delivery and ROSC in the field as well as survival.

Results:
Included were 882 adult non-traumatic OHCA cases with VF or VT as first known rhythms; mean (±SD) age was 60 ± 15 years, 71% male, bystander witnessed 56%, bystander resuscitation attempt 43%, public arrest location 26%, EMS response time 4.7 ± 2.3 min, 26.9% (237) had ROSC in the field, 14.9% (131) survived to hospital discharge; 93.4% (824) of all patients were shocked, while 6.6% (58) were not shocked. Of the 6.6% (58) who were not shocked, 12.1% (7) achieved ROSC in the field and 8.6% (5) survived to hospital discharge. For those not shocked in the field, the unadjusted and adjusted odds ratios for ROSC were 0.354 (95% CI 0.158-0.791, p=0.011) and 0.189 (95% CI 0.039-0.911, p=0.038), respectively; and for survival to hospital discharge they were 0.522 (95% CI 0.205-1.331, p=0.173) and 0.498 (95% CI 0.088-2.810, p=0.430), respectively.

Conclusions:
In the DFW ROC site, 6.6% of OHCA victims with an initially shockable rhythm did not receive a shock, which was significantly associated with decreased ROSC in the field. More patients survived who were shocked in the field, but this difference was not significant after adjustment for Utstein variables.