bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 17335: Dietary Carbohydrate Quality Affects Plasma Lipid Profile and the Microbiome
Authors: Matthan Nirupa R , Kane Anne V , Johnson William Evan , Manimaran Solaiappan , Faits Tyler , Lichtenstein Alice H
Published: July 2021

Considerable data is available on the effect of carbohydrate (carb) quantity on CVD risk factors but data for carb quality is limited. Our objective was to determine the relative comparability for an isocaloric exchange of
unrefined-carb
(endosperm+germ+bran, e.g., whole wheat flour),
refined-carb
(endosperm only, e.g., white flour) and
simple-carb
(sucrose, e.g., high fructose corn syrup), on cardiometabolic risk factors and the gut microbiome. All foods/beverages (60%E total carb, 15%E protein, 27%E fat [7%E SFA, 10%E MUFA, 10%E PUFA], 80mg cholesterol/1000 kcal) were provided to study subjects (n=11 men and women, 65 years, BMI 27.5 kg/m
2
, LDL-C ≥100 mg/dL) for 5 weeks (randomized, single-blind, cross-over design). Body weight was maintained constant. At the end of each diet phase plasma lipid profile, inflammatory factors and glucose homeostasis were determined using standard methods. Fecal microbiota taxa was characterized by 16S rRNA sequencing and data analyzed using QIIME and PathoScope. Plasma LDL-C levels differed among diets (125 ± 29 mg/dL
b
, 129 ± 29 mg/dL
a,b
and 136 ± 24 mg/dL
a
,
unrefined-, simple- and refined-carb
, respectively). Carb quality had no significant effect on HDL-C, TG, FFA, glucose, insulin, CRP or IL-6 levels. There were 21 genera that had a mean relative abundance (RA) of ≥1% and 4 genera (Roseburia, Oscillospira, Ruminococcus and Coprococcus) varied significantly across diets but after multiple testing adjustment, only Roseburia RA variations remained significant ( 2.58%
a
, 0.99%
b
, and 0.81%
b
,
unrefined-, simple- and refined-carb
, respectively). Interesting trends were observed between the RA of the following genera and plasma lipids: Roseburia was negatively associated with LDL-C (r=0.28, p=0.097) and HDL-C (r=-0.39, p=0.022); Oscillospira was negatively associated with TG (r=-0.53, p=0.097), and Anaerostipes was positively associated with TG (r=0.40, p=0.0585) levels. These data suggest that carb quality alters the RA of butyrate-producing bacteria, presumably leading to higher short chain fatty acid production, with subsequent alterations in plasma lipids. This study provides novel information about the impact of carb quality on the phylogenetic structure and functional capacity of the fecal microbiome.
Abstract 17336: Marked Improvement in BP Control Albeit With Recent Decline and Persistence of Racial Disparities in Veterans 2000 to 2014
Authors: Fletcher Ross D , Amdur Richard L , Kheirbek Raya , Papademetiou Vasilios , Maron David D , Faselis Charles , Jones Ronald E
Published: July 2021

Background:
The VA Electronic Health Record (VAEHR) contributes to effective management and control of hypertension and stores data longitudinally. We examined associations of BP control with age, race, ethnic group, and hypertensive drug treatment.

Methods:
In the VAEHR, vital signs were analyzed from 2000 through 2014 and medication records from 2004 to 2014. Patients with elevations >140 systolic or >90 diastolic on three separate days were considered hypertensive. Prescription coverage gaps due to late filling and renewals were examined to compute each patient’s % of days covered per month.

Results:
Of 8,813,000 patients followed in the VA system, 3,160,606 were hypertensive. In the total population BP control rates improved from 41.3% in 2000 to 74.6%.in 2010, but gradually declined to 71.3% by 2014. African Americans increased from 40.1% in 2000 to 70.8% in 2010 and declined to 67.4% in 2014 while Whites increased from 42.0% in 2000 to 75.7% in 2010 and fell to 72.4% in 2014. Hispanic control rates were initially 2% worse but are similar to Whites since 2004. While the increase was 5% better in Whites and Hispanics than in African Americans the decline in control rate of 3.3% (p<.0001) starting in 2010 was similar in all racial and ethnic groups (fig.), and in all age groups. For ACEi, alpha blockers, beta blockers, and diuretics, the average coverage per month was 72% for Whites and 67% for African Americans. This 5% disparity did not change after 2010. These gaps can be reduced using “Park a Prescription” to maintain coverage while waiting for drug renewal.

Conclusions:
Data from VAEHR over a 14 year period shows a marked improvement over 30% for the first 10 years but a slow decline of 3.3% in the last 4 years. Eliminating drug gaps, which occur in all races, and improving treatment of hypertension should increase BP control rates to and above previous levels.

Figure:
Percent of hypertensive patients with controlled BP each month, stratified by race improving each summer.
Abstract 17345: Particulate Matter and Risk of Incident Cardiovascular Disease in a Nationwide Cohort of Men
Authors: Hart Jaime E , Chen Jarvis T , Puett Robin C , Yanosky Jeff D , Rimm Eric B , Rexrode Kathryn M , Wellenius Gregory A , Laden Francine
Published: July 2021

Introduction:
Chronic exposures to particulate matter (PM) have been associated with cardiovascular disease (CVD) morbidity and mortality. We examined the impact of long-term exposures to PM on the risk of incident coronary heart disease (CHD) and stroke among members of the nationwide all-male Health Professionals Follow-Up Study (HPFS) prospective cohort.

Methods:
HPFS members were followed biennially between 1986-2006 to obtain information on incident disease and to update information on CVD risk factors. Time-varying ambient PM
10
, PM
2.5-10
, and PM
2.5
for the previous 12 months were calculated from monthly predictions at the address level. Multivariate adjusted Cox proportional hazards models were used to estimate [HR (95%CI)] for the association between each fraction of PM and each outcome among 43,371 CVD-free members of the HPFS, adjusting for risk factors and other potential confounders. We also assessed effect modification by region of the country, BMI, smoking status, and comorbidities (hypercholesterolemia, high blood pressure, and diabetes). Sensitivity analyses were conducted restricting the population to men who provided residential (N=15,395), as opposed to work, addresses.

Results:
The mean (SD) levels of 12-month average PM
10
, PM
2.5-10
, and PM
2.5
were 20.7 (6.2), 8.4 (4.7) and 12.3 (3.4) μg/m
3
. In the full population, there was only modest evidence of increased risks of incident CHD or stroke with increasing PM exposures. Associations with stroke were modified by region, hypercholesterolemia, high blood pressure, and diabetes, with larger effects among those with comorbid conditions and in the Northeast and South. CHD, but not stroke, dose-responses were stronger among those who provided residential as opposed to work addresses; each 10 μg/m
3
increase, was associated with increases in overall CHD [1.10 (95%CI: 1.01-1.20), 1.09 (0.97-1.23), and 1.14 (0.98-1.32) for PM
10
, PM
2.5-10
, and PM
2.5
, respectively].

Conclusions:
In this cohort of US men, PM exposures were only modestly associated with elevated risks of CHD and stroke. Comorbidities and region modified the associations with stroke, and residential ambient exposures were more associated with CHD than work ambient exposure.
Abstract 17348: Clinical Outcomes in Acute Coronary Syndrome Patients Following Coronary Artery Bypass Grafting in Relation to Timing of Ticagrelor Discontinuation: Insights From the CAPITAL Registry
Authors: Russo Juan J , James Tyler E , Malhotra Nikita , Goubran Daniel , Rubens Fraser D , Bourke Michael , Dupuis Jean-Yves , Chan Vincent , Singh Kuljit , Ruel Marc T , So Derek Y
Published: July 2021

Background:
We sought to assess in-hospital clinical outcomes in ACS patients undergoing CABG in relation to the duration of ticagrelor discontinuation prior to surgery.

Methods:
We identified consecutive ACS patients who underwent CABG after having received ticagrelor. Patients were divided into 3 groups based on the timing of surgery after discontinuation of ticagrelor (<48 hours, 48 hours to <5 days, 5 days or more). We then compared clinical outcomes following CABG in relation to the duration of ticagrelor discontinuation prior to surgery. Clinical variables evaluated included postoperative bleeding, need for surgical reopening or blood transfusions, and length of stay in the intensive care unit (ICU).

Results:
Of 664 ACS patients undergoing CABG between January 2012 and March 2015, 53 received ticagrelor prior to CABG. Ticagrelor had been discontinued <48 hours prior to CABG in 22 patients (41%); 48 hours to <5 days in 19 (36%); and 5 days or more in 12 (23%). Patients who underwent CABG <48 hours after ticagrelor discontinuation were more likely to require blood transfusions and a prolonged ICU stay (defined as >3 days). In addition, they had numerically higher, but non-statistically significant, rates of postoperative bleeding. Patients who underwent CABG 48 hours to <5 days after ticagrelor discontinuation had similar rates of postoperative bleeding and duration of ICU stay compared to patients who waited at least 5 days.

Conclusions:
A significant proportion of ACS patients (77%) who require CABG undergo surgery before the guideline recommended ticagrelor discontinuation period of 5 days. Patients who undergo CABG <48 hours after ticagrelor discontinuation are more likely to require postoperative blood transfusions and a prolonged ICU stay. Notably, patients who undergo CABG 48 hours to <5 days after ticagrelor discontinuation have similar postoperative outcomes compared to patients who undergo CABG after 5 days of ticagrelor discontinuation.
Abstract 17370: Multiple Pregnancy Factors and Later Hypertension in Swedish Women From the Vasterbotten Intervention Programme
Authors: Parikh Nisha , Norberg Margareta , Ingelsson Erik , Cnattingius Sven , Vasan Ramachandran S , Domellöf Magnus , Håkan Jan , Edstedt Bonamy Anna-Karin
Published: July 2021

Introduction:
Pregnancy is considered a maternal cardiometabolic stress test. However, it is uncertain when considered together, which set of pregnancy characteristics independently relate to later hypertension (HTN) in women.

Methods:
We used Swedish Medical Birth Register data linked with the Vasterbotten Intervention Programme cohort from Northern Sweden. Using logistic regression analysis in crude and multivariable adjusted models, we related pregnancy factors in any prior pregnancy with HTN at age 40 years in parous women free of prepregnancy HTN. Pregnancy factors included parity, age at first delivery, infertility ≥ 5 years, preeclampsia, delivering a small for gestational age baby (SGA, < 3rd percentile for birthweight), gestational age (shortest), placental abruption and gestational diabetes. We defined HTN as systolic BP ≥ 140 and/or DBP ≥ 90 mmHg and/or antihypertensive use. Multivariable models were adjusted for all pregnancy factors as well as for potential confounders including household income, education, smoking, alcohol intake and body mass index.

Results:
Among n=15,900 women, 1,535 women (9.6%) had HTN at age 40 years. In multivariable models, younger age at first birth, preeclampsia, gestational age < 32 weeks and SGA, were associated with HTN (Table). Gestational diabetes and stillbirth were related to HTN in unadjusted models but not in multivariable models. Parity, infertility and placental abruption were not related to HTN at age 40 years in crude or multivariable models. Conclusions: Younger age at first birth, preeclampsia and delivering a very preterm or small for gestational age baby were independently associated with maternal hypertension at age 40 years upon accounting for sociodemographic and lifestyle factors. Our findings, if confirmed, raise the possibility that earlier and more frequent BP screening may be desirable in women with these pregnancy characteristics.
Abstract 17375: In Utero Particulate Matter Exposure Produces Heart Failure and Electrical Remodeling at Adulthood
Authors: Long Victor P , Tanwar Vineeta , Gorr Matthew W , Baine Stephen H , Bonilla Ingrid M , Carnes Cynthia A , Wold Loren E
Published: July 2021

Introduction:
In utero exposure to particulate matter through perinatal development has been demonstrated to produce cardiac dysfunction during adulthood. It is unknown what effect exposure to air pollution during the in utero period alone has on cardiac dysfunction and electrical remodeling in adulthood. We tested the hypothesis that adult mice exposed to concentrated particulate matter in utero would demonstrate global cardiac dysfunction as well as cellular electrical remodeling at adulthood.

Methods:
Female FVB mice were exposed either to filtered air (FA) or particulate matter with diameter less than 2.5 μm (PM2.5) at a concentration of ~ 51.69 μg/m3 for 6 h/day, 7 days/wk (consistent with exposure in a large metropolitan city) beginning at plug formation throughout pregnancy. Cardiac function was assessed via ECHO in male offspring at 12 wks of age, followed by sacrifice and isolation of ventricular cardiomyocytes from both groups of mice for electrophysiological recordings.

Results:
ECHO identified increased LVESd (2.25 ± 0.20 FA, 2.61 ± 0.35 PM2.5, P=0.0001) and LVEDd (3.89 ± 0.03 FA, 3.99 ± 0.038 PM2.5, P=0.04) dimensions and reduced PWTs (1.40 ± 0.05 FA, 1.26 ± 0.04 PM2.5, P=0.04) in mice exposed in utero to PM2.5. Morphological alterations were associated with lower systolic function as indicated by reduced fractional shortening% (43.6 ± 2.1 FA, 33.2 ± 1.6 PM2.5, P=0.0009) in PM2.5 exposed mice compared to FA controls. Electrophysiological recordings revealed significant prolongation of the action potential at 90% repolarization (APD90) in PM2.5 exposed mice compared to FA. (FIGURE)

Conclusions:
In utero exposure to relevant levels of particulate matter results in dilated cardiomyopathy and electrical remodeling. Future studies are warranted to determine the causes of, and the exposure thresholds resulting in this adverse cardiac remodeling.
Abstract 17379: Atrial Fibrillation Mutations in β3 Subunits Enhance DIII Voltage Sensing Domain Coupling to Channel Activation Which Inhibits Lidocaine Blockade
Authors: Zhu Wandi , Hsu Eric J , Li Bicong , Schubert Angela R , Varga Zoltan , Silva jonathan R
Published: July 2021

Background:
Co-assembly of cardiac Na
+
channels (Na
v
1.5) with β subunits modifies channel gating, expression, and post-translational modification. β subunit mutations have been linked to the Brugada and Long QT Syndromes, and atrial fibrillation (AF).

Hypothesis:
We tested whether β
3
subunits regulate Nav.1.5 ionic current and drug response by modulating the voltage sensing domains (VSDs).

Methods:
The Na
V
1.5 α subunit contains four domains (DI-DIV), each with its own voltage sensing domain (VSD). We previously created four DNA constructs that carried a cysteine within a single VSD. Channels expressed in
Xenopus
oocytes and these cysteines were labeled with TAMRA-MTS fluorophores. Ionic current and fluorescence emission that tracked VSD conformation were simultaneously recorded using the cut-open configuration with and without β
3
.

Results:
Steady state inactivation is significantly right shifted by β
3
(V
1/2
= -88.9 ± 1.1 SEM (with, +β
3
) and -97.8 ± 1.5 (without, -β
3
), p=0.002, n=4). β
3
also

right shifts DIII-VSD activation (V
1/2
= -93.0±2.3 +β
3
, V
1/2
= --114.8±0.8 -β
3
, p=0.001, n=4), while modestly left-shifting channel activation, suggesting enhanced DIII-VSD to pore coupling (V
1/2GV
-V
1/2FV
=55.0 ± 4.0 +β
3
, V
1/2GV
-V
1/2FV
=73.6 ± 2.4 -β
3
, n=4). DI and DII were not affected, while DIV was modestly shifted, consistent with DIII/DIV cooperativity. Extracellular domain AF-linked β
3
mutations, R6K and L10P, further enhance DIII-VSD to pore coupling (V
1/2GV
-V
1/2FV
=34.1 ± 5.8, (R6K), V
1/2GV
-V
1/2FV
=41.5 ± 4.7 (L10P), n=4). β
3
nearly abolishes stabilization of the DIII-VSD by lidocaine (DIII FV shift by lidocaine: ΔV
1/2
lido=-27.71 ± 12.23 (+β
3
), ΔV
1/2
lido=-65.44 ± 3.83 (-β
3
), n=3). The conservative R6K mutation exacerbates this effect, suggesting a cation-pi interaction with Na
V
1.5. W1684 is co-localized with the DIII-VSD, and W1684A disrupted β
3
modification of channel gating and the DIII lidocaine interaction.

Conclusions:
β
3
modifies Nav1.5 gating by increasing DIII-VSD coupling to the pore via interaction with W1684. AF β
3
mutants further enhance DIII-VSD to pore coupling. The differential lidocaine response caused by WT and AF β
3
mutants suggests a molecular mechanism whereby the lidocaine response is patient and heart-chamber specific.
Abstract 17382: Gender Difference in Presentation, Management and Outcome of Patients With Acute Myocardial Infarction: A Sub-analysis of J-MINUET Study
Authors: Nakama Yasuharu , Ishihara Masaharu , Fujino Masashi , Ogawa Hisao , Nakao Koichi , Yasuda Satoshi , Noguchi Teruo , Ozaki Yukio , Kimura Kazuo , Suwa Satoru , Fujimoto Kazuteru , Morita Takashi , Shimizu Wataru , Saito Yoshihiko , Hirohata Atsushi , Morita Yasuhiro , Inoue Teruo , Okamura Atsunori , Uematsu Masaaki , Hirata Kazuhito , Hirata Kazuhito , Tanabe Kengo , Shibata Yoshisato , Owa Mafumi , Hokimoto Seiji , Nishimura Kunihiro , Miyamoto Yoshihiro , Kawagoe Takuji , Dai Kazuoki
Published: July 2021

Purpose:
Several studies have reported gender difference in presentation, management and outcome in patients with acute myocardial infarction (AMI). In this study, we focused the impact of age on gender difference in mortality after AMI.

Methods:
Between July 2012 and March 2014, 3283 patients were admitted to the 28 hospitals participating to the J-MINUET group within 48 hours after the onset of AMI. AMI was diagnosed by universal definition (type 1 or type 2). Patients were divided into 5 strata according to their age: those with age <55 years, 55-64 years, 65-74 years, 75-84 years and ≥85 years.

Results:
There were 813 women (24.8%). Women were significantly older than men (74.5±11.8 years vs 66.6±12.3 years, P<0.001). Women had longer time from onset to admission, more NSTEMI, atypical symptom other than chest pain, Killip class ≥2, CKD and type 2 MI. They also had less diabetes and current smoking habits. Although most of the patients received urgent angiography (93.1%), it was less frequent in women (90.4% vs 94.0%, P<0.001). Among patients who underwent primary PCI (85.1%), achievement of final TIMI-3 flow was similar (91.2% vs 92.0%, P=0.53). In-hospital mortality was significantly higher in women than men (9.6% vs 5.5%, P<0.001). When patients were stratified according to their age, there was a liner increase in the prevalence of women as age advanced: 10.6% in <55 years, 15.1% in 55-64 years, 19.8% in 65-74 years, 35.6% in 75-84 years and 53.6% in ≥85 years (P<0.001). There was no significant gender difference in mortality in each stratum (Figure). Multivariate analysis showed that women was no more an independent predictor of death after adjusting age (OR 1.29, 95%CI 0.95-1.75, P=0.10), or age and other variables (OR 1.19, 95%CI 0.79-1.76, P=0.40).

Conclusions:
Women had higher in-hospital mortality than men after AMI even in the contemporary troponin era. However, their high mortality was mostly explained by their advanced age.
Abstract 17383: Transplantation of Anti-microRNA-377-modified Bone Marrow-derived Progenitor Cells Attenuates Myocardial Infarction-induced Lv Dysfunction in Mouse
Authors: Joladarashi Darukeshwara , Garikipati Venkata Naga Srikanth , Thandavarayan Rajarajan A. , verma Suresh K. , Mackie Alexander R. , Khan Mohsin , Krishnamurthy Shashirekha , Suresh Babu Sahana , Jeyabal Prince , Kishore Raj , Krishnamurthy Prasanna
Published: July 2021

Cardiac diseases are the predominant cause of human mortality in the United States and around the world. MicroRNAs (miRNA/miR) are small non-coding RNAs that have been shown to modulate a wide range of biological functions under various pathophysiological conditions. MiRNA act as molecular switches of gene expression and are thought to regulate complex cardiac signaling and transcriptional circuits during cardiac development and disease. However, its effects on endothelial progenitor cells (EPC) biology and function, particularly in the context of cell-based therapy for cardiomyopathy are not fully understood. The purpose of this study was to determine the miRNA profile of EPCs in response to chronic inflammatory stimuli and evaluate if miRNA-377 impairs differentiation and function of mouse bone marrow-derived EPCs after transplantation in myocardial ischemic conditions. MiRNA array profile of EPCs in response to inflammatory stimuli (LPS, 20ng/ml) for 12 hrs, EPC migration and invitro vascular tube formation was analyzed. GFP-labeled EPC (transfected with either anti-miR-377 or control-anti-miR) were transplanted intramyocardially after induction of MI in mice. miRNA array data from EPCs in response to inflammatory stimuli has indicated modulation of number of miRNAs related to angiogenesis with a robust decrease in miR-377. Pre-miR-377 transfection in EPCs inhibits their migration P<0.05) and vascular tube formation ability (P<0.05). Furthermore, EPCs treated with miR-377 mimic showed decrease in protein expression of HAND2. Interestingly, in a relevant mouse model of myocardial infarction (MI), intramyocardial transplantation of miR-377-silenced (anti-miR-377 transfected, GFP-labeled) EPCs promote neovascularization (at 28 days, post-MI) leading to improvement in myocardial repair (reduced fibrosis and infarct size). Echocardiography showed LV function was significantly improved in mice receiving miR-377-silenced EPCs compared to control-miR-transfected EPCs. Taken together, these data suggest that inhibiting miR-377 in EPCs might promote their engraftment and angiogenic ability after transplantation into ischemic myocardial tissue, possibly through activation of HAND2 signaling axes.
Abstract 17392: Gastrointestinal Bleeding With Edoxaban versus Warfarin: Results From the ENGAGE AF-TIMI 48 Trial
Authors: Aisenberg James , Friedman Kathryn , Desai Jay , Weitz Jeffrey I , Giugliano Robert , Ruff Christian T , Nordio Francesco , Mercuri Michele , Choi Youngsook , Bower Laura , Antman Elliot , Braunwald Eugene
Published: July 2021

Background:
There is more major gastrointestinal bleeding (M-GIB) with most NOACs than with warfarin. The clinical impact of this finding is poorly understood.

Methods:
The ENGAGE AF-TIMI 48 trial compared the efficacy and safety of higher-dose (HD-E: 60 mg/ 30mg) or lower-dose (LD-E: 30 mg/15 mg) edoxaban regimens with dose-adjusted warfarin for prevention of stroke and systemic embolism in non-valvular atrial fibrillation. ISTH definitions for major and life-threatening (LT) bleeding events were utilized. In this pre-specified analysis, we investigated the adjudicated M-GIB events utilizing pre-defined severity and outcome endpoints.

Results:
Although the risk of M-GIB was higher with HD-E than with warfarin, the risk of LT or fatal GIB was similar (figure), and surgery for GIB was required less frequently with HD-E than warfarin (HR 0.37; 95%CI, 0.16-0.88; p=0.03). The risk for M-GIB-related permanent drug discontinuation was similar with HD-E and warfarin (HR 0.96; 95% CI, 0.67-1.37, p=0.8), as were the risks of hospitalization (HR 1.14; 95%CI, 0.92-1.40, p=0.2) and Hgb decrease > 5 g/dL (HR 1.01; 95%CI, 0.74-1.38; p=0.9). The risks of M-GIB and of LT or fatal GIB were lower with LD-E than with warfarin (Figure), as were the risks of M-GIB-related permanent drug discontinuation (HR 0.51; 95% CI, 0.33-0.78, p=0.002), hospitalization (HR 0.67; 95%CI, 0.53-0.85; p=0.001), Hgb decrease > 5 g/dL (HR 0.58; 95%CI, 0.40-0.84; p=0.003), and M-GIB requiring transfusion of > 2 units of red cells (HR 0.66; 95%CI, 0.50-0.89; p=0.006). Fatal GIB occurred in 2, 3 and 7 patients treated with HD-E, LD-E and warfarin, respectively.

Conclusions:
M-GIB and LT-GIB with edoxaban are dose-dependent. Although the risk of M-GIB is higher with HD-E than warfarin, the risk of LT-GIB or fatal GIB is similar and the severity and outcomes are no worse than with warfarin. The risks of M-GIB, and of LT-GIB or fatal GIB, are lower with LD-E than warfarin.
Abstract 17402: Pathological Findings of Takotsubo Cardiomyopathy Relating to Chatecholamine Toxicity: The Study Using Human Left Ventricular Endomyocardial Biopsy Specimens in the Acute Phase
Authors: Nakano Tomoya , Onoue Kenji , Sakaguchi Yasuhiro , Hatakeyama Kinta , Kamon Daisuke , Dote Yoko , Nakada Yasuki , Takitsume Akihiro , Nakagawa Hitoshi , Seno Ayako , Ueda Tomoya , Kumazawa Takuya , Nishida Taku , Soeda Tsunenari , Okayama Satoshi , Takeda Yukiji , Watanabe Makoto , Kawata Hiroyuki , Kawakami Rika , Okura Hiroyuki , Saito Yoshihiko
Published: July 2021

Introduction:
Takotsubo Cardiomyopathy (TTC) is characterized by transient hypokinesis of the left ventricular (LV) apex and mid-ventricular regions, and hyperkinesis of the LV base, without significant coronary artery stenosis. The precise pathogenic mechanism of TTC remains unknown. Earlier reports assumed that catecholamine excess is involved in the pathogenesis of TTC, from the elevation of plasma catecholamine concentration or by 123I-metaiodobenzylguanidine myocardial scintigraphy. However, there have been no pathological findings that directly support this scenario in human, so far. In this study, we investigated clinical and pathological features in TTC heart including expression of G-protein receptor kinase 2 (GRK2), which is a marker for acute desensitization of β-adrenergic receptors (β-ARs), and compared with those in non-TTC heart.

Methods and Results:
The clinical and pathological features from 20 TTC patients (TTC group) and non-TTC patients (non-TTC group) were analyzed. In TTC patients, LV biopsy was performed at the acute phase. Non-TTC group of patients consisted of 14 patients with ventricular tachycardia or conduction disorder, who underwent LV biopsy to rule out primary myocardial diseases. Pathological data showed that the contraction band was more frequently observed in TTC than in non-TTC group (p=0.017) (Figure A), and the percentage of interstitial fibrosis area of TTC was higher than that of non-TTC group (12.1±7.7% vs 7.4±3.0%, p=0.036) (Figure B). Moreover, the percentage of GRK2 positive stained area in TTC was greater than in non-TTC group (49.0±17.8% vs 15.7±11.9%, p<0.001) (Figure C).

Conclusions:
The present study demonstrates up-regulation of GRK2 for the first time in human TTC, and supports the involvement of catecholamine toxicity in the pathogenesis of TTC.
Abstract 17403: Prognositic Significance of T peak - T end Interval in Transthyretin Cardiac Amyloidosis
Authors: Sugrue Alan , Killu Ammar M , Hai JoJo , Joppa Stehpanie , Lin Grace , Grogan Martha , Dispenzieri Angela , Brady Peter
Published: July 2021

Introduction:
The T peak - T end interval (Tpe) is a measure of transmural dispersion of repolarisation with prolongation of this interval linked to an increased risk of ventricular arrhythmias and sudden death. Patients with cardiac amyloid experience a high rate of sudden cardiac death.

Objective:
To determine the prognostic utility of the Tpeak-Tend interval in patients with transthyretin (TTR) cardiac amyloidosis.

Methods:
Of the 240 patients who underwent evaluation for TTR amyloidosis at our tertiary referral center from 1966 to 2010, 39 met inclusion criteria (65 excluded for AF, 66 BBB/Paced Rhythm, 25 CAD, 21 other). Inclusion criteria were presence of histological diagnosis of TTR amyloid and confirmed cardiac involvement by echocardiogram or biopsy and absence of atrial fibrillation (AF) or bundle branch block/paced rhythm on the index surface ECG, or history of coronary heart disease (CAD). Tpe was measured in leads V3 and V5. Cox proportional hazards model were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Kaplan-Meier curves were used to estimate overall survival and differences between curves were estimated using log rank. Primary endpoints were death or heart transplantation.

Results:
Of the 39 patients, 85% were male, and 69% were mTTR. Mean age 66.4 ± 13.9 years. Mean follow up period of 4.2 ± 3.2 years, 25 died and 5 received heart transplants. Median survival was 3.8 years, with 5 year survival 34%. On univariate analysis, Tpe in lead V3 was predictive of adverse outcome, HR per 10msec, 1.195 (1.051-1.370). Further multivariate analysis, in a model accounting for age, gender, Lead V3 Tpe was independently associated with survival, HR per 10msec, 1.207, (1.094-1.411, p=0.009).

Conclusions:
The Tpe interval in Lead V3 at diagnosis is a novel, noninvasive independent predictor of survival in transthyretin cardiac amyloidosis patients in sinus rhythm.
Abstract 17415: Recombinant Human BDNF Can Mimic Effects of Exercise Training in Mice
Authors: Takada Shingo , Kinugawa Shintaro , Matsushima Shouji , Yokota Takashi , Mizushima Wataru , Furihata Takaaki , Matsumoto Junichi , Tsuda Masaya , Fukushima Arata , Okita Koichi , Tsutsui Hiroyuki
Published: July 2021

Background:
Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, has been known to be increased by exercise training (ET) and associated with exercise capacity, which are dependent on mitochondrial function in the skeletal muscle (SKM). We thus hypothesized that an increase in BDNF and an activation of its binding receptor, tropomyosin-related kinase B (TrkB), could increase the exercise capacity by enhancing mitochondrial function in SKM in mice. Therefore, we investigated whether an administration of recombinant human (rh)BDNF into sedentary (SED) mice could mimic the effect of ET on exercise capacity and SKM.

Methods and Results:
C57BL/6J mice randomly assigned either SED (n=20) or ET (n=10), SED mice was divided into 2 groups of the treatment with vehicle (phosphate-buffered saline; n=10) or rhBDNF (10 mg/kg body weight/day, s.c.; n=10), for 5 weeks. ET was performed by swimming for 90 min/day and 5 times/week. SKM weight did not differ among groups. The work (distance x body weight) and peak oxygen uptake (VO2) evaluated by treadmill test were significantly increased in ET+vehicle compared to SED+vehicle (work 24±1 vs 32±1 J and peak VO2 150±2 vs 166±2 mL/kg/min, p<0.05) and also in SED+rhBDNF to the same extent (work 29±1 and peak VO2 170±2). Serum BDNF levels was significantly increased in SED+rhBDNF compared to SED+vehicle, whereas it did not change in ET+vehicle. BDNF mRNA and protein expressions, and TrkB mRNA were increased in SKM from ET+vehicle compared with SED+vehicle (respectively, p<0.05), whereas they did not change in SED+rhBDNF. Phosphorylation of TrkB, AMP-activated protein kinase (AMPK) and Sirt-1, and PGC-1α protein levels were increased in SED+rhBDNF and ET+vehicle compared with SED+vehicle (respectively, p<0.05). Mitochondrial complex activities and citrate synthase activity were in parallel with these results. In C2C12 myotubes, rhBDNF significantly increased mRNA levels related to mitochondrial function and these effects were completely inhibited by anti-TrkB antibody or AMPK inhibitor, compound C.

Conclusions:
rhBDNF can mimic the effects of ET on exercise capacity. BDNF-TrkB pathway may play an important role in the beneficial effects of ET on the exercise capacity and SKM function.
Abstract 17457: Does Additional Complex Fractionated Atrial Elecrogram Guided Ablation After Linear Ablation Improve Clinical Outcome of Catheter Ablation for Longstanding Persistent Atrial Fibrillation? A Prospective Randomized Study
Authors: Kim Tae-Hoon , Uhm Jae-Sun , Kim Jong-Youn , Joung Boyoung , Lee Moon-Hyoung , Pak Hui-Nam
Published: July 2021

Introduction:
Although long-lasting circumferential pulmonary vein isolation (CPVI) is a corner stone of catheter ablation for atrial fibrillation (AF), it is not clear whether additional linear or complex fractionated atrial electrogram (CFAE)-guided ablations improve clinical outcome in patients with long-standing persistent AF (L-PeAF).

Hypothesis:
The purposes of this study were to compare CFAE maps before and after linear ablation, and to test whether additional CFAE ablation after linear ablation improves clinical outcome of L-PeAF.

Methods:
This study enrolled 119 consecutive L-PeAF patients (male 72.8%, 61.7±10.6 years old) who underwent RFCA. After baseline CFAE mapping, we conducted CPVI and linear ablations (posterior box lesion and anterior line). If AF maintained after linear ablation, we mapped CFAE again, and randomly assigned the patients to linear ablation group (Line, n=45) and additional CFAE ablation group (CFAE+Line, n=48). The patients whose AF terminated or changed to AT were excluded from randomization and classified as AF-Stop group (n=26). We compared pre- and post-linear ablation CFAE maps and clinical outcomes of CFAE+Line, Line, and AF-Stop groups.

Results:
1. Mean CFAE-cycle length (CL) was significantly prolonged (203.65±40.35 ms to 264.17±39.03 ms, p<0.001) and CFAE area was reduced (15.49±14.95% to 7.95±9.36%, p<0.001) after linear ablation. Post-linear ablation CFAE was mainly located at left atrial (LA) appendage, septum, and posterior inferior LA. 2. There were no differences in total procedure time (p=0.441), ablation time (p=0.144), and procedure-related complication rate (p=0.955) among three groups. 3. During 17.4±10.5 month follow-up period, clinical recurrence rates were 30.4% in CFAE+Line group, 12.8% in Line group, and 16.7% in AF-Stop groups, respectively (Log rank, p=0.138). 4. Additional CFAE ablation after linear ablation did not improve clinical outcome of catheter ablation at all in patients with L-PeAF (HR 2.11, 95% CI 0.91 - 4.89, p=0.082).

Conclusions:
Linear ablation prolonged CFAE-CL and localized CFAE area in patients with L-PeAF. However, CFAE guided ablation in addition to linear ablation and CPVI did not improve clinical outcome of catheter ablation.
Abstract 17471: Cardiorenal Syndrome Patients With High NT-proBNP and Cystatin C Levels and Patients With Irreversible Cardiorenal Syndrome Identified by Persistently High Levels of Cystatin C Have Worse Outcomes in Cardiac Resynchronization Therapy: The BIOCRT Study
Authors: Contractor Jigar , Szymonifka Jackie , Deano Roderick C , Chatterjee Neal A , Januzzi James L , Singh Jagmeet P , Truong Quynh A
Published: July 2021

Introduction:
Cardiorenal syndrome comprises of a heterogeneous group of acute and chronic cardiac and renal dysfunction. We examine the association of a dual marker strategy using amino-terminal pro brain natriuretic peptide (NT-proBNP, heart failure) and cystatin C (CysC, renal function) with major adverse cardiac events (MACE) in cardiac resynchronization therapy (CRT) patients.

Methods:
In 92 patients (age 66±13; 80% male; ejection fraction 26±7%), NT-proBNP and CysC levels were measured at CRT implantation, and 1 month. NT-proBNP>1000 pg/mL and CysC>1mg/L were considered high. At baseline, cardiorenal patients were defined as having high NT-proBNP and CysC. One month after implant, we categorized CRT patients as (1) irreversible cardiorenal if CysC was persistently high, (2) progressive cardiorenal with low transition to high CysC, (3) reversible cardiorenal with high transition to low CysC, and (4) "normal" with stable low CysC. MACE was defined as death, cardiac transplant, left ventricular assist device, and heart failure hospitalization by 2 years.

Results:
There were 25 (27%) MACE. Prior to CRT, 34 (37%) patients had cardiorenal syndrome. Compared to patients with low NT-proBNP and CysC levels, cardiorenal patients had >6-fold risk of MACE (adjusted HR 6.3, p=0.02) with an estimated 52% probability of having MACE (Figure A). One month after CRT, 33 (36%) patients were irreversible, 15 (16%) progressive, 7 (8%) reversible, and 37 (40%) "normal". Compared to "normal" and reversible patients (referent), irreversible patients had >4-fold risk of MACE (adjusted HR 4.7, p=0.002) with an estimated 52% probability of having MACE (Figure B) while progressors had similar MACE risk (adjusted HR 1.0, p=1.0).

Conclusions:
CRT patients with cardiorenal syndrome, especially irreversible, have worse prognosis compared to those with acute renal injury or "normal" renal function. Cardiorenal status by NT-proBNP and CysC can identify high-risk CRT patients.
Abstract 17510: The First Prediction Model for Response to Autologous Bone Marrow-derived Mononuclear Cells After Myocardial Infarction Based on the REPAIR-AMI Trial
Authors: Zwetsloot Peter-Paul , Assmus Birgit , Koudstaal Stefan , Gremmels Hendrik , Erbs Sandra , Lauer Bernward , Haberbosch Werner , Doevendans Pieter A , Sluijter Joost P , Zeiher Andreas M , Chamuleau Steven
Published: July 2021

Background:
Administration of autologous bone marrow-derived mononuclear cells (BM-MNC) resulted in favorable outcomes after myocardial infarction (MI) compared to placebo in the REPAIR-AMI trial. Pre-clinical studies have shown that individual risk factors negatively influence cell function. To date, it is not known how these risk factors modify treatment effect in clinical trials and if potential (non-)responders can be identified.

Aim:
To investigate the effect of individual risk factors on functional outcome after BM-MNC therapy and to establish a prediction model for treatment response in patients with MI.

Methods:
Data from the REPAIR-AMI trial were used, consisting of 186 patients who had complete baseline and follow-up measurements. We performed univariable and multivariable linear regression with 18 predefined baseline characteristics using the difference in baseline EF and after 4 months (ΔEF4) as primary outcome. Our main goal was to identify interaction terms of predictors with BM-MNC treatment; i.e. effect modifiers of treatment response. An individual estimate of treatment effect over placebo (ΔΔEF4) was created by extrapolating an ‘untreated’ reference value for ΔEF4, based on the placebo-arm and comparing it to the observed value after treatment. Treatment response was defined as a ΔΔEF4 of >5% (so 5% over a predicted placebo value). Discrimination was quantified by the area under the ROC-curve (AUC).

Results:
The predictors age, weight, baseline EF and ESV showed an interaction with cell treatment in multivariable analysis with backward selection. Subsequently, the prediction model for individual ΔΔEF4 included age (-0.18/year, p=0.008), weight (+0.16/kg, p=0.01), baseline EF (-0.46/%, p=0.0001) and ESV (-0.09/ml, p=0.06). The predictive capacity for response to therapy showed an AUC of 79.2% (95% CI 69.7-88.6), which retained 74.8% (95% CI 65.0-84.5) after shrinkage.

Conclusion:
Response to BM-MNC administration after MI is influenced by age, weight, and baseline cardiac parameters. Using these continuous predictors, potential treatment responders can be accurately identified. Interestingly, an adverse risk-factor profile was associated with greater response, with potential implications for future patient selection.
Abstract 17525: Warfarin Promotes Progressive Coronary Arterial Calcification: Insights From Serial Intravascular Ultrasound
Authors: Andrews Jordan , Bayturan Ozgur , Shao Mingyuan , Stegman Brian , Elshazly Mohamed , Kapadia Samir , Tuzcu E. Murat , Nissen Steven , Nicholls Stephen , Puri Rishi
Published: July 2021

Background:
Warfarin blocks the synthesis and activity of matrix Gla protein (MGP), a vitamin K-dependent inhibitor of arterial calcification. The impact of warfarin on coronary arterial calcification in vivo is unknown. This study compared serial changes in coronary percent atheroma volume (PAV) and calcium index (CaI) in patients treated with and without warfarin.

Hypothesis:
Serial changes in coronary CaI are greater in warfarin-treated patients compared with those not on warfarin, independent of changes in PAV

Methods:
In a patient-level analysis of 8 prospective randomized trials using serial coronary intravascular ultrasound, we compared changes in PAV and CaI in matched arterial segments in patients with coronary artery disease treated with (n=171) and without (n=4129) warfarin during an 18-24-month period.

Results:
Patients (age 57.9±9.2 yrs; male 73%; prior and concomitant statin use: 73 and 97% respectively) demonstrated an overall increase in PAV by 0.18±0.06% (p=0.003 compared with baseline) and CaI [median (IQR)] by 0.04 (0.00, 0.11) (p <0.001 compared with baseline). Following propensity-weighted adjustment for clinical trial, clinical characteristics and laboratory parameters, there was no difference in annualized ΔPAV in the presence and absence of warfarin treatment (0.08±0.05 vs. 0.13±0.04%, p=0.41). Following adjustment for PAV, a greater annualized increase in CaI was observed in warfarin treated patients [median (IQR) 0.03 (0.0-0.08) vs. no-warfarin: 0.02 (0.0-0.06) p<0.001)]. In a sensitivity analysis evaluating a 1:1 matched cohort (n=164 per group), significantly greater annualized changes in CaI were also observed in warfarin-treated patients. In a multivariable model, warfarin independently associated with an increasing CaI [Odds Ratio (95% confidence interval) 1.12 (1.01, 1.24), p=0.027].

Conclusion:
Warfarin therapy associates with progressive coronary atheroma calcification, independent of changes in atheroma volume. The impact of these changes on plaque stability and cardiovascular outcomes require further investigation.
Abstract 17557: Programmed Lower Rate Limit in Cardiac Resynchronization Therapy Defibrillators: Is There One Best Approach?
Authors: Olshansky Brian , Richards Mark , Sharma Arjun D , Jones Paul W , Wold Nicholas , Perschbacher David L , Wilkoff Bruce L
Published: July 2021

Introduction:
Recent remote follow-up data analysis suggests that Lower Rate Limit (LRL) programming at 40 beats per minute (bpm) is associated with lower mortality than higher LRL in patients receiving cardiac resynchronization defibrillators (CRT-d) devices.

Purpose:
We evaluated: 1. if LRL programming in CRT-d devices is based on implanting center or if it varies from patient-to-patient within centers and 2. if LRL programming is associated with survival.

Method:
The ALTITUDE remote follow-up database was analyzed for dual-chamber CRT-d devices implanted 2006-2011. LRL programming near implant was assessed. Patients were included if LRL remained constant during follow-up. Centers were included with >25 implants. Mortality was determined from the Social Security Death Index.

Results:
Of 64,482 patients receiving CRT-d devices (not in chronic atrial fibrillation), 56,501 were from centers implanting >25 devices. Of these, 4,683 were implanted in centers where most patients (>75%) received the same LRL (homogeneous); 51,818 were implanted in centers with variable LRL programming (heterogeneous). No difference in overall survival existed between the two approaches to LRL programming. However, in centers that varied LRL programming, LRL<60 bpm was associated with better 5-year survival (p<0.001) (figure).

Conclusion:
Most patients in the ALTITUDE database received CRT-D devices from centers that vary LRL programming. At these centers, LRL <60 bpm programming is associated with better survival but the mechanism of benefit is unknown. Alternatively, LRL <60 bpm programming for all patients does not confer survival benefit.
Abstract 17562: GPCR Gβγ Signaling Mediates Renal Dysfunction and Fibrosis in Heart Failure Mice
Authors: Kamal Fadia A , Travers Joshua G , Schafer Allison E , Ma Qing , Devarajan Prasad , Blaxall Burns C
Published: July 2021

Background:
Cardiorenal syndrome type 2 (CRS2), the development of chronic kidney disease (CKD) secondary to chronic heart failure (CHF), is clinically associated with increased incidence of organ failure and reduced survival. Heart and kidney damage in CRS2 is greatly caused by chronic stimulation of the adrenergic and endothelin receptors as a result of elevated neurohormonal signaling of the sympathetic nervous system (SNS) and its downstream endothelin (ET) system, respectively. These receptors belong to the superfamily of G protein-coupled receptors (GPCRs). While chronic GPCR stimulation and its associated upregulated interaction between the G-protein βγ subunit (Gβγ), the GPCR-kinase 2 (GRK2) and β-arrestin are known to be central to various cardiovascular diseases, their role in kidney diseases are by far unknown and beg investigation.

Objective:
CRS2 animal studies utilize combine ischemic cardiac injury and renal injury, which is of poor clinical relevance. Our study investigates: (1) the development of chronic kidney disease (CKD) in a model of non-ischemic CHF without inducing surgical kidney injury, aiming to establish a more clinically relevant CRS2 model. (2) The possible salutary effect of renal GPCR-Gβγ inhibition in CKD developed in the established CRS2 model.

Methods and results:
We utilized transverse aortic constriction (TAC) as a non-ischemic hypertrophic murine CHF model. Twelve weeks after TAC, mice developed CKD secondary to CHF suggesting a CRS2 model. This was associated with elevated renal GPCR-Gβγ signaling and ET system expression. Importantly, systemic pharmacologic Gβγ inhibition by gallein attenuated these renal pathological changes in parallel with alleviated CHF. A direct effect of gallein on the kidney was subsequently confirmed in a bilateral ischemia reperfusion acute kidney injury (AKI) mouse model where it attenuated renal dysfunction, tissue damage and ET system activation, indicating a direct role for GPCR-Gβγ signaling in AKI. Further, in vitro studies in mouse embryonic fibroblasts showed a key role for ET receptor-Gβγ signaling in fibroblast activation.

Conclusion:
Our data suggest TAC as a clinically relevant CRS2 model and GPCR-Gβγ inhibition as a novel therapeutic approach for CRS2 and AKI.
Abstract 17575: Looking Beyond Left Ventricular Ejection Fraction: Investigating the Utility of Multi-factorial Computational Modeling to Predict Sudden Cardiac Death Following Acute Coronary Syndrome in the MERLIN-TIMI36 Trial
Authors: Van Esbroeck Alex , Saeed Mohammed , Scirica Benjamin M , Stultz Collin M , Guttag John V , Singh Satinder , Morrow David A , Syed Zeeshan
Published: July 2021

Introduction:
Guidelines to prevent sudden cardiac death (SCD) following acute coronary syndrome (ACS) are widely based on cutoffs defined on left ventricular ejection fraction (LVEF) with limited use of other available data.

Methods:
We investigated the improvement in predicting post-ACS SCD using a multi-factorial model that integrates an assessment of left ventricular dysfunction through echocardiography with a broader set of other parameters collected routinely during hospitalization for ACS. Patients in the MERLIN-TIMI36 trial were admitted within 48 hours of ischemic symptoms for non-ST-elevation ACS and followed for a median of 348 days. SCD was adjudicated by a blinded clinical events committee. Data from 4,404 patients with LVEF and other clinical parameters routinely collected during index hospitalization (demographic, comorbidity, history, laboratory, electrocardiographic, and medication variables) were used to train and validate a logistic regression model to predict SCD using stepwise backward elimination and leave-one-out cross-validation.

Results:
The stepwise elimination process retained age, history of congestive heart failure, ST depression, beta blocker use, BNP, LVEF, and ischemia and ventricular tachycardia on continuous ECG as variables in the model. The model achieved significant improvements in discrimination, calibration and reclassification relative to LVEF, and demonstrated further utility in stratifying patients with mild/moderate left ventricular dysfunction or normal systolic function (Table 1). The model also resulted in higher sensitivity without increasing false positives relative to the LVEF<=30% rule (38% increase in correct predictions of SCD).

Conclusions:
Risk stratification for post-ACS SCD is significantly improved using multi-factorial models to integrate information in LVEF with other clinical parameters routinely collected during hospitalization.