bluuebunny/crossref_metadata_2025_split huggingface dataset:
P1562Outcomes of nonagenarians with ST elevation myocardial infarction
Authors: Cepas Guillen P L , Borrego-Rodriguez J , Flores-Umanzor E , Fernandez-Valledor A , Vazquez S , Echarte Morales J C , Menendez-Suarez P , Iglesias Garriz I , Perez De Prado A , Regueiro A , Brugaletta S , Freixa X , Masotti M , Fernandez-Vazquez F , Sabate M 
Published: October 2019

Abstract

Background
Developed countries are facing a sustained increase in life expectancy. Elderly people represent the fastest growing portion of cardiovascular patients. However, nonagenarians with ST-segment elevation myocardial infarction (STEMI) are often underrepresented in clinical trials as prolonged follow-up may be compromised by limited life expectancy. The aim of this retrospective study is to analyse the clinical presentation, risk factors, co-morbidities, outcomes of nonagenarian patients presenting with STEMI.

Methods
We included all consecutive nonagenarians presenting with STEMI admitted in 2 academic centers between 2007 and 2017. There were no exclusion criteria. We collected demographic, clinical, and procedural data. All-cause mortality was assessed in-hospital, at 6 months and at 1-year follow-up.

Results
A total of 140 patients (mean age 91.6 years [91.3–92]; 59% females) were included. The number of patients increased over the years (from 6.5 cases per year before 2012 to 14.4 cases per year after 2012). One out of 5 patients presented disability or dependence for activities of daily living (ADL). Emergent catheterization was performed in 70% of our patients, and primary percutaneous coronary intervention (pPCI) in 57% (n=80). The use of bare metal stent was preponderant (72%) in this cohort. Successful revascularization of the culprit vessel was achieved in 90% of patients. Dual antiplatelet therapy with aspirin and clopidogrel was used in 97% of patients. Overall, in-hospital mortality was 22%, increased up to 27% at 6 months and up to 34% at 1-year follow-up. In-hospital mortality was lower in pPCI group than in conservative group (13.7% versus 31.6%, adjusted OR: 0.17, 95% CI: 0.04–0.67, P<0.01). One-year mortality was also lower in pPCI group than in conservative group (26% versus 45%, P<0.01). Multivariable analysis identified mechanical complications (adjusted OR: 28.1, 95% CI: 3.18–247.7, P<0.01), Killip class (III/IV) (adjusted OR: 4.19, 95% CI: 3.37–22.3, P<0.01) and pPCI (adjusted OR: 0.40, 95% CI: 0. 16- 0. 95, P<0.05) as independent predictors of all-cause mortality at 1 year.

Conclusions
STEMI in nonagenarians is becoming more and more common. pPCI may be also the preferred strategy in this high-risk cohort. The hemodynamic compromise (Killip class III/IV), the presence of complications related to myocardial infarction and early revascularization may be related to prognosis of these patients.
P1565Better adherence to lipid lowering guidelines in secondary prevention may result in substantial reduction in cardiovascular events
Authors: Odesjo H , Bjorck S , Hjerpe P , Manhem K , Rosengren A , Adamsson Eryd S 
Published: October 2019

Abstract

Introduction
The preventive effect of lipid lowering treatment in secondary prevention after coronary heart disease (CHD) is well documented. In 2015, regional guidelines recommend an LDL cholesterol of ≤1.8 mmol/L for patients with established CHD but the adherence to these guidelines is low.

Purpose
Our aim was to predict potential reductions in cardiovascular disease (CVD) events defined as acute myocardial infarction or stroke if patients: 1) with low-dose/less potent or no statin were treated with Atorvastatin 80 mg, or 2) all reached LDL ≤1.8 mmol/L.

Methods
In total, 37 120 patients with established CHD in a primary care regional register 2015 were studied. Predicted number of CVD events were calculated with actual treatment, with improved treatment and with lowered LDL. For risk estimation we used data from a Cox Proportional Hazards risk estimation model based on patients from 2010 (n=52 042) in combination with data from the literature on effect of statin treatment and LDL reduction. A risk reduction of 22% for CVD events per 1 mmol/L reduction in LDL was used in our model.
The risk prediction model included age, sex, diabetes mellitus, a history of heart failure and/or atrial fibrillations, treatment with acetylic salicylic acid and stroke or AMI past year. Smoking and BMI were excluded due to missing data but sensitivity analysis has shown only small differences in results.

Results
In total, 18% of included patients reached LDL ≤1.8 mmol/L and 32% had no statin treatment. Based on actual LDL levels and treatments, the predicted number of CVD events over 5 years was 9209/37120. If all patients with no statin or less potent statin treatment had been given atorvastatin 80 mg this would lead to a reduction of CVD events by 14% (7901 vs 9209). The largest gain, 33% reduction, occurred when adding statins to patients without previous treatment (1970 vs 2937). Furthermore, if all patients were to reach LDL ≤1.8 mmol/L the predicted number of events would be reduced by 18% (7577 vs 9209).

Conclusion
There is a substantial potential to reduce the number of CVD events in the large population of patients with established CHD in primary care by improved adherence to lipid treatment guidelines.

Acknowledgement/Funding
Närhälsan R&D Health Care, R&D Centre Gothenburg and Södra Bohuslän. the Swedish state under the Agreement concerning research and education of doctor
P1575Cardiovascular toxicity following modern multiple myeloma therapy in Japanese cohort
Authors: Shibata T , Nohara S , Nagafuji K , Fukumoto Y 
Published: October 2019

Abstract

Background
Multiple myeloma (MM) is a plasma cell dyscrasia accounting for approximately 13% of hematologic malignancies. Patients with MM have an increased risk of cardiovascular adverse events (CAEs) due to disease burden and/or anti-myeloma treatment-related risk factors. However, little is known about the incidence of cardiovascular toxicity of patients with MM.

Methods
We analyzed 42 consecutive patients (Male/Female 22/20, age 67±10 years old) who received anti-MM therapies between October 2016 and September 2018 from our University Cardio-REnal Oncology (CREO) registry. We examined the incidence of CAEs through January 2019 including congestive heart failure and cardiomyopathy (CHF/CM), ischemic cardiac event, newly symptomatic arrhythmias included atrial fibrillation or flutter requiring treatment, and venous thromboembolism (VTE).

Results
Within the 408-day median follow-up period (range 15–844 days), CAEs occurred in 23.8% (n=10); CHF/CM in 11.9%, newly diagnosed atrial fibrillation in 4.8%, VTE in 4.8%, vasospastic angina in 2.4%, and death in 28.6%. There were no significant differences between CAEs group and non-CAEs group in terms of sex, body mass index (BMI), incidence of hypertension, ischemic heart disease, prior history of heart failure, cardiovascular medications, left ventricular ejection fraction, serum high-sensitivity troponin-I, estimated glomerular filtration rate, blood urea nitrogen and N-terminal pro-brain natriuretic peptide levels at the time of enrollment. The use of various types of proteasome inhibitors and immunomodulatory drugs were not associated with the increased risk of CAEs. By multivariate analysis, a history of prior anti-myeloma therapies was identified as an independent risk factor for CAEs.

Conclusion
CAEs were significantly associated with the recurrent MM in Japanese MM patients.
P1586Research network in Africa (RNA): antihypertensive drugs strategies in 12 African countries
Authors: Kane A , Cavagna P , Diop I B , Gaye B , Mipinda J B , Macquart De Terline D , Limbole E , Narayanan K , Houenassi M C , Koffi F , N'goran Y , Marijon E , Kramoh K E , Jouven X , Antignac M 
Published: October 2019

Abstract

Background
High Blood Pressure is the worldwide leading global burden of disease risk factor. In Sub-Saharan Africa, the number of adults with raised blood pressure has alarmingly increased from 0.59 to 1.13 billion between 1975 and 2015. Blood pressure-lowering medicines are cornerstone of cardiovascular risk reduction. Data on management of anti-hypertensive drugs in sub-Saharan Africa are squarce.

Purpose
Our study aims to describe antihypertensive drugs strategies in Africa.

Methods
We conducted a cross-sectional survey in urban clinics during outpatient consultation specialized in hypertension cardiology departments of 29 medical centers from 17 cities across 12 African countries (Benin, Cameroon, Congo, Democratic Republic of Congo, Gabon, Guinea, Ivory Coast, Mauritania, Mozambic, Niger, Senegal, Togo). Data were collected on demographics, treatment and standardized BP measures were made among the hypertensive patients attending the clinics. Country income was retrieved from the World Bank database. All analyses were performed through scripts developed in the R software (3.4.1 (2017–06–30)).

Results
A total of 2198 hypertensive patients (58.4±11.8 years; 39.9% male) were included. Among whom 2123 (96.6%) had at least one antihypertensive drug. Overall, 30.8% (n=653) received monotherapy and calcium-channel blockers (49.6%) were the most common monotherapy prescribed follow by diuretics (18.7%). Two-drug strategies were prescribed for 927 patients (43.6%). Diuretics and Angiotensin-converting enzyme inhibitors was the combination most frequently prescribed (33.7%). Combination of three drugs or more was used in 25.6% (n=543) of patients. The proportion of drugs strategies differed significantly according to countries (p<0.001), monotherapy ranged from 12.7% in Niger to 47.1% in Democratic Republic of the Congo (figure). Furthermore we observed a significantly difference of strategies between low and middle income countries (55.3% and 44.7% of monotherapy respectively) (p<0.001). According to hypertension grades 1, 2 and 3, the proportion of three-drugs or more combination was 25%, 28% and 34% in middle-income and lower in low-income countries (18%, 19% and 25%). Furthermore, Grade 3 hypertension in low income countries was still treated with monotherapy (36%) instead of 19% in middle income countries (p<0.01).
Antihypertensive strategies by country

Conclusion
Our study described antihypertensive drugs use across 12 sub-Saharan countries, and identified disparities specific to the income context. Inequity in access to drugs combination is a serious barrier to tackle the burden of hypertension in Africa.
P1593VEGFR1-PLC signaling is implicated in normal spontaneous firing of cardiac pacemaker cells
Authors: Vinogradova T , Tarasov K , Tarasova Y , Lakatta E 
Published: October 2019

Abstract

Spontaneous firing of sinoatrial node cells (SANC) is regulated by sarcoplasmic reticulum (SR) generated local subsarcolemmal calcium releases (LCRs). LCRs appear during diastolic depolarization (DD) and activate an inward sodium-calcium exchange current to accelerate the DD rate and thus spontaneous SANC firing. Vascular endothelial growth factor (VEGF) receptors VEGFR1 and VEGFR2 activate PLC, and suppression of VEGFR-PLC signaling decreases calcium transients and contractility in ventricular myocytes. We tested the idea that VEGFR-PLC signaling may contribute to normal spontaneous beating of SANC.
We observed that expression of VEGFR1 (assessed by RT-qPCR) in rabbit sinoatrial node was comparable to that of β1-adrenergic receptors, but less than that in ventricle. The pan VEGFR1/2/3 inhibitor PTK787/ZK222584 (10 μmol/L) in a time-dependent manner: (1) suppressed spontaneous SANC beating rate by ∼50% (perforated patch-clamp technique); (2) markedly decreased the LCR size and number per each spontaneous cycle (confocal microscopy, calcium indicator Fluo-3) and prolonged the LCR period (the interval between action potential-induced calcium transient and occurrence of subsequent LCR). The PTK787/ZK222584-induced increase in the LCR period (from 348.2±30.3 to 619.9±103.4 msec; P<0.05) predicted the concomitant increase in the spontaneous cycle length (from 405.6±31.1 to 702.1±105.1 msec; P<0.05), suggesting that calcium cycling could be a major target of VEGFR-dependent regulation of SANC firing. All effects of PTK787/ZK222584 were reversible upon washout.
To elucidate whether signaling of VEGFR1 or VEGFR2 regulated spontaneous SANC firing, we employed a selective VEGFR2 inhibitor ZM-323881 (5 μmol/L), which suppressed spontaneous beating rate in only 2 of 10 SANC. These results indicate that VEGFR1, but not VEGFR2, is likely a key receptor that modulates automaticity in majority of SANC. To clarify downstream targets from VEGFR1 we employed PLC inhibitor U-73122, which decreased the LCR size, number and prolonged the LCR period. The inactive analog U-73343 was without effect. Because LCRs are critically dependent upon the SR calcium load, supplied by L-type calcium current (ICa,L), we examined effects of U-73122 on ICa,L. U-73122, but not U-73343, markedly suppressed ICa,L amplitude by ∼50%, leading to a decrease in the calcium influx and, as a result, to decrease in the LCR parameters, prolongation of the LCR period and spontaneous SANC cycle length. Thus, basal VEGFR1 signaling activates PLC, which modulates intracellular SR calcium cycling and LCR characteristics in SANC. We conclude that VEGFR1-PLC is a novel mechanism involved in the regulation of normal automaticity of cardiac pacemaker cells.

Acknowledgement/Funding
Intramural Research Program, National Institute on Aging, NIH
P1602Basic electrophysiological modifications induced by carvedilol in unstrectched and stretched ventricular myocardium
Authors: Parra G , Solera J , Del Canto Serrano I , Soler C , Genoves P , Arias-Mutis O , Zarzoso M , Such-Miquel L , Alberola A M , Such L , Chorro F J 
Published: October 2019

Abstract

Background
Acute regional ventricular stretch (ARVS) is a pathophysiologic event that may occur in certain situations, originating arrhythmogenic effects through the mechanoelectrical feedback. Mechanical effects of stretch originate calcium-related changes as sarcoplasmic recticulum Ca2+ overload that can trigger Ca2+ diastolic leaks (store-overload-induced Ca2+ release, SOICR), mediated by the cardiac ryanodine receptor (RyR2). SOICR seems to be implicated in the mechanisms underlying stretch-induced arrhythmias. Carvedilol can inhibit the overload of Ca2+ through blocking of beta-adrenergic receptors, and also suppress the release of Ca2+ induced by the SOICR.

Purpose
The aim of this investigation was to study the effects of carvedilol on the changes in ventricular refractoriness produced by AVRS, directly related with reentrant phenomenon and life-threatening arrhythmias.

Methods
Eleven adult male New Zealand White rabbits (3–3.5 kg) were heparinized (2500 IU) and euthanized by intravenous injection of sodium thiopental (100 mg/kg), according to European Ethic Guidelines. The hearts were excised, isolated and perfused in a Langendorff system. A pacing electrode and a recording multielectrode (121 electrodes) were placed on the left ventricle epicardium. The ARVS was produced by an “ad hoc” device introduced into the left ventricle. The ventricular effective and functional refractory periods (VERP, VFRP) were determined by the ventricular extrastimulus test with a basic cycle length of 250 ms, previously and at the third minute of ARVS, in control conditions and under Carvedilol (1 μM) infusion. The pacing threshold was determined for each situation and the stimulus amplitude was twice the diastolic threshold. A Student's t-test was used. Significance was reached when p<0.05.

Results
Myocardial stretch reduced VERP and VFRP with respect to pre-stretch values under control conditions (VERP: 110±13 vs 99±16 ms, VFRP: 119±13 vs 113±13 ms, p<0.05; n=10). No stretch-induced modifications of refractoriness were observed under carvedilol action (VERP: 139±18 vs 140±17 ms, VFRP: 161±29 vs 157±15 ms, ns; n=8). Before stretching, there were differences between control and carvedilol conditions (VERP: 110±13 vs 139±18 ms, VFRP: 119±13 vs 161±29 ms, p<0.001), and during stretch VERP and VFRP were significantly higher under carvedilol perfusion than in control conditions (VERP: 99±16 vs 140±17 ms, VFRP: 113±13 vs 157±15 ms, p<0.001).

Conclusion
The beta-adrenergic blocker and ryanodine receptor antagonist, carvedilol, attenuates the intrinsic electrophysiological modifications on refractoriness produced by myocardial acute local stretch.
P1603Nicorandil suppresses ischemia-induced cardiac interstitial norepinephrine enhancement and ventricular arrhythmia in hypertrophic hearts
Authors: Kobara M , Naseratun N , Watanabe Y , Toba H , Nakata T 
Published: October 2019

Abstract

Background
Myocardial infarction (MI) is a major cause of death in western countries and Japan, and hypertension is a major risk factor of MI. In hypertensive heart, acute myocardial infarction often leads to lethal ventricular arrhythmia. Nicorandil, an ATP sensitive potassium channel (KATP) opener, is usually used in the treatment of acute myocardial infarction. The effects of nicorandil on ischemic myocyte are fully defined. On the other hand, KATP in neuroterminals is known to regulate norepinephrine release, but the effect of nicorandil on ischemic norepinephrine release in cardiac tissue has remained unexplored.

Purpose
We examined whether nicorandil suppressed norepinephrine release via neuronal KATP and ventricular arrhythmia during acute ischemia in pressure overload-induced hypertrophic hearts.

Methods
SD Rats were divided into two groups; abdominal aortic constriction (AAC) group and sham-operated (Sham) group. Four weeks after constriction, cardiac geometry and function were examined using echocardiography. Then, myocardial ischemia was induced by the left anterior descending artery occlusion for 100 minutes in the presence or absence of intravenous infusion of nicorandil. Cardiac interstitial norepinephrine concentration in ischemic region was measured using the microdialysis method and concentration of cyclic AMP, a second messenger of norepinephrine, in cardiac tissue was measured by ELISA. Ventricular arrhythmias were monitered by ECG during whole ischemic period.

Results
Four weeks after constriction, remarkable left ventricular wall thickening was observed in AAC group. Before ischemia, ventricular arrhythmia was not found in both groups. Number of ventricular arrhythmia, including ventricular tachycardia and ventricular fibrillation, was increased in early ischemic period (- 40 min) in both groups, and was grater in AAC group. Before ischemia, interstitial norepinephrine concentration in cardiac tissue was higher level in AAC group than in Sham group. Ischemia obviously increased norepinephrine concentration in both groups time dependently and AAC further increased norepinephrine than Sham group. Concentration of cyclic AMP in cardiac tissue was raised in early ischemic period (- 40 min) and then gradually decreased. Nicorandil significantly suppressed the number of ventricular arrhythmias, and abolished the ventricular tachycardia and fibrillation without hemodynamic alterations. Nicorandil also attenuated norepinephrine and cAMP enhancement in acute ischemic period in both groups.

Conclusion
Ischemia-induced ventricular arrhythmia was more frequent and severe in hypertrophic hearts and interstitial norepinephrine enhancement may play a role in this ischemic arrhythmia. Nicorandil suppressed ischemia-induced interstitial norepinephrine release by neuronal KATP opening, which attenuated ventricular arrhythmias in normal and hypertrophic hearts.
P1608Inhibition of GATA4 dimerization suppress hypertrophic responses
Authors: Shimizu S , Sunagawa Y , Hara K , Hishiki A , Katanasaka Y , Miyazaki Y , Funamoto M , Nurmila S , Shimizu K , Wada H , Hasegawa K , Hashimoto H , Morimoto T 
Published: October 2019

Abstract

Introduction
Hypertrophic signals eventually reach the nuclei of cardiomyocytes, change patterns of gene expression, and cause the development of heart failure. During the development of heart failure, intrinsic histone acetyltransferase called p300 induce GATA4 acetylation. Acetylated GATA4 increases its DNA binding, up-regulates cardiac hypertrophic response genes, and lead to heart failure. A zinc finger protein, GATA4 is the transcription factor that expression level is high in heart. It has been reported that GATA1, the same GATA family, regulates transcriptional activity through its homo-dimerization. However, GATA4 homo-dimerization and its relationship to hypertrophic responses are still unknown.

Purpose
To clarify the relationship between GATA4 homo-dimerization and transcriptional activity and investigate whether inhibition of this homo-dimerization become therapeutic target for cardiac hypertrophy.

Methods
GST pull-down and DNA pull-down assay were performed using GST fusion full length and deletion mutants of GATA4 and biotin-conjugated ET-1 promoter probe including a GATA element. Recombinant C-zinc finger domain (256–326), including C-zinc finger motif (256–295) and acetylation site (308–326) was cross-linked using glutaraldehyde and subjected to silver staining. An expression plasmid with three GATA4-acetylation site mutant-conjugated with nuclear localization sequence (3xG4D) was constructed. Immunoprecipitation and western blotting were performed using nuclear extract from HEK293T cells expressing p300, GATA4, and 3xG4D. Luciferase assay was using ANF and ET-1 promoter sequences. Neonatal rat cultured cardiomyocyte expressed 3xG4D and then stimulated with phenylephrine (PE) for 48 hours. Next cardiomyocytes stained with α-actinin antibody and measured the cell surface area.

Results
The acetylation site of GATA4 was required for the dimerization of GATA4. But, C-zinc finger motif (256–295) and the acetylation site were required for the DNA binding. Recombinant C-zinc finger domain formed not only a homo-dimer but also a multimer. Co-expression of p300 increased the formation of homo-dimer as well as the acetylation of GATA4 in HEK293T cells. The GATA4 homo-dimer was disrupted by acetyl-deficient GATA4 or HAT-deficient p300 mutant. Overexpression of 3xG4D prevented the dimerization of GATA4, but not acetylation of GATA4. The result of luciferase assay showed that overexpression of 3xG4D prevented p300/GATA-induced ANF and ET-1 promoter activities. Furthermore, overexpression of 3xG4D inhibited phenylephrine-induced cardiomyocyte hypertrophy.

Conclusions
These results suggest that GATA4 dimerization may play an important role in hypertrophy-response gene activation. Thus, it is likely that inhabitation of GATA4 dimerization become therapeutic target for cardiac hypertrophy.