bluuebunny/crossref_metadata_2025 huggingface dataset:
P1517Risk of acute kidney injury in transcatheter aortic valve implantation procedures and impact on 30-day outcome
Authors: Sgura F A , Arrotti S , Magnavacchi P , Tondi S , Gabbieri D , Vitolo M , Pennacchioni A , Autieri A , Boriani G
Published: October 2019

Background

Transcatheter aortic valve implantation (TAVI) is a safe and effective procedure for patients with symptomatic aortic stenosis who do not qualify for surgery. Nevertheless, post-procedure acute kidney injury (AKI) is a frequent complication and it is associated with worse outcomes.

Aim

To assess the impact of acute kidney injury (AKI) occurring immediately after the TAVI procedure on patients' outcome.

Methods

We conducted a multicenter retrospective study on patients treated with TAVI from 2010 to 2018. The assigned treatment, the selection of the device (self-expandable/balloon-expandable valve) and the type of approach used were determined by each individual Center on the basis of the patient's characteristics and the choice of the operator. All patients had an intermediate or high Society of Thoracic Surgeons (STS) score. Basal creatinine and glomerular filtrate (using the body mass index, sex and age) were evaluated for each patient. According to the KDIGO criteria, AKI is defined as an increase in serum creatinine (SCr) ≥0,3mg/dl within 48 hours or an increase in SCr ≥1.5 times baseline or urine volume <0,5ml/kg/h for 6 hours. The incidence of post procedural AKI and its correlation with the short-term mortality and outcomes was evaluated as primary end point (stroke/TIA/RIND, cardiac tamponade, bleeding, vascular complications, cardiocirculatory arrest with subsequent ROSC, definitive pacemaker implantation, postoperative atrial fibrillation, left bundle branch block de novo).Postoperative outcomes were defined according to the updated Valve Academic Research Consortium 2 definitions

Results

A total of 371 pts were analysed. Mean age was 82.3±5.9 and the majority of the pts had an STS score>10 (97.6%). Incidence of Acute kidney Injury (AKI) stage 3 post TAVI, according to VARC-2 criteria, was 16,2%. In patient with AKI, the hospitalization time was longer 18,7±6,1 days vs 8,4±6,1 days without AKI (p<0,01). Patients with AKI had an increased risk of in hospital mortality (OR 50,0; 95% CI 5,2–390,16; p<0,01) and 30 day mortality (OR: 5,88; 95% CI 2,08–16,60; p<0,01). Acute Kidney Injury instead was more common in patients treated with transapical access (OD 3,9-CI 95% 2,16–7,07; p<0,01) or with PAD (OR 1,87 - CI 95% 1,03–3,41; p=0,03)

AKI and short term mortality

Conclusion

Acute kidney injury is a frequent complication after TAVI. AKI seems to be the strongest predictor for 30 day mortality and increases the hospitalization time. AKI was more common in patients treated with a transapical approach or if they presented a PAD. In contrast, pre-procedural chronic kidney disease did not seem to correlate directly with an increased risk of AKI.
P1524Women are from venus and face barriers for AMI treatment
Authors: Mehta S , Botelho R , Niklitschek S , Fernandez F , Cade J , Prudente M , Cavalcanti R , Dusilek C , Hamdan N , Hurtado E , Lacativa M , Frauenfelder A , Vieira D , Torres M A , Pinto G
Published: October 2019

Background

The Latin American Telemedicine Infarct Network (LATIN), a program for managing population-based AMI care, has utilized an innovative hub-spoke strategy and remote guidance to expand medical access in remote parts of Brazil, Colombia, Mexico, and Argentina. Based on the Global Lumen Organization for Women (GLOW) project, that has previously demonstrated gender inequalities and worse outcomes for women who undergo Primary PCI, our research explored the management of female patients in our network.

Purpose

To demonstrate gender disparities in a telemedicine-guided, population based AMI program.

Methods

Meta-analysis of >750,000 patients within LATIN. Telemedicine was employed as a screening tool to accurately diagnose AMI. According to the duration of chest pain and transfer time, AMI patients were triaged into guidelines-based pathways of thrombolysis, pharmaco-invasive management or Primary PCI. Resource allocation was identical for men and women.

Results

Data from 784,395 screened patients reveals broad gender disparities. The critical results yielded that female patients have a lower prevalence of STEMI diagnosis and treatment regardless of the technique – PCI, pharmaco-invasive or CABG (p<0.01). These findings assume more significance given the fact that more women than men, were screened through the Telemedicine pathway.

Conclusions

LATIN gender data signals the urgency to demand better AMI care for women.
P1525Impact of renal function on silent myocardial ischemia and long-term outcomes in asymptomatic patients with diabetes mellitus
Authors: Wakabayashi K , Toshiaki T S , Shibata K S , Furuya T F , Sato C S , Nishikura T N , Fukuoka H F , Ikeda N I , Honda Y H , Kikuchi M K , Miyoshi F M , Tanno K T
Published: October 2019

Introduction

Coronary artery disease (CAD) is a major cause of the morbidity and mortality in diabetic patients, however aggressive screening for CAD in asymptomatic patients is not recommended in guidelines. Chronic kidney disease (CKD) is one of serious co-morbidity and such patients especially tends to be observed without angiography to avoid contrast induced nephropathy. It is well known that systemic atherosclerosis worsens renal function. Thus, chronic kidney disease (CKD) may be associated with potential myocardial ischemia and worse clinical outcomes in asymptomatic DM patients.

Purpose

To determine the impact of CKD on the incidence of silent myocardial ischemia (SMI) and the long-term outcomes in asymptomatic patients with DM.

Methods

A total of 461 consecutive patients with DM were prospectively studied from July 2011 to August 2017. All patients were asymptomatic and self-sufficient in daily life. They underwent the ergometer exercise test. Coronary angiography was performed when the stress test was positive, or the patients did not achieve 90% of target heart rate. Primary end point was major adverse cardiac and cerebrovascular events (MACCE) including death, non-fatal myocardial infarction and stroke.

Results

SMI was diagnosed in 81 patients. The incidence of SMI increased with higher stage of CKD as shown in Figure. The median follow-up duration from diagnosis was 35 (15–57) months in the overall cohort of 461 diabetic patients. SMI patients had worse clinical outcomes (Figure). Among 81 patients with SMI, severe CKD group (≥ stage 3a) had worse long-term outcomes. After adjustment of age, gender and coronary risk factors, eGFR was independently associated with MACCE in diabetic patients with SMI [HR0.96, 95% CI (0.923–0.996), p=0.028].

Incidence of SMI and Kaplan-Meier curves

Conclusions

The incidence of potential CAD was high in CKD and the long-term outcomes of those patients were poor in asymptomatic DM. CKD patients should be aggressively screened for CAD and more intensively treated in our daily practice of DM.
P1534Short time and short term of high-intensity intermittent exercise training reduces arterial stiffness via upregulation of endothelial nitric oxide signalling
Authors: Hasegawa N , Fujie S , Horii N , Uchida M , Iemitsu M
Published: October 2019

Introduction

Conventionally, as an exercise mode which leads to reduction of arterial stiffness, it is well used that moderate-intensity continuous exercise training (MICT). High-intensity interval training (HIIT), such as HIIT program with a total exercise time of 15–30 min is highly time-effective as an exercise mode for which reduces risks of cardiovascular disease. Recent study showed that even shorter HIIT leads to an effective reduction in arterial stiffness. Therefore, HIIT is an effectively exercise therapy which can use in patients with cardiovascular diseases. Although MICT induces vasodilation by acceleration of nitric oxide (NO) production via upregulating arterial endothelial NO synthase (eNOS)/protein kinase B (Akt) signalling pathway, an underlying mechanism of HIIT effects remains unclear.

Purpose

This study aimed to clarify the effects of short HIIT on arterial stiffness and arterial NO production in rats.

Methods

Forty 10-week-old male Sprague-Dawley rats were randomly divided into four groups; CON: 8-week sedentary control, MICT: treadmill running for 60 min at 30m/min, 5 days/wk for 8weeks, HIIT: fourteen 20 sec swimming sessions with a weight equivalent to 14–16% of each body weight and 10 sec pause was allowed between exercise sessions, 4 days/wk for 6 weeks from 12-week-old, and RT: ladder climbing, 8–10sets/day, 3 days/wk for 8 weeks groups (n=10 each group). After training session, we measured aortic pulse wave velocity (aortic PWV) as an index of arterial stiffness and plasma nitrite/nitrate (NOx) concentrations and phosphorylation of eNOS and Akt in the aorta.

Results

Aortic PWV was significantly reduced in both MICT and HIIT groups as compared to CON and RT groups (P<0.05), whereas there was no difference between RT and CON groups. Additionally, arterial phosphorylations of eNOS and Akt and plasma NOx levels were significantly elevated in both MICT and HIIT groups as compared to CON and RT groups (P<0.05), whereas there was no difference between RT and CON groups. Moreover, HIIT-induced reduction of aortic PWV and increase in eNOS and Akt phosphorylations and plasma NOx levels were equal to these MICT effects. Arterial eNOS phosphorylation was negatively correlated with aortic PWV in all groups (r=−0.38, P<0.05). Further study was conducted whether a single-bout high-intensity intermittent exercise accelerates NO production. After acute high-intensity intermittent exercise, plasma NOx levels were significantly elevated (P<0.05).

Conclusion

These results suggest that HIIT increases NO production via the upregulation of arterial Akt/eNOS signalling pathway, resulting in the reduction of arterial stiffness, despite a reduction in total exercise volume as compared with MICT.

Acknowledgement/Funding

JSPS KAKENHI (#17H02182 and #16K13059 for M. Iemitsu; #18H06423 for N. Hasegawa)
P1535Clinical impact of carotid plaque score rather than carotid intima-media thickness on atherosclerotic cardiovascular disease
Authors: Tada H , Nakagawa T , Okada H , Nakahashi T , Mori M , Sakata K , Kawashiri M , Takamura M
Published: October 2019

Background

Carotid intima-media thickness (cIMT) assessed by ultrasound has been widely accepted as a surrogate marker of atherosclerotic cardiovascular disease. On the other hand, carotid plaque score (cPS) reflecting throughout the carotid artery plaque burden may be better marker.

Methods

We retrospectively examined 2,035 patients who underwent carotid ultrasonography between January 2006 and December 2015 at our University Hospital. Median follow-up period was 4 years. We used Cox models that adjusted for established risk factors of ASCVD, including age, gender, hypertension, diabetes, smoking, and serum lipids to assess the association of cIMT as well as cPS with major adverse cardiac events (MACE). MACE was defined as all-cause mortality or rehospitalization for a cardiovascular-related illness

Results

During follow-up, 243 participants experienced MACE. After adjustment for established risk factors, cPS was associated with MACE (hazard ratio [HR] = 3.38 for top quintile vs. bottom quintile of cPS; 95% confidence interval [CI] 1.82 to 6.27; P-trend = 1.4×10–8), while cIMT was not (HR = 0.88, P=0.57). Addition of the cPS to established risk factors significantly improved risk discrimination (C-index 0.726 vs. 0.746; P=0.017)

Conclusion

As a marker, cPS, rather than cIMT can identify 20% of individuals who are at more than three-fold increased risk for MACE. Targeting diagnostic or therapeutic interventions to this subset may prove clinically useful.
P1538Low energy intake predicts readmission of elderly heart failure patients independently of nutritional status
Authors: Shimomura K , Katano S , Yano T , Ohori K , Honma S , Watanabe A , Ishigo T , Fujito T , Nagano N , Koyama M , Kouzu H , Hashimoto A , Miura T
Published: October 2019

Background

Malnutrition is frequently present and closely associated with poor clinical outcomes in elderly heart failure (HF) patients. Our previous study showed that low energy intake (EI) is associated with worse functional status in elderly HF inpatients after cardiac rehabilitation, but significance of EI in prediction of hospital readmission has not been elucidated fully.

Purpose

We examined whether low EI is a predictor of readmission for cardiac events in elderly HF patients.

Methods

We retrospectively retrieved data for 298 HF patients aged ≥65 years (median age of 77 years, interquartile range [IQR]: 71 - 82, female: 53%) who admitted to our institute for diagnosis and treatment of HF. Medical records were reviewed with regard to demography, medical history, comorbidities, medications, laboratory data, echocardiograms, functional status, nutritional status and total energy intake. Nutritional status was assessed using the Mini Nutritional Assessment Short Form (MNA-SF) and total EI per day were calculated at discharge by a registered dietitian and a trained physical therapist. The primary endpoint was readmission due to cardiovascular events including worsening HF, arrhythmia, angina pectoris and myocardial infarction during a 1-year follow-up period.

Results

The median period of follow-up was 235 days (IQR: 78–365 days). The 1-year readmission rate for cardiovascular events was 54.4%. The cutoff values of MNA-SF score and EI, calculated by ROC curve analysis to predict the primary endpoint, were 7 points (area under the curve [AUC]: 0.59, sensitivity: 0.65, specificity: 0.50) and 31.8 kcal/kg/day (AUC: 0.59, sensitivity: 0.83, specificity: 0.35), respectively. Patients with low MNF-SF score (≤7) or low EI (≤31.8 kcal/kg/day) had significantly higher readmission rate during a 1-year follow-up period than did the patients with high MNF-SF score or EI (MNA-SF: 60.7% vs. 45.6%, p<0.01, EI: 60.4% vs. 36.8%, p<0.01), respectively. When patients were classified into four groups using cutoff values of MNA-SF score and EI, 1-year readmission rate was significantly higher in patients with low EI than in those with high EI regardless of MNF-SF scores. In multivariate Cox proportional hazard analyses adjusted for known prognostic factors in addition to age and gender, hazard ratios (HR) were significantly higher in patients with high MNA-SF score and low EI (adjusted HR: 2.81, 95% confidential interval [CI]: 1.15 - 9.32, p=0.02) and low MNA-SF score (≤7) and low EI (adjusted HR: 4.16, 95% CI: 1.72 - 13.72, p<0.01) than those with high MNA-SF score and high EI.

Kaplan-Meier curves of readmission rates

Conclusions

Low energy intake is a nutritional status-independent predictor of 1-year readmission rate in elderly HF patients.
P1556Cardiovascular risk in white-coat hypertension individuals stratified by their nocturnal blood pressure dipping status
Authors: Liakos C , Karpanou E , Grassos C , Markou M , Vyssoulis G , Tousoulis D
Published: October 2019

Background/Introduction

Nocturnal blood pressure (BP) dipping status, defined by the night-to-day BP ratio, has been correlated with the cardiovascular (CV) risk in patients with arterial hypertension. The risk is higher in those with less than normal or no drop in nocturnal BP while data in extreme dippers are inconsistent. On the other hand, white-coat hypertension (WCHT), defined as an elevated office BP despite a normal out-of-office BP, is characterized by a lower CV risk than that of sustained hypertension and rather comparable with that of true normotension.

Purpose

The present study assessed the possible relation between the nocturnal BP dipping status and the underlying CV risk in WCHT individuals.

Methods

Among all individuals examined in our outpatient anti-hypertensive units over the past 15 years, 2310 (42% men, 52.2±13.1 years of age) were diagnosed with WCHT (increased office BP: 156.4±10.0/99.6±6.2 mmHg and normal 24-hour ambulatory BP: 122.4±6.3/75.3±5.4 mmHg) and were enrolled in the study. A night-to-day BP ratio (from the 24-hour ambulatory BP monitoring) 0.8–0.9 defined Normal nocturnal BP Dipping, <0.8 Extreme Dipping, 0.9–1 Mild Dipping and >1 Absence of Dipping. The underlying 10-year CV risk of death in the studied population was calculated with the Hellenic version of the HeartScore (Hellenic Score), as proposed by the current 2018 European Society of Hypertension guidelines, based on age, gender, smoking status, systolic BP and total cholesterol levels.

Results

From 2310 individuals studied, 1208 (52.3%) were found with Normal Dipping, 386 (16.7%) with Extreme Dipping, 622 (26.9%) with Mild Dipping and 94 (4.1%) with Absence of Dipping. Hellenic Score was 3.21±4.67% in subjects with Normal Dipping, 3.49±4.97% in those with Extreme Dipping, 3.66±5.04% in those with Mild Dipping, 6.21±7.29%, in those with Absence of Dipping (p for trend<0.05) and 3.50±4.99% in the whole cohort of the studied population.

Conclusions

Nocturnal BP dipping status is closely associated with the underlying CV risk of WCHT individuals. Extreme Dipping, Mild Dipping and especially Absence of Dipping increase CV risk thus necessitating closer follow-up of these individuals and possibly faster initiation of BP-lowering drug treatment.
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

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

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

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

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

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

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

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

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.
P1625A pivotal role for cytotoxic CD8+ T cells in development of cardiac fibrosis
Authors: Kyaw T , Kanellakis P , Toh B H , Bobik A
Published: October 2019

Background/Introduction

Pressure overload-induced cardiac fibrosis increases myocardial stiffness leading to reductions in cardiac performances and cardiac failure. CD8+ T cells have been shown to accumulate during development of fibrosis but their role has not been defined.

Purpose

We examined the role and significance of CD8+ T cells in development of cardiac fibrosis.

Methods

Trans-aortic constriction (TAC) or 2-kidney-1-clip (2K1C) procedures were used to generate pressure overload-induced cardiac fibrosis in mice. Rat anti-mouse CD8β (lyt-3) monoclonal antibody (clone YTS 156.7) was used to deplete CD8+ T cells. A mixed bone marrow chimera strategy was used to specifically delete innate receptor Natural Killer Group 2D (NKG2D) or cytotoxin perforin from CD8+ T cells.

Results

Depleting CD8+ T cells in mice subjected to TAC or 2K1C-renal hypertension attenuated left ventricular fibrosis by 93% and 84% without affecting blood pressure. In TAC mice this was associated with a 68% reduction in apoptotic cardiomyocytes, a 74% reduction in macrophage accumulation, a 65% reduction in TGF-beta positive cells and a 95% reduction in TGF-beta positive macrophages, whilst CD4+ T cells were unaffected. Cardiomyocytes in regions of developing cardiac fibrosis contained cytoplasmic DNA and expressed the NKG2D ligand, Rae-1, indicative of activation of a DNA damage response; CD8+ T cells expressed the NKG2D receptor. Deletion of the NKG2D receptor from CD8+ T cells attenuated cardiac fibrosis by 82%; deletion of cytotoxin perforin has similar effects.

Conclusion(s)

We conclude that CD8+ T cells contribute to development of cardiac fibrosis by targeting stressed/damaged cardiomyocytes via an NKG2D-Rae-1 cytotoxic mechanism inducing their apoptosis. Macrophages then accumulate in the heart in response to increased numbers of apoptotic cardiomyocytes, clearing the apoptotic cells through engulfment and increasing their expression of the pro-fibrotic factor TGF-beta1.

Acknowledgement/Funding

The National Health and Medical Research Council of Australia
P1627Increased pericardial fibrosis and cardiac dysfunction in smooth muscle cell-specific SOCS3 deficient mice
Authors: Yanai T , Yasukawa H , Mawatari K , Sasaki T , Takahashi J , Nohara S , Shimozono K , Shibata T , Okabe K , Yamamoto M , Fukumoto Y
Published: October 2019

Background

Suppressor of cytokine signaling-3 (SOCS3) is an intrinsic negative-feedback regulator of signal transducer and activator of transcription-3 (STAT3) signaling pathway. We have previously shown that myocardial SOCS3 plays an important role in cardiac hypertrophy and survival; however, the role of SOCS3 in smooth muscle cells in cardiovascular pathophysiology remains elusive. In this study, we determined whether STAT3 and SOCS3 in smooth muscle cells would play a role in cardiovascular pathophysiology.

Methods and results

To target inactivation of the SOCS3 gene to smooth muscle cells, SOCS3-flox mice were bred with transgenic mice expressing Cre recombinase under control of the mouse SM22-α promoter (sm-SOCS3-KO mice). Left ventricular weight to body weight ratio was significantly increased in sm-SOCS3-KO mice compared with wild-type mice at 52 weeks of age (p<0.05). Echocardiographic analyses of sm-SOCS3-KOmice showed significantly decreased cardiac function compared with wild-typefrom 52 weeks of age (p<0.05). Interestingly, Sirius-red staining revealed that thickness of pericardium in sm-SOCS3-KOmice was markedly greater compared with wild-typemice at 52 weeks of age (p<0.05). Cardiac interstitial fibrosis in sm-SOCS3-KOmice was also greater compared with wild-typemice (p<0.05). Western blot analyses showed that phosphorylated STAT3 was significantly increased in sm-SOCS3-KOhearts compared with wild-typemice at 52 weeks of age (p<0.05), whereas no significant differences were observed at 7 weeks of age. Immunostaining revealed that phosphorylated STAT3 positive cells were in thickened pericardial area in sm-SOCS3-KOhearts. Some infiltrated inflammatory cells were also found in thickened pericardial area in sm-SOCS3-KOmice hearts.

Conclusion

These results suggest that STAT3 and its negative-feedback regulator SOCS3 in smooth muscle cells play an important role in the pathogenesis of pericardial fibrosis and cardiac dysfunction.
P1632A possible independent contribution of liver stiffness to the development of heart failure in its early stage
Authors: Iwasaki Y , Tomiyama H , Shiina K , Matsumoto C , Kimura K , Fujii M , Takata Y , Yamashina A , Chikamori T
Published: October 2019

Background

Heart failure (HF) is a heterogeneous condition. The reduced liver blood flow and hepatic congestion associated with HF causes liver damages leading to liver sclerosis. Fibrosis 4 score (FIB-4 score), a marker of liver sclerosis, is easily calculated from age, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) level and blood platelet count (PLT). Liver stiffness is known to be associated with vascular damages, including arterial stiffness and central hemodynamics. These vascular damages also cause the new onset of HF. However, it remains to be clarified whether liver stiffness is a direct risk factor for HF or whether its association with HF is mediated by vascular damage. We conducted cross-sectional and prospective longitudinal studies to examine whether FIB-4 score is directly associated with the serum NT-pro-BNP levels or the association is mediated by arterial stiffness and/or abnormal central hemodynamics.

Methods and results

In 3,040 health Japanese subjects with serum NT-pro-BNP levels <125 pg/ml, the FIB-4 score was calculated, and the serum NT-pro-BNP levels, brachial-ankle pulse wave (baPWV) velocity, radial augmentation index (rAI), second peak of the radial pressure waveform (SBP2) and PP2 (SBP2 – diastolic blood pressure) were measured. These parameters were measured again after a 3-year interval in 2,135 subjects. Pearson's correlation analysis demonstrated that FIB-4 score was significantly correlated with baPWV, rAI, SBP2, PP2 and the log-transformed the serum NT-pro-BNP levels. Multivariate linear regression analysis demonstrated a significant cross-sectional association of the FIB-4 scores with the log-transformed the serum NT-pro-BNP levels (beta = 0.08, p<0.01), but not with the baPWV, rAI, SBP2 and PP2. The change of serum NT-pro BNP levels during the study period was significantly higher in subjects with increase of the FIB-4 score during the study period (8.2±22.5 pg/ml) than that in those with decrease/no change (5.4±22.3 pg/ml) (p<0.05). The change of FIB-4 score during the study period was significantly associated with the change of the serum NT-pro-BNP levels during the study period (beta = 0.09, p<0.01).

Conclusion

Liver stiffness may have a significant direct association with the development of HF from the early stage, without the mediation of arterial stiffness and/or abnormal central hemodynamics. Therefore, the FIB-4 score appears to serve as a direct risk factor for HF from the early stage, and its association with HF may not be mediated by vascular damages.