bluuebunny/crossref_metadata_2025 huggingface dataset:
P4404Prognostic value of novel nocturnal oxygen saturation metrics in patients with obstructive sleep apnoea and high cardiovascular event risk
Authors: Linz D , Loffler K , Sanders P , Catcheside P , Anderson C , Redline S , McEvoy D , Baumert M
Published: October 2019

Aim

To determine prognostic value of novel oximetry-derived metrics in patients with obstructive sleep apnoea (OSA) and high cardiovascular (CV) event risk.

Methods and results

Ancillary study of the Sleep Apnoea CV Endpoints (SAVE) randomised controlled trial, which investigated the effects of CPAP treatment on secondary CV event outcomes in 2687 participants with moderate-severe OSA and established CV disease. Associations between baseline characteristics, standard sleep and pulse oximetry-derived metrics, and CV outcomes were determined in Cox proportional hazards regression models stratified for treatment allocation. Metrics evaluated included: oxygen desaturation index, time below 90% oxygen saturation (SpO2), average SpO2across recordings (mean SpO2), across episodic desaturation events (desaturation SpO2), and baseline interpolated through episodic desaturation events (baseline SpO2); duration and desaturation/resaturation time ratio of episodic desaturation events; and mean and standard deviation of pulse rate. No SpO2 metric was associated with the composite outcome. Mean and baseline SpO2 were negatively associated with heart failure (hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.69–0.95; P=0.009 and 0.78, 0.67–0.90; P=0.001, respectively) and myocardial infarction risk (0.86, 0.77–0.95; P=0.003 and 0.81, 0.73–0.90; P<0.001, respectively) and marginally positively associated with stroke risk (1.09, 1.00–1.20; P=0.065 and 1.13, 1.02–1.26; P=0.020, respectively). Desaturation duration and desaturation/resaturation time ratio, with established risk factors, predicted heart failure (area under the receiver-operating-characteristic curve 0.86, 95% CI 0.79–0.93).

Conclusions

Higher mean and baseline SpO2 were associated with reduced risk of heart failure and myocardial infarction, and small increases in stroke rate. Desaturation shape may have predictive utility for future CV events.

Clinical trial registration: clinicaltrials (NCT00738179).
P4414Effects of lorcaserin on the cardiometabolic risk factors in overweight or obese patients: a systematic review and meta-analysis
Authors: Kuo H H , Liu M E , Lin P L , Liu L.Y.-M
Published: October 2019

Introduction

Lorcaserin is a selective serotonin 2c receptor agonist approved as an anti-obesity agent. The additional cardiometabolic benefits associated with lorcaserin have not been conclusively established.

Purpose

To examine the effects of lorcaserin on blood pressure, heart rate and other metabolic parameters in overweight or obese patients from randomized controlled clinical trials (RCTs).

Methods

A literature search was conducted on PubMed, EMBASE, and Cochrane Central using search terms: “lorcaserin”, “Belviq”, and “randomized controlled trials” without language restrictions. RCTs with a follow-up period of at least 24 weeks were included for the meta-analysis.

Results

Five studies with 9349 patients in the lorcaserin group and 9370 patients in the placebo group were included. Compared with placebo, lorcaserin not only reduced weight (mean difference [MD] = −3.03 kg, 95% CI: −3.42, −2.63, P<0.ehz745.08171, I2 =68%), waist circumference (MD=−2.27 cm, 95% CI: −2.71, −1.83, P<0.ehz745.08171, I2=57%) and BMI (MD=−1.11 kg/m2, 95% CI: −1.27, −0.96, P<0.ehz745.08171, I2=68%), but also improved SBP (MD=−0.75 mmHg, 95% CI: −1.12, −0.38, P<0.0001, I2=0%), DBP (MD=−0.70 mmHg, 95% CI: −0.93, −0.48, P<0.ehz745.08171, I2=0%), heart rate (MD=−0.94 bpm, 95% CI: −1.28, −0.60, P<0.ehz745.08171, I2=0%), LDL (MD=−1.47 mg/dL, 95% CI: −2.21, −0.74, P<0.0001, I2=0%), HDL (MD=0.55 mg/dL, 95% CI: 0.08, 1.01, P=0.02, I2=18%), triglycerides (MD=−8.71 mg/dL, 95% CI: −12.14, −5.28, P<0.ehz745.08171, I2=71%), and fasting plasma glucose (MD=−5.69 mg/L, 95% CI: −9.5, −1.87, P=0.003, I2=93%). Our findings support that lorcaserin has consistent and favourable effects on blood pressure, heart rate, and all criteria of metabolic syndrome.

Summary of lorcaserin effects

Conclusion

Lorcaserin improved all cardiometabolic parameters modestly in addition to its weight loss effect in overweight or obese patients. More research is needed to determine its long-term cardiovascular benefits.
P4420Is exercise-induced cardiac troponin release caused by skeletal muscle injury?
Authors: Paana T , Jaakkola S , Tuunainen E , Wittfooth S , Bamberg K , Petterson K , Kallio P , Heinonen O , Airaksinen K E J
Published: October 2019

Background

Cardiac troponins (cTn) are highly sensitive and specific markers for cardiac injury and a key element in the diagnosis of acute coronary syndrome. Strenuous exercise is known to induce increases in cTn, but the causative factors remain ambiguous. It is also equivocal whether exercise induced skeletal muscle injury is associated with cTn elevation.

Purpose

The aim of this study was to identify independent predictors for the rise in cardiac troponin T (cTnT) and I (cTnI) concentration and to focus on the relationship between skeletal muscle injury measured by skeletal troponin I (skTnI) and cTn elevations after a marathon race in a large group of male recreational runners.

Methods

A total of 40 recreational runners participating in the marathon in our city were recruited. The study included baseline visit (prerace) and immediate post-race sampling.

Results

The post-marathon cTnT concentration rose above the reference limit in 38 (95%) participants and the detection limit for cTnI was exceeded in 34 (85%) participants. Similarly, a 10-fold increase in skTnI concentration was observed and elevated post-race values were seen in all participants. There was no significant correlation between the post-race cTnT or cTnT change and post-race skTnI (Spearman's rho = 0.249, p=0.122, rho = 0.285, p=0.074). However, post-race cTnI and change in cTnI were associated with post-race skTnI (rho = 0.404, p=0.01, rho = 0.460, p=0.003) and creatine kinase (r=0.368, p=0.019) concentration. Subjective exertion or self-reported muscle symptoms did not correlate with post-race cTnT, cTnI or skTnI levels.

Post-Race cTnT <40 Post-Race cTnT ≥40 p-value n=18 n=22 Age, years 53.3±12.2 44.0±11.9 0.002 Active training, years 12.0 (9.3) 17.0 (15.8) 0.190 Muscle symptoms 7 (38.9) 11 (52.4) 0.523 Creatinine kinase, ug/l 406 (137) 399 (319) 0.163 N-terminal proBNP ng/l 137±168 158±277 0.783 Skeletal Troponin I, ng/ml 28.6 (41) 56.7 (143) 0.199

Figure 1

Conclusions

Cardiac troponin became abnormal in almost all runners after marathon race. The exercise-induced rise in cardiac troponin I is related to simultaneous release of skeletal troponin I. The mechanism of this association remains uncertain, but clinicians should be cautious when interpreting post-exercise troponin levels without clinical symptoms and signs of myocardial ischemia.
P4430Physical activity in leisure time: complying with the recommendations of clinical practice guidelines increases maximum oxygen consumption
Authors: Tojal Sierra L , Garcia Mancebo S , Torres Fernandez M , Juanes Dominguez I , Saez De Buruaga E , Salaverria I , Alonso Gomez A , Aros F
Published: October 2019

Introduction/Objectives

The promotion of physical activity is a universal recommendation for prevention of cardiovascular diseases. Clinical practice guidelines recommend at least 150 min/week of moderate or severe physical activity or ≥75 min of severe intensity.Our objective was to analyze whether reaching the physical activity levels recommended in the clinical practice guidelines evaluated by validated questionnaires and accelerometry, is associated with higher level of VO2 max.

Methods

We conducted a prospective cross-sectional study of 243 participants in the PREDIMED PLUS study (site: Vitoria-Gasteiz), (82 women), 65±4,9 years old, with metabolic syndrome and overweight/obesity. They performed a maximum exercise testing with expired gas analyses. Physical activity in leisure time was evaluated using subjective methods: self-reported questionnaires REGICOR and RAPA 1 and objective methods: chair test and accelerometry (91 subjects). Sedentarism was analyzed with the Nurses Health Study questionnaire and accelerometry

Results

Subjects who claimed to comply with the recommendations of the PA guidelines in the REGICOR questionnaire achieved higher maximum oxygen consumption (21.3±4.6 vs 18±4.4 ml/kg/min; P<0.001) and those who reported more physical activity in the RAPA 1 test showed a maximum oxygen consumption 18% higher than the less active group (P < . 001). However, those who performed ≥150 min/week of moderate/intense physical activity by accelerometry did not differ significantly from those who did not (21.1±4.7 vs 19.9±4.7 ml/kg/min; P: 0.644).

Conclusions

Subjects with metabolic syndrome and overweight/obesity who claim to meet PA recommendations in the REGICOR and RAPA tests achieve higher máximum oxygen consumption
P4432Coronary microvascular dysfunction in inflammatory bowel disease: Restored after enterectomy
Authors: Kakuta K , Dohi K , Yamamoto T , Fujimoto N , Shimoyama T , Umegae S , Ito M
Published: October 2019

Background

Inflammatory bowel disease (IBD) is a complex multisystem disease characterized by chronic inflammation, which can lead to coronary microvascular dysfunction (CMD).

Purpose

We aimed to investigate the presence and the severity of CMD in Crohn's disease (CD) and ulcerative colitis (UC) by assessing coronary flow reserve (CFR) using transthoracic Doppler echocardiography, and to elucidate the influence of enterectomy on CMD.

Methods

Thirty-seven IBD patients (22 CD patients: 39±12 years, 15 UC patients: 52±17 years), and 30 age- and gender-matched control subjects (46±12 years) who have comparable risk factors for coronary artery disease were enrolled. Smokers were excepted from the present study. For CFR measurement, coronary flow velocity was recorded at rest and during hyperemia in the left anterior descending coronary artery induced by intravenous infusion of adenosine triphosphate (0.14 mg/kg/min), and a CFR ≤2.5 calculated as the ratio of hyperemic to basal peak and mean diastolic velocity defined CMD. CFR measurement was repeated before and within 1 year after enterectomy. Serum or plasma cytokines were also measured before and after enterectomy.

Results

The median disease duration of CD and UC patients were 12 and 6 years. Although none of control subjects had CMD, 38% in IBD patients (CD: 41%, UC: 33%) had CMD. CFR was similarly and significantly lower in CD and UC patients than Control subjects (CD: 2.92±1.03*, UC: 2.99±0.65*, and Control: 3.84±0.75, *p<0.05 vs. Control). Serum levels of TNF-α, IL-6 and hs-CRP were significantly higher in CD and UC patients than Control subjects. Multiple linear regression analysis showed that the presence of IBD and mean diastolic flow velocity at baseline were independently associated with reduced CFR among all study participants (β=−0.324 and −0.614, p=0.001, respectively). CFR in IBD patients with both CMD and non-CMD significantly improved after enterectomy, and the extent of CFR improvement was greater in patients with CMD than those with non-CMD (Figure). Serum levels of IL-6 and hs-CRP significantly reduced among all IBD patients.

Conclusion

IBD was associated with CMD, which improved after enterectomy.
P4439Increased risk of out-of-hospital cardiac arrest in patients with psoriasis - a nationwide case-control study
Authors: Mohr G H , Barcella C A , Kragholm K , Rajan S , Sondergaard K B , Pallisgaard J L , Wissenberg M , Lindhardsen J , Ahlehoff O , Skov L , Lippert F K , Torp-Pedersen C , Gislason G
Published: October 2019

Background

Chronic inflammatory disorders such as psoriasis have been associated with cardiovascular diseases and linked to proarrhythmogenic electrocardiographic changes, including QT-prolongation. However, evidence regarding the risk of out-of-hospital cardiac arrest with a history of psoriasis is lacking.

Purpose

To investigate the association between psoriasis and out-of-hospital cardiac arrest.

Methods

Through the nationwide Danish Cardiac Arrest Registry, we identified adult out-of-hospital cardiac arrest patients of presumed cardiac cause with and without psoriasis between June 2001 and December 2014. The odds of cardiac arrest were estimated using conditional logistic regression in a case-control design where we matched up to nine controls per case on age, sex and ischemic heart disease. The models were adjusted for comorbidities, concomitant pharmacotherapy and socioeconomic position.

Results

A total of 32,447 out-of-hospital cardiac arrest cases were included and matched with 291,999 controls from the general population. The median age was 72 years, 67% were male and 29% had ischemic heart disease. A total of 607 (1.9%) cases and 4662 (1.6%) controls had psoriasis. Compared with cardiac arrest cases without psoriasis, cases with psoriasis had same age (p=0.718) and gender distribution (p=0.794), higher prevalence of comorbidities such as congestive heart failure (25.7% vs 20.2%, p=0.001), chronic kidney disease (8.9% vs 6.2%, p=0.008) and chronic obstructive pulmonary disease (19.0% vs 14.7%, p=0.005) but had same prevalence of cerebral vascular disease (15.8% vs 14.5%, p=0.351) and peripheral vascular disease (13.3% vs 11.1%, p=0.078). In unadjusted and adjusted analyses, psoriasis was significantly associated with increased odds of cardiac arrest (odds ratio (OR) 1.18 [95% confidence interval (CI) 1.08–1.28] and OR 1.13 [95% CI 1.04–1.23], respectively) (Figure 1).

Conclusion

In this nationwide case-control study, psoriasis was significantly associated with increased odds of out-of-hospital cardiac arrest. Focus on risk factors and prevention of cardiovascular disease in patients with psoriasis is warranted.

Acknowledgement/Funding

None
P4455The controversial role of genetics behind premature CAD: a plausible excuse for the young?
Authors: Sousa J , Mendonca M , Pereira A , Mendonca F , Neto M , Monteiro J , Sousa A C , Freitas S , Henriques E , Freitas A I , Borges S , Ornelas I , Drumond A , Palma Dos Reis R
Published: October 2019

Introduction

The complex interaction between genes and environmental factors contribute to individual-level risk of coronary artery disease (CAD), often resulting in premature CAD. The role for genetic risk scores in premature CAD is still controversial.

Objective

To evaluate the importance of conventional risk factors and of a genetic risk score in younger and older patients with coronary artery disease

Methods

From a group of 1619 pts with angiographic documented CAD from the GENEMACOR study, we selected 1276 pts admitted for ACS and analysed them in 2 groups (group A: ≤50 years, n=491 pts, 87.2% male, mean age 44±4.9 and group B: >50 years, n=785 pts, 75.2% male, mean age 57±4.2). Univariate analysis was used to characterize the traits of each group and we used ROC curves and respective AUCs to evaluate the power of genetics in the prediction of CAD, through a Genetic Risk Score (GRS).

Results

99.3% of the young patients had at least one modifiable risk factor, 18.4% had 2 modifiable risk factors and 75.2% had 3 or more modifiable risk factors. The pattern of risk factors contributing to CAD were different among groups: family history (A: 27.5%, B: 21.4%, p=0.015) and smoking habits (A: 64.8%, B: 42.9%, p<0.001) were more frequent among patients under 50, and traditional age-linked factors like hypertension (A: 58%, B: 75.7%, p<0.001), diabetes (A: 21.6%, B: 38.6%, p<0.001) were more common in the older group. Acute ST-elevation myocardial infarction was more frequent among the young (A: 55.4%, B: 47.4%, p=0.006), as non-ST clinical presentation was higher among elder patients. Regarding angiographic presentation, single vessel CAD was higher in group A (A: 50.3%, B: 40.9%, p<0.001), while multivessel diasease was higher in group B (A: 33.3%, B: 53.9%, p<0.001). At a mean follow-up of 5 years, older patients had a worst prognosis, registering a higher rate of cardiovascular death (A: 4.1%, B: 8.6%, p=0.002) and higher MACE (A: 26.8%, B: 31%, p=0.128),. Adding the genetic risk score (GRS), we achieved only a slight improvement in the AUC for predicting CAD (0.796->0.805, p=0.0178 and 0.748->0.761, p=0.0007 in patients under and over 50, respectively).

Conclusion

Coronary artery disease is not all the same, as premature CAD shares a unique and specific pattern of risk factors, clinical presentation, angiographic severity and prognosis. Genetics should not be used as an excuse to justify premature CAD, as there is frequently more than one potentially reversible risk factor present even in young patients and the additive predictive value of GRS is modest.
P4457Cardiac screening is improved by the addition of vectorcardiography
Authors: Cortez D , Morrell H
Published: October 2019

Background

The most common cause of sudden cardiac death in the United State of America is hypertrophic cardiomyopathy, while other causes such as left ventricular hypertrophy, ion-channelopathies, and other causes are also significant. Screening programs typically involve electrocardiograms with mainly false positive results. Little data regarding EKG and echocardiographic screening combined have been published.

Methods

During 2016–2019, over 15000 patients were screened by the Heartfelt Cardiac screening program. Screening electrocardiograms and echocardiograms including parasternal short/long axis, 4-chamber views, coronary assessment with color doppler and subcostal views with color doppler for assessment of septal defects, were performed.

Results

15,329 patients were screened under 35 years of age, mean age 17 years, with 36 hypertrophic cardiomyopathy patients, 61 borderline left ventricular hypertrophy patients noted, 30 patients with left ventricular dysfunction were noted, 47 patients with mitral valve prolapse, 27 patients with atrial septal defects, 39 patients with Wolf-Parkinson-White, 21patients with ideopathic dilated cardiomyopathy were discovered. Screening electrocardiography was helpful for Wolf-Parkinson-White identification, while echocardiogram was most helpful for detection of the above other defects. Screening EKG only identified 45% of those patients with myocardial disease (per above) with the modified Seattle Screening and ESC screening criteria.

Conclusion

Screening echocardiogram adds value for screening athletes under 35 years at risk for sudden cardiac death. Consideration of cost-effective echo screening should be considered as part of routine screening.
P4459The influence of the polymorphism BUD13-ZNF259 rs964184 on coronary disease according to age
Authors: Pereira A , Mendonca M , Sousa J A , Mendonca F , Neto M , Rodrigues R , Sousa A C , Freitas A I , Henriques E , Rodrigues M , Ornelas I , Drumond A , Palma Dos Reis R
Published: October 2019

A recent GWAS study found a significant association between the BUD13-ZNF259 rs964184 polymorphism, dyslipidemia and the onset of coronary disease (CAD). This variant encoding zinc finger protein (ZPR1) interacts with the receptor tyrosine kinase at cellular level, increasing oxidative stress, inflammatory response and atherogenesis. There are no studies of the effect of this variant on the Portuguese population.

Objective

Investigate the association of BUD13-ZNF259 rs964184 with dyslipidemia and its impact on CAD risk. Evaluate its impact in different age groups of our population.

Methods

A case-control study was performed with 3050 subjects (1619 coronary patients with 53.3±8 years; 78.9% male and 1431 controls with 52.8±8 years; 76.6% male) from the GENEMACOR study population. Traditional risk factors (smoking, dyslipidemia, diabetes, family history, hypertension, body mass index, alcohol consumption, physical inactivity) and others considered new, such as creatinine clearance, pulse wave velocity, homocysteine, fibrinogen, lipoprotein (a), APOB and PCR (hs) were investigated. BUD13-ZNF259 variant was genotyped and analyzed using the dominant model (CG + GG vs. CC). Bivariate and multivariate analyzes (logistic regression) were used to estimate the ORs and 95% CI, after adjusting for potential confounding factors, in 3 different age groups (<45; 45–55; >55).

Results

BUD13-ZNF259 polymorphism presented an independent and significant risk of CAD (OR=1.58; 95% CI: 1.07–2.32; p=0.019) only in the group of young coronary patients <45 years (n=482 patients), as well as dyslipidemia (OR=2.04; 95% CI: 1.26–3.31; p=0.003). After binary logistic regression entering with the interaction between dyslipidemia and the dominant model ZNF259 (CG + GG vs. CC), we verified an association with CAD risk (OR= 1.78; 95% CI: 1.08–2.95; p=0.025).

Conclusion

BUD13-ZNF259 rs964184 variant showed a significant risk for the onset of CAD in the young population (<45 years). The impact of the interaction of ZPR1 protein with tyrosine kinase (Syk) at the cellular level seems to be more relevant in young patients. This aspect may represent a possible prophylactic and therapeutic target, especially in coronary disease in young people.
P4463The pineal hormone melatonin inhibits doxorubicin-induced mitochondrial dysfunction and apoptosis in cardiomyocytes
Authors: Kasi Ganeshan T , Bell J D , Chong N W
Published: October 2019

Background

Heart failure (HF) is a major end-point of cardiovascular diseases (CVD). The pathogenesis of HF is mostly unresolved but involves metabolic alterations. Treatment of animals and cardiomyocytes with β-adrenergic receptor agonists induces HF. Mitochondrial dysfunction and HF are common complications of anticancer drugs such as doxorubicin (DOX). Melatonin synthesis dramatically decreases with age and in patients with CVD.

Purpose

The aim of this study was to investigate whether DOX-induced cardiac dysfunction can be attenuated by melatonin.

Methods

The Seahorse XF analyser was utilised (with the XFp Cell Energy Phenotype kit) to measure oxygen consumption rate [OCR; oxidative phosphorylation (OXPHOS)] and extracellular acidification rate (ECAR; glycolysis) in living rat cardiomyocyte-derived H9c2 cell line. Mono-layers of cells were treated with cardiotoxic drugs [isoproterenol (ISO, 100μM) or DOX (0.1μM)] for 24hr with and without melatonin co-treatment (MEL, 1μM). Cyan ADP flow cytometry was used to examine the anti-apoptotic properties of MEL (1μM) on DOX-treatment (0.5μM, 24hr). Data are given as mean±SEM (n=separate experiments) and analysis was performed using ANOVA and two-tail unpaired Student's T-test, as applicable.

Results

Isoproterenol-treatment increased peak OCR of H9c2 cells by ∼30% which was inhibited by MEL [CON, 384±17; ISO, 496±33; ISO+MEL, 412±31pmol/min; n=3 (six replicates); CON vs. ISO, p<0.05; ISO vs. ISO+MEL, p<0.05; CON vs. ISO+MEL, p>0.05]. Doxorubicin-treatment decreased OCR by ∼40% which was reversed by MEL [CON, 934±69; DOX, 554±52; DOX+MEL, 858±97pmol/min; n=3 (six replicates); CON vs. DOX, p<0.05; DOX vs. DOX+MEL, p<0.05; CON vs. DOX+MEL, p>0.05]. ISO and DOX significantly increased (∼30%) and decreased (∼25%) ECAR respectively (n=3, p<0.05) which was not inhibited by MEL. Melatonin alone had no significant effect on OCR and ECAR. Melatonin inhibited DOX-induced apoptosis in H9c2 cells [CON, 6.3±0.8%; DOX, 22±1.8%; DOX+MEL, 11±1.7%, n=4 (two replicates); CON vs. DOX, p<0.001; DOX vs. DOX+MEL, p<0.004; CON vs. DOX+MEL, p>0.05].

Conclusions

ISO and DOX-treatment induced mitochondrial dysfunction in H9c2 cells by alteration of OXPHOS and glycolysis; changes in OXPHOS were prevented by MEL. These data indicate that DOX-induced apoptosis in cardiac cells may be mediated, at least in part, by OXPHOS dysfunction which was attenuated by MEL treatment.
P4466Empagliflozin improves heart function after myocardial infarction in the rat
Authors: Goerg J , Sommerfeld M , Kintscher U , Lauer D , Kulikov A , Ivkin D , Okovityi S , Kaschina E
Published: October 2019

Background

Selective Sodium-glucose cotransporter 2 (SGLT2) inhibition with Empagliflozin reduced progression of left ventricular dysfunction and improved tolerance of physical exercise in heart failure by normoglycemic rats. Here, we hypothesized that Empagliflozin prevents cardiac dysfunction after myocardial infarction (MI).

Purpose

This study aimed to investigate whether Empagliflozin protects the heart in the early phase after experimental MI in normoglycemic rats.

Methods

MI was induced in Wistar rats via permanent ligation of the left coronary artery. Treatment with Empagliflozin (1 mg/kg/daily per os) was started after MI and continued for 7 days. Sham operated and vehicle treated animals served as controls (n=8). Hemodynamic parameters were measured via transthoracic echocardiography and intracardiac Samba catheter. Glucose concentration was determined in serum and urine. Protein expression of Na+/H+ exchanger isoform-1 (NHE-1), sodium bicarbonate co-transporter (NBC), Sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA), transforming growth factor beta 1 (TGF-beta1), Smad2 in the left ventricle were also studied. Additionally, NHE-1 regulation was investigated in cardiomyocyte cell line H9c2.

Results

Systolic heart function was improved in Empagliflozin treated MI animals compared to vehicle as demonstrated by Global Longitudinal Strain (GLS) (20,9% vs. 16,6%; p<0.05). E/A ratio was decreased by tendency and blood pressure was not affected. Ejection fraction (p<0.05), fractional shortening (p<0.05), stroke volume (p<0.01) were increased in Empagliflozin treated control rats as compared with the sham group. Moreover, application of Empagliflozin (1mg/kg, i.v. bolus) to healthy rats in 30 min increased maximal pressure in the left ventricle as compared with vehicle (110,5±15,3 mmHg vs 79,1±11,9 mmHg; p<0.05). Parallel, dP/dtmax was increased while dP/dtmin was decreased by tendency. Empagliflozin treatment did not affect glucose concentration in serum and urine. Treatment of cardiac H9c2 cells with Empagliflozin (1μM) down-regulated NHE-1 by 27%.

Conclusion

SGLT2 inhibitor Empagliflozin improved systolic function in the early phase post MI independently from glucose regulation. The cardioprotective mechanisms of SGLT2 inhibitors may involve cardiac NHE-1 exchanger inhibition.
P4477Editing of myosin phosphatase as a novel approach for sensitization of vascular smooth muscle to vasodilators (NO/cGMP/ROS) and lowering of blood pressure in hypertension
Authors: Fisher S , Reho J J , Meddeb M , Ursitti J , Htet M
Published: October 2019

Background

Despite the many drugs for treatment of hypertension, it remains inadequately treated in >50% of patients and the number one contributor to cardiovascular mortality world-wide. Thus new targets and treatment strategies are badly needed. Myosin Phosphatase (MP) is a viable target: it is the primary effector of vascular smooth muscle relaxation and a critical mediator of signaling pathways regulating vessel tone.

Purpose

We are using complementary/ translatable approaches to test the hypothesis: editing of the Myosin Phosphatase Regulatory (Targeting) subunit (MYPT1), by shifting the expression of naturally occurring isoforms, will sensitize vascular smooth muscle to NO/cGMP/ROS mediated vasorelaxation and thereby lower BP in models of hypertension. A further goal is to determine mechanisms by which these signals activate MP thereby causing vasorelaxation.

Methods

LoxP sites were inserted in introns flanking alternative Exon24 (E24) of Mypt1. Mice were crossed with smMHCCreER mice and treated with Tamoxifen for smooth muscle specific deletion of E24 (SMcKO E24).Skipping E24 codes for a Mypt1 isoform that contains a C-terminal leucine zipper (LZ) motif required for cGMP-dependent protein kinase (cGK1) binding and NO/cGMP/ROS activation of MP. Second, we developed and tested guide RNAs for the purpose of AAV-CRISPR/CAS9 editing of Mypt1 E24 as a treatment for hypertension. Effect of editing is tested in otherwise normal mice and in the AngII sub-pressor model of hypertension.

Results

SMcKO E24 mice had mean BP that was 15+3 mmHg lower than control (n=5; p<0.05). Mesenteric arteries from these mice were significantly more sensitive to DEA/NO mediated relaxation (EC50: 2.1+0.5 nM vs 18.2+5.6 mM; n=5–6, p<0.05). Experiments testing response to AngII infusion are in progress and will be presented at the meeting. Preliminary biochemical assays support a 2-pool model, in which NO/cGMP/ROS activates the LZ+ pool, while contractile agonists inhibit the LZ- pool of MP, in the control of BP/ blood flow. We have generated a number of AAV Crispr/Cas9 gRNAs and validated their efficacy of editing of Mypt1 E24 in vitro. Experiments are in progress to test their efficacy and effect on BP in vivo.

Conclusion

These studies support that editing of Mypt1 E24 could be a novel strategy for vasodilator sensitization and effective lowering of blood pressure in humans with hypertension, thereby having a substantial impact on CV mortality world-wide.

Acknowledgement/Funding

NIH
P4479The association of LEPR rs1137101 polymorphism with the incidence of left ventricular hypertrophy in patients with obstructive sleep apnea and hypertension
Authors: Sobieraj P , Bielicki P , Plywaczewski R , Brzoska K , Barnas M , Kumor M , Jonczak L , Stepkowski T , Piechuta A , Chazan R , Sliwinski P , Kruszewski M
Published: October 2019

Background/Introduction

Obstructive sleep apnea (OSA) is one of the most common respiratory disease which is considered as a risk factor for cardiovascular disease and death. Although coexistence of OSA and arterial hypertension may be attributed to well-known common environmental risk factors for both diseases, a genetic background should be considered. LEPR rs1137101 polymorphism was reported to be associated with coronary artery disease and heart failure. Left ventricular hypertrophy is a part of hypertension-mediated organ damage assessment and an independent risk factor for adverse outcome in patients with hypertension.

Purpose

This study is aimed to establish the relationship between LEPR rs1137101 polymorphism and left ventricular hypertrophy in patients with OSA and arterial hypertension.

Methods

Consecutive patients with newly diagnosed OSA confirmed by polysomnography underwent genotyping for the single nucleotide polymorphisms of LEPR (rs1137101).

LVH was diagnosed using standard 12-lead electrocardiogram according to the current European Society of Cardiology guidelines. Logistic regression was used to assess the relationship between LEPR rs1137101 polymorphisms and LVH.

Results

From 600 subjects diagnosed with OSA, 427 subjects with hypertension were included for further analysis (25.1% women, 74.9% men). In analyzed subpopulation mean age was 58.5±9.4 years, body mass index 33.7±6.6 kg/m2, apnea-hypopnea index 43.1±23.6/hour. In 34 (8.0%) subjects LVH was diagnosed. Genotyping revealed, that 123 (28.8%) subjects were LEPR rs1137101 AA homozygotes, 202 (47.3%) LEPR rs1137101 A/G heterozygotes and 102 (23.9) LEPR rs1137101 G/G homozygotes.

Logistic regression showed, that LEPR rs1137101 A/A polymorphism vs A/G and G/G was associated with increased risk of LVH (odds ratio: 2.08, 95% confidence interval: 1.02–4.25, p=0.03). The relationship was significant also after adjustment for age, sex, apnea-hypopnea index and current smoking status (odds ratio: 2.28, 95% confidence interval: 1.08–4.83, p=0.03).

Conclusions

Our study shows a possible link between the polymorphism of the LEPR rs1137101 polymorphism and LVH in patients with OSA and arterial hypertension.

Acknowledgement/Funding

The study received financial support from the Polish National Science Centre (710/N-COST/2010/0)
P4488Organotypic culture of the epicardium: a new tool for cardiovascular research
Authors: Maselli D , Johnson R D , Szilveszter Matos R , Chiappini C , Camelliti P , Campagnolo P
Published: October 2019

Background

The epicardium, the most external layer of the heart, is composed of a layer of epithelial cells and underlying connective tissue. Following myocardial infarction, epicardial cells are activated and provide a source of paracrine factors and progenitor cells. In the border zone of the ischaemic tissue, the activated epicardial cells support cardiac and vascular regeneration by releasing pro-angiogenic and pro-survival factors, and by differentiating towards multiple cell lineages. During this process, activated epicardial cells migrate to the site of injury where they contribute to both post-ischemic remodelling and fibrosis. There is limited knowledge of the cellular and molecular regulation of these processes in large animals and humans, in part due to the lack of robust and representative models.

Purpose

In this project, we developed an ex vivo 3D organotypic model derived from porcine hearts, amenable to culture, which enables structural, molecular and cellular studies of the epicardium.

Methods

Thin epicardial/cardiac tissue slices (EpCardio-TS) were obtained by using a vibratome to cut the first layer of tissue from the epicardial side of porcine heart cubes. Slices were cultured for up to 72h in a bioreactor that uses a 3D printed chamber connected to a control system that allows maintenance and adjustment of culture conditions, and ensures continuous media flow. Local intracellular delivery of fluorescent quantum-dots (Qdots) was performed using nanoneedle chips to track epicardial cells, whilst cell fate is visualised in 3D by performing immunofluorescence on decolourised slices.

Results

Intact EpCardio-TS obtained from porcine heart included a viable epicardium, expressing typical epicardial markers (wt-1, mesothelin, uroplakin), and an electrically active myocardium. Live/dead staining showed epicardial (67.8±16.2%, N=5) and myocardial (40.8±28.6%, N=3) viability, and TUNEL assay confirmed low levels of apoptosis (6.3±5.1% of wt-1+ epicardial cells N=1). Moreover, the presence of proliferating epicardial cells (PCNA+), the increase in wt-1+ cells, and the increase in epicardial gene expression (Tbx18 and TCF21) suggested that cells maintain their progenitor phenotype and undergo activation in culture. Nanoinjection of fluorescent Qdots to EpCardio-TS localized them to the wt-1+ cells on the slice surface, presenting a strategy to mark the epicardial layer. This, combined with the successful decolourisation of the slices, provides an in vitro platform to track the role of epicardial cells in cardiac remodelling and fibrosis.

Conclusions

EpCardio-TS represents a robust ex vivo model merging the complexity of a 3D organotypic culture with the simplicity of the in vitro culture. EpCardio-TS are amenable to culture and cell tracking, and can therefore find application in toxicology and gene therapy screening for the modulation of epicardial interactions with myocardial and non-myocardial cells of the heart.
P4517Heart failure in elderly and very elderly hospitalized patients: an epidemiological analysis from the REPOSI registry
Authors: Proietti M , Marra A M , Salzano A , Romiti G F , Mannucci P M , Nobili A , Cittadini A
Published: October 2019

Introduction

Epidemiological data about heart failure (HF) in the elderly and, in particular, very elderly patients are lacking.

Purpose

To provide the epidemiological profile of elderly and very elderly HF patients in terms of prevalence, associated clinical factors, burden of multimorbidity and functional status.

Methods

Overall cohort of the REgistro POliterapie SIMI (REPOSI) was used to assess study aims. REPOSI is an Italian Nationwide Registry of elderly hospitalized patients in Internal Medicine and Geriatric wards. HF diagnosis was assessed at hospital admission according to ICD-9 code 428.XX.

Results

Among the 7003 patients originally enrolled, a total of 1095 (15.6%) patients reported a diagnosis of HF at hospital admission. Prevalence of HF progressively increased according to age strata, up to 26.8% in patients ≥90 [Figure]. A logistic regression analysis found that increasing age, body mass index and total cumulative illness rating scale (CIRS) were associated with HF (Table). Moreover, atrial fibrillation, chronic kidney disease, chronic obstructive pulmonary disease and polypharmacy (≥5 drugs) were associated with HF, while liver disease and neoplasm were inversely associated (Table). According to CIRS severity index and comorbidity index quartile, HF patients reported more likely values in the highest quartile than those without HF (47.4% vs. 26.6%, p<0.001 and 34.4% vs. 18.5%, p<0.001 respectively). According to short blessed test, geriatric depression scale and Barthel index, patients with HF had significantly more cognitive impairment and dementia, depression and dependent from others in daily activities than those without HF (all p<0.001).

Prevalence of HF according to Age Strata

Conclusions

In a cohort of elderly patients hospitalized in Internal Medicine and Geriatric wards HF was highly prevalent, in particular in those very elderly. HF was associated with several clinical factors, emphasizing a stronger clinical complexity. HF patients were more burdened with multimorbidity and showed an impaired functional status.

Acknowledgement/Funding

None
P4523Impact of comorbiditity on the predictive value of acute kidney injury in patients admitted for acute decompensated heart failure: a prospective study
Authors: Kayama K , Yamada T , Morita T , Furukawa Y , Tamaki S , Iwasaki Y , Kawasaki M , Kikuchi A , Kawai T , Seo M , Abe M , Nakamura J , Fukunami M
Published: October 2019

Background

Comorbidities are associated with poor clinical outcome in patients with chronic heart failure, and acute kidney injury (AKI) also provides prognostic information in patients with heart failure. However, there is no information available on the impact of comorbidities on the prognostic value of AKI in patients admitted for acute decompensated heart failure (ADHF).

Methods

We prospectively studied 357 consecutive ADHF patients with survival discharge. Patients with hemodialysis were excluded. Comorbidity was measured with the Age-adjusted Charlson comorbidity index (ACCI) which is commonly used for the evaluation of the comorbid condition which is weighted and scored, with additional points added for age. AKI was defined as an absolute increase in serum creatinine of 0.3mg/dl or more during hospitalization. The endpoint was all-cause death (ACD).

Results

During a follow-up period of 2.2±1.4 years, 97 patients had ACD. At multivariate Cox analysis, ACCI (p<0.0001) and AKI (p=0.0061) were significantly and independently associated with ACD. Patients with high ACCI (≥5: determined by ROC analysis) had a significantly greater risk of ACD (39% vs 16%). In the subgroup of high ACCI, patients with AKI had a significantly higher risk of ACD (60% vs 35%), whereas there was no significant difference in the risk of ACD between with and without AKI (15% vs 16%) in the subgroup of low ACCI.

Conclusions

The presence of AKI was associated with the increased risk of mortality in ADHF patients with higher comorbidity burden but not in those without them.
P4524His bundle pacing in patients pacemaker indication and with mildly reduced ejection fraction
Authors: Gardas R , Jarosinki G , Sznjader R , Biernat J , Goscinska-Bis K , Golba K S
Published: October 2019

Background

Right ventricular pacing (RVP) can be harmful and in a number of patients leads to deterioration of left ventricle function. The deleterious effect of RVP is particularly visible in patients with reduced ejection fraction. His bundle pacing (HBP) allows ventricular stimulation without electrical and mechanical dyssynchrony and should not be associated with deterioration of left ventricle function. In some patients HBP restores electrical and mechanical synchrony.

Objective

The aim of the study is to evaluate effect of HBP on left ventricle function in patient with reduced left ventricle ejection fraction (LVEF.

Methods

Twenty-one patients with indication for permanent pacing and with (LVEF) between 35 and 50% were included into the study. Age 71,9±10,44. Men 76,2%. 13 (61,9%) patients with permanent atrial fibrillation. In 33,3% of patients there were intraventricular conduction delay (IVCD), 3 (14,3%) with LBBB, 3 (14,3%) with RBBB and 1 (4,8%) with nonspecific IVCD. 6 patients were upgraded from previously implanted pacemaker. Mean QRS duration 133,6±37,85. Baseline ejection fraction (EF) 42,6±3,21%. Clinical and echocardiographic evaluation were performed at baseline and after 6–12 months of follow up.

Results

QRS duration narrowed from 133,6±37,85ms to 114,3±16,90ms (p=0,033) with HBP. HBP was associated with reduction of end systolic left ventricular volume (LVES) from 91,5±31,10ml to 75,9±38,56ml (p=0,0058). EF improved from 42,6±3,21% to 48,3±7,39% (p=0,0006). Improvement in EF in patients without myocardial infarction (MI) was better (42,6±3,23% to 49,5±8,04%, p=0,0053) than in patients with MI (42,6±3,37% to 47,0±6,79%, p=0,062). Increase in EF was also better in patients with atrial fibrillation (42,7±3,19% to 49,9±8,20%, p=0,0017) than int patients with sinus rhythm (42,4±3,46% to 45,6±5,28%, p=0,17). Functional capacity assessed by NYHA class improved significantly from 2,4±0,59 to 1,7±0,58.

Ejection Fraction

Conclusion

His bundle pacing is associated with th significant clinical and echocardiographic improvement in patients with mildly reduced left ventricular ejection fraction and indication for permanent pacing. After 6–12 moths of HBP pacing the improvement in EF is greater in patients with atrial fibrillation and without myocardial infarction.
P4526Implant procedure and lead handling characteristics of a novel active fixation quadripolar lead: Results from the Attain Stability Quad clinical trial
Authors: Faerestrand S , Crossley G H , Philippon F , Yee R , Kong M H , Kloppe A , Bongiorni M G , Delnoy P P H M , Shelby L , Van Ginneken M M E , Jackson K P
Published: October 2019

Background

Dislodgements of left ventricular (LV) leads are still a challenging problem in cardiac resynchronization therapy (CRT). The Attain Stability Quad (ASQuad) MRI SureScan 4798 steroid-eluting, quadripolar LV lead has a side-helix to enable the lead to be actively fixated to the vessel wall. The uniquely designed active fixation can be advantageous in vessels that are wide or have short take-offs. Further, the helix easily elongates to allow for future extraction.

Purpose

To report on the handling, performance and safety of ASQuad LV lead in a large clinical study.

Methods

The ASQuad clinical study is a prospective clinical trial from 50 centers in 10 countries enrolling CRT candidates implanted with the ASQuad LV lead. Aside from evaluating safety and effectiveness of the LV lead, the trial specifically collected data on parameters related to lead stability during and post implant.

Results

Of 440 enrolled patients (74.8% male, average age 70±11 years) that underwent an implant attempt, 426 (96.8%) were successfully implanted. The helix was mostly affixed in the mid to basal lateral position (62%), followed by mid to basal posterior position (29%). The lead tip placement was most often mid lateral or mid posterior (77%), and in a vein with diameter greater than the pacing electrode diameter (>5.1 French) in the majority (60%) of procedures. Among all subjects (n=421) who underwent pacing capture thresholds (PCT) tests before and immediate after guide catheter slitting, 98% reported ≤1 V difference in PCT, and 86% were within 0.5 V. The interquartile range for the difference in PCT was −0.1 to 0.1 V. The mean PCT at implant for all subjects at the final selected LV pacing vector was 1.15±0.70 V at 0.5 ms pulse width. The average LV lead implant time was 16±21 minutes. Targeted pacing location was achieved in 97% of successful implants, and 98% of implanters reported good or fair stability after guidewire removal. The overall handling of the LV lead was rated as acceptable by implanters in 99% of cases. Three patients (0.7%) experienced LV lead dislodgement post implant, and these complications were resolved by repositioning of the lead (0 and 1-day post implant) in two and by lead replacement when noted at 90 days follow-up in one.

Conclusions

The ASQuad LV lead was implanted with a high rate of success and ability to achieve the targeted pacing location. Lead handling and stability following guidewire removal were rated as acceptable by nearly all implanters. The side-helix likely improved LV lead stability since 98% of the subjects had ≤1 V difference in PCT before and after catheter slitting during implant procedures, and by demonstrating a low post implant lead dislodgement rate.

Acknowledgement/Funding

Sponsored by Medtronic
P4531Early and late superresponse to cardiac resynchronization therapy
Authors: Kuznetsov V A , Enina T N , Soldatova A M , Petelina T I , Shirokov N E , Salamova L A
Published: October 2019

Background

Superresponders to cardiac resynchronization therapy (CRT) demonstrate significant reverse remodeling, improvement in cardiac function, decrease in inflammatory mediators and markers of cardiac fibrosis. It is not clear if superresponse (SR) can be early or late and if the time of SR to CRT is associated with different degree of biochemical improvement.

Aim

To assess structural and functional heart parameters, sympathetic activity, levels of biomarkers of myocardial fibrosis, inflammatory and neurohormonal mediators in patients with various time of SR to CRT.

Methods

The study enrolled 82 superresponders to CRT (decrease in left ventricular end-systolic volume (LVESV) >30%) (mean age 60.4±9.3 years; 80.5% men, 19.5% women; 54.9% with ischemic etiology of heart failure). Patients were divided into two groups: group 1 (n=19) – SR was achieved within 24 months (14.0 [8.0; 21.0] months); group 2 (n=63) - SR was achieved after 24 months (59 [43.0; 84.0] months). Echocardiographic parameters, plasma levels of epinephrine, norepinephrine, NT-proBNP, interleukin (IL) 1β, IL-6, IL-10, tumor necrosis factor alpha (TNF-α), metalloproteinase (MMP) 9, tissue inhibitors of metalloproteinase (TIMP) 1 and 4 were evaluated.

Results

At baseline there were no differences in demographic, clinical and echocardiographic characteristics between the groups. Levels of epinephrine (1.1 [0.1; 2.2] ng/ml vs 2.1 [0.7; 3.4] ng/ml; p=0.049) and IL-10 (1.8 [1.5; 3.5] pg/ml vs 3.9 [2.7; 5.1] pg/ml; p=0.019) were significantly higher in group 2. Both groups demonstrated significant improvement in echocardiographic parameters. On follow-up left ventricular (LV) end-systolic dimension (p=0.041), LV end-diastolic dimension (p=0.049), LVESV (p=0.014), LV end-diastolic volume (p=0.045) were lower in group 2. In group 1 IL-6 (p=0.047), TNF-α (p=0.047) decreased significantly and there was a tendency for IL-1β (p=0.064) and norepinephrine (p=0.069) levels to increase. In group 2 levels of IL-1β (p<0.001), IL-6 (p=0.030), IL-10 (p=0.003), TNF-α (p<0.001), TIMP-1 (p=0.010) and epinephrine (p=0.024) decreased significantly while MMP-9/TIMP-1 (p=0.023) increased as compared to baseline levels. Additionally there was a tendency for NT-proBNP level to decrease in group 2 (p=0.069). Follow-up level of norepinephrine (7.8 [2.9; 17.2] ng/ml vs 1.1 [0.2; 8.7] ng/ml; p=0.011 was lower and MMP-9/TIMP-4 level was higher (0.058 [0.044; 0.091] vs 0.092 [0.064; 0.111]; p=0.013) in group 2. Diverse trends were observed in IL-10 (0.4 [−0.6; 1.2] pg/ml in group 1 vs −2.3 [−3.4; −0.5] pg/ml in group 2; p=0.007) and norepinephrine (4.0 [−5.2; 14.3] ng/ml in the group 1 vs −1.2 [−11.6; 4.0] ng/ml in the group 2; p=0.015) between the groups.

Conclusion

CRT modulates sympathetic, neurohumoral, immune and fibrotic activity. Late SR to CRT is associated with decrease of sympathetic and inflammatory activity and more pronounced LV reverse remodeling.