bluuebunny/crossref_metadata_2025 huggingface dataset:
P626Higher fitness is associated with improved survival among cancer patients
Authors: Fardman A , Banschick G D , Rabia R , Segev S , Klempfner R , Fourey D , Percik R , Grossman E , Maor E
Published: October 2019

Background

Cardio-respiratory fitness (CRF) is a known predictor of cardiovascular morbidity and mortality. However, data on the association of CRF with survival following a diagnosis of cancer is limited.

Purpose

To evaluate the association between CRF in a large cohort of asymptomatic adults and a probability of survival after subsequent cancer diagnosis.

Methods

We evaluated asymptomatic self-referred adults aged 40–79 years who were screened annually at a tertiary medical center. All subjects were free of cardiovascular disease and cancer at baseline and completed maximal exercise stress test according to the Bruce protocol. Fitness was categorized into age- and sex-specific quintiles (Q) according to Bruce protocol treadmill time with Q1-Q2 defined as low fitness and Q3-Q5 as higher fitness. Cancer data was available from a national cancer registry. The primary end point was all-cause mortality.

Results

Final study population in included 15,800 subjects. Mean age was 51±8 years and 72% were men. During median follow up of 13 years (IQR 7–16) 1,312 (8%) subjects developed cancer and 486 (3%) died. Most common cancer types were prostate in 302 (23%) and breast cancer in 189 (14%) patients. No difference was found in distribution of major cancer types between different fitness categories. Univariate Cox regression with cancer as a time dependent covariate showed that subjects who developed cancer during follow up were 19 times more likely to die (95% CI 15.5–22.5, p<0.001). Kaplan Meier analysis showed that the cumulative probability of death from the time of cancer diagnosis was significantly lower among high fitness patients (34% ± 4% vs. 25% ± 3%, p Log rank = 0.008; Figure 1). Multivariate interaction analysis with cancer as a time dependent covariate showed that cancer-related risk of death was fitness-dependent, such that in the lower fitness group cancer was associated with 18 folds increased risk of death (95% CI: 13.5–23) whereas among high fitness group the risk of death was lower (HR=13; 95% CI: 10–17; p for interaction = 0.048).

Conclusions

Low CRF is associated with worse survival among subjects diagnosed as having cancer during follow up. These findings support the effectiveness of fitness assessment in preventive health care settings.
P628Association of outpatient cardiac rehabilitation with mortality and morbidities in patients with acute myocardial infarction
Authors: Seki T , Takeuchi M , Kawasoe S , Takeuchi K , Miki R , Ueshima K , Kawakami K
Published: October 2019

Background/Introduction

Outpatient cardiac rehabilitation (CR) is commonly recommended for patients with acute myocardial infarction (AMI). However, the survival benefit has recently been contested, especially with no survival benefit having been found in non-Western countries.

Purpose

To investigate whether outpatient CR, under current real-world clinical practice, is associated with lower mortality and morbidity risks in patients with AMI.

Methods

The retrospective cohort study was conducted from January 2011 to June 2016 (final date of follow-up: July 31, 2016) with a nation-wide administrative database for acute-care hospitals in Japan. Data for 7,411 patients were analyzed, with 5,654 fulfilling the inclusion criteria of being admitted for AMI and receiving both percutaneous coronary intervention and inpatient CR between January 2011 and December 2014. We compared patients who participated in outpatient CR at least once within 180 days of discharge and who did not. To account for measured baseline imbalances between outpatient CR participants and non-participants, 1:1 propensity-score matching was performed. The primary outcome was a composite of all-cause death and recurrence of AMI after the landmark time-point of day 180 after discharge. Secondary outcomes included all-cause death, recurrence of AMI, and heart failure.

Results

Among 5,654 patients (mean [SD] age, 66.8 [12.4] years; 21.2% female; median follow-up period [IQR] 1.44 [0.87 to 2.27] years), 730 (12.9%) received outpatient CR. Of 1,458 propensity-score matched patients, outpatient CR participants did not show a significantly lower risk of the primary outcome than non-participants (1.38 vs. 2.12 per 100 patient-years; hazard ratio [HR], 0.71 [95% CI, 0.32 to 1.61]). Similarly, outpatient CR participation was not associated with lower risks of all-cause death (0.68 vs. 1.31 per 100 patient-years; HR, 0.83 [95% CI, 0.25 to 2.73]), recurrence of AMI (0.69 vs. 0.88 per 100 patient-years; HR, 0.56 [95% CI, 0.19 to 1.66]) or heart failure (2.01 vs. 2.06 per 100 patient-years; HR, 0.89 [95% CI, 0.47 to 1.72]), respectively.

Conclusion

Among patients with AMI who received percutaneous coronary intervention and inpatient CR, outpatient CR was not associated with lower risks of mortality and morbidities. The survival benefit of outpatient CR should be reaffirmed under current real-world clinical practice, especially in non-Western countries.
P635The addition of yoga to aerobic exercise programs reduces global cardiovascular risk
Authors: Pandey A , Huq N , Chapman M , Fongang A , Poirer P
Published: October 2019

Introduction

Regular physical activity may modulate the inflammatory process and be cardio-protective. Yoga is a form of exercise that may have cardiovascular benefits. The effects of yoga on global cardiovascular risk have not been adequately described. The purpose of this study is to determine whether the addition of yoga to a regular exercise regimen reduces global cardiovascular risk.

Methods

Sixty consecutive individuals with essential hypertension were recruited in a lifestyle intervention program. All individuals with known hypertensive end organ damage, known cardiovascular diseases, as well as those taking medications/supplements that affected blood pressure, blood sugar, cholesterol or vascular inflammation were excluded. Participants were randomized to either a yoga group or similar duration stretching control group. Participants, over the 3-month intervention regimen, performed 15 minutes of either yoga or stretching in addition to 30 minutes of aerobic exercises thrice weekly. Blood pressure, cholesterol levels and hs-CRP were measured, and Reynold's Global Cardiovascular Risk Score was calculated at baseline and at the end of the 3-month intervention program.

Results

At screening, there were no statistically significant differences between the groups in any measured parameters or the 10-year risk of a cardiovascular event as measured by the Reynolds Risk Score. (8.2 vs. 9.0%; yoga vs. control group) After the 3-month intervention period, there was a statistically significantly greater decrease in the Reynold's Risk Score in the yoga vs. the control group. (7.0 vs. 8.4%, p=0.003, relative reduction 13.2 vs. 6.5%, p<0.0001)

Baseline and 3 Month Outcomes

Conclusions

In patients with essential hypertension on no medications and with no known end organ damage, the practice of yoga incorporated into a 3-month exercise intervention program was associated with significant greater improvement in the Reynold's Risk of a 10-year cardiovascular event, when compared to the control stretching group. If these results are validated in more diverse populations over a longer duration of follow up, yoga may represent an important addition to traditional cardiovascular disease prevention programs.
P645Low levels of low density lipoprotein cholesterol and cardiovascular, cancer and all-cause mortality outcomes
Authors: Sung K , Lee J Y , Lee S J
Published: October 2019

Aims

The effect of low concentrations of low density lipoprotein-cholesterol (LDL-C) on cardiovascular disease (CVD) cancer and all-cause mortality is still controversial. In a large, young, well characterized, relatively healthy occupational cohort (Kangbuk Samsung health study, KSHS), we tested associations between low levels of LDL-C concentration, and CVD, cancer and all- cause mortality. To validate these associations, we analyzed data from another cohort (Korean genome and epidemiology study, KoGES).

Methods and results

347,971 subjects in KSHS (mean age 39.6 years, 57.4% men) were studied over a mean follow up of 5.64±3.27 years. All subjects treated with any lipid lowering therapy were excluded. After excluding the data from subjects who died during the first 3 years of follow up, five groups were defined according to baseline LDL-C concentration (<70, 70–99, 100–129, 130–159, ≥160 mg/dL). Hazard ratios (HR and 95% CIs) for all-cause mortality, CVD and cancer mortality were estimated using Cox proportional hazards models. In the KoGES validation cohort, 182,943 subjects (mean age 53.1 years, 34.6% men) were studied over a mean follow up of 8.57±2.59 years with same methods. 2,028 deaths (897 from cancer and 282 from CVD) occurred during follow-up in KSHS. The lowest LDL-C group (LDL<70 mg/dL) had a higher risk of all-cause mortality (HR 1.95, 1.55–2.47), CVD mortality (HR 2.02, 1.11–3.64) and cancer mortality (HR 2.06, 1.46–2.90) compared to the reference group (LDL 120–139 mg/dL). This association was more prominent in men than in women. In the validation cohort, 2,338 deaths (1,823 from cancer and 199 from CVD) occurred during follow-up. The lowest LDL-C group (LDL<70 mg/dL) had a higher risk of all-cause mortality (HR 1.81, 1.44–2.28). Men in the lowest LDL-C group had a higher risk of CVD mortality (HR 3.15, 1.21–8.21) and cancer mortality (1.34, 0.99–1.82) in the KoGES cohort.

Conclusions

Low levels of LDL-C concentration are strongly and independently associated with increased risk of cancer, CVD and all-cause mortality especially in men.
P653PCSK-9 inhibitors and acute coronary syndrome in hyperlipidemic patients: a systematic review and meta-analysis
Authors: Asbeutah A A , Asbeutah A M , Abu-Assi M A , Welty F K
Published: October 2019

Introduction

Hyperlipidemia has been associated with several adverse cardiac and cerebrovascular events. Treatment with statins has proven to reduce the risk of cardiovascular events, however not all patients could reach adequate low-density lipoprotein targets or tolerate statin therapy. This has led to a recent increase in the use of PCSK-9 inhibitors for management of uncontrolled hyperlipidemia.

Purpose

Effect of PCSK-9 inhibitors on the reduction of acute coronary events in patients with hyperlipidemia.

Methods

A systematic search of electronic databases for published phase 2 or 3 randomized controlled trials involving hyperlipidemic adults on PCSK-9 inhibitors was conducted. Trials involving evolocumab or alirocumab were included in the analysis. The end points of myocardial infarction and unstable angina were computed together as the composite outcome of acute coronary events. Meta-analysis using a random effects model, with dichotomous outcomes expressed as odds ratios (OR) with 95% confidence intervals (CI), was performed.

Results

Thirty randomized controlled trials comprising 62,961 patients were included in the meta-analysis, including the recently published ODYSSEY OUTCOMES trial with 18,942 patients. Analysis was stratified according to PCSK-9 inhibitor, either evolocumab or alirocumab. In the stratified analysis, evolocumab was associated with a significantly lower rate of acute coronary events with an OR: 0.79 (95% CI, 0.72–0.87; P<0.001). In contrast, alirocumab was not associated with a significantly lower rate of acute coronary events with an OR: 0.71 (95% CI, 0.47–1.10; P=0.12). For the combined group, compared with no PCSK-9 inhibitor therapy, PCSK9 inhibitor therapy was associated with a significantly lower rate of acute coronary events (4.3% versus 5.8%; OR: 0.81 (95% CI, 0.75–0.87; P<0.001). The modest reduction of risk of acute coronary events of 1.5% translates into a number needed to treat of 67. Neither publication bias, nor significant heterogeneity was observed in the analysis.

Acute coronary events

Conclusions

PCSK-9 inhibitor therapy significantly reduces the risk of acute coronary syndrome when compared to the usual standard of care in adults with uncontrolled hyperlipidemia.
P686Cancer is not associated with increased cardiac and bleeding events after 2nd- and 3rd-generation drug-eluting stents implantation
Authors: Muramatsu Y , Minami Y , Ishida K , Kato A , Katsura A , Sato T , Kakizaki R , Nemoto T , Hashimoto T , Fujiyoshi K , Meguro K , Shimohama T , Ako J
Published: October 2019

Background

Previous studies demonstrated the impact of concomitant cancer on the increased risk of adverse cardiac and bleeding events after percutaneous coronary intervention (PCI). However, the impact in this 2nd- and 3rd-generation drug-eluting stent (DES) era remains to be elucidated.

Purpose

To clarify the impact of cancer on clinical outcomes in patients after 2nd- or 3rd -generation DES implantation.

Methods

A total of 932 patients who underwent PCI with 2nd- or 3rd -generation DES were included. Patients who were diagnosed with cancer after PCI were excluded from the present cohort. The incidence of major adverse cardiac events (MACE) including cardiac death, myocardial infarction and target or non-target vessel revascularization, and bleeding events was compared between the patients with cancer or the history of treatment for cancer (cancer group, n=140) and the patients without cancer (no cancer group, n=792). Bleeding events were evaluated according to the Thrombolysis in Myocardial Infarction definition. Further comparisons were performed between the 2 groups (cancer group, n=126; no cancer group, n=252) after the adjustment of baseline clinical characteristics using 1:2 propensity score-matching analysis.

Results

The incidence of MACE at median 577 [340–1043] days after the PCI was comparable between the 2 groups in both unadjusted (15.0% vs. 15.0%, p=0.984) (Panel A) and adjusted cohorts (14.3 vs. 13.1%, p=0.796), although the incidence of all cause death in the cancer group was significantly greater than the no cancer group (15.1 vs. 9.5%, p=0.007, in the adjusted cohort). The increased risk of MACE was not observed in any types of cancer or treatment (Panel B). The incidence of bleeding events was also comparable between the 2 groups (4.0 vs. 2.0%, p=0.297, in the adjusted cohort).

Conclusion

The increased incidence of MACE and bleeding events in patients with cancer was not demonstrated after the 2nd- or 3rd-generation DES implantation. Further studies are required to clarify the safety and efficacy of PCI in patients with cancer.
P698The KCa2 channel inhibitor AP14145, but not dofetilide or ondansetron, provides functional atrial selectivity in guinea pig hearts
Authors: Bentzen B H , Kirchhoff J E , Skarsfeldt M A , Abildgaard L , Edvardsson N , Soerensen U S , Grunnet M , Diness J G
Published: October 2019

Background and purpose

Prolongation of cardiac action potentials is considered antiarrhythmic in the atria but can be proarrhytmic in ventricles if the current carried by Kv11.1-channels (IKr) is inhibited. The current mediated by KCa2-channels, IKCa, is considered a promising new target for treatment of atrial fibrillation.

Selective inhibitors of IKr— (dofetilide) and I-KCa (AP14145) were used to compare the effects on ventricular and atrial repolarisation. Ondansetron which has been reported to be a potent blocker of both IKr and IKCa was included to examine its potential atrial antiarrhythmic properties.

Methods

The expression of KCa2- and Kv11.1-channels in the guinea pig heart was investigated using qPCR. Whole-cell patch clamp technique was used to investigate the effects of dofetilide, AP14145, and ondansetron on IKCa and/or IKr. The effect of dofetilide, AP14145, and ondansetron on atrial and ventricular repolarisation was investigated in isolated hearts. A novel atrial paced in vivo guinea pig model was further validated using AP14145 and dofetilide.

Results

AP14145 increased AERP (29 ms ex vivo and 38 ms in vivo) without prolonging QTcB both ex vivo and in vivo. In contrast, dofetilide increased QTcB (41 ms) and, to a lesser extent, AERP (16 ms) in isolated hearts and prolonged QTcB (61ms) with no effects on AERP in the in vivo guinea pig model. Ondansetron did not inhibit IKCa, but did inhibit IKr in vitro. Ondansetron prolonged ventricular (25 ms), but not atrial repolarisation ex vivo.

Conclusion

IKCa inhibition by AP14145 selectively increased atrial repolarisation whereas IKr inhibition by dofetilide and ondansetron increases ventricular repolarisation to a larger extent than atrial repolarisation. Data support that IKCa inhibition may be of value in treating atrial fibrillation without causing adverse effects in the ventricles.

Acknowledgement/Funding

Innovation Fund Denmark and Wellcome Trust
P699Mechanisms of action of the small conductance Ca2+-activated K+-channel modulator AP30663, a novel compound being developed for treatment of atrial fibrillation in man
Authors: Bomholtz S H , Simo-Vicens R , Abildgaard L , Edvardsson N G , Soerensen U S , Grunnet M , Diness J G , Bentzen B H
Published: October 2019

Background

Small conductance Ca2+-activated K+-channels (SK-channels) are a promising new atrial selective target for treatment of atrial fibrillation (AF). AP30663 is a small molecule inhibitor of SK-channels that is effective in converting vernakalant-resistant AF in tachy-paced pigs. Detailed understanding of the molecular mechanism of AP30663 is important for the development of SK channel inhibition for use in man.

Purpose

To establish the electrophysiological profile, mechanism of action and efficacy in prolonging atrial refractoriness ex vivo of AP30663.

Methods

AP30663 potency and mechanism of action were established by whole cell and inside-out patch clamp recordings of expressed SK channels. The ion channel selectivity profile of AP30663 was investigated on heterologous expressed channels. Effects of AP30663 or vehicle (DMSO) on atrial refractoriness (AERP) and ventricular repolarization (QTcB) were investigated on isolated perfused guinea pig hearts.

Results

AP30663 was found to be a selective negative allosteric modulator of SK channels (IC50=0.77±x0.13 μM) with no or minor effects on a panel of other cardiac ion channels, including hERG/KV11.1, (IKr), KV7.1/KCNE1 (IKs), KV4.3/KChiP2 (Ito), Kir2.1 (IK1), Kir3.1/Kir3.4 (IKACh), KV1.5 (IKur), NaV1.5 (INa) and CaV1.2 (ICa). AP30663 inhibited the SK-channel by right-shifting the calcium activation curve of the SK-channel (the EC50 of Ca2+ increased from 0.43±0.02 μM (control, n=6) to 1.37±0.05 μM (in the presence of 7μM AP30663, n=6).

In isolated guinea pig hearts, administration of vehicle had no effect on AERP or QTcB. AP30663 significantly prolonged the AERP in 3 μM (to 131±6% of baseline) and 10 μM (to 165±3% of baseline) without any effects on the QTcB.

Conclusion

AP30663 is a selective negative allosteric modulator of SK channels, acting by means of shifting the calcium dependence of SK-channel activation. AP30663 prolonged atrial refractoriness without affecting the QT-interval in isolated perfused heart preparations. These properties support continued development of AP30663 for treatment of AF in man.

Acknowledgement/Funding

Innovation Fund Denmark, Wellcome Trust
P707Endothelial function and testosterone deficiency in men with type 2 diabetes mellitus
Authors: Khripun I , Vorobyev S , Khripun A , Kogan M , Belousov I
Published: October 2019

Background

To date, the currently available data aboutthe effect of testosterone (T) on the cardiovascular system of men are highly controversial. The particular interest is its effect on the endothelium in men with type 2 diabetes mellitus (T2DM) having a high risk of vascular complications.

The purpose of this work was to evaluate the effect of endogenous T on function of endothelium in men with T2DM.

Methods

The study included 204 men, aged 40–65 years, with T2DM. Patients underwent clinical examinations, analysis of carbohydrate metabolism, evaluation of biochemical parameters of endothelial function such as nitric oxide (NO), endothelial synthase type 3 (eNOS3), VCAM-1, ICAM-1, p- and e-selectins, endothelin. The ultrasound assessment of flow-mediated dilatation of the brachial artery (FMD-BA) and intima-media thickness (IMT) of brachial arteries were performed. Patients were divided into 2 groups: 1 – 93 men with late onset hypogonadism established according to EAU 2015 criteria and 2 – 111 men having normal level of endogenous T and absence of clinical symptoms of hypogonadism. Statistical analysis of the data was carried out using the Mann-Whitney U-test (STATISTICA 10 software package).

Results

The parameters of carbohydrate metabolism and the duration of T2DM were comparable in two groups. The concentrations of NO (85.0 [60.4; 210.4] vs 137.5 [87.8; 281.5] μmol/l, p=0.001) and eNOS3 (192.2 [109.6; 407.3] vs 293.3 [117.1; 686.2] pg/ml, p=0.03) were lower in the 1st group compared to the 2nd one. There was an increase in the levels of VCAM-1 by 32.6% and ICAM-1 by 43% (p<0.0001), p-selectin by 19.5% (p=0.003) in the 1st group compared to the 2nd group. The endothelium-dependent FMD-BA was less pronounced (9.4 [6.9; 13.0] vs 12.2 [10.0; 16.7] %, p=0.0007) and had a delay in time of dilation by 33.3% in patients with hypogonadism compared to eugonadal men. There was an increase in IMT (1.0 [0.9; 1.2] vs 0.9 [0.7; 1.1] mm, p=0.03) in the 1st group compared to the 2nd.

Conclusion

T deficiency in men with T2DM leads to endothelial dysfunction, decreasing secretory and vasomotor function of endothelium. This indicates the raise of cardiovascular risk and predicts progression of vascular complications in men with T2DM and late onset hypogonadism.

Acknowledgement/Funding

Supported by Russian Science Foundation, grant #14-25-00052.
P713Short term treatment of a low dose erythropoietin improves vascular function in a rat model of insulin resistance
Authors: Toba H , Yamaoka A , Sakurai S , Tanaka Y , Miyamoto A , Nessa N , Watanabe Y , Kobara M , Nakata T
Published: October 2019

Background/Introduction

Erythropoietin (EPO) exerts haematopoiesis-independent cardiovascular and renal protective effects by binding to EPO receptors expressed in hearts, arteries, and kidneys. We have reported that EPO inhibits vascular and renal injury in rat models of hypertension and type 1 diabetes. Recent studies report that EPO improves glucose tolerance in insulin resistant animals.

Purpose

This study investigated whether EPO would inhibit vascular and renal dysfunction in the setting of insulin resistance.

Methods

Rats were treated with sucrose (12% in drinking water) for 10 weeks to induce insulin resistance. EPO (3 times/week, s.c) was administered at the dose of 150U/kg for 10 weeks from the beginning (group A) or at the dose of 75U/kg for the last 4 weeks (group B) of sucrose treatment. Blood pressure was measured every second week by the tail-cuff method. HOMA-IR, haematocrit, and urinary protein excretion were measured. Using isolated aortas, acetylcholine-induced vasorelaxation under phenylephrine-induced pre-contraction was examined. Aortic sections were stained with haematoxylin-eosin.

Results

Both groups A and B showed higher haematocrit levels compared with the control and sucrose alone-treated groups. Sucrose treatment increased HOMA-IR (7.7±2.0 vs. 24±4.5, p<0.05), which was attenuated in groups A (3.6±0.9) and B (9.7±4.0). EPO treatment (150U/kg) had no effects on blood pressure for the first 4 weeks but caused time-dependent increases in blood pressure from the 6th week. Increased proteinuria and impaired aortic vasorelaxation in sucrose-treated rats were exacerbated by EPO (150U/kg) maybe because of hypertension (Control 122±2mmHg, Sucrose 125±2mmHg, group A 148±5mmHg), one of the major side effects of EPO. According to these results, we treated a half dose of EPO only for the last 4 weeks (group B). A lower dose of EPO treatment for a shorter period did not increase proteinuria (Control 15±2mg/day, Sucrose 25±3mg/day, group B 24±3mg/day) despite a mild increase in blood pressure (132±2mmHg). Impaired endothelium-dependent vasodilation and aortic thickening in the aorta of sucrose alone-treated rats were attenuated by lower and shorter EPO treatment (group B).

Conclusions

EPO inhibited insulin resistance and vascular injury in sucrose-induced insulin resistant rats. Further investigation into the mechanisms of tissue protective effects of EPO, especially focusing on the effects on insulin signalling in not only hepatic and muscle cell but also vascular and renal cells, will be needed.
P724Antibody treatment against pathological pancreatic islet amyloid polypeptide (IAPP) aggregates restores endothelial dysfunction in human-IAPP transgenic rats
Authors: Taheri A , Doytcheva P , Tarasco E , Gut W , Engeli M , Hugentobler L , Lutz T A , Osto E
Published: October 2019

Background

Islet amyloid polypeptide (IAPP; or amylin) is produced in pancreatic B-cells and co-secreted with insulin in response to nutrients. In insulin resistance and type 2 diabetes (T2D), higher secretion and impaired processing of IAPP results in its aggregation, contributing to amyloid-induced apoptosis of pancreatic B-cells. Insight into IAPP's role in diabetic endothelial dysfunction is scarce.

Purpose

Rats transgenic for human IAPP (hIAPP), which in contrast to rodent IAPP produces amyloid deposits and contributes to diabetes due to B-cell failure, were studied to understand the mechanisms of endothelial dysfunction in T2D and test the vasoprotective actions of an anti-hIAPP antibody.

Methods

Male hemizygous transgenic Sprague-Dawley rats with islet B-cell expression of hIAPP (TG) and wild-type (WT) controls were sacrificed at 2, 3, 6- and 9-months age to assess endothelial function. In a second experiment, TG rats received weekly injections of antibody against aggregated hIAPP (3 mg/kg; TG-Ab) from 3–12 months of age; TG and WT controls received PBS. Oral glucose tolerance was assessed before harvesting. At the respective time points (12 mts in exp. 2), thoracic aortic rings were isolated and subjected to ex vivo isometric tension recording. After contraction with norepinephrine (NE 1x10–7 mol/L), cumulative relaxation responses were performed to glucagon-like peptide-1 (GLP-1; 10–12 to 10–6 mol/L) and insulin (10–11 to 10–6 mol/L). Pancreas and aortic arch samples were used for immunostaining of hIAPP antibody engagement.

Results

GLP-1 and insulin-mediated vasodilation was impaired in 3 month-old TG rats compared to WT. Glucose intolerance appeared in TG rats at 6 months in comparison to WT (p<0.0001), indicating that endothelial dysfunction in TG rats precedes the onset of glucose intolerance. Anti-hIAPP antibody showed selectivity against aggregated IAPP in pancreatic islets, but there was no target engagement in the aortic arch, questioning a pathogenic role of IAPP deposition in the aortic wall. At 12 months, glucose control in TG-Ab rats was improved in comparison to TG control rats (p<0.013). Vasodilatation in TG-Ab rats was restored in response to GLP-1 (35.5% ± 4.6 vs. 16.0% ± 3.1 in TG controls), similar to that of WT rats (35.5% ± 6.5). Vasodilatation in response to insulin (48.9% ± 4.2) was improved in comparison to both TG (29.4% ± 3.0) and WT controls (32.5% ± 5.7) (p<0.0001; 2-way ANOVA, n=6–11 for all groups.

Conclusion

Early endothelial dysfunction develops in hIAPP rats compared to WT. Endothelial dysfunction is restored by the anti-hIAPP antibody treatment via improved oral glucose tolerance, but it remains unclear whether this effect is due to a local action in the aorta or a secondary effect, e.g. due to a reduction in pancreatic IAPP deposition.
P725Molecular genetics of familial hypercholesterolemia in Israel revisited
Authors: Durst R , Ken Ibe U K I , Shpitzen S S , Schurr D S , Futema M F , Whittall R W , Humphries S H , Leitersdorf E L
Published: October 2019

Objective

Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the genes for LDL receptor (LDLR), apolipoprotein B (APOB) and Proprotein convertase subtilisin/kexin type9 (PCSK9). The purpose of the current investigation was to define the current spectrum of mutations causing FH in Israel.

Methods

New families were collected through the MEDPED (Make Early Diagnosis Prevent Early Death) FH program. Molecular analysis of the LDLR, PCSK9 and APOB genes were done using High Resolution Melt and direct sequencing in 67 index cases. A 6-SNP LDL-C gene score calculation for polygenic hypercholesterolaemia was done using TaqMan genotyping.

Results

Mean serum cholesterol was 7.48±1.89mmol/L and the mean serum LDL-C was 5.99±1.89mmol/L. Mutations in the LDLR and APOB gene were found in 24 cases (35.8%), with 16 in LDLR, none in PCSK9 and one, p.(R3527Q) in the APOB gene, which is the first APOB mutation carrier identified in the Israeli population. Of the LDLR mutations, two were novel; p.(E140A) and a promoter variant, c.-191C>A. The c.2479G>A p.(V827I) in exon 17 of the LDLR gene was found in 8 patients (33.3% of the mutations) with modestly elevated LDL-C but also in a compound heterozygous patient with a clinical homozygous FH phenotype, consistent with this being a “mild” FH-causing variant. A significantly higher 6-SNP LDL-C score was found in mutation-negative cases compared with a normal Caucasian cohort (p=0.03), confirming that polygenic inheritance of common LDL-C raising SNPs can produce an FH phenocopy.

Conclusions

The results indicate a different spectrum of genetic causes of FH from that found previously, in concordance with the heterogeneous and changing origins of the Israeli population, and confirm that a polygenic cause is also contributing to the FH phenotype in Israel.
P728Subclinical atherosclerosis and its progression are modulated by perilipin-2 through a feed-forward loop between LXR and autophagy
Authors: Ehrenborg E , Saliba Gustafsson P , Pedrelli M , Gertow K , Pourteymour S , Baldassarre D , Tremoli E , De Faire U , Humphries S E , Goncalves I , Orho-Melander M , Boren J , Eriksson P , Magne J , Parini P
Published: October 2019

Background

Hyperlipidemia is a major risk factor for cardiovascular disease and atherosclerosis is the underlying cause of both myocardial infarction and stroke. We have previously shown that the Pro251 variant of perilipin-2 reduces plasma triglycerides and may therefore be beneficial for atherosclerosis development.

Purpose

We sought to delineate putative beneficial effects of the Pro251 variant of perlipin-2 on subclinical atherosclerosis and the mechanism by which it acts.

Methods

A pan-European cohort of high-risk individuals where carotid intima-media thickness has been assessed was adopted. Human primary monocyte-derived macrophages were prepared from whole blood from individuals recruited by perilipin-2 genotype, or from buffy coats from the our University hospital blood central.

Results

The Pro251 variant of perilipin-2 is associated with decreased intima-media thickness at baseline and 30 months follow-up. Using human primary monocyte-derived macrophages from carriers of the beneficial Pro251 variant we show that this variant increases autophagy activity, cholesterol efflux, and a controlled inflammatory response. Through extensive mechanistic studies we demonstrate that increase in autophagy activity is accompanied with an increase in LXR activity and that LXR and autophagy reciprocally activate each other in a feed-forward loop, regulated by CYP27A1 and 27OH-cholesterol.

Conclusions

For the first time, we show that perilipin-2 affects susceptibility to human atherosclerosis through activation of autophagy and stimulation of cholesterol efflux. We demonstrate that perilipin-2 modulates levels of the LXR ligand 27OH-cholesterol and initiates a feed-forward loop where LXR and autophagy reciprocally activate each other; the mechanism by which perilipin-2 exerts its beneficial effects on subclinical atherosclerosis.

Acknowledgement/Funding

The Swedish Research Council, Swedish Heart-Lung Foundation, Marianne and Marcus Wallenberg's Foundation, Swedish Medical Society
P732Maternal high-fat diet promotes the expansion of abdominal aortic aneurysm in adult offspring by enhancing osteoclast-like macrophage differentiation
Authors: Saburi M , Yamada H , Wada N , Motoyama S , Sugimoto T , Kubota H , Miyawaki D , Wakana N , Matoba S
Published: October 2019

Background and objective

Maternal high-fat diet (HFD) has been shown to modulate vascular function and remodeling in adult offspring. Here, we investigated the impact of maternal HFD on abdominal aortic aneurysm (AAA) formation.

Methods and results

Eight-week-old female wild-type mice (C57BL/6) were fed a HFD or normal diet (ND) one week prior to mating and received during pregnancy and lactation. In eight-week-old offspring of both genders, AAA was induced with the application of 0.5M calcium chloride (CaCl2) on the infrarenal aorta. Male offspring of HFD-fed dams (O-HFD) showed a significant increase in maximum outer diameter of AAA at 1, 4 and 8 weeks after surgery compared with offspring of ND-fed dams (O-ND) (P<0.05). The lengths of outer circumference assessed by histological analysis were increased in O-HFD (P<0.05). Likewise, female O-HFD showed a greater length of outer circumference than female O-ND (P<0.05). While the number of F4/80-positive cells at 1 wk after surgery was comparable between the male O-HFD and O-ND, the percentage of MMP-9/F4/80 double-positive cells was significantly increased in male O-HFD. Consistently, fluorescent image of abdominal aorta taken by IVIS at 1 wk after surgery revealed a 2-fold increase in MMP activity (P<0.01). Intriguingly, F4/80-positive cells in male O-HFD showed a 2.5-fold increase in co-staining with tartrate-resistant acid phosphate (TRAP), typical marker of osteoclast-like macrophages which abundantly secrete proteases than classically activated macrophages (M1), while the percentage of TNF-α/F4/80 double-positive cells was comparable between the 2 groups. Pharmacological inhibition of osteoclastogenesis by zoledronic acid (ZA) (100μg/kg) completely abolished the exaggerated AAA development in male O-HFD to a similar extent of that in male O-ND, while AAA development in male O-ND mice did not change even after ZA treatment. Furthermore, in vitro TNF-α-induced osteoclast differentiation of bone marrow-derived macrophages (BMDMs) showed a significantly higher number of TRAP-positive cells, accompanied by increased calcitonin receptor mRNA expression. Western blotting analysis showed that protein expression level of NFATc1, master regulator of osteoclastogenesis, was significantly higher in BMDM of O-HFD than O-ND.

Conclusion

Our findings demonstrate that maternal HFD accelerates CaCl2-induced AAA expansion, accompanied by the exaggerated accumulation of osteoclast-like macrophages and augmented activity of MMPs. Inhibition of macrophages skewing toward osteoclast-like cells could be a potential therapeutic target for preventing AAA development.
P737Endothelial ERK2/thromboxane receptor pathway induces endothelial dysfunction, insulin resistance and steatohepatosis through superoxide with high fat high sucrose diet
Authors: Sato A , Satoh Y , Endo S , Kimura T , Osaki A , Horii S , Ito K , Kagami K , Namba T , Adachi T
Published: October 2019

Introduction

Metabolic syndrome (MetS) is well known as the risk of cardiovascular diseases associated with endothelial dysfunction and induces steatohepatosis. Insulin resistance is a major character of MetS, which affects intracellular signaling pathways and endothelial function. Extracellular signal-regulated kinase (ERK) is a major component of insulin signal and many of vasoactive peptides, which were released in MetS, can activate it in endothelium. However, the role of endothelial ERK in nitric oxide (NO) bioactivity in MetS in in vivo has been unknown.

Purpose

The aim of this study is to clarify the role of endothelial ERK2 on NO bioactivity in mice model of MetS.

Methods and results

We created endothelial specific ERK2 knock out mice (EE2KO) crossing Tie2-Cre mice and ERK2 flox mice and fed them with normal or high-fat/high-sucrose diet (HFHSD) for 24 weeks. Serum glucose and insulin levels and HOMA-IR were lowered in EE2KO with HFHSD without changing body weight. In wild type mice (WT) with HFHSD, nonalcoholic fatty liver disease (NAFLD) activity score, fibrosis score and serum ALT level were increased, all of which were blunted in EE2KO. EE2KO with HFHSD lowered systolic blood pressure (WT: 123.7±5.83 mmHg, EE2KO: 101.4±3.66 mmHg, P<0.01, N=8) without changing heart rate, which was increased to the same levels with L-NAME, an endothelial NO synthase inhibitor, in both groups. Serum NO levels measured with serum nitrite/nitrate concentrations were increased in EE2KO with HFHSD (WT: 23.10±3.74 μmol/l, EE2KO: 41.71±6.73 μmol/l, P<0.05, N=12). Endothelial function was assessed with the isometric tension measurement of aortic rings with acetylcholine (ACh). ACh-induced relaxation was improved in EE2KO with HFHSD. Superoxide production of aorta from EE2KO was lowered than WT with HFHSD in dihydroethidium (DHE) staining. S18886, an antagonist of the thromboxane A2-prostanoid (TP) receptor, decreased superoxide production of aorta in DHE staining resulting in improving endothelial function in the isometric tension measurement of aortic rings. Oral administrations of S18886 decreased systolic blood pressure, serum fasting glucose and insulin levels, and surprisingly improved steatohepatosis by decreasing NAFLD activity score and fibrosis score.

Relaxation of aortic rings with ACh

Conclusions

Endothelial ERK2/TP receptor pathway increases superoxide production and decreased NO bioactivity, resulting in deteriorating endothelial function, insulin resistance and steatohepatosis, which were improved by antagonist of the TP receptor in mice model of MetS. The present study indicates that ERK2/TP pathway could be a therapeutic target for complications of MetS.
P750Role of circulating endothelial cells post-heart transplantation
Authors: Rywik T , Braniewska A , Kowalik I , Firczuk M , Kozar-Kaminska K , Wojciechowska A , Kasprzyk-Pawelec A , Sobieszczanska-Malek M , Leszek P , Rozentryt P , Zielinski T
Published: October 2019

Background

The role of endothelial progenitor cells (EPC) in heart transplantation (HT) is not well defined. Thus, the aim of this study was to evaluate prospectively the dynamic changes of circulating EPC levels in relation to post-HT rejection risk.

Methods

There were 27 HT recipients who had EPC from peripheral blood quantified during 6 months follow-up after HT. Patients were monitored regularly, by right ventricular endomyocardial biopsy assessment, for cellular rejection (ACR) defined as grade ≥2 or an antibody-mediated rejection (AMR) characterized by histopathological changes recorded as AMR1H. The primary end-point was acute rejection, either AMR or ACR.

Results

ACR and AMR were observed in 7 (25.9%) and 6 (22.2%) subjects respectively. EPC levels, after logarithmic transformation, immediately post-HT were alike regardless of ACR status, however patients with lower EPC were at risk of AMR at 1 month (Table 1). On the other hand patients with a significant reduction of EPC at 1 month post-HT compared with HT were less likely to have either ACR or AMR (p=0.0003). During longer post-HT observation (12 months) patients had similar EPC levels regardless of the rejection events. Dynamic changes in EPC levels are presented in figure. Nonetheless, greater changes in EPC expressed by coefficient of variation were associated with the risk of either AMR or ACR compared to the participants without rejection (mean [lower–upper quartile]) 15 [13–18] vs 8 [5–13]; p=0.02) and (22 [14–26] vs 8 [5–13]; p=0.01) respectively.

EPC by rejection – 1st month following HT ACR (+) AMR (+) ACR (−) and AMR (−) p^ p p N=3 (mean± SD) N=4 (mean± SD) N=20 (mean± SD) ACR (+) vs ACR (−) and AMR (−) AMR (+) vs ACR (−) and AMR (−) EPC log HT 5.14±1.55 3.81±1.01 5.30±0.88 0.0325 0.97 0.025 EPC log M1 4.97±0.59 3.69±1.33 4.15±1.29 0.4160 0.55 0.78 Delta EPC log M1-HT -0.17±1.98* −0.12±1.30* −1.15±1.18# 0.2195 0.44 0.32 ACR – acute cellular rejection; AMR or – acute antibody-mediated rejection; EPC log – endothelial progenitor cells after logarithmic transformation; HT – within 24 hours post-transplantation; M1 – at 1-month post-transplantation; Delta EPC log M1-HT – difference in EPC log between M1 and HT. #p=0.0003 for the difference between M1 vs HT; *p=ns for the difference between M1 vs HT; ^pP – for the difference among the groups.

Changes in EPC level post-HT

Conclusions

Early reduction of EPC levels was predictive of a lower risk of ACR or AMR. Greater dynamic changes of EPC during 6 months of observation were associated with a higher risk of rejection suggesting an important role of EPC in the pathological processes post-HT. Thus our findings suggest significant role of EPC post-HT with respect to rejection status.

Acknowledgement/Funding

Intramural research grant from the Institute of Cardiology
P757Methamphetamine-associated cardiomyopathy: a case-controlled study of clinical characteristics, management and outcomes
Authors: Wang T K M , Kueh A , Gabriel R , Sutton T , Lund M , Kerr A , Looi J L
Published: October 2019

Background

Methamphetamine-associated cardiomyopathy (MAC) is an increasingly diagnosed condition with poor prognosis, and there remains paucity of literature including how MAC differs from other cardiomyopathies. We compared the characteristics and outcomes MAC patients with non-ischaemic cardiomyopathy controls at our centre.

Methods

Clinical profile, management and outcomes were prospectively assessed in consecutive patients with MAC at our hospital from 2006–2018. They were compared with randomly chosen controls with non-ischaemic dilated cardiomyopathy of similar age-group (20–65 year).

Results

Both groups had 62 patients followed for 3.0±2.9 years. MAC patients were younger, with higher proportion of Maori ethnicity, unemployment and cardiogenic shock during index admission and lower proportion of Pacific ethnicity, cardiovascular risk factors and atrial fibrillation. MAC patients also had higher peak NT-proBNP, lower ejection fraction, and lower attendance rate to outpatient appointments. There was no index admission mortality in both groups. MAC had higher mortality and trend to higher heart failure re-admissions rates during follow-up (Figure 1). Amongst MAC patients, baseline left ventricular end diastolic diameter and failure of improvement in right ventricular systolic function by one category during follow-up were independent predictors of mortality, while failure of improvement of left ventricular ejection fraction by one category predicted heart failure readmission.

Figure 1

Conclusions

MAC patients were younger but sicker on presentation, with higher mortality and trend towards higher heart failure readmission rates during medium-term follow-up than controls. Adherence to therapy and attendance to appointments may improve cardiac systolic function over time to reduce adverse clinical endpoints.
P768Cardiopulmonary exercise testing for assessing frailty status in stable elderly patients with heart failure
Authors: Hirashiki A , Kawashima K , Nomoto K , Kokubo M , Shimizu A , Arai H
Published: October 2019

Introduction

Frailty is a syndrome associated with aging that produces subclinical dysfunction across multiple organ systems and leads to increased risk of mortality. The Kihon Checklist (KCL) was developed by the Japanese Ministry of Health, Labor and Welfare to identify older persons in need of care; it is a reliable tool for predicting general frailty in older adults. There is little information about the relationship between frailty status and exercise capacity.

Purpose

To investigate whether cardiopulmonary exercise testing (CPX) parameters are associated with frailty in stable elderly patients with heart failure (HF).

Methods

Ninety-two stable elderly patients with HF were evaluated by using CPX and the total KCL (t-KCL). A t-KCL score of 0–3 was classified as robust, 4–7 as pre-frail, and ≥8 as frail. Diagnostic performance (DP) -plot analysis was used to assess the utility of CPX parameters to distinguish between the presence and absence of frailty.

Results

Mean age, left ventricular ejection fraction, plasma brain natriuretic peptide, peak work rate (WR), peak VO2, and t-KCL score were 81.7 years, 57.8%, 182 pg/mL, 49.6 W, 13.2 mL/kg/min, and 10.7, respectively. t-KCL score was significantly correlated with peak VO2 (r=−0.53, p<0.001) and peak WR (r=−0.63, p<0.001). In the patients with frailty (n=63), peak WR was significantly lower than that in patients without frailty (n=29; 40.8 and 71.0 W, respectively, p<0.001). Multivariate analysis revealed that peak WR was the only significant independent predictor of frailty (β=−0.111, p<0.001). In the DP-plot analysis, a cut-off value for peak WR of 51.9 W was the best predictor of frailty (accuracy; 0.706, Figure).

Cut-off value for peak WR

Conclusions

Frailty status was significantly associated with peak WR in stable elderly patients with HF. CPX may be useful for assessing frailty status in stable elderly patients with HF.
P788Discharge echocardiographic parameters of RV and LV function but not of changes in cardiac unloading are related to 12-month prognosis during hospitalization for acute decompensated heart failure
Authors: Monney P , Barras N , Tzimas G , Abdurashidova T , Regamey J , Yerly P , Hugli O , Hullin R
Published: October 2019

Introduction

Acute decompensated heart failure (ADHF) is associated with a high mortality and rehospitalization rate. The aim of this study was to assess whether echocardiographic markers of systolic and diastolic function, and their changes under treatment during hospitalization for ADHF, would predict 12-months mortality.

Methods

Adult patients admitted to our emergency department for ADHF between June 2015 and January 2018 were included if a complete transthoracic echocardiography (TTE) could be obtained within 12 hours of admission. TTE was repeated upon discharge. Baseline clinical and echocardiographic characteristics were collected on admission and at discharge, and outcome at 12 months was obtained by telephone interview. All parameters are given as median [interquartile range].

Results

A total of 221 patients were identified but 45 excluded because of in-hospital death (n=8), early transfer to another hospital (n=31) or refusal to perform discharge TTE (n=6), leaving 176 patients for final analysis. Age was 83 [74–87] years, 95 (54%) were men and 89 (51%) were in sinus rhythm. Baseline TTE was performed within 6.6h [4.1–11.9] of admission and median duration of hospital stay was 13 days [9–19]. Admission ejection fraction (EF) was 45% [37–54] (29% HFrEF, 37% HFmrEF, 34% HFpEF). Between admission and discharge, significant changes were observed for global longitudinal LV strain (−10.3 [−7.2 to 15.1] to −11.8% [−8.1 to 15.0], p=0.017), mitral E velocity (100 [80–124] to 96 cm/s [74–117], p=0.001), E/e' ratio (16 [12–20] to 15 [11–19], p=0.003, RV basal diameter (41 [36–45] to 41mm [34–44], p=0.007), tricuspid regurgitation gradient (41 [34–52] to 35 mmHg [28–44], p=0.0001 and vena cava diameter (22 [19–26] to 19 mm [15–23],. Deaths occurred in 35 (20%) at 12 months follow-up. In our multivariable model, none of the changes in TTE parameters was predictive of mortality. Age (OR 1.09, p0.01), LVEF (OR 0.95, p0.02) and TAPSE (OR 0.86, p0.01) measured at discharge, but not LV or RV strain, were identified as independent predictors of 12-months mortality (see figure).

Survival according to LVEF and TAPSE

Conclusion

Several changes in TTE parameters were observed during hospitalization for ADHF, reflecting effective cardiac unloading with diuretic treatment. However, none of these changes appears to have prognostic significance. LVEF and TAPSE at discharge were identified as the only independent echocardiographic predictors of 12-months mortality, in addition to age.

Acknowledgement/Funding

Swiss Heart Foundation