bluuebunny/crossref_metadata_2025 huggingface dataset:
254New possibilities of thrombolytic therapy in patients with STEMI according to a multicenter clinical study FRIDOM1
Authors: Gerasimets E
Published: October 2019

Aim

To assess the efficacy and safety of the single bolus of a new Russian genetically engineered drug Fortelyzin® in comparison with the single bolus of drug Metalyse® in ST-segment elevation myocardial infarction patients with12 hours after symptoms onset.

Materials and methods

Clinical trial took place from 2014 to 2016 in 11 clinical centers in Russia, the study was planned as a non-inferiority study with an assessment of the main results of intention to treat. The study included 382 STEMI patients, who were randomized to the Fortelyzin® and Metalise® groups. Fortelyzin® was administered by bolus at a dose of 15 mg regardless of body weight, Metalise® was administered by bolus at a dose of 30–50 mg depending on body weight. Thrombolytic therapy was accompanied by anticoagulant, double antiplatelet therapy in standard dosages with subsequent planned or emergency percutaneous coronary intervention (PCI). The observation was carried out within 30 days from the moment of randomization.

Results

The reperfusion according to 90 min ECG data occurred in 80% and according to coronary angiographic data (TIMI 2 + TIMI 3) in 70%. The “no less effective” rating, conducted by the difference in the CAG criterion (TIMI 2 + TIMI 3) in the Fortelyzin® and Metalise® groups, was equal to 0.81% and did not go beyond the limit of the clinical significance of 12.5. The primary final combined point which includes the sum of deaths from any causes + repeated myocardial infarction + cardiogenic shock, in the Fortelyzin® and Metalise® groups was 12.63% and 12.56% (p>0.99), respectively. In a clinical study, no intracranial hemorrhage was observed in both groups. In the Fortelyzin® and Metalise® groups, one patient was observed with large bleeding according to TIMI and GUSTO classification. Minor bleeding was observed in the Fortelyzin® group – 3.7%, in the Metalysis® group – 10.5% (p=0.02).

Conclusion

In the clinical trial FRIDOM1, it was demonstrated that a single bolus administration of Fortelyzin® at a dose of 15 mg in combination with anticoagulant and double antiaggregant therapy followed by PCI, is no less effective and safe than the use of Metalise®.

Trial Registration: ClinicalTrials.gov NCT02301910

Acknowledgement/Funding

SuperGene
281Impact of complications on VA-ECMO support for cardiopulmonary support: analysis of 8,351 adult patients in Germany from 2007 to 2015
Authors: Becher P M , Schrage B , Schmack B , Sinning C , Fluschnik N , Waldeyer C , Seiffert M , Neumann J T , Bernhardt A M , Reichenspurner H , Zeymer U , Thiele H , Blankenberg S , Twerenbold R , Westermann D
Published: October 2019

Background

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used for treatment of patients with critical cardiopulmonary failure. However, utilization of VA-ECMO support must be carefully weighed against possible complications. Therefore, we investigated the incidence and impact of complications on VA-ECMO support in one of the largest datasets of VA-ECMO therapy.

Material and methods

We analyzed complications and outcomes of all VA-ECMO procedures performed in Germany from 2007 to 2015 by using administrative data from the German Federal Health Monitoring System. For the present analyses all cases treated with VA-ECMO between 2007 and 2015 were identified and selected by the primary procedural code (OPS) for VA-ECMO (OPS code 8852.3).

Results

Among 8,351 patients undergoing VA-ECMO between 2007 and 2015, there were significant changes in complication rates over time such as increase in acute kidney injury (from 35.9% in 2007–2012 to 44.6% in 2013–2015), major bleeding (from 11.3% in 2007–2012 to 19.5% in 2013–2015 and abdominal ischemia (from 4.5% in 2007–2009 to 7.2% in 2013–2015). The incidence of stroke and limb ischemia did not differ over time. Procedure-related and ischemic complications were more frequently observed in non-survivors as compared to survivors (12.2% versus 15.3%, p<0.001) except for major bleeding (20.9% in survivors versus 15.0% in non-survivors, p<0.001). Multivariate analyses retained stroke and acute kidney injury as being significantly associated with 30-day in-hospital mortality, with respective OR [95% CI] of 1.7 [1.0–2.9] and 1.2 [1.1–1.3].

Conclusion

In one of the largest registries, major bleeding and ischemic events are the most common complications on VA-ECMO support. Ischemic complications seem to influence outcome more than bleeding complications. However, only stroke and acute kidney injury were independently associated with higher mortality rates. These findings should be incorporated in risk-benefit stratification when initiation of VA-ECMO and in prevention of complications to avoid additional morbidity and mortality in these critically ill patients.
P313ADGRL2 is an essential surface molecule for cardiac lineage specification and heart development
Authors: Cho H J , Lee C S , Lee J W , Yang H M , Kim H S
Published: October 2019

Background

Specific surface markers that enable monitoring of cell subsets would be valuable for establishing the conditions under which pluripotent stem cells (PSCs) differentiate into cardiac progenitor cells (CPCs) and cardiomyocytes (CMCs).

Methods and results

To verify whether a specific marker is expressed during heart development, we assessed its expression using the CLARITY technique. After immersion in a solution with a refractive index matching that of the CLARITY hybrid, the mouse embryo became transparent. After immunostaining the cleared embryo sample, Adgrl2 was exclusively observed in cardiac cells expressing α-SA at embryonic day E9.5 and E10.5. Our clarified 3D images and movies show that four chambers of the heart are fully developed at E10.5 but not at E9.5. At E9.5, Adgrl2 is observed at the ventricle and atrium, while Adgrl2 is present in all chambers of the heart at E10.5. Next, we performed LacZ (β-Gal) staining in heterozygous Adgrl2 KO embryos to evaluate Adgrl2 expression. As a result, LacZ staining showed that Adgrl2 was predominantly expressed in the heart during the embryonic developmental stage. Adgrl2 knockout in mice was embryonically lethal because of severe heart, but not vascular, defects. To examine the use of Adgrl2 as a bona fide CPC marker during heart development, we tracked Adgrl2 expression during early embryonic development. The heart of Adgrl2−/− embryos at E10.5 exhibited occlusion of the RV, and the expression levels of Gata4 and Nkx2.5 were not as high as those in wild-type and Adgrl2+/− embryos. Interestingly, the heart of Adgrl2−/− embryos, unlike those of wild-type and Adgrl2+/− embryos between E13.5 and E15.5 had a single ventricle revealing a ventricular septal defect. The specific expression pattern of Adgrl2 in PSC-derived cardiac lineage cells as well as in embryonic heart, adult mice, and human heart tissues.

Conclusion

We demonstrate that Adgrl2 plays a pivotal and functional role across all strata of the cardiomyogenic lineage, as early as the precursor stage of heart development. These findings shed light on heart development and regeneration.

Acknowledgement/Funding

Grants from “Strategic Center of Cell and Bio Therapy” (grant number: HI17C2085) and “Korea Research-Driven Hospital” (HI14C1277)
P329Residual platelet reactivity after pre-treatment with ticagrelor prior to primary percutaneous coronary intervention is associated with suboptimal myocardial reperfusion
Authors: Roule V , Heudel T , Lemaitre A , Bignon M , Ardouin P , Sabatier R , Blanchart K , Beygui F
Published: October 2019

Background

The evidence of a clinical benefit of P2Y12 inhibitor pre-treatment in primary percutaneous coronary intervention (PCI) and the relation between the level of platelet inhibition and myocardial reperfusion with newer potent P2Y12 inhibitors remain unclear.

Objectives

We aimed to assess the relationship between platelet reactivity at the time of primary PCI after pre-treatment with aspirin and ticagrelor and the post-PCI myocardial blush grade (MBG).

Methods

We prospectively included 61 patients. Platelet reaction units for ticagrelor (PRU) and aspirin reaction units (ARU) were measured using the point-of-care test VerifyNow before PCI. The high on-ticagrelor (PRU >208) and on-aspirin (ARU ≥550) platelet reactivity (HPR and HaPR) were assessed. Patients were divided into two groups according to MBG 3 or <3.

Results

MBG 3 was identified in 28 (46%) patients. Mean PRU was lower in such patients as compared to those with MBG <3 (155.82±90.91 vs 227.42±65.18; p=0.001) while mean ARU was similar between groups. HPR and HaPR were observed in 30 (49.2%) and 11 patients (18%), respectively. HPR but not HaPR was more frequent in the group with impaired MBG (66.7 vs 28.6%; p=0.003 and 21.2 vs 14.3%; p=0.48 respectively).

Table 1. Platelet reactivity results Verify Now at admission All Final Blush <3 Final Blush 3 p n=61 (100%) n=33 (54%) n=28 (46%) PRU P2Y12 194.56±85.32 227.42±65.18 155.82±90.91 0.001 Base 193.54±49.01 194.79±45.68 192.07±53.48 0.83 Inhibition of platelet aggregation (%) 15.61±29.85 5.7±17.55 27.29±36.79 0.007 ARU 463.97±76.45 472.58±72.5 453.82±81 0.34 PRU >208 30 (49.1%) 22 (66.7%) 8 (28.6%) 0.003 ARU ≥550 11 (18%) 7 (21.2%) 4 (14.3%) 0.48 Verify Now at day 1 n=57 n=30 n=27 p PRU P2Y12 40.86±41.43 47.27±45.87 33.74±35.35 0.21 Base 196.98±36.19 193.67±30.67 200.81±41.97 0.47 Inhibition of platelet aggregation (%) 79.8±17.96 76.37±20.54 83.77±13.78 0.11 ARU = Aspirin reaction units; PRU = P2Y12 reaction units.

Conclusion

In conclusion, our study shows that higher PRU and the subsequent HPR at the time of primary PCI, after pretreatment with ticagrelor, are the only correlates of post PCI MBG. These findings support the earliest possible loading with ticagrelor prior to primary PCI.

Acknowledgement/Funding

The study was supported by grants from Terumo. The funder has no role in any step of the study.
P577Early experience with the first pacemakers to directly connect with smart devices for remote monitoring
Authors: Tarakji K , Zweibel S , Seiler A , Roberts P , Shaik N , Silverstein J , Patwala A , Mittal S , Molon G , Augello G , Porfilio A , Holloman K , Varma N , Sears S , Turakhia M
Published: October 2019

Background

Remote monitoring is associated with improved patient outcomes; however, adoption and adherence to remote monitoring via home-based consoles remains suboptimal. BlueSync technology in new generation pacemaker and CRT-P models enables the implanted device to communicate directly with patient-owned, Bluetooth-equipped smartphones/tablets and an app (MyCareLink Heart). The app can automatically retrieve information from the cardiac device and transmit the data to the remote network, eliminating the need for traditional remote monitoring consoles.

Objectives

To characterize the communication process between implanted pacemakers and smart device remote monitoring apps by assessing the success of prescheduled remote transmissions in the first month of follow-up. Additionally, to assess the feedback of both patients and clinicians about the process of device pairing.

Methods

Enrollment in the BlueSync Field Evaluation began in April 2018 and was completed November 2018. Follow-up is ongoing. Prior to enrollment in the evaluation, patients completed the device pairing process with the app using their own compatible smartphone or tablet. Patient and clinician questionnaires were completed at the time of the device pairing process. After enrollment, successful completion of scheduled transmissions occurring in the first month were analyzed.

Results

Preliminary data includes 241 enrolled patients with mean age of 64.7±15.5 yrs (min 20, max 90 yrs), who completed device pairing between their implanted device and their smart device app. Of enrolled patients, 79% felt that the device paring was easy to do, 85% were satisfied with the amount of time it took to complete it, and 93% felt that they would be comfortable using the app. Clinicians reported that 67% of the device pairings took less than 20 minutes and 78% felt patients would be able to use the app independently. At the time of analysis 174 patients had at least one scheduled transmission within the first month, and collectively had a total of 322 scheduled transmissions. Out of these, 309 (96%, 95% CI: 93%-98%) were successfully completed.

MyCareLink Heart App

Conclusions

Initial experience with the world's first app based remote monitoring system for Bluetooth enabled pacemakers demonstrated success to scheduled transmissions in the first month across a wide range of patient ages. Patients and clinicians reported high satisfaction with this novel technology.

Acknowledgement/Funding

Medtronic PLC
P578Use of a smartphone application to increase adherence to medical treatment in patients with acute coronary syndrome: a randomized clinical trial
Authors: Garmendia C M , Miranda P , Verello E , Goyeneche M A , Furmento J F , Hasseb S , Trivi M , Costabel J P
Published: October 2019

Background

Adherence to cardiovascular medications following acute coronary syndrome (ACS) hospitalization is generally poor and is associated with increased risk of rehospitalization and mortality. There are still significant opportunities to identify simple and low-cost interventions that improve medication adherence and clinical outcomes.

Purpose

To evaluate the use of a digital platform for smartphones to improve adherence to medical treatment and outcomes for 90-days post discharge in patients hospitalized for ACS with or without ST-elevation.

Methods

This was a unicentric, single-blinded, randomized controlled trial enrolling 90 patients with an ACS event requiring hospitalization. The intervention consisted of a smartphone application which allowed for the loading of medication prescription together with reminder of the daily compliance. Patients in the intervention group (n=46) were equipped with the smartphone application. Patients in the control group (n=44) received written and oral instructions as per standard of care. The primary outcome was adherence to medical treatment measured at 90-days post discharge using the 8-item Morisky Medication Adherence Scale (MMAS-8). The secondary outcome was a composite of re-hospitalizations for ACS, consultations to the emergency department (ED), or unplanned visits to the clinic.

Results

The mean age of the population was 63.2±9.9 and 75.6% were male. At 90 days, 64.7% of patients using the smartphone application were adherent compared with 20.5% of patients in the control group (p<0.001). Patients in the intervention group had higher adherence (mean MMAS-8 score 7.52±1.25) compared with the control group (mean MMAS-8 score 6.47±1.23; p<0.001). The secondary outcome measures showed that there were no significant differences in patients using the smartphone application versus the standard of care (4.3% vs 15.9%, p=0.07, respectively).

Table 1 Variables Global (n=90) Control (n=44) Intervention (n=46) p MMAS-8 score 7±1.34 6.47±1.23 7.52±1.25 <0.001 Adherents 40 (44.4%) 9 (20.5%) 31 (67.4%) <0.001 Events 9 (10.1%) 7 (15.9%) 2 (4.3%) 0.071 ED consultations 9 7 2 Score assessment 8.85±1.4

Conclusions

In patients with ACS, the use of a smartphone application increased the medication adherence compared with the standard of care. These data suggest that there is potential for a simple, low-cost intervention to help patients adhere to medications.

ClinicalTrials.gov unique identifier: NCT03766789.
P582Real-world experience with ehealth telemonitoring in patients with hypertension
Authors: Blok S , Somsen G A , Stavrov B , Tulevski I I , Van Den Born B J H , Winter M M
Published: October 2019

Background

Hypertension is the strongest modifiable risk factor for cardiovascular disease worldwide, while incidence and prevalence remain high. Home-monitoring is known to improve blood pressure in patients with hypertension. Despite promising results, few home monitoring programs have successfully been integrated into daily care and little evidence exists on their cost-effectiveness. The Dutch HartWacht eHealth program, initiated in June 2016, is one of the first eHealth programs that is fully reimbursed and integrated into clinical practice.

Purpose

The purpose of the study is to demonstrate the effect of an integrated and cost-effective telemonitoring program in a real-life setting.

Methods

In the HartWacht program patients with uncontrolled hypertension (office BP >140/90) receive a blood pressure monitor that is connected to their smartphone and integrated with their personal electronic patient file. Measurements are checked by a dedicated health care team. If values exceed pre-defined thresholds, patients are contacted by the team for swift therapeutic action. In this study, the first results of the program are evaluated.

Comparisons were made between last office blood pressure before the program; average blood pressure of first week of home measurement (twice daily, morning and evening); and blood pressure of home measurement at three, six and twelve months after start.

Results

122 patients started the HartWacht program for hypertension (female: 57 (46.7%); mean age: 61.2 (±9.5) years; mean follow-up: 13.4 (±7.6) months; mean number of anti-hypertensive drugs at start of HartWacht: 1.8 (±0.9); mean number of medication changes per year during follow-up (including changes in dose): 1.0 (±1.6); mean number of contact moments per year during follow-up (including calls with nurse or cardiologist): 4.9 (±5.0)). At final follow-up, 67 patients participated at least one year. Others started later or stopped the program, mainly because of reaching normotensive values (n=22; home BP <135/85).

The mean last office systolic blood pressure (SBP) measurement (n=122) was 157.9 mmHg (±19.2). The mean home SBP in the first week (n=120) was 139.9 mmHg (±13.9). After 3 months the mean home SBP lowered to 133.8 mmHg (±14.9), a significant decrease compared to week 1 (mean: 6.1 (±13.8), p<0.001). After this moment the mean home SBP was stable: 132.5 mmHg (±12.6) at six months (n=99) and 132.2 mmHg (±12.4) at 12 months (n=67).

No correlation was found between the number of medication adaptations and/or contact moments with the healthcare team and reaching target values.

Conclusion

This integrated eHeatlh telemonitoring program demonstrates significant and persistent blood pressure reduction in a real-life setting. As measurements are continuously monitored, swift therapeutic action is guaranteed. The Dutch HartWacht program has proven to be cost-effective, is reimbursed, and has the potential to be scaled up (inter-)nationally.
P601Heart disease and pancreatic iron in thalassemia major
Authors: Meloni A , Pistoia L , Restaino G , Renne S , Giunta N , Righi R , Giuliano P , Riva A , Giovangrossi P , Vitucci A , Positano V , Pepe A
Published: October 2019

Background

Some preliminary data have postulated a correlation between pancreatic iron overload and heart iron and function in thalassemia major (TM) patients.

Purpose

In the present multicenter study we explored systematically the link between pancreatic iron and heart disease in a large cohort of TM patients.

Methods

We considered 880 TM patients (467 M, mean age 37.83±10.05 years) enrolled in the E-MIOT (Extension-Myocardial Iron Overload in Thalassemia) project. T2* measurements were performed over pancreatic head, body and tail and global value was the mean. Myocardial iron overload (MIO) was quantified using a T2* segmental approach. Biventricular function parameters were assessed by cine images. Late gadolinium enhancement (LGE) images were acquired to detect myocardial fibrosis.

Results

A significant correlation between pancreatic and cardiac iron was reconfirmed in this more numerous population and a normal pancreas T2* showed negative predictive value of 100% for cardiac iron.

LGE sequences were acquired in 273 TM patients and 84 (30.77%) of them showed macroscopic myocardial fibrosis. Global pancreas T2* values were significantly lower in patients with fibrosis (7.38±6.19 ms vs 11.91±9.79 ms; P<0.0001).

Sixty-four patients had at least one cardiac complication (arrhythmias, heart failure, pulmonary hyperthension, vascular disease). Patients with cardiac complications showed a significant lower global pancreas T2* (7.83±5.61 ms vs 12.76±10.34 ms; P=0.024). Specifically, global pancreas T2* values were significantly lower in patients with heart failure as well as in patients with arrhythmias and all patients with one of these two diseases had a pathologic global pancreas T2* value (see Figure).

Conclusion

Pancreatic iron is a strong predictor not only for cardiac iron, but also for cardiac complications supporting a more profound link between pancreatic iron and heart disease in TM.
P6093D echocardiography versus cardiovascular magnetic resonance in the evaluation of the right ventricle in patients with congenital heart disease after pulmonary valve replacement
Authors: Pluchinotta F R , Panebianco M , Piazza L , Tarzia P , Fusini L , Pepi M , Giugno L , Chessa M , Carminati M , Bussadori C
Published: October 2019

Background

Cardiac MR (CMR) is the gold standard for right ventricular (RV) quantification. Three-dimensional echo (3DE) is a relatively new technique which may offer a rapid alternative for the examination of the right heart. The purpose of this study was to investigate the clinical significance and interchangeability of these modalities to evaluate patients with congenital heart disease (CHD) who underwent percutaneous pulmonary valve implantation (PPVI) for RV outflow tract dysfunction.

Methods

36 patients who underwent PPVI were evaluated with 3DE and CMR to quantify the RV. RV volumes and ejection fraction (EF) were measured for both imaging techniques with commercially available softwares (Tomtec-Germany for 3DE and Medimatic-Netherlands for CMR data). Paired t-test, Bland-Altman analysis, and Pearson's correlation analysis were used as most appropriate to compare both measured techniques with CMR regarded as the reference standard.

Results

86% of the patients (31 patients) had adequate image quality on 3DE and was included in the study. Patients underwent both 3D echo and CMR within a mean of 9 days of each other and at a mean time of 3 years after PPVI. Compared to CMR, 3D echo significantly underestimated volumes in all patients and overestimate RV ejection fraction (EF). Mean RV End-diastolic Volumes (EDV) and End-Systolic Volumes (ESV) were significantly greater when measured by CMR compared to 3D echo (EDV: 99 ml/m2 vs. 85 ml/m2; p<0.01, ESV: 52 ml/m2 vs. 41 ml/m2; p<0.01). Mean RV EF was lower when measured by CMR compared to 3D echo (48% vs 52%; p<0.05). Linear regression analysis showed high correlation coefficients between 3DE and CMR (r=0,68 for EDV, r=0,62 for ESV, and r=0,57 for EF; p<0.001). Bland-Altman analysis demonstrated that for both RV EDV and RV ESV there was a significant and systematic under-estimation of volume by 3D echo compared to CMR. Both 3DE and CMR measurements were found to be highly reproducible in terms of intra-observer variability.

Conclusions

Statistically significant and clinically meaningful differences in volumetric measurements were observed between 3DE and CMR in the evaluation of RV volumes and function in patients with CHD after PPVI. Despite linear regression and Bland-Altman analysis showed that the two techniques are related and present some degree of agreement, 3D Echocardiography systematically underestimates volumes and overestimates EF and this would have to be considered in the clinical practice.
P620The prognostic value of the ratio of transmitral early filling velocity to early diastolic strain rate in type 1 diabetes patients
Authors: Lassen M H , Biering-Soerensen T B S , Joergensen P G J , Andersen H U A , Rossing P R , Jensen M T J
Published: October 2019

Background

Cardiovascular disease is one of the main causes of morbidity and mortality in patients suffering from type 1 diabetes mellitus. It is of great importance to identify early signs of cardiac pathology such as elevated left ventricular (LV) filling pressure. The ratio of transmitral early filling velocity to early diastolic strain rate (E/e'sr) has in recent studies proved to be an accurate measure of left ventricular (LV) filling pressure. Furthermore, E/e'sr has demonstrated strong prognostic value across different study populations.

Purpose

The aim of this study was to assess the prognostic value of E/e'sr in a large cohort of patients with type 1 diabetes mellitus in relation to cardiovascular morbidity and mortality.

Methods

In this prospective study, 1082 patients with type 1 diabetes mellitus (mean age 50±15 years, 53% male, mean duration of diabetes 26 years) underwent a comprehensive echocardiographic examination including both conventional measurements and two-dimensional speckle tracking in which E/e'sr along with other echocardiographic measurements were obtained. The primary outcome was defined as a major cardiac event (heart failure, stroke, myocardial infarction or cardiovascular death).

Results

During follow-up (median: 6.2 years, IQR: 5.7, 6.9) 144 (13.3%) met the composite outcome. E/e'sr was significantly associated with the composite outcome (E/e'sr: HR 1.36 95% CI [1.25–1.47], p<0.001, per 0.10m increase) (figure). E/e'sr remained an independent predictor after multivariable adjustment for age, gender, duration of diabetes, BMI, HbA1c, smoking status, level of physical activity, systolic blood pressure, cholesterol level, eGFR, albuminuria, LV ejection fraction, LV dimensions and left atrial volume index (E/e'sr: HR 1.16 95% CI [1.04–1.28], p=0.006, per 0.10m increase). Interestingly, E/e'sr was especially good as a prognosticator in female patients (p for interaction = 0.008) in a univariable model: (female: HR 1.53 95% CI [1.37–1.71], p<0.001, per 0.10m increase) (male: HR 1.23 95% CI [1.10–1.38], p<0.001, per 0.10m increase). In the same multivariable model as before, E/e'sr remained an independent predictor of the outcome in female patients whereas the same was not true for male patients (female: HR 1.39 95% CI [1.18–1.66], p<0.001, per 0.10m increase) vs (male: HR 1.05 95% CI [0.92–1.21], p=0.46, per 0.10m increase).

Conclusion

In patients with type 1 diabetes, E/e'sr provides independent prognostic information regarding cardiovascular morbidity and mortality. Furthermore, E/e'sr seems to have stronger prognostic value in female patients with type 1 diabetes.
P627Patterns of physical activity over 22 years and mortality: the HUNT Study, Norway
Authors: Moholdt T , Moe B , Nilsen T I L
Published: October 2019

Background

The majority of studies relating physical activity (PA) to mortality have assessed PA using one baseline measure. Important questions in a preventive perspective are whether you can compensate for prior physical inactivity by taking up PA at a later stage in life and whether being physically active earlier in life can confer benefits even if you become inactive later. We investigated how patterns of PA over 22 years associated with all-cause and cardiovascular disease (CVD) mortality.

Methods

We used data from the prospective population-based HUNT Study in Norway, including 10,491 men and 12,655 women aged ≥20 years who participated at HUNT in 1984–86 and 2006–08. PA was categorised into inactive, <2 h/week or ≥2 h/week, making nine categories of patterns of PA over 22 years. All-cause and CVD mortality were assessed from the national Cause of Death Registry, with follow-up until the end of 2013. We used Cox regression to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for all-cause and CVD mortality within categories of PA patterns, compared to the reference category of individuals who reported ≥2 h/week at both examinations. Estimates were adjusted for baseline age, sex, body mass index, smoking, education level and blood pressure.

Results

Individuals who were inactive in both 1984–86 and in 2006–08 had increased risk of all-cause mortality (HR 1.99, 95% CI 1.48–2.67) and CVD mortality (HR 2.68, 95% 1.47–4.86) compared to those who were physically active ≥2 h/week at both examination. The HRs for all-cause and CVD mortality were 1.60 (1.22–2.15) and 1.90 (1.06–3.42), respectively, for those who reported PA of <2h/week at both examinations. Individuals who went from being physically active in 1984–86 to inactive in 2006–08, had a comparable risk of all-cause and CVD mortality as those who were inactive at both examinations. Overall, the mortality risk was still increased in those who took up PA between the two examinations, compared to the reference category.

Physical activity & all-cause mortality.

Discussion

Individuals who remained physically inactive or who decreased their PA over 22 years had substantially increased all-cause and CVD mortality risk. Taking up PA only attenuated the risk but a high level of sustained PA was associated with the lowest risk.

Acknowledgement/Funding

Funded by the Norwegian Health Association
P634Motivation for physical activity predicts effect of cardiac rehabilitation in an elderly cardiac population
Authors: Mikkelsen N , Dall C , Holdgaard A , Frederiksen M , Rasmusen H , Prescott E
Published: October 2019

Background

Motivation for physical activity is a psychological parameter that is sparsely described in secondary prevention, and it is plausible that motivation contributes to differential effect of CR.

Purpose

To investigate if motivation, measured using the behavioural regulation in exercise questionnaire (BREQ-2), predicts VO2peak in elderly cardiac patients before and after CR.

Methods

Prospective cohort study (Danish cohort from the EU-CaRE study) of elderly patients with ischemic or valvular disease enrolled in CR. Motivation for physical activity was measured using the BREQ-2 questionnaire at baseline, which measures five constructs of motivation and a summed score. VO2peak was measured before and after CR by a cardiopulmonary exercise test (CPET). The impact of motivation on VO2peak was examined using standardized multiple regression analyses.

Results

203 patients performed the baseline tests. 182 (90%) completed CR and had full data available. Dropout was not associated with motivation. VO2peak at baseline was 18 ml/kg/min (SD±5.1) and was associated with motivation score: for each SD increase in motivation VO2peak was 1.05 (0.43–1.69) ml/kg/min higher (p<0.01). Mean improvement was 2.3 (12%) ml/kg/min (SD±4.3). Higher motivation was positively associated with VO2peak (0.78 (0.33–1.24) pr. SD improvement (p=0.01) after adjusting for age, sex, depression, comorbidities and baseline VO2peak (Table). Subscales of the BREQ2 indicate that internal but not external motivation drives this positive association.

Predictors of change in VO2peak Age and sex adjusted Multiple adjusted model Motivation (RAI pr. SD) 0.57 (0.12 to 1.01)* 0.78 (0.33 to 1.24)** Baseline VO2peak (pr. SD) −0.56 (−1.16 to 0.21) −1.30 (−1.94 to −0.66)*** Age (pr. SD) −0.84 (−1.85 to 0.18) −1.00 (−2.01 to −0.01)* Sex (male) −0.18 (−1.21 to 0.85) 0.74 (−0.28 to 1.76) Previous smoker −0.23 (−1.22 to 0.77) −0.37 (−1.34 to 0.59) Current smoker −1.43 (−3.00 to 0.14) −1.89 (−3.36 to −0.40)* Diabetes (Yes) −1.37 (−2.50 to −0.24)* −1.62 (−2.78 to −0.48)** Kidney disease (Yes) −0.98 (−2.37 to 0.42) −1.45 (−2.84 to −0.06)* PHQ-9 (pr. SD) 0.22 (−0.24 to 0.69) 0.21 (−0.24 to 0.66)

Conclusion

In elderly cardiac patients, level of motivation is important to achieve benefits of CR. Future studies should address if motivation measured with BREQ-2 can be applied as a screening tool for elderly patients to provide more personalized intervention.
P664Impact of dynamic change in the status of metabolic syndrome associated with the risk of atrial fibrillation: a nationwide population-based study
Authors: Lee S , Choi E K , Lee S R , Han K , Cha M J , Oh S
Published: October 2019

Background/Introduction

Metabolic syndrome (MetS) is a well-known risk factor for new-onset atrial fibrillation (AF). However, there is a paucity of information on whether the change of MetS status has an impact on the risk of new-onset AF.

Objective

We aimed to evaluate the risk of AF according to the change of MetS status and to find whether components of metabolic syndrome control may affect AF risk.

Methods

A total of 7,565,531 subjects (≥20-year-old, mean age 47.2±13.7 years, male 55.6%) without prevalent AF who underwent 2 times of serial health checkup were identified from the Korean National Health Insurance Service. MetS was defined as having ≥3 of the following risk factors: increased waist circumference (ethnicity-specific, in Asian, ≥80 cm in women or ≥90 cm in men), increased triglycerides (≥150 mg/dL), decreased high-density lipoprotein-cholesterol level (<40 mg/dL in males, <50 mg/dL in females), increased blood pressure (≥130/85 mmHg), and increased fasting glucose level (≥100 mg/dL). Subjects stratified into four groups according to the change of MetS status during the follow-up period: 1,388,850 patients persistent MetS in the serial checkup (MM group), 608,158 in previous healthy but newly diagnosed MetS at 2nd checkup (HM group), 798,555 in the previous MetS but became healthy in 2nd checkup (MH group), and 4,769,968 patients without MetS in both (HH group). Incident AF was followed up till December 2017.

Results

Among those with MetS, 798,555 patients had improved to be healthy (10.6%). In those previous without MetS, 608,158 patients had newly diagnosed as MetS (8.0%) in 2nd checkup. During a mean follow-up of 7.9±0.9 years, incident AF was diagnosed in 135,600 patients (2.3 per 1000 person-year). MM, MH, and HM groups showed an increased risk of AF compared to HH group (Figure). Also, MH group showed a lower risk of AF compared to those with MM group. Regardless of the type of component that meets the MetS criteria, the risk of AF became different according to changing the number of MetS components. The risk of AF increased as the number of MetS components increased, whereas the risk of AF decreased as the number of MetS components decreased.

Risk of AF according to change of MetS

Conclusion

The risk of AF showed association with the dynamic change of MetS status and the variation in the number of MetS components. AF risk was reduced by the improvement in metabolic syndrome and each of MetS components.
P666Anti-platelet therapy in the primary prevention of cardiovascular disease in patients with chronic obstructive pulmonary disease: randomised controlled proof of concept trial (APPLE COPD-ICON 2)
Authors: Kunadian V , Wilson N , Stocken D , Ali H , McColl E , Burns G , Howe N , Fisher A , De Soyza A
Published: October 2019

The APPLE COPD-ICON2 trial is a prospective 2x2 factorial, double blinded proof of concept randomised controlled trial targeting patients with chronic obstructive pulmonary disease (COPD) at high risk of cardiovascular disease. The primary goal was to investigate if antiplatelet therapy (APT) will produce the predefined cut-off of platelet inhibition measured using the Multiplate test. We also assessed inflammatory biomarkers in serum.

Patients were randomised to Aspirin plus placebo, ticagrelor plus placebo, Aspirin plus ticagrelor or placebo only for 6 months. The primary outcome is inhibition of arachidonic acid (ASPI-test, cut-off <40) and adenosine diphosphate (ADP-test, cut-off <46) induced platelet aggregation at 6 months based on intention to treat (ITT) and sensitivity per protocol (PP) analyses. Safety outcomes included rates of major/minor bleeding.

Of 543 patients screened, 120 were recruited (mean age of 67.5 years). The ITT response rate to Aspirin was 48.3% (95% confidence interval [CI] 35.8–61.0%) according to ASPI-test and the response rate to ticagrelor was 41.4% (95% CI 29.3–54.6%) according to ADP-test. The PP ASPI-test response rate to Aspirin was 68.3% (95% CI 52.3–80.9%) and the PP ADP-test response rate to ticagrelor was 68.8% (95% CI 50.4–82.6%). There were no differences between the groups in the changes in Quality of Life using questionnaires (EQ5D 5L, St. George's COPD-C), inflammatory markers, carotid intima media thickness and vascular stiffness from baseline to 6-months. There were 5 type 1 bleeds according to the BARC criteria recorded in this study; 2 in the placebo arm, 2 in the Aspirin arm, and 1 in the ticagrelor arm. The MRC Dyspnoea score, FEV1 and FVC was similar across the groups.

Primary outcome measures Aspirin No Aspirin Ticagrelor No Ticagrelor ITT analysis set* n 60 60 58 62   Baseline No. of responders 1 6 4 1 % (95% CI) 1.7 (0.2, 11.3) 10 (4.5, 20.8) 6.9 (2.6, 17.3) 1.6 (0.2, 10.9)   6 months No. of responders 29 7 24 2 % (95% CI) 48.3 (35.8, 61) 11.7 (5.6, 22.8) 41.4 (29.3, 54.6) 3.2 (0.8, 12.3) PP analysis set** n 41 45 32 54   6 months No. of responders 28 7 22 2 % (95% CI) 68.3 (52.3, 80.9) 15.6 (7.5, 29.6) 68.8 (50.4, 82.6) 3.7 (0.9, 14.0) *Descriptive statistics for the primary outcome of response for the comparative groups at baseline and 6 months for the ITT analysis set and **PP analysis set. Note that response is ASPI response in the Aspirin and No Aspirin columns and ADP response in the ticagrelor and No ticagrelor columns.

Primary outcome measure

Nearly one third of COPD patients did not have a platelet response to antiplatelet therapy with Aspirin and ticagrelor. These findings support the high pro-thrombotic milieu and the need for further research in COPD patients.

Acknowledgement/Funding

Astra Zeneca (Funder reference number ISSBRIL0303)
P692Chemoradiation therapy to patients with lung cancer exacerbates thoracic aortic calcification
Authors: Miki T , Miyoshi T , Ichikawa K , Miyauchi S , Soh J , Toyooka S , Nakamura K , Morita H , Ito H
Published: October 2019

Introduction

Development of chemoradiation therapy (CRT) has improved mortality in patients with cancer. Whereas, it is emerging problem that cancer-survivors suffer from cardiovascular diseases, and the association between modern CRT and the increase in future cardiovascular events is suggested. Meanwhile, previous studies showed that thoracic aortic calcification (TAC) detected by computed tomography (CT), a marker of atherosclerosis, was associated with all-cause mortality and cardiovascular events. However, the influence of CRT on TAC progression remains unclear.

Purpose

The purpose of this study was to evaluate whether CRT would exacerbate TAC.

Methods

A total of 68 patients who treated lung cancer at our hospital between 2011 and 2015 were retrospectively analyzed (mean 62 year-old, male 78%): 35 patients underwent surgical treatment after induction CRT (CRT group) and 33 patients underwent surgical treatment alone (control group), extracted by propensity score matching by age, sex, smoking status, and diseased side. The volume of TAC between 2nd and 12th thoracic vertebrae was quantitatively measured with CT imaging, at baseline and at 1 year follow-up. The annual percent change in TAC was compared between the CRT and the control group. Moreover, the independent relationship between implementation of CRT and the progression of TAC was assessed by multivariate logistic regression analysis, adjusting for age, gender, conventional atherosclerotic risk factors and baseline aortic calcification volume.

Results

Patients in the CRT group received radiation (mean 47.3±4.0 Gy) and chemotherapy: 2 courses of cisplatin with docetaxel (34 cases) or vinorelbine (1 case). The prevalence of dyslipidemia, taking statins and diabetes drugs were significantly higher in the control groups (17% vs. 39%; p=0.041, 11% vs. 33%; p=0.029, 3% vs. 18%; p=0.044, respectively). Baseline C-reactive protein level was significantly higher in the CRT group (0.255 vs. 0.115; p=0.034). In univariate analysis, the annual percent change in TAC volume was significantly increased in the CRT group compared with the control group (37.6% vs. 23.3%; p=0.006). Multivariate logistic regression analysis demonstrated that CRT was an independent factor associated with the progression of TAC volume, even after adjustment for baseline calcification volume and coronary risk factors (OR, 3.90; 95% CI, 1.32–11.47; p=0.014).

Conclusion

CRT to patients with lung cancer exacerbates thoracic aortic calcification, which may result in future cardiovascular events.
P712Non-neuronal cholinergic system prevents coronary vascular dysfunction in diabetic heart
Authors: Saw E , Tsuchimochi H , Pearson J T , Yoshihiko K , Schwenke D O , Fronius M , Katare R
Published: October 2019

Background

Diabetic individuals suffer extensive myocardial damage during ischemia due to impaired ATP production and coronary vascular dysfunction. The cardiomyocytes possess a non-neuronal cholinergic system (NNCS) as it has choline acetyltransferase (ChAT) to synthesize acetylcholine (ACh). ACh released from cardiomyocytes activates hypoxia-inducible factor-1 pathway in an auto/paracrine manner under non-hypoxic condition. Activation of this pathway via NNCS promotes angiogenesis and is a promising mechanism to target ischemia in diabetes.

Aim

To investigate if activation of NNCS could improve the coronary vasculature in diabetic heart.

Methods

Type-2 diabetic db/db mice with ventricle-specific ChAT transgene (db/db-ChAT-tg) and control db/db mice of 12- and 24-weeks old were used. Catheterization of the jugular vein and carotid artery was performed in combination with synchrotron radiation microangiography to visualize the in-vivo coronary circulation. Changes of the coronary circulation to ACh (10μg/kg/min) and sodium nitroprusside (SNP, 10μg/kg/min) were assessed. Immunofluorescence analysis was performed to measure the density of arterioles and capillaries ex-vivo.

Results

In comparison to db/db mice, the number of second and third order vessels was higher in the db/db-ChAT-tg mice of 12- and 24-weeks old under baseline condition. In response to ACh and SNP, number of third order vessels were further increased in the db/db-ChAT-tg mice of both ages. However, the magnitude of the diameter changes in db/db-ChAT-tg mice was comparable to that in db/db mice of both ages. Besides, the db/db-ChAT-tg mice had increased density of arterioles and capillaries compared to the db/db mice of both ages.

Conclusion

NNCS-induced angiogenesis prevents coronary vascular dysfunction in diabetic heart.
P7142-AG impacts on endothelial cell activation and endothelial cell viability in vitro and impairs endothelial repair in vivo
Authors: Jehle J , Danisch M , Bagheri S , Avraamidou E , Tiyerili V , Pfeifer P , Bindila L , Lutz B , Zimmer A , Nickenig G
Published: October 2019

Background

The endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) is a known modulator of inflammation and few studies have addressed its influence on myeloid cells in the context of atherogenesis. However, the impact of 2-AG on endothelial cell function has not been studied before.

Methods

Endothelial repair was studied in two treatment groups of wildtype mice following electrical denudation of the common carotid artery at a length of 3000 μm. One group received the monoacylglycerol lipase (MAGL)-inhibitor JZL184 [5 mg/kg i.p.], which impairs 2-AG degradation and thus causes elevated 2-AG levels, the other group received vehicle. The residual endothelial gap at five days in either group was visualized by Evan's blue staining. In vitro, the effect of 2-AG on human coronary artery endothelial cell (HCAEC) viability was assessed by an XTT-based assay. Endothelial activation was studied by an adhesion assay of THP-1 monocytes to 2-AG-preconditioned HCAEC. HCAEC migration, ROS-production, expression of NADPH oxidases, and secretion of inflammatory cytokines were assessed by Boyden chamber, qPCR, and colorimetric assays.

Results

Treatment with JZL184 produced a significant increase in 2-AG levels and impaired reendothelialisation in wildtype mice following electrical injury of the common carotid artery. The residual denudation at 5 days yielded 2291±286 μm in JZL184-treated animals vs. 1505±223 μm in vehicle treated controls (n=18–19; p<0.05). In vitro, JZL184 significantly reduced viability of HCAEC at 24 hours (0.31±0.10 vs. 1.00±0.08; n=3; p<0.01). Finally, 2-AG promoted HCAEC activation resulting in a significant increase in THP-1 monocyte adhesion to HCAEC following pre-treatment of HCAEC with 2-AG (0.17±0.03 THP-1 cells per HCAEC vs. 0.07±0.01 THP-1 cells per HCAEC; n=3; p<0.05). Besides, HCAEC migration, ROS-production, expression of NADPH oxidases and secretion of inflammatory cytokines were unaffected by 2-AG.

Conclusion

Elevated 2-AG levels appear to hamper endothelial repair and to promote HCAEC activation and cell death. Our data suggest that besides its influence on myeloid cells, 2-AG is also adverse to endothelial integrity which might promote early atherosclerotic lesion formation. Thus, decreasing vascular 2-AG levels might represent a promising therapeutic strategy for the prevention of atherosclerosis and coronary heart disease.
P731High-density lipoproteins rescue diabetes-impaired angiogenesis by restoring cellular metabolic reprogramming responses to hypoxia
Authors: Bursill C , Primer K R , Solly E , Psaltis P J , Tan J T M
Published: October 2019

Background

We have previously identified that high-density lipoproteins (HDL) rescue hypoxia-induced angiogenesis in diabetes, however the underlying mechanisms remain unknown. A central component of hypoxia-induced angiogenesis is the reprogramming of endothelial cell (EC) metabolism to improve tolerance of hypoxia at the site of injury/repair, including following myocardial infarction. Pyruvate dehydrogenase kinase 4 (PDK4) suppresses mitochondrial respiration in hypoxia to decrease oxygen consumption and preserve cell survival. Diabetes impairs this adaptation to hypoxia, causing cellular dysfunction and may underlie delayed angiogenic responses to ischaemia in hyperglycaemia.

Purpose

To determine the role of metabolic reprogramming in angiogenesis and diabetes and the effect of reconstituted HDL (rHDL).

Methods and results

Using an in vitro functional angiogenesis assay, siRNA-mediated knockdown of PDK4 impaired human coronary artery endothelial cell (HCAEC) tubulogenesis in hypoxia by 82% versus siScrambled controls (P<0.0001). HCAECs were treated with rHDL (20μM, apolipoproteinA-I + phosphatidylcholine) or PBS (vehicle) and exposed to glucose (5 or 25 mM, 72 h), then normoxia or hypoxia (1.2% O2, 6 h). PDK4 expression was increased by 65% in hypoxia versus the normoxia control (P<0.05). By contrast, in high glucose PDK4 expression failed to increase in response to hypoxia. Incubation with rHDL rescued this impairment and elevated PDK4 expression by 40% in hypoxia and in high glucose (P<0.01), versus the PBS control. In parallel, rHDL rescued high glucose-impaired tubulogenesis in hypoxia by 64% versus the PBS/normoxia control (P<0.001). We next used a murine model of diabetic wound healing that tracks angiogenesis in the wound bed. We found daily topical application of rHDL (50μg/wound/day) increased wound angiogenesis by 10% (as assessed by Laser Doppler perfusion imaging) and promoted CD31+ neovessel formation by 46% in diabetic wounds, supporting an increased rate of wound closure in diabetic animals of 30% (P<0.05). rHDL treated wounds from diabetic mice had a striking increase in PDK4 gene (180%) and protein expression (350%) in the early-mid stages (24 h and 3-day time points, P<0.05) post-wounding, when the angiogenic response to wound ischaemia is most important.

Conclusions

We have demonstrated that the key protein controlling the metabolic reprogramming response to hypoxia, PDK4, plays an important role in endothelial cell angiogenesis. We also show that the PDK4 and angiogenesis responses to hypoxia are impaired in high glucose and can be rescued by rHDL. In vivo we find that topical rHDL increases wound angiogenesis and PDK4 levels, explaining the enhanced rate of wound closure in diabetic mice and has implications for improving cardiovascular outcomes for diabetic patients following myocardial infarction.