bluuebunny/crossref_metadata_2025 huggingface dataset:
P6137Trends in mortality of sudden cardiac death in Brazil
Authors: Moreira H , Silva G L S , Sahium G M B , Faria M M , Pereira J P S , Faria R B C C
Published: October 2019

Background

Sudden cardiac death (SCD) is the most feared manifestation of heart disease. In the past few decades, substantial progress has been made in our understanding of SCD and in its prevention. However, there is no data concerning population incidence of SCD in Brazil.

Purpose

To estimate trends of mortality for SCD in Brazil between 1996 and 2015.

Methods

Data from death certificates in Brazil from 1996 to 2015 were obtained by consulting the Mortality Information System (SIM) national database. SCD was defined as deaths occurring out of the hospital (residence or public way) with an underlying cause of death reported as a cardiac disease (ICD-9 code 390–398, 402, or 404–429; ICD-10 code I00-I09, I11, I20-I51). Annual death rates (deaths/100,000 inhabitants) were calculated for the population aged ≥20 years and standardized by the direct method to the 2010 Brazilian Census population. Trend analyses in the period were performed using Poisson regression.

Results

In 2015, there were 200,372 cardiac disease deaths among Brazilian adult population, of which 63,390 (31.6%) were defined as SCD. Over this 20-years period, 1,002,648 deaths were attributed to SCD, and coronary heart disease was the underlying cause on 59% of death certificates. The adjusted mortality rate ranged from 52.9 in 1996 to 39.7 deaths/100,000 inhabitants in 2015 (R2=0.685, P<0.001). This reduction in SCD mortality was more pronounced among women (50.4 to 34.0 deaths/100,000 inhabitants; R2=0.785, P<0.001) than men (59.7 to 49.9 deaths/100,000 inhabitants; R2=0.477, P=0.03). With the exception of individuals aged 20 to 39 years, in the all other age groups this reduction in mortality was also significant.

Conclusions

This data gives an insight into the pattern of SCD deaths in a big developing country. Despite the inherent limitations in collecting information based on death certificates, in addition to the absence of a clear national standardized definition of SCD, it is possible to affirm that there was a reduction in mortality due to SCD in the last 20 years in Brazil. Prospective surveillance programs would enable more accurate determination of SCD burden in the community.
P6138Quality of clinical trial evidence on devices and drugs approved to treat coronary artery disease
Authors: Stefanini G G , Naci H , Cao D , Malanchini G , Sturla M , Byrne R , Baber U , Reimers B , Condorelli G , Mossialos E , Windecker S , Mehran R
Published: October 2019

Background

Regulatory approval of drugs and devices follow two different pathways. Whether different approval pathways underlie meaningful differences in quality of clinical trial evidence is unknown. We aimed to compare the quality of evidence of clinical trials that served as a basis for approval by the U.S. Food and Drug Administration (FDA) of drugs and devices used for the treatment of coronary artery disease.

Methods

FDA databases were searched for devices (i.e., coronary artery drug-eluting stents) and drugs (i.e., agents targeting atherothrombosis) approved between January 1st, 2001 and December 31st, 2017. FDA medical reviews were screened to identify trials that served for approval purposes. The pre-specified primary outcome was the prevalence of randomized trials used for approval (i.e. number of randomized trials/overall number of trials).

Results

A total of 97 trials were identified, 39 serving for approval of 13 devices and 58 serving for approval of 8 drugs. Devices were evaluated by fewer trials per item as compared with drugs (3.0±1.4 vs. 7.3±5.3, P=0.012) with similar study size (501 [100–1314] vs. 379 [183–904] patients per trial, P=0.55). Trials evaluating devices were less frequently randomized (56.4% vs. 94.8%, P<0.001) and more frequently designed powered for clinical endpoints (53.8% vs. 17.2%, P<0.001) as compared to those evaluating drugs. Use of randomization declined over time among trials supporting FDA approval of devices. In addition, significant differences were present between trials evaluating devices and those evaluating drugs in terms of study design, comparator used, blinding to treatment allocation, primary hypothesis, primary endpoint, and type of patients included.

Use of randomized trials for approval

Conclusions

There are substantial differences in clinical trial evidence serving for FDA approval of devices and drugs used for treatment of coronary artery disease. The lower degree of randomized evidence used for approval of devices as compared to drugs raises some concerns, particularly in view of its decline over time.
P6142LATIN telemedicine - expanded umbrella of cost-effective ami coverage for 100 million people
Authors: Torres M A , Mehta S , Botelho R , Fernandez F , Cade J , Prudente M , Cavalcanti R , Dusilek C , Bojanini F , De Los Rios O , Alcocer Gamba M , Frauenfelder A , Matheus C , Vieira D , Mazzini J
Published: October 2019

Background

AMI is a unique entity where the immediate diagnosis can be made by a single test, the EKG. Despite this matchless attribute of easy diagnosis, developing (and some developed) countries lack resources and efficient pathways for urgent and reliable diagnosis of AMI. With Latin Telemedicine Infarct Network (LATIN), we have previously presented Telemedicine as a pragmatic solution for urgent and accurate diagnosis of AMI. In this work, we reveal pathways of scalable population-based AMI management models.

Purpose

To utilize telemedicine as a foundation pillar for creating cost-effective and global models of AMI management.

Methods

LATIN pilot tested the hypothesis of remote guidance of AMI management and expanded access by creating a hub and spoke, STEMI systems of care that exploited regional resources. A highly efficient, web-based, cloud-computing prototype was developed and scrupulously monitored with a new metric of time to telemedicine diagnosis (TTD). STEMI systems of care were created to efficiently triage the diagnosed patients for being treated with thrombolysis, pharmaco-invasive management or Primary PCI. This stratagem had enormous provincial variability and was constrained mainly by ambulance structure. Telemedicine and IT costs were forced lower and enabled a cost-effective process to hugely provide access to 100 million patients located in poorer regions of Colombia, Brazil, Mexico, and Argentina. Education and training have formed the mantra for LATIN and stakeholder development, and ambulance systems development has remained immutable goals.

Results

Almost 800,000 patients were successfully screening through LATIN with a cost for accurate STEMI diagnosis of < $3, a tele accuracy that exceeded 95% and with TTD <4 minutes. A total of 8,440 (1.1%) of patients were diagnosed with AMI in this manner and 3,924 (46.5%) urgently reperfused, mainly with Primary PCI (3,048, 77.8%). D2B times have been lowered now to 51 minutes but this is fortuitous, as several PCI-capable facilities are small, and direct transfer to the catheterization laboratory is easy. Door in and Door out times and transport times remain high as a large number of patients are denied by insurance and other payers for treatment. Overall, mortality is 5.2%.

Conclusions

Global financial and philanthropic institutions should contemplate models analogous to LATIN for saving the lives of millions of poor patients in developing countries from AMI.
P6150Clinical outcomes and downstream investigations following computed tomographic coronary angiography (CTCA) performed for evaluation of ambulatory patients with chest pain of recent onset
Authors: Lehru D , Mortimer N , Doshi S N , Zaphiriou A , George S , Khan S Q , Ludman P F , Townend J N , Nadir M A
Published: October 2019

Background

National Institute of Clinical Excellence guideline (NICE, CG95) recommends CTCA as a 1st line diagnostic test for evaluation of ambulatory patients with suspected stable angina based on its high sensitivity and low cost. This has led to increasing demand for CTCA across the National Health Service (NHS) in order to comply with the NICE recommendation.

Purpose

We studied the utility and effectiveness of CTCA in the evaluation of ambulatory patients with suspected stable angina attending rapid access chest pain clinic (RACPC) in a large tertiary hospital in the UK.

Methods

The study included consecutive patients attending RACPC over a pre-specified period of 6-months who were suspected of having stable angina and hence, referred for CTCA. The data were collected on demographics, CTCA results including incidental finding and downstream investigations. All patients had a minimum of 12-months follow up for clinical outcomes.

Results

A total of 170 patients were referred for CTCA (mean age = 56.8 years, male = 53.5%) out of the 388 consecutive patients who were reviewed in the RACPC during the 6-month period. CTCA was non-diagnostic in 48/170 (28.2%) cases (Breathing artefact 35%, Severe Coronary Calcification 31%, Elevated heart rate/Ectopy 30%) while 63/170 (37.1%) of patients had incidental extra-cardiac findings. Amongst patients with incidental findings, 17/63 (27.0%) underwent further investigations. A total of 54/170 (31.7%) of patients were recommended to have downstream cardiac investigations such as a stress test (DSE/MRI/MPS) (23/170, 15.8%) while 31/170 (18.2%) were referred for invasive coronary angiography. Revascularisation procedures (PCI n=7.6%, CABG n=4.7%) were required in 21/170 (12.4%) patients. Based on 2017 NHS tariffs, overall average cost-per-patient with the initial CTCA approach was £122.11 excluding downstream investigations and £548.43 including the cost of downstream cardiac investigations.

Incidental Findings after CTCA

Conclusions

Our study suggests that a CTCA based approach is associated with non-diagnostic information in at least 1:4 patients and incidental extracardiac findings in 1:3 patients. Further downstream cardiac investigations are required in around 1:3 patients after a CTCA carried out for evaluation suspected stable angina. The NICE recommendation is based on the low initial cost of CTCA and high sensitivity, however, taking in to account the additional cost of downstream investigations, the average cost per patient of this approach is significantly (4.5 times) higher.

Acknowledgement/Funding

None
P6155Early computed tomographic evaluation for out-of-hospital cardiac arrest survivors: the CT-FIRST trial
Authors: Branch K R , Gatewood M O , Kudenchuk P , Lee J C , Strote J , Petek B J , De Boer I , Carlbom D , Shuman W P , Counts C R , Sayre M R , Gunn M
Published: October 2019

Background

Patients surviving an out-of-hospital cardiac arrest (OHCA) commonly present without an obvious etiology, but computed tomography (CT) can provide rapid, comprehensive anatomic evaluation of potential OHCA causes.

Purpose

To assess the diagnostic capabilities of whole body CT imaging in OHCA survivors.

Methods

From 11/2015 to 2/2018, the CT-FIRST (CT Feasibility In Resuscitated patient for Sudden death Triage) protocol enrolled 104 OHCA survivors without obvious OHCA cause to an early (<6 hours from hospital arrival) dual source Sudden Death CT (SDCT) scan protocol that included a non-contrast head, ECG-gated cardiac/thoracic angiography, and non-gated venous phase abdominal CT's. Cardiac CT analysis was blinded, but other SDCT findings were clinically available. Patients needing urgent cardiac catheterization or hemodynamically unable to tolerate CT were excluded. Primary endpoints were SDCT diagnosis compared to OHCA causes from adjudicated record review, and any significantly altered therapy based on SDCT. Acute coronary syndrome by SDCT was conservatively assumed if >50% stenosis was identified in major coronary artery(ies).

Results

SDCT scans identified 39% (41/104) of all OHCA causes and 95% (41/43) of causes potentially identifiable with SDCT (Table). No inappropriate treatments resulted from SDCT findings. SDCT changed or expedited treatments in 21/23 (95%) patients, including antibiotics, anticoagulants, and invasive evaluations or treatments. SDCT found or confirmed resuscitation complications including liver/spleen laceration (n=5), pneumothorax (n=7), and hemopericardium (n=1).

N=104 OHCA Cause SDCT Diagnosis of OHCA Cause N (%) N (%) Acute coronary syndrome 13 (13%) 13 (100%) Cardiomyopathy 8 (8%) 7 (88%) Pneumonia 11 (11%) 11 (100%) Hemorrhagic stroke 3 (3%) 3 (100%) Pulmonary embolism 4 (3%) 4 (100%) Perforated viscus 2 (2%) 2 (100%) Gut necrosis 1 (1%) 1 (100%) Pulmonary hemorrhage 1 (1%) 1 (100%) Substance use 22 (21%) 0 (0%) Unknown 7 (7%) 0 (0%) Other 32 (31%) 0 (0%)

Conclusion

This pilot study suggests the SDCT protocol has considerable promise to diagnose OHCA causes and complications of resuscitation, as well as change clinical treatment.

Acknowledgement/Funding

Medic One Foundation
P6160Long term prognosis of intramural course of coronary arteries in patients with hypertrophic cardiomyopathy assessed by coronary CT angiography
Authors: Nassar M , Arow Z , Monakier D , Zusman O , Shafir G , Kornowski R , Hamdan A
Published: October 2019

Background

The prognostic value of an intramural course of the coronary arteries detected by coronary CTA in patients with hypertrophic cardiomyopathy (HCM) is not well-known.

Purpose

To evaluate in patients with HCM, who were referred for coronary computed tomography angiography (CTA), whether an intramural course of a coronary artery is associated with a worse outcome compared to HCM patients without an intramural course of the coronary arteries.

Methods

The study population consisted of 92 patients with HCM who were referred for coronary CTA and who did not have obstructive CAD. During follow-up, the occurrence of unstable angina pectoris that required hospitalization, myocardial infarction, and all-cause mortality was evaluated (i.e. adverse cardiac events).

Results

Using coronary CTA, 57 patients (62%) had an intramural course of coronary arteries. Patients with HCM were followed over 5.5±3.5 years. The composite of adverse cardiac events occurred in 17/57 (29.8%) patients with, and 11 out of 35 (31.4%) patients without intramural course (P=0.87). The event rate of unstable angina pectoris requiring hospitalization (28.1% vs. 22.9%), myocardial infarction (1.8% vs. 8.6%), and all case mortality (0.0% vs. 0.0%) was similar in patients with and without an intramural course.

Conclusion

Intramural course of coronary arteries in patients with HCM was frequently observed by coronary CTA, but it was not associated with worse cardiovascular clinical outcome.
P6177Impact of relative flow reserve derived from dynamic computed tomography perfusion imaging for detection of functionally significant stenosis
Authors: Uetani T , Akazawa Y , Kinoshita M , Seike F , Sasaki Y , Higashi H , Fujii A , Aono J , Nagai T , Nishimura K , Inoue K , Ikeda S , Yamaguchi O
Published: October 2019

Background

Quantitative myocardial perfusion imaging with CT is increasingly used for the diagnosis of coronary artery disease. Relative flow reserve (RFRCT) derived from dynamic stress CT perfusion (CTP) is defined as the ratio between myocardial blood flow (MBF) in the stenosis-related territory and MBF in the non-stenosis-related territory.

Purpose

We sought to evaluate whether RFRCTcan be used as a non-invasive method for detection of functionally significant coronary artery stenosis compared with stress MBF.

Methods

This study was retrospectively included 31 consecutive patients (40 vessels) with coronary artery disease and examined with CT angiography, CTP, coronary angiography, and FFR. RFRCT and stress MBF results were compared with invasive FFR using a threshold of 0.80.

Results

The RFRCT values were significantly correlated to FFR values (R2=0.788, P<0.0001, Fig 1). The area under the receiver operator curve was larger for RFRCT (0.961) compared with stress MBF (0.837, Fig 2). The diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of RFRCT were 92.5%, 84.2%, 100%, 100%, and 87.5%, respectively.

Figures 1 & 2

Conclusions

RFRCT was superior to stress MBF for detecting abnormal FFR in patients with stable coronary artery disease.
P6190Dynamic stress CTP with a whole-heart coverage scanner in addition to cCTA and FFRCT
Authors: Baggiano A , Guglielmo M , Muscogiuri G , Fusini L , Del Torto A , Andreini D , Mushtaq S , Conte E , Annoni A , Formenti A , Mancini E , Guaricci A I , Bartorelli A L , Pepi M , Pontone G
Published: October 2019

Background

Recently, new techniques such as dynamic stress computed tomography perfusion (stress-CTP) emerged as potential strategies to combine anatomical and functional evaluation in a one-shot scan. However, previous experience used technology that was associated with high radiation exposure.

Purpose

The aim of the study is to test the diagnostic accuracy of integrated evaluation of dynamic myocardial computed tomography perfusion (CTP) on top of coronary computed tomography angiography (cCTA) plus FFR computed tomography derived (FFRCT) by using a whole-heart coverage CT scanner as compared to invasive coronary angiography (ICA) plus clinically indicate invasive fractional flow reserve (FFR).

Methods

Eighty-five consecutive symptomatic patients scheduled for ICA were prospectively enrolled. All patients underwent rest cCTA followed by stress dynamic CTP with a whole-heart coverage CT scanner. FFRCT was also measured by using the rest cCTA dataset. The diagnostic accuracy to detect functionally significant CAD in a vessel-based model of cCTA alone, cCTA+FFRCT, cCTA+CTP or cCTA+FFRCT+CTP were assessed and compared by using ICA and invasive FFR as reference. The overall effective dose of dynamic CTP was also measured.

Results

The prevalence of obstructive CAD and functionally significant CAD were 77% and 57%, respectively. The sensitivity and specificity of cCTA alone, cCTA+FFRCT and cCTA+CTP, were 83% and 66%, 86% and 75%, 73% and 86%, respectively. Both the addition of FFRCT and CTP improves the area under the curve (AUC: 0.876 and 0.878, respectively) as compared to cCTA alone (0.826, p<0.05). The sequential strategy of cCTA+FFRCT+CTP showed the highest AUC (0.919, p<0.05) as compared to all other strategies. The mean ED for cCTA and stress CTP was 2.8±1.2 and 5.3±0.7 mSv, respectively.

Conclusions

The addition of dynamic stress CTP on top of cCTA and FFRCT provides additional diagnostic accuracy with acceptable radiation exposure.
P6203Intramyocellular lipid saturation as a new metabolic biomarker
Authors: Mezincescu A M , Ahearn T , Rudd A E , Cheyne L , Scally C , Horgan G , Philip S , Delibegovic M , Lobley G , Thies F , Gray S , Henning A , Dawson D K
Published: October 2019

Background

Endurance trained athletic healthy volunteers (Athl-HV) and type 2 diabetes patients (T2D) have higher levels of lipids in their skeletal myocytes compared to healthy controls. Despite apparently similar metabolic storage, they are at opposite ends of insulin sensitivity and cardio-metabolic risk.

Purpose

We investigated if the degree of saturation of the IntraMyoCellular Lipids (IMCL) will differentiate Athl-HV from T2D; and explored if an exercise intervention will induce changes in the IMCL saturation.

Methods

Male, age matched Athl-HV and T2D were enrolled (n=25/group). Athl-HV had ≥5 years endurance training, T2D were sedentary. Subjects were studied at baseline and after an exercise intervention (4 week deconditioning in Athl-HV and supervised bike training at ≥65% of peakVO2, 5 hours/week x 8 weeks in T2D). All subjects underwent cardio-pulmonary exercise testing (CPET), blood sampling for insulin sensitivity (QUICKI*) and single voxel 1H-magnetic resonance spectroscopy (1H-MRS) of the right vastus lateralis. 1H-MRS was acquired on 3T Philips Achieva with a 16-channel coil, point-resolved spectroscopy, variable pulse power and optimized relaxation delay water suppression and analysed in LCModel. We derived fractional lipid mass (fLM) and fractions of saturated (fSL) and unsaturated (fUL) lipids. Data were analysed by t tests, shown as mean±SEM, statistical significance p<0.05.

Results

CPET and insulin sensitivity are presented in Table 1. T2D had higher fLM in the skeletal muscle compared to Athl-HV, at baseline (p=0.003) and after the exercise intervention (p=0.009), Figure 1A. At baseline, T2D had a different phenotype with a lower fSL and higher fUL compared to Athl-HV (82±3 vs 88±1% and 18±3 vs 12±1%, p=0.02 for both). Whilst deconditioning did not attract any significant changes in either fSL or fUL in Athl-HV (88±1 to 86±1% and 12±1 to 14±1, p=0.2), in contrast, with exercise training T2D significantly increased fSL (82±3 to 88±1%) and decreased their fUL (18±3 to 12±1%) (both p=0.01). Figure 1B and 1C.

CPET and insulin sensitivity results Athl-HV Baseline Athl-HV Deconditioning p value T2D Baseline T2D After Training p value VO2 peak, (mL/kg/min) 45.0±0.9† 41.7±0.9‡ <0.0001 23.6±0.6† 30.3±0.6‡ <0.0001 QUICKI* 0.346±0.002† 0.343±0.003‡ 0.2 0.308±0.004† 0.317±0.004‡ 0.02 *QUICKI: Quantitative Insulin Sensitivity Check Index; †Athl-HV vs T2D at baseline p≤0.001, ‡Athl-HV vs T2D after exercise intervention p≤0.001.

Figure 1

Conclusion

We demonstrate for the first time, in vivo, significant differences in the IMCL amount and saturation between Athl-HV and T2D. IMCL saturation was changed by exercise training in T2D to mirror the phenotype seen in Athl-HV uncovering a new, independent biomarker of improved cardio-metabolic health.

Acknowledgement/Funding

British Heart Foundation Project Grant no. PG/15/88/31780
P6209Relationship between skin autofluorescence levels and clinical outcomes in heart failure patients undergoing cardiac rehabilitation
Authors: Kunimoto M , Shimada K , Yokoyama M , Honzawa A , Yamada M , Matsubara T , Fukao K , Kadoguchi T , Fujiwara K , Miyazaki T , Yamamoto T , Takahashi T , Fujiwara T , Amano A , Daida H
Published: October 2019

Background

Advanced glycation end-products, indicated by skin autofluorescence (SAF) levels, could be prognostic predictors of all-cause and cardiovascular mortality in patients with diabetes mellitus (DM) and renal disease. However, the clinical usefulness of SAF levels in patients with heart failure (HF) who underwent cardiac rehabilitation (CR) remains unclear.

Purpose

The purpose of this study was to investigate the prognostic value of SAF levels in patients with HF who underwent CR.

Methods

This study enrolled 204 consecutive patients with HF who had undergone CR at our university hospital between November 2015 and October 2017. Clinical characteristics and anthropometric data were collected at the beginning of CR. SAF levels were noninvasively measured with an autofluorescence reader. The major adverse cardiovascular event (MACE) was a composite of all-cause mortality and unplanned hospitalization for HF. Follow-up data concerning primary endpoints were collected until November 2018.

Results

Patients' mean age was 68.1 years, and 61% were males. Patients were divided into two groups according to the median SAF levels (high and low SAF groups). Patients in the high SAF group were significantly older, had a higher prevalence of chronic kidney disease, and histories of coronary artery bypass surgery; however, there were no significant between-group differences in sex, prevalence of DM, left ventricular ejection fraction, and physical function. During a median follow-up period of 623 days, 25 patients experienced all-cause mortality and 34 were hospitalized for HF. Kaplan–Meier analysis showed that patients in the high SAF group had a higher incidence of MACE (log-rank P<0.05), whereas when patients were divided into two groups according to the median hemoglobin A1c level, no significant between-group difference was observed for the incidence of MACE (Figure). After adjusting for confounding factors, Cox regression multivariate analysis revealed that SAF levels were independently associated with the incidence of MACE (hazard ratio: 1.74, 95% confidence interval: 1.12–2.65, P<0.05).

Figure 1

Conclusion

SAF levels were significantly associated with the incidence of MACE in patients with HF and may be useful for risk stratification in patients with HF who undergo CR.
P6214How to improve long-term prevention in young patients after myocardial infarction - the IPP-Y study
Authors: Wienbergen H , Retzlaff T , Erdmann J , Michel S , Mata Marin L A , Wettwer T , Schmucker J , Osteresch R , Munz M , Fach A , Hambrecht R
Published: October 2019

Background

Patients who experienced myocardial infarction (MI) at a young age are of special medical and socioeconomic interest; cardiovascular risk factor control to prevent recurrent events is crucial in this specific cohort.

Objectives

The purpose of the study was to evaluate long-term risk factor control in young MI-patients in clinical practice and investigate the effects of a modern intensive prevention program in a prospective randomized trial. In a genetic substudy it was analyzed if prevention effects were depending on individual genetic risk.

Methods

Patients who had MI at age of ≤45 years were revisited after a mean period of 5.7±4.0 years to evaluate long-term risk factor control. Furthermore a 12-months intensive prevention program in young MI-patients (IPP-Y), coordinated by non-physician prevention assistants and including personal teachings, telephone contacts, clinical and telemetric control of risk factors, was compared to usual care in a randomized trial. Primary endpoint of the randomized trial was prevention success, defined as improvement of one of the risk factors smoking, LDL cholesterol or physical inactivity without deterioration of the others. As the opposite prevention failure was defined as deterioration of one of the risk factors without improvement of the others. Genetic risk was assessed by polygenetic risk scores, based on 163 SNPs.

Results

Only a minority of the 277 young patients after MI achieved guideline-recommended risk factor targets at long-term follow-up visits: mean body mass index was 29.9±5.1 kg/m2, just 14.8% had a body mass index <25 kg/m2. More than one third (38.3%) were persistent or recurrent smokers. Mean LDL cholesterol level was 94±38 mg/dl, only 27.1% of the patients achieved LDL cholesterol levels <70 mg/dl.

However, the long-term prevention program IPP-Y led to a higher rate of the primary endpoint prevention success (IPP-Y: 49% vs. UC: 27%, p<0.05) and a lower rate of prevention failure (IPP-Y: 15% vs. UC: 38%, p<0.05) compared to usual care after 12 months (see figure). Telemetric control of risk factors as part of the prevention program was used by 71.4% of the patients.

In the genetic subanalysis prevention effects were found in both, patients with high genetic risk as well as patients with low genetic risk assessed by polygenetic risk scores (p=0.79 high vs. low genetic risk).

Effects of IPP-Y during 12 months

Conclusions

To our knowledge this is the first study on young patients with MI that demonstrates insufficient long-term risk factor control in clinical practice and significant effects of an intensive prevention program. Prevention effects were independent from individual genetic risk.

Acknowledgement/Funding

This work was supported by the Stiftung Bremer Herzen, Bremen, Germany and the Stiftung Bremer Wertpapierbörse, Bremen, Germany
P6225Uric acid visit-by-visit variability is an independent risk factor of CHD - and all-cause mortality
Authors: Goldbourt U
Published: October 2019

Variability of serum uric acid (SUA) has been seldom examined in connection with long-term morbidity and mortality. We present results from a study of male civil servants and municipal employees, estimating associations of visit-by-visit variability of SUA with long-term all-cause as well as cause-specific mortality.

Patients and methods

There were 10,059 men, aged 40–65, tenured civil servants and municipal employees in the territories of the three most populated urban areas. Of these, 8822 participated in three extensive examinations in 1963, 1965 and 1968 and underwent assessment of diabetes and coronary morbidity status. We conducted analysis examining whether the standard deviations of Z-scores of SUA (SUA-Z), across the three study visits, predicted fatal outcomes. SUA-Z was defined as the difference between the individual SUA and the mean of SUA, divided by the standard deviation (SD) for the pertinent examination, namely separately for the 1963, 1965 and 1968 means and SD. Hazard ratios (HR) associated with the SD of SUA-Z were calculated for 18-yr stroke and CHD mortality (1968 to 1986) and the 18-yr all-cause mortality associated with quartiles of the above variability. The lowest quartile served as the referent, adjusting for age. A subsequent model adjusted additionally for the baseline value of SUA as well as for baseline frequency of diabetes mellitus and coronary heart disease (CHD)

Results

Multivariate analysis of 18-yr CHD mortality (1968–1986, 906 deaths among 8822 men) yielded a significant association with the 1963–1968 SD of SUA-Z with age adjusted HR of CD mortality of 0.99, 1.12 and 1.43 for quartiles 2 to 4 respectively (P using Mantel trend test=0.0002). Further adjustment for baseline prevalence of diabetes and CHD somewhat decreased the above HR estimates to 0.98, 1.04 and 1.29, respectively, with a HR=1.15 (95% CI, 1.07–1.23) per 1 mg/Dl increment of the 1963 SUA serum level.

The results for the 18-yr all-cause mortality (2836 deaths, 1968–1986) strongly indicated increasing age-adjusted mortality risk with increasing SD of SUA-Z: HRs= 1.08 (95% CI,0.97–1.21), 1.15 (1.03–1.28), and 1.37 (1.23–1.51). No association was observed between the SD of SUA-Z and 18 years stroke mortality. Sensitivity analysis, incorporating the last (1968) SUA levels assessed, rather than the 1963 ones, yielded virtually identical HRs.

Conclusion

In this cohort of tenured male workers, with diverse occupation, higher variability of SUA measurement taken in 1963–5-8 were clearly predictive of 18-year CHD and all-cause mortality, above and beyond the SUA levels proper.
P6266Circulating microparticules of patients with coronary artery disease up-regulate the expression of sodium-glucose cotransporters 1 and 2 in coronary artery endothelial cells: role of angiotensin II
Authors: Park S , Belcastro E , Hasan H , Bruckert C , Marchandot B , Kibler M , Toti F , Auger C , Jesel L , Ohlmann P , Morel O , Schini-Kerth V
Published: October 2019

Introduction

Circulating microparticles (MPs) from patients with coronary artery diseases (CAD) have been shown to promote endothelial senescence and dysfunction involving the pro-oxidant local angiotensin system. Sodium-glucose cotransporters (SGLTs)2 inhibitors decreased the risk of cardiovascular disease in patients with type 2 diabetes and this effect appears to be independent of glycemic control. Moreover, high glucose and H2O2 have been shown to cause a redox-sensitive upregulation of SGLT1 and 2 in coronary artery endothelial cells (ECs).

Aim

Therefore, this study examined whether angiotensin II (Ang II, a potent NADPH oxidase-dependent inducer of oxidative stress) and CAD MPs stimulate SGLT1 and 2 expression in ECs, and assessed their role in the induction of endothelial dysfunction.

Methods

ECs were isolated from porcine coronary arteries. The protein expression level was assessed by Western blot analysis and immunocytochemical staining, oxidative stress using dihydroethidium staining, and senescence by senescence-associated beta-galactosidase activity (SA-beta-gal activity). Circulating CAD MPs were collected from blood samples of patients (61–79 year) with established cardiovascular disease.

Results

Control ECs expressed low levels of SGLT1 and SGLT2 proteins. Exposure of ECs to Ang II caused a time- and concentration-dependent increase in the protein level of SGLT1 and SGLT2 with a significant increase observed at concentrations as low as 10 nM. Exposure of ECs to CAD MPs (10 nM PhtdSer eq) from 3/5 patients increased the SGLT1 and SGLT2 protein level. An increased SGLT1 and SGLT2 immunofluorescence signal was also observed in response to Ang II and H2O2. Ang II increased the level of oxidative stress, SA-beta-gal activity, senescence markers (p53, p21 and p16), VCAM-1, MCP-1, tissue factor (TF) and the local angiotensin system (ACE, AT1R), and down-regulated that of eNOS. CAD MPs from 4/5 patients decreased eNOS level and from 5/5 patients increased VCAM-1 level. All the Ang II-induced effects were prevented by the dual SGLT1/2 inhibitor LX-4211 and the selective SGLT2 inhibitor, empagliflozin.

Conclusions

The present findings indicate that CAD MPs and Ang II upregulate the expression of SGLT1 and SGLT2 protein levels in ECs, and that they promote endothelial dysfunction. They further suggest that inhibition of SGLT1 and/or SGLT2 might be an attractive strategy to protect the arterial wall and, hence, the development of cardiovascular diseases.

Acknowledgement/Funding

Unrestricted research grant from Boehringer Ingelheim Pharma GmbH & Co. KG
P6270Empagliflozin reduces the total burden of first and recurrent hospitalisations in patients with type 2 diabetes and established cardiovascular disease
Authors: McGuire D , Zinman B , Inzucchi S E , Anker S D , Wanner C , Kaspers S , Von Eynatten M , Johansen O.-E , Elsasser U , Pocock S , Fitchett D , Jamal W , Hantel S , Lund S S
Published: October 2019

Background and aims

The EMPA-REG OUTCOME trial included patients with type 2 diabetes (T2D) and established atherosclerotic cardiovascular (CV) disease. Empagliflozin reduced the risk of 3-point major adverse CV events (MACE; composite of CV death, myocardial infarction [MI], or stroke) by 14%, CV death by 38% and hospitalisation for heart failure (HF) by 35% vs placebo in analyses of time to first event. We assessed the effect of empagliflozin on all-cause hospitalisation in post-hoc analyses of all (first and recurrent) events.

Materials and methods

Patients were randomised to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo in addition to standard of care. We assessed the effects of empagliflozin pooled vs placebo on first event of all-cause hospitalisation using Cox regression and all (first and recurrent) events of all-cause hospitalisation using a negative binomial model.

Results

A total of 7020 patients were treated (4687 empagliflozin; 2333 placebo, mean [SD] age 63 [9] years, 71% male, 47% with history of MI, 23% with history of stroke, 10% with HF). In this analysis, 1725/4687 (36.8%) empagliflozin patients and 925/2333 (39.6%) placebo patients experienced an event leading to hospitalisation. The adjusted hazard ratio (HR; 95% CI) vs placebo for first all-cause hospitalisation using the Cox regression model was 0.89 (0.82, 0.96; p=0.0033; Figure); In analyses of all (first and recurrent) hospitalisation events, there were 3168 events in the empagliflozin group and 1863 in the placebo group. The adjusted event rate ratio (95% CI) vs placebo was 0.83 (0.76, 0.91; p<0.0001; Figure).

Conclusion

In the EMPA-REG OUTCOME trial, risk reductions with empagliflozin were seen in both first and all hospitalisation events and were numerically more favourable in analyses of all events vs analyses of first events. These analyses expand on the favourable CV effects of empagliflozin by also showing a reduction in the total burden of hospitalisation events in patients with T2D and established CV disease.

Acknowledgement/Funding

Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance
P6284The antioxidant MitoQ protects against intestinal disturbances in the experimental autoimmune model of myocarditis
Authors: Gallardo I , Gutierrez B , Hernandez M , Cabero I , Alvarez Y , Simon I , Munoz J C , San Roman J A , Cachofeiro V , Nieto Callejo M L
Published: October 2019

Purpose

Myocarditis and dilated cardiomyopathy represent the acute and chronic phases of an inflammatory disease of the myocardium, for which no standardized treatment is currently available in clinical practice. Myocardial fibrosis an oxidative stress are pathogenic factors associated with these processes. However, new research has found that gut health can be linked to some cardiac conditions. Thus, in this study we investigated whether intestinal disturbances are present in myocarditis, using a murine experimental autoimmune model (EAM) that mimics human myocarditis, as well as the potential beneficial effect of treatment with the mitochondrial antioxidant, MitoQ.

Methods and results

EAM was induced in BALB/c mice with a myocardiogenic peptide and mice were treated with MitoQ (50 mg/kg/day, i.p). On day 21 (acute phase), we assessed signs of heart injury (e.g. hypertrophy, fibrosis, oxidative stress) and parameters related to gut damage such as accumulation of reactive oxigen species (superoxide anion: O2·−), inflammation (IL-1β, IL-33, TNFα), microbial translocation (sCD14; intestinal fatty acid binding protein, I-FABP) and mucins in serum and/or intestine. MitoQ teatment significantly reduced the high heart weight/body weight ratio (HW/BW) of EAM mice, a characteristic hallmark of cardiac hyperthropy. Histological analysis of hearts showed presence of fibrosis (Sirius Red stain) and high O2·− levels (DHE stain) in EAM mice whereas these effects were not detectable in cardiac tissue from healthy or MitoQ-treated EAM mice. In addition, the enhanced O2·− ions (DHE stain) and mucin loss (Alcian Blu/PAS stain) found in colon, ileum, jejunum and duodenum sections from EAM mice were attenuated by MitoQ treatment. The systemic markers associated to intestinal barrier disruption, sCD14 and I-FABP, were found strongly increased in serum from EAM mice, and MitoQ prevents this rise. The beneficial MitoQ effects were also associated with a decrease in the pro-inflammatory cytokines TNFα, IL-33 and IL-1β, both in serum and colonic tissue of treated-EAM mice, as well as a reduction of the myeloperoxidase activity in colon, compared with untreated EAM mice.

Conclusion

Our data show that in addition to the heart, the intestinal tissue is also damaged in the preclinical model of experimental autoimmune myocarditis, and that MitoQ treatment could reverse this profile. Since there are systemic markers released from the intestine, therapeutic strategies targeting to prevent the intestinal oxidative stress and its associated gut barrier dysfunction, could contribute to the amelioration of the disease.

Acknowledgement/Funding

SAF2016-81063; CIBERCV
P6285Protective effects of exercise on vascular function are mediated by NADPH oxidase 4
Authors: Morawietz H , Langbein H , Shahid A , Hofmann A , Mittag J , Bornstein S R , Brunssen C
Published: October 2019

Background/Introduction

Physical activity is one of the most potent strategies to prevent endothelial dysfunction. Recent evidence indicates vaso-protective properties of H2O2 produced by main endothelial NADPH oxidase isoform 4 (Nox4) in the vasculature.

Purpose

Therefore, we hypothesized that Nox4 connects physical activity with vaso-protective effects.

Methods and results

Analysis of endothelial function by Mulvany myograph showed endothelial dysfunction in wild-type as well as in Nox4−/− mice after 20 weeks on high-fat diet. Access to voluntary running wheels during high-fat diet prevented endothelial dysfunction in wild-type but not in Nox4−/− mice. Mechanistically, exercise led to increased H2O2 release in the aorta of wild-type mice with increased phosphorylation of eNOS pathway member AKT serine/threonine kinase 1 (Akt1), subsequently. Both effects were diminished in aortas of Nox4−/− mice. Deletion of Nox4 also led to decreased capacity for intracellular calcium release and reduced phenylephrine-mediated contraction, whereas potassium-induced contraction was unaffected. H2O2 scavenger catalase reduced phenylephrine-contraction in wild-type mice. Supplementation of H2O2 increased phenylephrine-induced contraction in Nox4−/− mice. Exercise induced key regulator of mitochondria biogenesis peroxisome proliferative activated receptor gamma, coactivator 1 alpha (Ppargc1a) in wild-type but not Nox4−/− mice. Furthermore, exercise induced citrate synthase activity and reduced mitochondria mass in the absence of Nox4. Thus, Nox4−/− mice became less active and ran less compared with wild-type mice.

Conclusions

Nox4 derived H2O2 plays a key role in exercise-induced adaptations of eNOS and Ppargc1a pathway and intracellular calcium release. Hence, loss of Nox4 diminished physical activity performance and vascular protective effects of exercise.

Acknowledgement/Funding

This work was supported by a research grant of the German Cardiac Society (DGK) (to H.L.) and DFG (Grant MO 1695/4-1 to H.M.).
P6310Risk predictors of cardiac allograft vasculopathy after heart transplantation: results from the United States Organ Procurement and Transplantation Network
Authors: Fluschnik N , Geelhoed B , Becher P M , Brunner F J , Schrage B , Knappe D , Bernhardt A , Blankenberg S , Kobashigawa J , Reichenspurner H , Schnabel R B , Magnussen C
Published: October 2019

Background

Cardiac allograft vasculopathy (CAV) is a major long-term complication after heart transplantation leading to chronic graft failure and increased mortality.

Purpose

The aim of this study was to determine recipient- and donor-related risk factors for the development of CAV in patients after heart transplantation.

Methods

Overall, data from 34,994 heart transplant recipients prospectively enrolled from July 2004 to March 2015 in the Organ Procurement and Transplantation Network (OPTN) were analyzed. Patients aged <18 years and those without information about CAV and re-transplantation were excluded. Multivariable-adjusted analyses were performed to identify recipient- and donor-related risk factors for new-onset CAV. The mean follow-up time was 66.8 months. Analyses are based on OPTN data as of March 6, 2017.

Results

Of 34,994 patients after heart transplantation, 12,668 (36.2%) patients developed CAV. Mean age was 52±12 years for the recipients (76.1% men) and 31±12 years for the donors (71.0% men), respectively.

In recipients, male sex (hazard ratio [HR] 1.14, 95% confidence interval [CI] 1.09–1.19, p<0.001), African American ethnicity (HR 1.11, 95% CI 1.06–1.17, p<0.001), body mass index (BMI) (HR per 5 kg/m2 increase 1.08, 95% CI 1.06–1.11, p<0.001) and smoking (HR 1.07, 95% CI 1.01–1.13, p=0.03) were associated with incident CAV. Moreover, recipients with ischemic (HR 1.30, 95% CI 1.09–1.55, p=0.003) and hypertrophic cardiomyopathy (HR 1.26, 95% CI 1.02–1.57, p=0.03) had a higher risk for new-onset CAV than patients with other cardiomyopathies.

In donors, age (HR 1.11, 95% CI 1.10–1.11, p<0.001), male sex (HR 1.28 95% CI 1.22–1.34, p<0.001), BMI (HR per 5 kg/m2 increase 1.04, 95% CI 1.02–1.05, p<0.001), smoking (HR 1.09, 95% CI 1.04–1.13, p<0.001), diabetes (HR 1.21 95% CI 1.09–1.36, p<0.001) and arterial hypertension (HR 1.13, 95% CI 1.07–1.20, p<0.001) were associated with new-onset CAV. Contrarily, African American (HR 0.93, 95% CI 0.88–0.98, p=0.007) and Hispanic ethnicity (HR 0.94, 95% CI 0.89–0.99, p=0.03) seemed to be protective.

Conclusion

Both recipient and donor male sex as well as the classical cardiovascular risk factors BMI and smoking were associated with incident CAV. On the donor side, additionally, diabetes and arterial hypertension were related to new-onset CAV. Diverse ethnicities were differentially related to new-onset CAV. Further studies are needed to clarify whether modification of cardiovascular risk factors as well as improved donor selection will reduce CAV burden.
P6316Hemodynamic response to rapid saline loading in heart transplant recipients
Authors: Kodeboina M , Di Gioia G , Colaiori I , Verstreken S , Goethals M , Dierckx R , Heggermont W , Bartunek J , Vanderheyden M
Published: October 2019

Introduction

A pulmonary capillary wedge pressure (PCWP) ≥25 mm Hg following volume load or exercise has been proposed as a partition value for detection of HfpEF. However, the hemodynamic response to volume challenge in heart transplant (Tx) recipients has never been studied.

Methods

24 heart Tx recipients (age: 65 years) with normal LV function (55±7%) and without rejection and graft vasculopathy underwent right heart catheterization to measure hemodynamic response to volume loading before and after a rapid saline infusion of 7mL/kg over 10 min. PCWP, right atrial pressure (RAP), mean pulmonary artery pressure (AP) were obtained and the PCWP and indexed (i) stroke volume (SV) data were used to construct Starling (SVindex/PCWP) curves. Pts were categorized in those with elevated filling pressures (Group A, n=13 pts) defined by a PCWP ≥15 mm Hg at rest or ≥25 mm Hg following volume loading vs those without (Group B, n=11 pts).

Results

No difference in age of donor and transplant heart, baseline hemodynamics and EF was noted between both groups. Saline infusion significantly increased PCWP and mean AP in both Groups (table 1) without any significant change in BP and heart rate. Interestingly saline infusion was associated with a significant rise in SV and SVi in Group B not in Group A pts. Moreover, in Group B pts the Starling curves revealed a larger SVi at any give PCWP compared to Group A pts (Fig.1).

Table 1 All (n=24) Group A (n=13) Group B (n=11) Baseline Volume Loading Baseline Volume Loading Baseline Volume Loading RAP (mm Hg) 5.3±4.1 9.2±4.8* 7.6±4.8 11.4±5.2* 3.8±2.5 7.3±1.9* Mean AP 18.4±5.4 24.1±5.9* 21.7±5.1 26.8±6.5** 14.9±2.4 20.8±2.6* PCWP 12.1±4.9 16.8±6.7* 15.0±4.9 19.8±6.5** 8.4±1.9 14.6±3.7* SV 71.4±19.6 72.5±23.6 73.2±6.2 72.4±6.2 69.2±14.6 79.2±3.9 SViml/m2) 37.4±9.2 37.9±11.2 36.7±7.1 38.7±9.9 35.3±6.0 40.5±5.2* *p<0.01 compared to baseline; **p<0.05 compared to baseline.

Figure 1

Conclusions

In the transplanted heart volume loading increases filling pressures and is able to unmask left ventricular diastolic dysfunction. Interestingly, those with HFpEF are characterized by a blunted Frank Starling response as evidenced by higher PCWP and failure to increase SV for any given PCWP. Further prospective studies are warranted to unravel the underlying mechanisms.