Non-fatal Outcomes Research Articles

The state of health in Pakistan and its provinces and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Understanding health trends and estimating the burden of disease at the national and subnational levels helps policy makers track progress and identify disparities in overall health performance. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides comprehensive estimates for Pakistan. Comparison of health indicators since 1990 provides valuable insights about Pakistan's ability to strengthen its health-care system, reduce inequalities, improve female and child health outcomes, achieve universal health coverage, and meet the UN Sustainable Development Goals. We present estimates of the burden of disease, injuries, and risk factors for Pakistan provinces and territories from 1990 to 2019 based on GBD 2019 to improve health and health outcomes in the country. We used methods and data inputs from GBD 2019 to estimate socio-demographic index, total fertility rate, cause-specific deaths, years of life lost, years lived with disability, disability-adjusted life-years, healthy life expectancy, and risk factors for 286 causes of death and 369 causes of non-fatal health loss in Pakistan and its four provinces and three territories from 1990 to 2019. To generate estimates for Pakistan at the national and subnational levels, we used 68 location-years of data to estimate Pakistan-specific demographic indicators, 316 location-years of data for Pakistan-specific causes of death, 579 location-years of data for Pakistan-specific non-fatal outcomes, 296 location-years of data for Pakistan-specific risk factors, and 3089 location-years of data for Pakistan-specific covariates. Life expectancy for both sexes in Pakistan increased nationally from 61·1 (95% uncertainty interval [UI] 60·0-62·1) years in 1990 to 65·9 (63·8-67·8) years in 2019; however, these gains were not uniform across the provinces and federal territories. Pakistan saw a narrowing of the difference in healthy life expectancy between the sexes from 1990 to 2019, as health gains for women occurred at faster rates than for men. For women, life expectancy increased by 8·2% (95% UI 6·3-13·8) between 1990 and 2019, whereas the male life expectancy increased by 7·6% (3·5-11·8). Neonatal disorders, followed by ischaemic heart disease, stroke, diarrhoeal diseases, and lower respiratory infections were the leading causes of all-age premature mortality in 2019. Child and maternal malnutrition, air pollution, high systolic blood pressure, dietary risks, and tobacco consumption were the leading all-age risk factors for death and disability-adjusted life-years at the national level in 2019. Five non-communicable diseases-ischaemic heart disease, stroke, congenital defects, cirrhosis, and chronic kidney disease-were among the ten leading causes of years of life lost in Pakistan. Burden varied by socio-demographic index. Notably, Balochistan and Khyber Pakhtunkhwa had the lowest observed gains in life expectancy. Dietary iron deficiency was the leading cause of years lived with disability for both men and women in 1990 and 2019. Low birthweight and short gestation and particulate matter pollution were the leading contributors to overall disease burden in both 1990 and 2019 despite moderate improvements, with a 23·5% (95% UI 3·8-39·2) and 27·6% (14·3-38·6) reduction in age-standardised attributable DALY rates during the study period. Our study shows that progress has been made on reducing Pakistan's disease burden since 1990, but geographical, age, and sex disparities persist. Equitable investment in the health system, as well as the prioritisation of high-impact policy interventions and programmes, are needed to save lives and improve health outcomes. Pakistan is facing several domestic and foreign challenges-the Taliban's return to power in Afghanistan, political turmoil, catastrophic flooding, the COVID-19 pandemic-that will shape the trajectory of the country's health and development. Pakistan must address the burden of infectious disease and curb rising rates of non-communicable diseases. Prioritising these three areas will enhance Pakistan's ability to achieve universal health coverage, meet its Sustainable Development Goals, and improve the overall health outcomes. Bill & Melinda Gates Foundation. For the Urdu translation of the abstract see Supplementary Materials section.

The impact of electronic health record discontinuity on prediction modeling.

To determine the impact of electronic health record (EHR)-discontinuity on the performance of prediction models. The study population consisted of patients with a history of cardiovascular (CV) comorbidities identified using US Medicare claims data from 2007 to 2017, linked to EHR from two networks (used as model training and validation set, respectively). We built models predicting one-year risk of mortality, major CV events, and major bleeding events, stratified by high vs. low algorithm-predicted EHR-continuity. The best-performing models for each outcome were chosen among 5 commonly used machine-learning models. We compared model performance by Area under the ROC curve (AUROC) and Area under the precision-recall curve (AUPRC). Based on 180,950 in the training and 103,061 in the validation set, we found EHR captured only 21.0-28.1% of all the non-fatal outcomes in the low EHR-continuity cohort but 55.4-66.1% of that in the high EHR-continuity cohort. In the validation set, the best-performing model developed among high EHR-continuity patients had consistently higher AUROC than that based on low-continuity patients: AUROC was 0.849 vs. 0.743 when predicting mortality; AUROC was 0.802 vs. 0.659 predicting the CV events; AUROC was 0.635 vs. 0.567 predicting major bleeding. We observed a similar pattern when using AUPRC as the outcome metric. Among patients with CV comorbidities, when predicting mortality, major CV events, and bleeding outcomes, the prediction models developed in datasets with low EHR-continuity consistently had worse performance compared to models developed with high EHR-continuity.

Forensic medical characteristic of articular injuries

Is to refine the mechanism of major joints' damage formation and qualification criteria of harm degree to the health in articular injuries. The number of patients equal 246, suffered in different circumstances, were examined. Damages of skin and soft tissues in the joints region without affection of internal structures (47%), intraarticular fractures with impaired articular surface congruence (18.0%) and periarticular fractures (15.8%) were the most frequent in non-fatal injuries' outcomes in pedestrians and cyclists suffered from collisions with moving vehicles. Dead pedestrians and cyclists injured in road traffic accidents (RTA) from the side of joints structure had the most frequent the periarticular fractures (6.8%), intraarticular fractures with impaired (14.5%) or intact articular surface congruence (6.5%). Dislocations (45.9%) and dislocation-fracture (54.1%) were common in mechanical injuries. Mostly, work ability was recovered for 1.5-2.0 months in the presence of periarticular fracture, and there was no permanent loss of general work ability. The permanent loss of general work ability exceed 33.0% in case of complicated intraarticular fractures of coxofemoral structures, and in the case of a similar injury of other joints was less than this value. The period of work ability recovery in the case of intraarticular fractures was 2.5-3 months, in the presence of complicated dislocations was from 3 to 6 months. The permanent loss of general work ability did not exceed 30%. The period of work ability recovery in patients with fracture-dislocation varied from 3 to 6 months. The permanent loss of general work ability in this case was from 20% to 60%. The severity of harm to the health was classified as moderate degree in the case of uncomplicated isolated injuries of joints structures, and as moderate or severe degree in the presence of complicated isolated injuries. Bruises of joints' soft tissues were evaluated as mild bodily injury causing a health disorder. Bruises of joints' soft tissues, as well as periarticular and intraarticular fractures in pedestrians and cyclists in the case of RTA are formed when falling on the road surface. Dislocations and fractures-dislocations of humerus and forearm occur as a result of an indirect injury mechanism. Articular injuries of femur are formed under the influence of traumatic force to the femur, exceeding the capability of coxofemoral joint (an indirect injury mechanism). Dislocations and fractures-dislocations in ankle joint are occurred as a result of an indirect injury mechanism and are caused by foot's flexion or rotation with great strength.

PS-C08-8: OUTCOMES FROM BLOOD PRESSURE REDUCTION IN PATIENTS WITH DIFFERENT BASELINE CARDIOVASCULAR RISK: SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED TRIALS

Objective: Blood pressure (BP) lowering is accompanied by reducing cardiovascular (CV) outcomes and death in hypertensive patients. No data are available for the effect of BP lowering in trials stratified according to baseline CV risk that was assessed according to SCORE-2. Design and method: A systematic review was conducted to identify randomized trials in electronic databases (Pubmed and CENTRAL, years: 1966 to 9/2021) for the effect of BP-lowering treatment against placebo or less aggressive BP reduction on 6 fatal or non-fatal CV outcomes and all-cause death. Selected studies reported outcomes in patients without a history of previous CV disease. In each study, we calculated baseline cardiovascular risk using SCORE-2. Risk ratios (RR) were calculated together with their 95% confidence interval (CI) under the random-effects model. Results: We included 54 studies (i.e., 12 trials with low-to-moderate CV risk, n = 21,192 patients; 13 trials with high risk, n = 66,886; and 29 trials with very high risk, n = 79,061). For a standard SBP/DBP reduction of 10/5 mmHg, the relative risk of the combined outcome of major CV events (i.e., myocardial infarction, stroke, and heart failure) was decreased by 27% (95% CI, 22–35%) in the category of very high-risk patients, and this reduction was significantly greater (P = 0.02) compared to high-risk trials (0.90 [95% CI, 0.77–1.04]). Moreover, CV death showed a significant reduction in the high-risk group compared to the low-moderate risk group (p = 0.005), as well as in the very high-risk group compared to the low-moderate risk group (p = 0.001). The same pattern was observed for all-cause death in the very high-risk group compared to the high-risk group (p = 0.045). Conclusions: The greatest outcome benefit from BP lowering in primary prevention is observed in patients at higher baseline cardiovascular risk as calculated by the SCORE-2.

Abstract 15919: Adverse Outcomes Related Amiodarone Toxicity in Early Rhythm Control of Patients With Atrial Fibrillation: A Nationwide Cohort Study

Background: Early rhythm control therapy was associated with a lower risk of adverse cardiovascular outcomes than usual care among patients who had recently (within 1 year) been diagnosed with atrial fibrillation (AF). In real-world data, the most commonly selected initial rhythm control strategy was the Class III anti-arrhythmic drug (AAD) amiodarone, but adverse outcomes related amiodarone toxicity was not well reported in this population. This study sought to investigate the fatal and non-fatal adverse outcomes related amiodarone toxicity in early rhythm control of patients with AF. Methods: Using the database of Korean National Health Insurance Service, we analyzed the adverse outcomes related amiodarone toxicity in 140,908 (rhythm control: 57,148, rate control: 83,760) patients with AF undergoing rhythm control or rate control therapy, initiated within 1 year of AF diagnosis, between 2005 and 2015. Results: The most commonly used rhythm control strategy was the class III drug amiodarone (22,877 (40.0%) of 57,148 patients in early rhythm control), followed by class Ic drugs. Patients with amiodarone for initial rhythm control strategy showed higher rate of interstitial lung disease (1.43% vs. 0.75%, p<0.001), sudden cardia arrest duet to Torsade de Pointes (0.31% vs. 0.17%, p=0.001), and hypothyroidism (16.5% vs. 8.12%, p<0.001). But incidence rate of bradycardia needing a temporary pacemaker, bradycardia needing a permanent pacemaker, and toxic hepatitis were higher in early rhythm control patients with other AADs compared to patients with amiodarone. Conclusions: The most commonly used rhythm control strategy was amiodarone in AF patients undergoing early rhythm control. Using amiodarone for the initial rhythm control strategy showed a higher rate of interstitial lung disease, sudden cardia arrest duet to Torsade de Pointes, and hypothyroidism. Attention should be paid to amiodarone toxicity in selecting rhythm control strategy for these patients.

Novel surgical quality metrics in abdominal aortic aneurysm repair.

Existing surgical quality metrics have limited utility, are primarily used for high-mortality procedures, and often fail to account for differences in non-fatal outcomes. Our objective was to develop more comprehensive, novel surgical quality metrics, for patients undergoing abdominal aortic aneurysm (AAA) repair. Non-ruptured open and endovascular AAA repair (EVAR) from the Vascular Quality Initiative database were studied, 2016-2019. A win was defined as AAA repair without major complication (in-hospital) or mortality (in-hospital or within 30days). Centers were divided into quality quartiles based on performance in two novel win-based metrics: (1) Wins Above Average (WAA) and (2) weighted Wins Above Average (wWAA). Patient-level and center-level analyses compared demographics and outcomes between "best" and "worst" quartiles, including wins, mortality, and failure to rescue (FTR) rates. Additional patient-level analyses were performed based on center stratification into volume quartiles. Correlation in surgical quality for open repair and EVAR was determined at centers performing both procedures. Overall, 3683 patients underwent open repair and 21,165 patients underwent EVAR. For open repair, crude rates of win, mortality, and FTR were 62.8%, 4.2%, and 10.3%, respectively. For EVAR, crude rates for win, mortality, and FTR were 94.4%, 1.1%, and 12.3%, respectively. When stratified by wWAA, patients undergoing open repair at "best" quartile centers had a higher win rate (72.0% vs 52.7%; risk ratio [RR], 1.37; 95% confidence interval [CI], 1.28-1.46) and lower mortality (3.1% vs 6.2%; RR, 0.50; 95% CI, 0.33-0.74) compared with "worst" quartile centers. Similarly, for EVAR, "best" quartile centers had a higher win rate (96.2% vs 92.1%; RR, 1.04; 95% CI, 1.03-1.05), lower mortality (0.4% vs 2.2%; RR, 0.19; 95% CI, 0.13-0.29), and a lower FTR rate (5.7% vs 17.9%; RR, 0.32; 95% CI, 0.18-0.56) compared with "worst" quartile centers. Stratification by volume showed that high-volume centers demonstrated improved wWAA for open repair (P= .04) but not for EVAR (P= .3) compared with low-volume centers. For centers that performed both open repair and EVAR, there was no correlation in quality as determined by wWAA (r=-0.056; P= .6). wWAA is a novel, risk-adjusted, complication-weighted surgical quality metric that also accounts for volume differences. wWAA successfully distinguishes high- and low-quality centers for both open AAA repair and EVAR. This methodology is potentially broadly applicable for measuring surgical quality.

Using individual-level stratification as an approach to integrating social inequalities into the burden of disease

Abstract Substantial social inequalities in almost all non-fatal and fatal health outcomes are one of the most consistent and universal epidemiological findings. Therefore, monitoring social inequalities in health is considered a key priority for researchers and policy makers. The Global Burden of Disease Injuries, and Risk Factors Study (GBD) is the most comprehensive worldwide observational epidemiological synthesis of data to date. However, currently, the GBD Study does not include the potential to stratify associated metrics, such as the disability-adjusted life years metric, by different socioeconomic factors, such as education or income level. Although The GBD Study does include the Socio-Demographic Index, this measure is only useful when comparing between, and not within, countries or regions. We conducted a Cox regression analysis using a national longitudinal prospective cohort study design and registry-based data linked at the individual-level. We stratified on educational groups and investigated cause-specific mortality rates over a 30-year period, adjusting for age, sex and 5-year age cohorts. We also calculate years of life lost (YLLs) stratified by educational groups, standardised by age, and presented for specific years - to investigate trends over time. We discuss the benefits and limitations of this “individual-level” stratification approach as one possible solution to the integration of social inequalities into the GBD study or when using a burden of disease framework approach more generally.

The state of health in Indonesia's provinces, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

SummaryBackgroundAnalysing trends and levels of the burden of disease at the national level can mask inequalities in health-related progress in lower administrative units such as provinces and districts. We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to analyse health patterns in Indonesia at the provincial level between 1990 and 2019. Long-term analyses of disease burden provide insights on Indonesia's advance to universal health coverage and its ability to meet the United Nations Sustainable Development Goals by 2030.MethodsWe analysed GBD 2019 estimated cause-specific mortality, years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted life-years (DALYs), life expectancy at birth, healthy life expectancy, and risk factors for 286 causes of death, 369 causes of non-fatal health loss, and 87 risk factors by year, age, and sex for Indonesia and its 34 provinces from 1990 to 2019. To generate estimates for Indonesia at the national level, we used 138 location-years of data to estimate Indonesia-specific demographic indicators, 317 location-years of data for Indonesia-specific causes of death, 689 location-years of data for Indonesia-specific non-fatal outcomes, 250 location-years of data for Indonesia-specific risk factors, and 1641 location-years of data for Indonesia-specific covariates. For subnational estimates, we used the following source counts: 138 location-years of data to estimate Indonesia-specific demographic indicators; 5848 location-years of data for Indonesia-specific causes of death; 1534 location-years of data for Indonesia-specific non-fatal outcomes; 650 location-years of data for Indonesia-specific risk factors; and 16 016 location-years of data for Indonesia-specific covariates. We generated our GBD 2019 estimates for Indonesia by including 1 915 207 total source metadata rows, and we used 821 total citations.FindingsLife expectancy for males across Indonesia increased from 62·5 years (95% uncertainty interval 61·3–63·7) to 69·4 years (67·2–71·6) between 1990 and 2019, a positive change of 6·9 years. For females during the same period, life expectancy increased from 65·7 years (64·5–66·8) to 73·5 years (71·6–75·6), an increase of 7·8 years. There were large disparities in health outcomes among provinces. In 2019, Bali had the highest life expectancy at birth for males (74·4 years, 70·90–77·9) and North Kalimantan had the highest life expectancy at birth for females (77·7 years, 74·7–81·2), whereas Papua had the lowest life expectancy at birth for males (64·5 years, 60·9–68·2) and North Maluku had the lowest life expectancy at birth for females (64·0 years, 60·7–67·3). The difference in life expectancy for males between the highest-ranked and lowest-ranked provinces was 9·9 years and the difference in life expectacy for females between the highest-ranked and lowest-ranked provinces was 13·7 years. Age-standardised death, YLL, and YLD rates also varied widely among the provinces in 2019. High systolic blood pressure, tobacco, dietary risks, high fasting plasma glucose, and high BMI were the five leading risks contributing to health loss measured as DALYs in 2019.InterpretationOur findings highlight that Indonesia faces a double burden of communicable and non-communicable diseases that varies across provinces. From 1990 to 2019, Indonesia witnessed a decline in the infectious disease burden, although communicable diseases such as tuberculosis, diarrhoeal diseases, and lower respiratory infections have remained a main source of DALYs in Indonesia. During that same period, however, all-ages death and disability rates from non-communicable diseases and exposure to their risk factors accounted for larger shares of health loss. The differences in health outcomes between the highest-performing and lowest-performing provinces have also widened since 1990. Our findings support a comprehensive process to revisit current health policies, examine the root causes of variation in the burden of disease among provinces, and strengthen programmes and policies aimed at reducing disparities across the country.FundingThe Bill & Melinda Gates Foundation and the Government of Indonesia.TranslationFor the Bahasa Indonesia translation of the abstract see Supplementary Materials section.

History of stroke in patients with heart failure: prevalence, baseline characteristics and clinical outcomes

Abstract Background Stroke is an important but neglected comorbidity in patients with heart failure (HF). Little is known about the characteristics and outcomes of HF patients with a history of stroke. Purpose To examine the prevalence of prior stroke in patients with HF and reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF), the clinical characteristics of patients with a history of stroke, and the clinical outcomes in patients with prior stroke compared to those without. Methods Individual patient data analysis using three recent HFrEF trials (ATMOSPHERE, PARADIGM-HF, and DAPA-HF) and HFpEF trials (CHARM-Preserved, I-Preserve, TOPCAT-Americas, and PARAGON-HF). Cox regression was used to analyze clinical outcomes. Results Among 20159 HFrEF patients enrolled, 1683 (8.3%) had a history of stroke and among the 13252 patients with HFpEF 1287 (9.7%) had a prior stroke. Compared to patients without stroke, those with stroke were slightly older and more likely to have a history of hypertension, myocardial infarction, atrial fibrillation, diabetes, carotid artery disease, and peripheral artery disease (for both HFrEF and HFpEF). Patients with a history of stroke had worse NYHA class and KCCQ scores, and a higher rate of fatigue; they also had a higher median NT-proBNP level and lower eGFR than those without prior stroke (whether HFrEF or HFpEF). Systolic BP, pulse pressure and LVEF did not differ susbtantialy between patients with and without a history of stroke. The table shows outcomes according to history of stroke or not, stratified by LVEF phenotype. During follow-up, all fatal and non-fatal outcomes were significantly more common in patients with a history of stroke. The augmentation of risk tended to be greater in patients with HFpEF than HFrEF, but was not statistically different. Conclusion Approximately 1 in 11 patients in recent HF trials had a history of stroke and these patients were at higher risk of fatal and non-fatal events than those without prior stroke. HF hospitalization as well as atherothrombotic events (myocardial infarction and stroke) were more common among patients with prior stroke – patients with prior stroke had at least 30% higher risk of all events examined, regardless of LVEF, and more than double incidence of repeat stroke. Funding Acknowledgement Type of funding sources: Other.

Effect of blood pressure reduction on cardiovascular outcomes in patients with different baseline cardiovascular risk: systematic review and meta-analysis of randomized trials

Abstract Background/Introduction Blood pressure (BP) lowering is accompanied by a reduction on cardiovascular (CV) outcomes and death in hypertensive patients. There is no data on the effect of lowering BP in patients stratified according to their baseline CV risk as indicated by SCORE 2. Purpose The aim of this meta-analysis was to demonstrate the impact of BP-lowering treatment on the occurrence of CV events in these previously reported patients. Methods A systematic review in electronic databases (Pubmed and CENTRAL, years: 1966 to 9/2021) was conducted to identify randomized trials that study the effect of BP-lowering treatment against placebo or less aggressive BP reduction on 6 fatal or non-fatal CV outcomes and all-cause death. Selected studies reported outcomes in patients without a history of previous CV disease. In each study, baseline cardiovascular risk was estimated using SCORE-2. Risk ratios (RR) were calculated together with their 95% confidence interval (CI) under the random-effects model. Results The analysis was composed of 54 studies, of which 12 trials included patients with low-to-moderate CV risk, (n=21,192 patients), 13 trials with high CV risk patients (n=66,886) and 29 trials with very high CV risk patients (n=79,061). For a standard SBP/DBP reduction of 10/5 mmHg, the relative risk of the combined outcome of major CV events (i.e., myocardial infarction, stroke, and heart failure) was decreased by 27% (95% CI, 22–35%) in the category of very high-risk patients. This reduction was significantly greater (p=0.02) compared to high-risk trials (0.90 [95% CI, 0.77–1.04]). CV death showed a significant reduction in the high-risk group of patients compared to the low-moderate risk group (p=0.005), as well as in the very high-risk group compared to the low-moderate risk group (p=0.001). The same pattern was observed for all-cause death in the very high-risk group compared to the high-risk group (p=0.045). Conclusions With the present meta-analysis, we observed that the greatest benefit from BP lowering in primary prevention in the occurrence of CV events and mortality is observed in patients at higher baseline cardiovascular risk, as calculated by the SCORE-2. Funding Acknowledgement Type of funding sources: None.

Association of fatal and non-fatal adverse health outcomes with urinary peptides reflecting collagen I turnover

Abstract Background Imbalance of collagen I (COL1) turnover, featured by increased synthesis and decreased degradation of collagen fibers, is a hallmark of fibrosis in the heart and blood vessels that associates with poor cardiovascular outcomes. Such as imbalance of COL1 turnover could be reflected in urine and serve as fingerprint for future adverse outcomes in general population, and high risk subjects. Purpose We hypothesize that imbalance of proteomic signatures of urinary peptides (UPs) reflecting COL1 turnover relate to adverse health outcomes in participants from a general population Methods We randomly recruited 776 participants (51.2% women; 50.5 years) from the Flemish Study on Environment, Genes and Health Outcomes cohort and measured UPs proteome by capillary electrophoresis coupled with mass spectrometry. Our analyses focused on 148 peptides of COL1 alpha-1 (COL1A1) chain that retained ≥70% signal in the whole sample. The primary endpoint included fatal and nonfatal cardiovascular endpoints. Secondary endpoints consisted of total mortality, fatal and nonfatal cardiac, coronary, and heart failure endpoints. Multivariate Cox proportional models, partial least squares analysis (PLS), log-likelihood test, and receiver operating characteristics (ROC) curve were applied. Results Over a median follow up of 12.4 years, 110 primary endpoints occurred, 61 participants died, 81, 41 and 24 experienced cardiac, coronary, and heart failure endpoints; respectively. In PLS analyses, upregulation of UPs signatures closer to C- and N-terminal locations of the COL1A1 chain whereas downregulation of mid-region UPs were associated with lower risk of adverse health outcomes. This pattern was inverted in subjects with cardiovascular disease, as upregulation of terminal and downregulation of mid region UPs increased risk. Adding UPs to a basic model including sex, age and usual cardiovascular risk factors significantly improved model performance between 2.54% to 4.93% (P≤0.001) for prediction of adverse health outcomes. In ROC plots, adding UPs to the basic model increased the area under the curve up to 4.00% (P<0.012). Conclusions UPs reflecting COL1 turnover predicted adverse health outcomes. The inverted up- and down regulations of UPs in between participants with and without previous cardiovascular diseases might be explained by a shift in the UPs signatures of COL1 fragments linked to distinct fibrotic processes. Urinary proteomic might have clinical importance in documenting the extent of collagen accumulation that relates to adverse health outcomes. In patients at high cardiovascular risk, modification of collagen I fibers turnover might be a potential treatment target Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): The European Union the European Research Council and the European Research Area Net for Cardiovascular Diseases.

Ordinal scoring of coronary artery calcification in low dose computed tomography is predictive factor of all-cause death and cardiovascular events

Abstract Background Lung cancer and cardiovascular disease (CVD) are leading worldwide mortality causes firmly related to smoking. Lung cancer screening (LCS) consisted in performing low-dose computed tomography (LDCT) offers an opportunity for simultaneous coronary artery calcification (CAC) assessment. Purpose The study aimed to determine the usefulness of the visual assessment of CAC in the prediction of all-cause death and non-fatal cardiovascular outcomes including myocardial infarction and stroke. Methods The study involved 6580 participants aged 50–79 years, current or former smokers with a cigarette smoking history of at least 30 pack-years, who were qualified for lung cancer screening program performed between April 2016 and May 2018. CAC was visually scored on ungated LDCT scans in the range of 0–12 based on the length of calcification involvement in four main coronary arteries. CAC severity was categorized into groups of 0, 1–3, 4–12. The primary outcome was all-cause mortality. The secondary outcome was major adverse cardiovascular events (composite of CVD death, nonfatal myocardiaI infarction, nonfatal stroke). The outcomes data were obtained by using the National Health Care Provider Registry of death and hospitalizations. The mean time of follow-up was 41.1 months (SD 8.3). Logistic regression analysis was used to determine the risk of mortality according to the CAC category adjusted for age, pack-years of cigarette smoking, and sex. Results The rate of all-cause death substantially increased in groups of higher CAC and it was consecutively 2.7% (89 of 3288 subjects) for a score of 0, 4.2% (66 of 1582 subjects) for a score of 1–3 and 8.3% (145 of 1742 subjects) for a score of 4–12. With the use of subjects with a CAC score of 0 as the reference group, adjusted for sex, age, and pack-years of smoking, a CAC score of at least 4 was a significant predictor of all-cause death (hazard ratio [HR], 1.89; 95% CI: 1.42; 2.52; P<0.05). Similar results were observed for the composite of CVD death, nonfatal myocardial infarction, nonfatal stroke with even greater significance. The rate of secondary outcames was 1.6% (51/3276) in a 0 score cohort, 3.0% (47/1570) in a 1–3 score cohort and 7.5% (130/1732) in a 4–12 score cohort. Both CAC score in the range 1–3 ([HR], 1.57; 95% CI: 1.05; 1.2.35; P<0.05), and 4–12 ([HR], 3.55; 95% CI: 2.50; 5.04; P<0.05) were a significant predictors of major adverse cardiovascular event incidence. Conclusions Visual assessment of CAC provides solid evidence of all-cause death and cardiovascular incidents independently of traditional coronary risk factors. Therefore evaluation of CAC in LDCT scans offers a unique opportunity for instituting CVD risk assessment in lung cancer screening program. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Centre for Research and Development of Poland.

Biomarker-based prediction of fatal and non-fatal cardiovascular outcomes in individuals of the general population with and without diabetes mellitus

Abstract Introduction Cardiovascular biomarkers may reflect different aspects of cardiovascular disease, including myocardial tissue damage (high-sensitive cardiac troponin [hs-cTn]), hemodynamic stress (N-terminal prohormone of brain natriuretic peptide [NT-proBNP)), or inflammation (high-sensitivity C-reactive protein [hs-CRP]). Purpose To determine the risk for fatal and non-fatal cardiovascular events in patients with diabetes mellitus (DM), a high-risk group for cardiovascular complications, after accounting for these biomarkers and to determine the risk associated with these biomarkers. Methods Harmonized data of population-based studies from the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomaCaRE) and MOnica Risk, Genetics, Archiving and Monograph (MORGAM) consortia were used to calculate hazard ratios (HRs, 95% confidence intervals [CI] per standard deviation) for these biomarkers adjusted for diabetes, patient characteristics and biomarkers for their association with the primary endpoint of fatal and non-fatal cardiovascular events during a median follow-up of 9.6 years (maximum 28 years). Additionally, a years-of-life-lost analysis was conducted stratified by prevalent diabetes and specific biomarker cut-offs known to be associated with increased risk for events (hs-cTnI >5 ng/L, NTproBNP >125 ng/L, hs-CRP >5mg/L). Results We included 95,302 individuals, of whom 6,501 had DM (6.8%). Cox-regression analysis revealed DM to be independently associated with the primary endpoint (2.1 [95% CI 1.9, 2.3], p<0.001) despite adjustment for clinical characteristics and biomarkers. Also, all three biomarkers were independent predictors themselves: log-transformed NT-proBNP 1.3 [95% CI 1.3, 1.4] p<0.001; log-transformed hs-CRP 1.2 [95% CI 1.1, 1.2] p<0.001; third-root-transformed hs-cTnI 1.1 [95% CI 1.0, 1.1] p=0.0038). The sex-, age- and cohort-adjusted HR for the primary endpoint according to absolute biomarker concentrations derived by cox-regression models using cubic splines is provided for the three biomarkers in Figure 1. Upon dichotomization of biomarkers, individuals with diabetes and at least one elevated biomarker lost a median of 15.5 healthy years because of the primary endpoint (Kaplan-Meier plot in Figure 2, with age on the x-axis). Conclusion Our findings confirm that diabetes confers a residual cardiovascular risk beyond adjustment for clinical characteristics and cardiovascular biomarker. Furthermore, biomarkers may aid in the identification of patients at highest risk, which should be considered in future models of risk prediction. Funding Acknowledgement Type of funding sources: None.

Should dual antiplatelet therapy be maintained beyond one year after a myocardial infarction? A cohort study within the French SNDS nationwide claims database

Abstract Background Dual antiplatelet therapy (DAPT), aspirin plus a P2Y12-i (clopidorel, prasugrel or ticagrelor), is recommended for one year after myocardial infarction (MI) for secondary prevention of cardiovascular disease (SP-CVD). Beyond one year maintaining DAPT is controversial. Purpose To compare the 3-year risk of a composite of MI, ischemic stroke (IS), major bleeding (MB) and death between DAPT and single antiplatelet therapy with aspirin (SAPT) beyond one year after MI. Methods All adults hospitalized in 2013 or 2014 for acute MI (trigger event) with intensive care unit stay were identified in the French SDNS nationwide claims database. Patients who survived at least one year without MI or MB, and with a DAPT medication possession ratio (MPR) ≥80% were included in a cohort study. All patients were followed for 3 years after the index date (defined 365 days after the MI trigger event), except right-censored observations for those who died or discontinued aspirin with a 60-day grace period. The 3-year hazard ratios (HR [95% CI]) were estimated using Cox proportional hazards risk model for outcomes including death, and Fine and Gray competing risks model for non-fatal outcomes, with a time-dependent variable for DAPT-SAPT exposure, and adjusted on a high-dimensional disease risk score (hdDRS) plus time dependent variables for SP-CVD drugs, oral antidiabetics, insulin, anticoagulants, NSAIDs, corticoids and proton pump inhibitors. HdDRS were estimated for the composite outcome, a composite of ischemic outcomes, and MB alone, and variables were selected using a combination of Principal Component Analysis and Lasso regression. Results From the 105,080 adults admitted in intensive care units for acute MI in 2013 or 2014, 53,399 were included in the cohort. The most common reasons for non-inclusion were death (n=12,012) and a DAPT MPR <80% (n=25,000). At index date, mean age was 65 years, with 74.6% men, 21.8% diabetes, 9.4% heart failure, 5.6% peripheral arterial disease, 72.2% with DAPT score ≤2, 61.9% Charlson index ≤1; 79.2% had a STEMI trigger event and 82.6% had cardiac revascularization (PCI 98.6%). P2Y12-i used at least once from the trigger event to the index date were clopidogrel (41.5%), ticagrelor (41.1%) and prasugrel (26.2%). Follow-up was 111,770 person-years and 4,268 composite outcomes were recorded. The 3-year HR of DAPT compared to SAPT was 1.21 [1.13–1.30] for the composite of MI, IS, MB and death, 1.22 [1.07–1.38] for MI, 0.98 [0.80–1.20] for IS, 1.89 [1.55–2.30] for MB and 1.16 [1.06–1.27] for death. Conclusions In this nationwide real-life population-based study in France, DAPT maintained beyond one year after MI is significantly associated with increased harm compared to SAPT with increased risks of 21% (IC95% [13–30]) for the composite of MI, IS, MB and death (net clinical benefit), 22% [7–38] for MI, 89% [55–130] for MB, 16% [6–27] for death, and no difference for IS. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): French Ministry of Health (PHRCN-18-0745)

Serum hepcidin levels and cardiovascular outcomes in patients on maintenance hemodialysis

Background Cardiovascular mortality is high in patients on maintenance hemodialysis. Different factors and plausible mechanisms have been explained for the increased risk. A recent concept of iron dysregulation and the related biomarker serum hepcidin was thought to be one of the novel markers of cardiovascular disease. We undertook this study to study the fatal and nonfatal cardiovascular events in dialysis population. Patients and methods All the patients who satisfied inclusion criteria were included in the study. All the patients have been on either twice-/thrice-weekly dialysis with polysulfone membrane of 1.3-m2 surface area. Serum hepcidin levels were estimated in blood samples using the appropriate techniques. All the patients were followed up for 18 months to assess the fatal and nonfatal cardiovascular outcomes. Results A total of 80 patients satisfied the criteria and were followed up. Mean serum hepcidin levels were 116.3 ± 32 ng/ml. On univariate analysis of factors influencing mortality, age, sex, and presence of comorbidities did not show significant association, but the levels of serum bicarbonate, albumin, creatinine, cholesterol, triglycerides, and the high-sensitivity C-reactive protein, hepcidin, showed a significant association with mortality. Serum hepcidin level of 120 ng/ml predicted mortality with a sensitivity of 100% and specificity of 85%. Conclusions Serum hepcidin is associated with all-cause mortality and cardiovascular mortality in patients on hemodialysis. Hepcidin levels may serve a good predictor of cardiovascular outcomes in patients on hemodialysis.

Novel Surgical Quality Metrics in Abdominal Aortic Aneurysm Repair

Existing surgical quality metrics are primarily used for high-mortality procedures and often fail to account for differences in nonfatal outcomes. Our objectives were to develop a novel comprehensive quality metric for abdominal aortic aneurysm (AAA) repair, and compare quality at centers where open and endovascular (EVAR) repair are both performed.

Physical activity from young adulthood to middle age and premature cardiovascular disease events: a 30-year population-based cohort study

BackgroundAlthough physical activity is generally protective of cardiovascular disease (CVD), less is known about how young adult physical activity relates to premature CVD events. The objective of this study was to determine the association between level and change in physical activity from young adulthood to middle age and incidence of premature CVD events before age 60.MethodsWe analyzed data collected across four urban sites from nine visits over 30 years of follow-up (1985–2016) from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a prospective community-based cohort study of 5115 Black and White women and men aged 18–30 years at baseline (1985–1986). Linear mixed models were used to develop individualized moderate-to-vigorous intensity self-reported physical activity trajectories per participant. Fatal and nonfatal coronary heart disease (CHD), heart failure, and stroke outcomes were analyzed separately and as a combined CVD event outcome.ResultsOverall, physical activity declined in young adults as they progressed through middle age. Lower physical activity scores (per 100 exercise units) in 18 year-olds were associated with higher odds of premature CHD (AOR 1.14, 95% CI 1.02–1.28), heart failure (AOR 1.21, 95% CI 1.05–1.38), stroke (AOR 1.20, 95% CI 1.04–1.39), and any CVD (AOR 1.15, 95% CI 1.06–1.24) events. Each additional annual 1-unit reduction in the physical activity score was associated with a higher annual odds of incident heart failure (1.07, 95% CI 1.02–1.13), stroke (1.06, 95% CI 1.00–1.13), and CVD (1.04, 95% CI 1.01–1.07) events. Meeting the minimum (AOR 0.74, 95% CI 0.0.57–0.96) and twice the minimum (AOR 0.55, 95% CI 0.34–0.91) Department of Health and Human Services physical activity guidelines through follow up was protective of premature CVD events.ConclusionsGiven recent trends in declining physical activity with age and associated premature CVD events, the transition from young adult to midlife is an important time period to promote physical activity.

Ebola virus infection induces a delayed type I IFN response in bystander cells and the shutdown of key liver genes in human iPSC-derived hepatocytes.

SummaryLiver damage and an exacerbated inflammatory response are hallmarks of Ebola virus (EBOV) infection. Little is known about the intrinsic response to infection in human hepatocytes and their contribution to inflammation. Here, we present an induced pluripotent stem cell (iPSC)-derived hepatocyte-like cell (HLC) platform to define the hepato-intrinsic response to EBOV infection. We used this platform to show robust EBOV infection, with characteristic ultrastructural changes and evidence for viral replication. Transcriptomics analysis revealed a delayed response with minimal early transcriptomic changes, followed by a general downregulation of hepatic function and upregulation of interferon signaling, providing a potential mechanism by which hepatocytes participate in disease severity and liver damage. Using RNA-fluorescence in situ hybridization (FISH), we showed that IFNB1 and CXCL10 were mainly expressed in non-infected bystander cells. We did not observe an inflammatory signature during infection. In conclusion, iPSC-HLCs are an immune competent platform to study responses to EBOV infection.

Within-Visit Blood Pressure Variability and Cardiovascular Risk in ELSA-Brasil Study Participants.

ResumoFundamentoA variabilidade da pressão arterial (VPA) tem valor prognóstico para desfechos cardiovasculares fatais e não fatais.ObjetivosEste estudo teve como objetivo avaliar a associação entre a VPA em uma única visita e o risco cardiovascular em participantes do Estudo Longitudinal de Saúde do Adulto (ELSA-Brasil).MétodosO presente estudo transversal foi conduzido com dados basais (2008-2010) de 14.357 participantes do ELSA-Brasil, sem história de doença cardiovascular. A VPA foi quantificada pelo coeficiente de variação de três medidas padronizadas da pressão arterial sistólica (PAS) realizadas com um oscilômetro. Medidas antropométricas e exames laboratoriais também foram realizados. O risco cardiovascular foi avaliado pelo estimador de risco de doença cardiovascular aterosclerótica (ASCVD), e se empregou a análise de regressão logística multivariada com nível de significância de 5%.ResultadosUm risco cardiovascular significativamente maior foi determinado por uma VPA elevada para ambos os sexos. Uma prevalência significativamente maior de alto risco foi observada mais em homens que em mulheres em todos os quartis, com a maior diferença observada no quarto quartil de variabilidade (48,3% vs. 17,1%). Comparações entre quartis por sexo revelaram um risco significativamente mais alto para homens no terceiro (OR=1,20; IC95%: 1,02 - 1,40) e no quarto quartis OR=1,46; IC95%: 1,25 -1,71), e para mulheres no quarto quartil (OR=1,27; IC95%: 1,03 - 1,57).ConclusãoAnálises de dados basais de participantes do ELSA-Brasil revelaram que a variabilidade da pressão arterial se associou com risco cardiovascular aumentado, especialmente nos homens.

Prognostic Value of Catestatin in Severe COVID-19: An ICU-Based Study.

Catestatin is a pleiotropic peptide with a wide range of immunomodulatory effects. Considering that patients with a severe COVID-19 infection have a major immunological dysregulation, the aim of this study was to evaluate catestatin levels in patients with COVID-19 treated in the intensive care unit (ICU) and to compare them between the fatal and non-fatal outcomes. The study included 152 patients with severe COVID-19, out of which 105 had a non-fatal outcome and 47 had a fatal outcome. Serum catestatin levels were estimated by an enzyme-linked immunosorbent assay in a commercially available diagnostic kit. The results show that catestatin levels were significantly lower in the fatal group compared to the non-fatal group (16.6 ± 7.8 vs. 23.2 ± 9.2 ng/mL; p < 0.001). Furthermore, there was a significant positive correlation between serum catestatin levels and vitamin D levels (r = 0.338; p < 0.001) while there was also a significant positive correlation between serum catestatin levels and growth differentiation factor-15 (GDF-15) levels (r = −0.345; p < 0.001). Furthermore, multivariate logistic regression showed that catestatin, GDF-15 and leukocyte count were significant predictors for COVID-19 survival. These findings imply that catestatin could be playing a major immunomodulatory role in the complex pathophysiology of the COVID-19 infection and that serum catestatin could also be a predictor of a poor COVID-19 outcome.