The predictive value of cardiovascular outcomes and mortality assessed by the C-reactive protein to albumin ratio in the UK Biobank.

BACKGROUND: The C-reactive protein/albumin ratio (CAR) seems to mirror disease severity and prognosis in several acute disorders particularly in elderly patients, yet less is known about if CAR is superior to C-reactive protein (CRP) in the general population. METHODS: Prospective study design on the UK Biobank, where serum samples of CRP and Albumin were used. Cox regression analyses were conducted to assess all-cause and cardiovascular mortality, myocardial infarction, ischemic stroke, and heart failure over a follow-up period of approximately 12.5 years. The Cox model was adjusted for established cardiovascular disease (CVD) risk factors, including age, sex, smoking habits, physical activity level, BMI level, systolic blood pressure, LDL-cholesterol, statin treatment, diabetes, and previous CVD, with hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Analyses were also stratified by sex, CRP level (< 10 and ≥ 10 mg/ml) and age (< 60 and ≥ 60 years). RESULTS: In total, 411,506 individuals (186,043 men and 225,463 women) were included. In comparisons between HRs for all adverse outcomes, the results were similar or identical for CAR and CRP. For example, both CAR and CRP, adjusted HRs for all-cause mortality were 1.13 (95% CI 1.12-1.14). Regarding CVD mortality, the adjusted HR for CAR was 1.14 (95% CI 1.12-1.15), while for CRP, it was 1.13 (95% CI 1.11-1.15). CONCLUSIONS: Within this study CAR was not superior to CRP in predictive ability of mortality or CVD disorders. CLINICAL TRIAL REGISTRATION NUMBER: Not applicable (cohort study).

The Human Phospholipase B-II Precursor (HPLBII-P) in Urine as a Novel Biomarker of Increased Glomerular Production or Permeability in Diabetes Mellitus?

Background: A previous report showed that the urine output of HPLBII-P in patients with diabetes mellitus and SARS-CoV-2 infection was increased as a sign of glomerular dysfunction. The aim of this report was to investigate the relation of the urine output of HPLBII-P to diabetes mellitus in two large community-based elderly populations, i.e., the ULSAM and PIVUS cohorts. Methods: HPLBII-P was measured by an ELISA in the urine of a community-based cohort of 839 men (ULSAM) collected at 77 years of age and in the urine of a community-based cohort of 75-year-old men, n = 387, and women, n = 401 (PIVUS). KIM-1, NGAL, and albumin were measured in urine and cathepsin S and cystatin C in serum. Results: HPLBII-P was significantly raised among males with diabetes in the ULSAM (p < 0.0001) and PIVUS cohorts (p ≤ 0.02), but not in the female cohort of PIVUS. In the female subpopulation of insulin-treated diabetes, HPLBII-P was raised (p = 0.02) as compared to women treated with oral antidiabetics only. In the ULSAM cohort, HPLBII-P was correlated to NGAL, KIM-1, and albumin in urine both in non-DM (all three biomarkers; p < 0.0001) and in DM (NGAL; p = 0.002, KIM-1; p = 0.02 and albumin; p = 0.01). Plasma glucose and HbA1c in blood showed correlations to U-HPLBII-P (r = 0.58, p < 0.001 and r = 0.42, p = 0.004, respectively). U-HPLBII-P and cathepsin S were correlated in the ULSAM group (r = 0.50, p < 0.001). No correlations were observed between U-HPLBII-P and serum creatinine or cystatin C. Conclusions: The urine measurement of HPLBII-P has the potential to become a novel and useful biomarker in the monitoring of glomerular activity in diabetes mellitus.

Circulating leptin is associated with adverse vascular changes in young adult survivors of childhood cancer.

INTRODUCTION: Proteomics may help discover novel biomarkers and underlying mechanisms for cardiovascular disease. This could be useful for childhood cancer survivors as they show an increased risk of cardiovascular disease. The aim of this study was to investigate circulating cardiovascular proteins in young adult survivors of childhood cancer and their relationship to previously reported subclinical cardiovascular disease. METHODS: Ninety-two cardiovascular proteins were measured in 57 childhood cancer survivors and in 52 controls. For proteins that were significantly different between childhood cancer survivors and controls, we performed correlations between protein levels and measures of peripheral arterial stiffness (carotid distensibility and stiffness index, and augmentation index) and endothelial dysfunction (reactive hyperemia index). RESULTS: Leptin was significantly higher in childhood cancer survivors compared to controls (normalized protein expression units: childhood cancer survivors 6.4 (1.5) versus 5.1 (1.7), p < 0.0000001) after taking multiple tests into account. Kidney injury molecule-1, MER proto-oncogene tyrosine kinase, selectin P ligand, decorin, alpha-1-microglobulin/bikunin precursor protein, and pentraxin 3 showed a trend towards group differences (p < 0.05). Among childhood cancer survivors, leptin was associated with anthracycline treatment after adjustment for age, sex, and body mass index (p < 0.0001). Higher leptin correlated with lower carotid distensibility after adjustment for age, sex, body mass index, and treatments with radiotherapy and anthracyclines (p = 0.005). CONCLUSION: This proteomics approach identified that leptin is higher in young asymptomatic adult survivors of childhood cancer than in healthy controls and is associated with adverse vascular changes. This could indicate a role for leptin in driving the cardiovascular disease burden in this population.

Heart failure outcomes by left ventricular ejection fraction in a contemporary region-wide patient cohort.

AIMS: This study aimed to characterize a contemporary population with subtypes of incident or prevalent heart failure (HF) based on reduced (HFrEF), mildly reduced, or preserved (HFpEF) left ventricular ejection fraction (LVEF) and to assess how outcomes, healthcare, treatments, and healthcare costs vary between each subtype of incident HF. METHODS AND RESULTS: Using Swedish data from the CardioRenal and Metabolic disease Heart Failure (CaReMe HF) study, updated to cover a more recent time period, this population-based study characterized patients from Stockholm County, Sweden, with incident HF (patients with a first HF diagnosis between 1 January 2015 and 31 December 2019) or prevalent HF (patients with a first HF diagnosis before 1 January 2020). Patients with incident HF had LVEF measured by echocardiography within ±90 days of their first HF diagnosis, and patients with prevalent HF within 5 years prior to the index date. The 13 375 patients with prevalent HF (39.2% women, mean age 73.9 years) had multiple comorbidities (cardiovascular diseases, chronic kidney disease, diabetes, and cancer). These were already highly prevalent at the time of the first HF diagnosis in the 8042 patients with incident HF (40.5% women, mean age 72.3 years). Patients with incident HFpEF received less specialist HF care at outpatient secondary care facilities following their first HF diagnosis than those with incident HFrEF. Patients with HFrEF had higher risks of complications and exerted a higher burden, in terms of care for and costs of HF, on the healthcare system. CONCLUSIONS: This study of contemporary patients with incident HF demonstrates that those with HFpEF and HFrEF differ considerably in terms of clinical presentation, prognosis, and care, highlighting a potential to improve HF outcomes.

Estimated Glomerular Filtration Rate, Albuminuria, and Adverse Outcomes: An Individual-Participant Data Meta-Analysis.

Importance: Chronic kidney disease (low estimated glomerular filtration rate [eGFR] or albuminuria) affects approximately 14% of adults in the US. Objective: To evaluate associations of lower eGFR based on creatinine alone, lower eGFR based on creatinine combined with cystatin C, and more severe albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes. Design, Setting, and Participants: Individual-participant data meta-analysis of 27 503 140 individuals from 114 global cohorts (eGFR based on creatinine alone) and 720 736 individuals from 20 cohorts (eGFR based on creatinine and cystatin C) and 9 067 753 individuals from 114 cohorts (albuminuria) from 1980 to 2021. Exposures: The Chronic Kidney Disease Epidemiology Collaboration 2021 equations for eGFR based on creatinine alone and eGFR based on creatinine and cystatin C; and albuminuria estimated as urine albumin to creatinine ratio (UACR). Main Outcomes and Measures: The risk of kidney failure requiring replacement therapy, all-cause mortality, cardiovascular mortality, acute kidney injury, any hospitalization, coronary heart disease, stroke, heart failure, atrial fibrillation, and peripheral artery disease. The analyses were performed within each cohort and summarized with random-effects meta-analyses. Results: Within the population using eGFR based on creatinine alone (mean age, 54 years [SD, 17 years]; 51% were women; mean follow-up time, 4.8 years [SD, 3.3 years]), the mean eGFR was 90 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 11 mg/g (IQR, 8-16 mg/g). Within the population using eGFR based on creatinine and cystatin C (mean age, 59 years [SD, 12 years]; 53% were women; mean follow-up time, 10.8 years [SD, 4.1 years]), the mean eGFR was 88 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 9 mg/g (IQR, 6-18 mg/g). Lower eGFR (whether based on creatinine alone or based on creatinine and cystatin C) and higher UACR were each significantly associated with higher risk for each of the 10 adverse outcomes, including those in the mildest categories of chronic kidney disease. For example, among people with a UACR less than 10 mg/g, an eGFR of 45 to 59 mL/min/1.73 m2 based on creatinine alone was associated with significantly higher hospitalization rates compared with an eGFR of 90 to 104 mL/min/1.73 m2 (adjusted hazard ratio, 1.3 [95% CI, 1.2-1.3]; 161 vs 79 events per 1000 person-years; excess absolute risk, 22 events per 1000 person-years [95% CI, 19-25 events per 1000 person-years]). Conclusions and Relevance: In this retrospective analysis of 114 cohorts, lower eGFR based on creatinine alone, lower eGFR based on creatinine and cystatin C, and more severe UACR were each associated with increased rates of 10 adverse outcomes, including adverse kidney outcomes, cardiovascular diseases, and hospitalizations.

The C-reactive protein Albumin ratio was not consistently associated with cardiovascular and all-cause mortality in two community-based cohorts of 70-year-olds.

C-reactive protein (CRP)/Albumin ratio (CAR) seems to mirror disease severity and prognosis in several acute disorders particularly in elderly patients, which we aimed to study. As method we use a prospective study design; the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; n = 912, women 50%; mean age 70 years, baseline 2001 and 2004, median follow-up 15.0 years, end of follow-up 2019) and the Uppsala Longitudinal Study of Adult Men (ULSAM, n = 924 mean age 71 years, baseline 1991-1995, median follow-up 15.6 years, end of follow-up 2016). Serum samples were used for analyses of CRP and Albumin. Cox regression analyses were performed for cardiovascular and all-cause mortality in models adjusting for several factors (age; physical activity; Interleukin-6; cardiovascular (CVD) risk factors: smoking, BMI level, systolic blood pressure, LDL-cholesterol, and diabetes), with 95% confidence interval (CI). When adjusting for age and CVD risk factors, CAR was significantly associated with cardiovascular mortality for meta-analyzed results from PIVUS and ULSAM, HR 1.09 (95% 1.01-1.18), but neither in PIVUS (HR 1.14, 95% CI 0.99-1.31) nor in ULSAM (1.07, 95% CI 0.98-1.17). Additionally, CAR was significantly associated with all-cause mortality in ULSAM 1.31 (95% CI 1.12-1.54) but not in PIVUS HRs 1.01 (95% 0.089-1.15). The predictive value of CAR was similar to CRP alone in PIVUS and ULSAM and slightly better than albumin for the prediction of CVD-mortality in ULSAM. In conclusion, CAR was not consistently associated with cardiovascular and all-cause mortality in the two cohorts. The prognostic value of CAR for long-term CVD-mortality was similar to CRP.

The complexity of kidney disease and diagnosing it - cystatin C, selective glomerular hypofiltration syndromes and proteome regulation.

Estimation of kidney function is often part of daily clinical practice, mostly done by using the endogenous glomerular filtration rate (GFR)-markers creatinine or cystatin C. A recommendation to use both markers in parallel in 2010 has resulted in new knowledge concerning the pathophysiology of kidney disorders by the identification of a new set of kidney disorders, selective glomerular hypofiltration syndromes. These syndromes, connected to strong increases in mortality and morbidity, are characterized by a selective reduction in the glomerular filtration of 5-30 kDa molecules, such as cystatin C, compared to the filtration of small molecules <1 kDa dominating the glomerular filtrate, for example water, urea and creatinine. At least two types of such disorders, shrunken or elongated pore syndrome, are possible according to the pore model for glomerular filtration. Selective glomerular hypofiltration syndromes are prevalent in investigated populations, and patients with these syndromes often display normal measured GFR or creatinine-based GFR-estimates. The syndromes are characterized by proteomic changes promoting the development of atherosclerosis, indicating antibodies and specific receptor-blocking substances as possible new treatment modalities. Presently, the KDIGO guidelines for diagnosing kidney disorders do not recommend cystatin C as a general marker of kidney function and will therefore not allow the identification of a considerable number of patients with selective glomerular hypofiltration syndromes. Furthermore, as cystatin C is uninfluenced by muscle mass, diet or variations in tubular secretion and cystatin C-based GFR-estimation equations do not require controversial race or sex terms, it is obvious that cystatin C should be a part of future KDIGO guidelines.

Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses.

BACKGROUND: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. METHODS: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. RESULTS: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. CONCLUSIONS: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

The relevance of geriatric assessments on the association between chronic kidney disease stages and mortality among older people: a secondary analysis of a multicentre cohort study.

BACKGROUND: age-adapted definition of chronic kidney disease (CKD) does not take individual risk factors into account. We aimed at investigating whether functional impairments influence CKD stage at which mortality increases among older people. METHODS: our series consisted of 2,372 outpatients aged 75 years or more enrolled in a multicentre international prospective cohort study. The study outcome was 24-month mortality. Kidney function was assessed by estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR). Geriatric assessments included handgrip strength, short physical performance battery (SPPB), cognitive impairment, dependency in basic activities of daily living (BADL) and risk of malnutrition. Analysis was carried out by Cox regression, before and after stratification by individual functional impairments. Survival trees including kidney function and functional impairments were also investigated, and their predictivity assessed by C-index. RESULTS: overall, mortality was found to increase starting from eGFR = 30-44.9 ml/min/1.73 m2 (hazard ratio [HR] = 3.28, 95% confidence interval [CI] = 1.81-5.95) to ACR = 30-300 mg/g (HR = 1.96, 95%CI = 1.23-3.10). However, in survival trees, an increased risk of mortality was observed among patients with impaired handgrip and eGFR = 45-59.9 ml/min/1.73 m2, as well as patients with ACR < 30 mg/g and impaired handgrip and SPPB. Survival tree leaf node membership had greater predictive accuracy (C-index = 0.81, 95%CI = 0.78-0.84 for the eGFR survival tree and C-index = 0.77, 95%CI = 0.71-0.81 for the ACR survival tree) in comparison with that of individual measures of kidney function. CONCLUSIONS: physical performance helps to identify a proportion of patients at an increased risk of mortality despite a mild-moderate impairment in kidney function and improves predictive accuracy of individual measures of kidney function.

The association between short-term, chronic localized and chronic widespread pain and risk for cardiovascular disease in the UK Biobank.

AIMS: The interplay between pain of different chronicity and cardiovascular disease (CVD) is incompletely understood. We aimed to investigate the association between different levels of chronic or nonchronic pain and risk of CVD. METHODS AND RESULTS: Participants in the UK Biobank who reported pain at baseline were divided into three groups according to pain duration and widespreadness. Participants reporting no pain were controls. Multivariable Cox regression was used to investigate the association between pain and incidence of myocardial infarction, heart failure, stroke, cardiovascular mortality, and composite CVD (defined as any of the before-mentioned cardiovascular events). Of 475 171 participants, 189 289 reported no pain, 87 830 reported short-term pain, 191 716 chronic localized pain, and 6336 chronic widespread pain (CWP). During a median of 7.0 years' follow-up, participants with chronic localized pain and CWP had, after adjustment for age, sex, established cardiovascular risk factors, physical activity, anxiety, depression, cancer, chronic inflammatory/painful disease, pain/anti-inflammatory medication, socioeconomic status, a significantly increased risk for composite CVD [hazard ratio (HR) 1.14, confidence interval (CI) 1.08-1.21, P < 0.001; and HR 1.48, CI 1.28-1.73, P < 0.001, respectively] compared with controls, with similar results when using the different specific CVDs as outcomes. Population attributable risk proportion for chronic pain as a risk factor for composite CVD was comparable with that of diabetes (8.6 vs. 7.3%, respectively). CONCLUSION: Chronic pain is associated with an increased risk for myocardial infarction, stroke, heart failure, and cardiovascular death independent of established cardiovascular risk factors, socioeconomic factors, comorbidities and medication. Our study, the largest to date, confirms and extends our understanding of chronic pain as an underestimated cardiovascular risk factor with important public health implications.

Addition of cystatin C predicts cardiovascular death better than creatinine in intensive care.

OBJECTIVE: Decreased kidney function increases cardiovascular risk and predicts poor survival. Estimated glomerular filtration rate (eGFR) by creatinine may theoretically be less accurate in the critically ill. This observational study compares long-term cardiovascular mortality risk by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation; Caucasian, Asian, paediatric and adult cohort (CAPA) cystatin C equation and the CKD-EPI combined creatinine/cystatin C equation. METHODS: The nationwide study includes 22 488 intensive care patients in Uppsala, Karolinska and Lund University Hospitals, Sweden, between 2004 and 2015. Creatinine and cystatin C were analysed with accredited methods at admission. Reclassification and model discrimination with C-statistics was used to compare creatinine and cystatin C for cardiovascular mortality prediction. RESULTS: During 5 years of follow-up, 2960 (13 %) of the patients died of cardiovascular causes. Reduced eGFR was significantly associated with cardiovascular death by all eGFR equations in Cox regression models. In each creatinine-based GFR category, 17%, 19% and 31% reclassified to a lower GFR category by cystatin C. These patients had significantly higher cardiovascular mortality risk, adjusted HR (95% CI), 1.55 (1.38 to 1.74), 1.76 (1.53 to 2.03) and 1.44 (1.11 to 1.86), respectively, compared with patients not reclassified. Harrell's C-statistic for cardiovascular death for cystatin C, alone or combined with creatinine, was 0.73, significantly higher than for creatinine (0.71), p<0.001. CONCLUSIONS: A single cystatin C at admission to the intensive care unit added significant predictive value to creatinine for long-term cardiovascular death risk assessment. Cystatin C, alone or in combination with creatinine, should be used for estimating GFR for long-term risk prediction in critically ill.

Proteins associated with incident metabolic syndrome in population-based cohorts.

BACKGROUND: The metabolic syndrome (MetS) identifies persons with clustering of multiple cardiometabolic risk factors. The underlying pathology inducing this clustering is not fully known. We used a targeted proteomics assay to identify associations of circulating proteins with MetS and its components, cross-sectionally and longitudinally. METHODS: We explored and validated associations of 86 cardiovascular proteins, assessed using a proximity extension assay, with the MetS in two independent cohorts; the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS, n = 996) and Uppsala Longitudinal Study of Adult Men (ULSAM, n = 785). The analyses were adjusted for smoking, exercise habits, education, and energy and alcohol intake. RESULTS: Nine proteins were associated with all five components of the MetS in PIVUS using FDR < 0.05 in a cross-sectional analysis. Of those nine proteins, only Interleukin-1 receptor antagonist protein (IL-1RA) was associated with all five components of the MetS in ULSAM using p < 0.05. IL-1RA levels were associated with incident MetS (n = 109) in PIVUS during a 5-year follow-up (HR 1.76 for a 1 SD change (95% CI 1.38, 2.24), p = 4.3*10-6). IL-1RA was however not causally related to MetS in a two-sample Mendelian randomization analysis using published data. CONCLUSION: Circulating IL-1RA was related to all five components of the MetS in a cross-sectional analysis in two independent samples, as well as to incident MetS in a longitudinal analysis. However, Mendelian randomization analyses did not provide support for a causal role for IL-1RA in the development of MetS.

The association between BMI and 90-day mortality in patients with and without diabetes seeking care at the emergency department.

BACKGROUND: The impact of body mass index (BMI) on mortality varies with age and disease states. The aim of this research study was to analyse the associations between BMI categories and short- and long-term mortality in patients with or without diabetes seeking care at the emergency department (ED) with acute dyspnoea. POPULATION AND METHODS: Patients aged ≥18 years at ED during daytime on weekdays from March 2013 to July 2018 were included. Participants were triaged according to the Medical Emergency Triage and Treatment System-Adult score (METTS-A), and blood samples were collected. Totally, 1,710 patients were enrolled, with missing values in 113, leaving 1,597 patients, 291 with diabetes and 1,306 without diabetes. The association between BMI and short-term (90-day) and long-term (mean follow-up time 2.1 years) mortality was estimated by Cox regression with normal BMI (18.5-24.9) as referent category, with adjustment for age, sex, METTS-A scoring, glomerular filtration rate, smoking habits and cardiovascular comorbidity in a fully adjusted model. The Bonferroni correction was also used. RESULTS: Regarding long-term mortality, patients with diabetes and BMI category ≥30 kg/m2 had a fully adjusted Hazard Ratio (HR) of 0.40 (95% confidence interval [CI]: 0.23-0.69), significant after the Bonferroni correction. Amongst patients without diabetes, those with underweight had an increased risk but only of borderline significance, whilst risks in those with overweight or obesity did not differ from reference.Regarding short-term mortality, risks did not differ from reference amongst patients with or without diabetes. CONCLUSIONS: We found divergent long-term mortality risks in patients with and without diabetes, with lower risk in obese patients (BMI ≥ 30 kg/m2) with diabetes, but no increased risk for patients without diabetes and overweight (BMI: 25-29.9 kg/m2) and obesity.

Impact of risk factors for major cardiovascular diseases: a comparison of life-time observational and Mendelian randomisation findings.

BACKGROUND: This study compared the strength and causality of associations between major risk factors for cardiovascular disease (CVD) and the four major CVDs: myocardial infarction, ischaemic stroke, heart failure and atrial fibrillation. Both a long-term follow-up in an observational cohort and Mendelian randomisation (MR) were used for this aim. METHODS: In the Uppsala Longitudinal Study of Adult Men study, 2322 men, all aged 50 years, were assessed for CVD risk factors and then followed for four decades regarding incident CVDs. The two-sample MR part used public available Genome-Wide Association Study (GWAS) data. RESULTS: In multivariate analyses, systolic blood pressure was overall by far the most important risk factor, since it was related to all four CVDs, both in observational and MR analyses. Body mass index was the second most overall important risk factor, being linked to all four CVDs, except ischaemic stroke, both in observational and MR analyses. Smoking was an important risk factor for ischaemic stroke and heart failure, both in observational and MR analyses, while low-density lipoprotein-cholesterol mainly was related to myocardial infarction. Diabetes was mainly a causal risk factor for incident myocardial infarction and heart failure. Neither HDL-cholesterol nor triglycerides were of major importance as risk factors in these multivariable models. CONCLUSION: By combining long-term observational data with genetic data, we show that the impact and causal role of specific established cardiovascular risk factors varies between different major CVDs. Systolic blood pressure was causally related to all four cardiovascular outcomes and was therefore, overall, the most important risk factor.

Strong Associations Between Early Tubular Damage and Urinary Cytokine, Chemokine, and Growth Factor Levels in Elderly Males and Females.

Acute tubular necrosis is associated with high mortality rates and it is important to develop new biomarkers for tubular damage. The aim of this study was to investigate the effect of early tubular damage on a large number of urinary cytokines, chemokines, and growth factors. We selected 90 urine samples from the Prospective Investigation of the Vasculature in Uppsala Seniors Study (41 males and 49 females). The tubular damage markers cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) were analyzed in the urine samples and urinary cytokine levels were analyzed with 2 multiplex assays (proximity extension assay). After adjustment for sex, body mass index, estimated glomerular filtration rate, smoking, and multiplicity testing using the false discovery rate approach, there remained 26 cytokines that correlated significantly with urine cystatin C, 27 cytokines that correlated with NGAL, and 66 cytokines that correlated with KIM-1. Tubular damage shows a strong association with urinary cytokines, chemokines, and growth factors. Our findings indicate that multiplex proteomics could be a promising new approach to explore the complex effects of tubular damage.

Association between Cardiorespiratory Fitness and Circulating Proteins in 50-Year-Old Swedish Men and Women: a Cross-Sectional Study.

BACKGROUND AND AIMS: A strong cardiorespiratory fitness is suggested to have beneficial effects on cardiovascular risk; the exact mechanisms underlying the cardioprotective effects of fitness remain uncertain. Our aim was to investigate associations between cardiorespiratory fitness and multiple plasma proteins, in order to obtain insights about physiological pathways associated with the effects of exercise on cardiovascular health. METHODS: In the Prospective investigation of Obesity, Energy and Metabolism (POEM) study (n=444 adults aged 50 years, 50% women), cardiorespiratory fitness was measured by a maximal exercise test on bicycle ergometer with gas exchange (VO2peak) normalized for body lean mass (dual-energy X-ray absorptiometry (DXA)). We measured 82 cardiovascular proteins associated with cardiovascular pathology and inflammation in plasma samples with a proximity extension assay. RESULTS: In sex-adjusted linear regression, VO2peak was associated with 18 proteins after Bonferroni correction for multiple testing (p<0.0006). Following additional adjustment for fat mass (DXA), fasting glucose (mmol/L), low-density lipoprotein (LDL, mmol/L), smoking status, waist/hip ratio, blood pressure (mmHg), education level, and lpnr (lab sequence number), higher VO2peak was significantly associated with lower levels of 6 proteins: fatty-acid binding protein-4 (FABP4), interleukin-6 (IL-6), leptin, cystatin-B (CSTB), interleukin-1 receptor antagonist (IL-1RA), and growth differentiation factor 15 (GDF-15), and higher levels of 3 proteins: galanin, kallikrein-6 (KLK6), and heparin-binding EGF-like growth factor (HB-EGF), at nominal p-values (p<0.05). CONCLUSIONS: We identified multiple novel associations between cardiorespiratory fitness and plasma proteins involved in several atherosclerotic processes and key cellular mechanisms such as inflammation, energy homeostasis, and protease activity, which shed new light on how exercise asserts its beneficial effects on cardiovascular health. Our findings encourage additional studies in order to understand the underlying causal mechanisms for these associations.

Plasma Protein Profile of Incident Myocardial Infarction, Ischemic Stroke, and Heart Failure in 2 Cohorts.

Background The aim is to study common etiological pathways for 3 major cardiovascular diseases (CVD), as reflected in multiple proteins. Methods and Results Eighty-four proteins were measured using the proximity extension technique in 870 participants in the PIVUS (Prospective Investigation of Uppsala Seniors Study) cohort on 3 occasions (age 70, 75, and 80 years). The sample was followed for incident myocardial infarction, ischemic stroke or heart failure. The same proteins were measured in an independent validation sample, the ULSAM (Uppsala Longitudinal Study of Adult Men) cohort in 595 participants at age 77. During a follow-up of up to 15 years in PIVUS and 9 years in ULSAM, 222 and 167 individuals experienced a CVD. Examining associations with the 3 outcomes separately in a meta-analysis of the 2 cohorts, 6 proteins were related to incident myocardial infarction, 25 to heart failure, and 8 proteins to ischemic stroke following adjustment for traditional risk factors. Growth differentiation factor 15 and tumor necrosis factor-related apoptosis-inducing ligand receptor 2 were related to all 3 CVDs. Including estimated glomerular filtration rate in the models attenuated some of these relationships. Fifteen proteins were related to a composite of all 3 CVDs using a discovery/validation approach when adjusting for traditional risk factors. A selection of 7 proteins by lasso in PIVUS improved discrimination of incident CVD by 7.3% compared with traditional risk factors in ULSAM. Conclusions We discovered and validated associations of multiple proteins with incident CVD. Only a few proteins were associated with all 3 diseases: myocardial infarction, ischemic stroke, and heart failure.

Poorly controlled ambulatory blood pressure in outpatients with peripheral arterial disease.

BACKGROUND: Patients with peripheral arterial disease (PAD) are generally less intensively managed than patients with coronary heart disease (CHD), despite that their risk of complications is believed to be equivalent. Identification of PAD patients at risk of poorly controlled blood pressure (BP) could lead to improved treatment, thus lowering the risk of cardiovascular (CV) complications. We aimed to describe the prevalence of poorly controlled cardiovascular (CV) risk factors, focusing on BP, in outpatients with PAD diagnosed in a vascular ultrasound laboratory. METHODS: Consecutive outpatients with carotid and/or lower extremity PAD were included (n = 402) and examined with blood sampling, clinical BP, and 24-h ambulatory BP measurements. A poorly controlled clinical BP was defined as ≥140/90 mmHg, ambulatory BP ≥130/80 mmHg, low-density lipoprotein (LDL)-cholesterol level ≥2.5 mmol/L, and glycated hemoglobin (HbA1c) level >53 mmol/mol in those with diabetes. RESULTS: Most of the patients had poorly controlled clinical (76.6%) and ambulatory BP (51.7%) profiles. Antihypertensive medications were prescribed in 84% of the patients. However, >40% of them used only 0-1 medication, and <25% of them used three or more agents. Clinical BP, a low number of medications, body mass index, and the presence of diabetes independently predicted a poorly controlled ambulatory BP. Nearly one-third of the patients were smokers, and most of the cohort had an LDL-cholesterol level of ≥2.5 mmol/L. An HbA1c level of >53 mmol/mol was present in 55% of diabetic patients. CONCLUSION: Poorly controlled clinical and ambulatory systolic BP profiles were common. In addition, suboptimal control of other important CV risk factors was detected. The findings of this study highlight the need for better preventive efforts against CV risk factors in outpatients with PAD.

Albumin Urinary Excretion Is Associated with Increased Levels of Urinary Chemokines, Cytokines, and Growth Factors Levels in Humans.

The aim of the present study was to study the associations between urine albumin excretion, and a large number of urinary chemokines, cytokines, and growth factors in a normal population. We selected 90 urine samples from individuals without CVD, diabetes, stroke or kidney disease belonging to the Prospective Investigation of the Vasculature in Uppsala Seniors Study (41 males and 49 females, all aged 75 years). Urinary cytokine levels were analyzed with two multiplex assays (proximity extension assays) and the cytokine levels were correlated with urine albumin. After adjustment for sex, body mass index (BMI), estimated glomerular filtration rate (eGFR), smoking and multiplicity testing, 11 biomarkers remained significantly associated with urine albumin: thrombospondin 2, interleukin 6, interleukin 8, hepatocyte growth factor, matrix metalloproteinase-12 (MMP-12), C-X-C motif chemokine 9, tumor necrosis factor receptor superfamily member 11B, osteoprotegerin, growth-regulated alpha protein, C-X-C motif chemokine 6, oncostatin-M (OSM) and fatty acid-binding protein, intestinal, despite large differences in molecular weights. In this study, we found associations between urinary albumin and both small and large urine proteins. Additional studies are warranted to identify cytokine patterns and potential progression markers in various renal diseases.

Cystatin C predicts long term mortality better than creatinine in a nationwide study of intensive care patients.

Decreased glomerular filtration rate (GFR) is linked to poor survival. The predictive value of creatinine estimated GFR (eGFR) and cystatin C eGFR in critically ill patients may differ substantially, but has been less studied. This study compares long-term mortality risk prediction by eGFR using a creatinine equation (CKD-EPI), a cystatin C equation (CAPA) and a combined creatinine/cystatin C equation (CKD-EPI), in 22,488 patients treated in intensive care at three University Hospitals in Sweden, between 2004 and 2015. Patients were analysed for both creatinine and cystatin C on the same blood sample tube at admission, using accredited laboratory methods. During follow-up (median 5.1 years) 8401 (37%) patients died. Reduced eGFR was significantly associated with death by all eGFR-equations in Cox regression models. However, patients reclassified to a lower GFR-category by using the cystatin C-based equation, as compared to the creatinine-based equation, had significantly higher mortality risk compared to the referent patients not reclassified. The cystatin C equation increased C-statistics for death prediction (p < 0.001 vs. creatinine, p = 0.013 vs. combined equation). In conclusion, this data favours the sole cystatin C equation rather than the creatinine or combined equations when estimating GFR for risk prediction purposes in critically ill patients.