Inflammatory markers as novel predictors of cardiovascular disease

Inflammation is widely considered to be an important contributing factor in atherogenesis and the risk of atherothrombotic complications. Baseline measurements of some inflammatory markers are known to be predictive risk factors for future cardiovascular disease (CVD) events in prospective epidemiological studies. Inflammatory markers dominant in the literature are acute phase response (APR)-associated and include fibrinogen, C-reactive protein (CRP) and, more recently, interleukin- (IL-) 6. This thesis reviews the literature and suggests the need for further research into novel inflammatory markers of CVD risk. The broad aim was to expand on limited existing data and ascertain if circulating levels of four novel inflammatory markers (tumour necrosis factor alpha [TNF alpha], IL-18, soluble CD40 ligand [sCD40L], and matrix metalloproteinase-9 [MMP-9]) are associated with classical cardiovascular risk factors, and with future CVD events in several epidemiological studies. In studies of pre-analytical variables, all four markers had commercially available assays acceptable for epidemiological use, but only IL-18 and TNF alpha displayed assay stability and the ability to be measured in plasma or serum. Due to limited serum samples, MMP-9 and sCD40L were less extensively measured. Results suggest a moderate positive association of MMP-9 with coronary heart disease (CHD) risk (although confounded by smoking and markers of general inflammation), while serum sCD40L may be moderately inversely related to CHD risk. More data is required for these markers. IL-18 and TNF alpha displayed similar degrees of short-term biological variability and regression dilution as CRP. Population distributions of both cytokines were consistent with limited previous reports. Both displayed associations with conventional vascular risk factors (such as age, gender, HDL cholesterol, and smoking), although interestingly, associations with epidemiological measures of obesity were poor. Both cytokines demonstrated moderate associations with vascular disease in a retrospective CHD study. In 3 prospective CHD or CVD studies, IL-18 demonstrated consistent but moderate associations with risk of vascular events in age- and sex-adjusted models (Odds ratio [OR]~1.6 in the top versus bottom third of the population). The association became borderline significant after adjustment for conventional risk markers. Associations of TNF alpha with risk of CHD in these studies were inconsistent, and more data are needed. In 3 prospective stroke studies, TNF alpha demonstrated some moderate associations with acute stroke outcome and recurrent stroke risk, but not with incident stroke in the elderly with vascular disease. IL-18 demonstrated no association with risk or outcome in any stroke study. Meta-analysis in 4 suitable prospective studies showed (in full adjustment models) that IL-18 (OR 1.18 [95% CI 0.95-1.48] comparing extreme thirds) and TNF alpha OR 1.05 [0.67-1.64]) have at best weak independent associations with CVD risk. Therefore these markers are unlikely to add significantly to clinical vascular risk prediction models, although these cytokines may still be of biological significance and potential therapeutic targets. More data is required for these markers. In conclusion IL-18, TNF alpha, MMP-9 and sCD40L may show weak associations with CVD. However, despite animal and tissue models indicating that they may play pivotal roles in atherogenesis, circulating concentrations of these inflammatory markers have limited independent vascular risk associations. Elevated circulating levels of APR-associated markers may sensitively reflect exposure to a wide range of adverse pro-inflammatory stimuli including lifestyle exposures, whereas some other inflammatory markers may not

Inflammatory markers as novel predictors of cardiovascular disease

Inflammation is widely considered to be an important contributing factor in atherogenesis and the risk of atherothrombotic complications. Baseline measurements of some inflammatory markers are known to be predictive risk factors for future cardiovascular disease (CVD) events in prospective epidemiological studies. Inflammatory markers dominant in the literature are acute phase response (APR)-associated and include fibrinogen, C-reactive protein (CRP) and, more recently, interleukin- (IL-) 6. This thesis reviews the literature and suggests the need for further research into novel inflammatory markers of CVD risk. The broad aim was to expand on limited existing data and ascertain if circulating levels of four novel inflammatory markers (tumour necrosis factor alpha [TNF alpha], IL-18, soluble CD40 ligand [sCD40L], and matrix metalloproteinase-9 [MMP-9]) are associated with classical cardiovascular risk factors, and with future CVD events in several epidemiological studies. In studies of pre-analytical variables, all four markers had commercially available assays acceptable for epidemiological use, but only IL-18 and TNF alpha displayed assay stability and the ability to be measured in plasma or serum. Due to limited serum samples, MMP-9 and sCD40L were less extensively measured. Results suggest a moderate positive association of MMP-9 with coronary heart disease (CHD) risk (although confounded by smoking and markers of general inflammation), while serum sCD40L may be moderately inversely related to CHD risk. More data is required for these markers. IL-18 and TNF alpha displayed similar degrees of short-term biological variability and regression dilution as CRP. Population distributions of both cytokines were consistent with limited previous reports. Both displayed associations with conventional vascular risk factors (such as age, gender, HDL cholesterol, and smoking), although interestingly, associations with epidemiological measures of obesity were poor. Both cytokines demonstrated moderate associations with vascular disease in a retrospective CHD study. In 3 prospective CHD or CVD studies, IL-18 demonstrated consistent but moderate associations with risk of vascular events in age- and sex-adjusted models (Odds ratio [OR]~1.6 in the top versus bottom third of the population). The association became borderline significant after adjustment for conventional risk markers. Associations of TNF alpha with risk of CHD in these studies were inconsistent, and more data are needed. In 3 prospective stroke studies, TNF alpha demonstrated some moderate associations with acute stroke outcome and recurrent stroke risk, but not with incident stroke in the elderly with vascular disease. IL-18 demonstrated no association with risk or outcome in any stroke study. Meta-analysis in 4 suitable prospective studies showed (in full adjustment models) that IL-18 (OR 1.18 [95% CI 0.95-1.48] comparing extreme thirds) and TNF alpha OR 1.05 [0.67-1.64]) have at best weak independent associations with CVD risk. Therefore these markers are unlikely to add significantly to clinical vascular risk prediction models, although these cytokines may still be of biological significance and potential therapeutic targets. More data is required for these markers. In conclusion IL-18, TNF alpha, MMP-9 and sCD40L may show weak associations with CVD. However, despite animal and tissue models indicating that they may play pivotal roles in atherogenesis, circulating concentrations of these inflammatory markers have limited independent vascular risk associations. Elevated circulating levels of APR-associated markers may sensitively reflect exposure to a wide range of adverse pro-inflammatory stimuli including lifestyle exposures, whereas some other inflammatory markers may not.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Impact of kidney function on cardiovascular risk and mortality: a comparison of South Asian and European cohorts

Evidence is limited on ethnic differences in associations between kidney function markers and mortality or cardiovascular disease (CVD). Baseline cross-sectional analysis and longitudinal follow-up study of a UK population-based cohort of 1,116 Europeans and 1,104 South Asians of predominantly Indian descent, age 52 ± 7 years at baseline (1988-1991). Kidney function was estimated using Cystatin C and creatinine-based chronic kidney disease (CKD) Epidemiology Collaboration estimated glomerular filtration rate (eGFR) equations, and urinary albumin-creatinine ratio (ACR). Mortality was captured at 27 years, and incident CVD at 22 years, from death certification, medical records and participant report. Longitudinal associations between eGFR/ACR and mortality/incident CVD were examined using Cox models. eGFRcys was lower and ACR higher in South Asians than Europeans. eGFRcys and -eGFRcreat were more strongly associated with outcomes in Europeans than South Asians. Conversely, associations between ACR and outcomes were greater in South Asians than Europeans, for example, for CVD mortality: HRs (95% CI) adjusted for CVD risk factors and ACR/eGFRcys as appropriate, p for ethnicity interaction: eGFRcys: Europeans: 0.76 (0.62-0.92), South Asians: 0.92 (0.78-1.07), p = 0.05, eGFRcreat: Europeans 0.81 (0.67-0.99), South Asians 1.18 (0.97-1.41), p = 0.002, ACR: -Europeans: 1.24 (1.08-1.42), South Asians: 1.39 (1.25-1.57), p= 0.23. Addition of all CKD measures to a standard CVD risk factor model modestly improved prediction capability in -Europeans; in South Asians only ACR contributed to improvement. Strong associations between ACR and outcomes in South Asians of predominantly Indian origin, and null associations for eGFRcys and eGFRcreat, suggest that ACR may have greater utility in CVD risk prediction in South Asians. Further work is needed to validate these -findings. [Abstract copyright: © 2019 S. Karger AG, Basel.

Circumbinary habitability niches

ABSTRACT: Binaries could provide the best niches for life in the Galaxy. Although counterintuitive, this assertion follows directly from stellar tidal interaction theory and the evolution of lower mass stars. There is strong evidence that chromospheric activity of rapidly rotating young stars may be high enough to cause mass loss from atmospheres of potentially habitable planets. The removal of atmospheric water is most critical. Tidal breaking in binaries could help reduce magnetic dynamo action and thereby chromospheric activity in favour of life. We call this the Binary Habitability Mechanism (BHM) that we suggest allows for water retention at levels comparable to or better than the Earth. We discuss novel advantages that life may exploit, in these cases, and suggest that life may even thrive on some circumbinary planets. We find that while many binaries do not benefit from BHM, high-quality niches do exist for various combinations of stars between 0.55 and 1.0 solar masses. For a given pair of stellar masses, BHM operates only for certain combinations of period and eccentricity. Binaries having a solar-type primary seem to be quite well-suited niches having wide and distant habitable zones with plentiful water and sufficient light for photosynthetic life. We speculate that, as a direct result of BHM, conditions may be suitable for life on several planets and possibly even moons of giant planets orbiting some binaries. Lower mass combinations, while more restrictive in parameter space, provide niches lasting many billions of years and are rich suppliers of photosynthetic photons

The novel urinary proteomic classifier HF1 has similar diagnostic and prognostic utility to BNP in heart failure

Aims: Measurement of B‐type natriuretic peptide (BNP) or N‐terminal pro‐BNP is recommended as part of the diagnostic workup of patients with suspected heart failure (HF). We evaluated the diagnostic and prognostic utility of the novel urinary proteomic classifier HF1, compared with BNP, in HF. HF1 consists of 85 unique urinary peptide fragments thought, mainly, to reflect collagen turnover. Methods and results: We performed urinary proteome analysis using capillary electrophoresis coupled with mass spectrometry in 829 participants. Of these, 622 had HF (504 had chronic HF and 118 acute HF) and 207 were controls (62 coronary heart disease patients without HF and 145 healthy controls). The area under the receiver operating characteristic (ROC) curve (AUC) using HF1 for the diagnosis of HF (cases vs. controls) was 0.94 (95% CI, 0.92–0.96). This compared with an AUC for BNP of 0.98 (95% CI, 0.97–0.99). Adding HF1 to BNP increased the AUC to 0.99 (0.98–0.99), P < 0.001, and led to a net reclassification improvement of 0.67 (95% CI, 0.54–0.77), P < 0.001. Among 433 HF patients followed up for a median of 989 days, we observed 186 deaths. HF1 had poorer predictive value to BNP for all‐cause mortality and did not add prognostic information when combined with BNP. Conclusions: The urinary proteomic classifier HF1 performed as well, diagnostically, as BNP and provided incremental diagnostic information when added to BNP. HF1 had less prognostic utility than BNP

Genetic analysis of over half a million people characterises C-reactive protein loci

Chronic low-grade inflammation is linked to a multitude of chronic diseases. We report the largest genome-wide association study (GWAS) on C-reactive protein (CRP), a marker of systemic inflammation, in UK Biobank participants (N = 427,367, European descent) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (total N = 575,531 European descent). We identify 266 independent loci, of which 211 are not previously reported. Gene-set analysis highlighted 42 gene sets associated with CRP levels (p ≤ 3.2 ×10−6) and tissue expression analysis indicated a strong association of CRP related genes with liver and whole blood gene expression. Phenome-wide association study identified 27 clinical outcomes associated with genetically determined CRP and subsequent Mendelian randomisation analyses supported a causal association with schizophrenia, chronic airway obstruction and prostate cancer. Our findings identified genetic loci and functional properties of chronic low-grade inflammation and provided evidence for causal associations with a range of diseases

Longitudinal changes in reproductive hormones through the menopause transition in the Avon Longitudinal Study of Parents and Children (ALSPAC)

We characterised changes in reproductive hormones—LH, FSH, SHBG and AMH—by chronological age and time around the menopause (reproductive age) in mid-life women and explored their associations with lifestyle and reproductive factors. We used data from 1608 women from a UK cohort who had repeat hormone measures and experienced a natural menopause. Multilevel models were used to assess: (i) changes in hormones (outcomes) by reproductive age and chronological age (these age variables being the key exposures) and (ii) associations of body mass index (BMI), smoking, alcohol intake, parity and age at menarche with changes in hormones by reproductive age. Both LH and FSH increased until ~ 5 and 7 years postmenopause, respectively, after which they declined, but not to premenopausal levels. SHBG decreased slightly until ~ 4 years postmenopause and increased thereafter. AMH decreased markedly before menopause and remained low subsequently. For all hormones, the best fitting models included both reproductive and chronological age. BMI, smoking and parity were associated with hormone changes; e.g., higher BMI was associated with slower increase in LH and FSH and decrease in AMH. Reproductive and chronological age contribute to changes in LH, FSH, SHBG and AMH across mid-life in women, and BMI, smoking and parity are associated with these hormone changes

The 'At-risk mental state' for psychosis in adolescents : clinical presentation, transition and remission.

Despite increased efforts over the last decade to prospectively identify individuals at ultra-high risk of developing a psychotic illness, limited attention has been specifically directed towards adolescent populations (<18 years). In order to evaluate how those under 18 fulfilling the operationalised criteria for an At-Risk Mental State (ARMS) present and fare over time, we conducted an observational study. Participants (N = 30) generally reported a high degree of functional disability and frequent and distressing perceptual disturbance, mainly in the form of auditory hallucinations. Seventy percent (21/30) were found to fulfil the criteria for a co-morbid ICD-10 listed mental health disorder, with mood (affective; 13/30) disorders being most prevalent. Overall transition rates to psychosis were low at 24 months follow-up (2/28; 7.1 %) whilst many participants demonstrated a significant reduction in psychotic-like symptoms. The generalisation of these findings may be limited due to the small sample size and require replication in a larger sample

Objectively measured physical activity and cardiac biomarkers: A cross sectional population based study in older men.

BACKGROUND: N-terminal pro-brain natriuretic peptide (NT-proBNP) and high sensitivity Troponin T (hsTnT) are markers of cardiac injury used in diagnosis of heart failure and myocardial infarction respectively, and associated with increased risk of cardiovascular disease. Since physical activity is protective against cardiovascular disease and heart failure, we investigated whether higher levels of physical activity, and less sedentary behaviour were associated with lower NT-proBNP and hsTnT. METHODS AND RESULTS: Cross sectional study of 1130 men, age 70-91years, from the British Regional Heart Study, measured in 2010-2012. Fasting blood samples were analysed for NT-proBNP and hsTnT. Physical activity and sedentary behaviour were measured using ActiGraph GT3X accelerometers. Relationships between activity and NT-proBNP or hsTnT were non-linear; biomarker levels were lower with higher total activity, steps, moderate/vigorous activity and light activity only at low to moderate levels of activity. For example, for each additional 10min of moderate/vigorous activity, NT-proBNP was lower by 35.7% (95% CI -47.9, -23.6) and hsTnT by 8.4% (95% CI -11.1, -5.6), in men who undertook <25 or 50min of moderate/vigorous activity per day respectively. Biomarker levels increased linearly with increasing sedentary behaviour, but not independently of moderate/vigorous activity. CONCLUSION: Associations between biomarkers and moderate/vigorous activity (and between hsTnT and light activity) were independent of sedentary behaviour, suggesting activity is driving the relationships. In these older men with concomitantly low levels of physical activity, activity may be more important in protecting against cardiac health deterioration in less active individuals, although reverse causality might be operating