OBJECTIVE:Blood pressure variability (BPV) has emerged as an independent risk factor for cardiovascular outcomes. This study evaluated the relationship between visit-to-visit BPV and cardiovascular events, renal outcomes, and mortality in individuals with and without diabetes, using data from the ASCOT trial. METHODS:BPV was assessed from SBP measurements collected over a 5-year follow-up in 18 528 participants from the ASCOT trial, including 4910 individuals with diabetes and 13 618 without diabetes Participants were stratified according to levels of SBP and BPV, and outcomes were compared using Cox proportional hazards models adjusted for baseline confounders. FINDINGS:There was a positive relationship between cardiovascular and renal outcomes and higher mean SBP in those with and without diabetes, but this association was markedly attenuated following adjustment for confounding variables.In those with diabetes, higher BPV (>13) was strongly associated with increased risks of nonfatal myocardial infarction (MI) and fatal coronary heart disease (CHD) [hazard ratio 1.76, 95% confidence interval (95% CI) 1.29-2.39], stroke (hazard ratio 2.41, 95% CI 1.67-2.90), total coronary events (hazard ratio 1.94, 95% CI 1.53-2.45), total CV events (hazard ratio 2.39, 95% CI 1.97-2.89), renal impairment (hazard ratio 1.69, 95% CI 1.26-2.26, P < 0.001), and mortality (hazard ratio 1.52, 95% CI 1.19-1.94) compared with the reference group (all P < 0.001). These associations, albeit attenuated, persisted after adjustment for confounders. In those with well controlled SBP (≤135 mmHg), elevated BPV conferred significant residual risk. Those allocated to amlodipine-based regimen had a significantly reduced risk of stroke (hazard ratio 0.74, 95% CI 0.56-0.97) and total cardiovascular events (hazard ratio 0.81, 95% CI 0.71-0.93) (vs those allocated to atenolol-based treatment), an effect partly attributable to BPV reduction. CONCLUSION:Long-term BPV is a critical cardiovascular and renal risk factor in individuals with diabetes and should be incorporated into risk assessment where feasible. On the basis of available evidence, long-acting calcium channel blockers should be incorporated into treatment strategies to improve cardiovascular outcomes.

Introduction and Aims Treatment-resistant hypertension (RHTN) patients have increased cardiovascular risks, and it is believed that RHTN may have genetic causes. It is also hypothesised that genetics may explain the inter-individual variability in antihypertensive drug response of patients.Our latest genome-wide association study (GWAS) for blood pressure (BP) reports 2,103 independent BP-associated genetic signals and provides powerful genetic risk scores (GRS). Therefore, we investigated whether BP-GRS are associated with RHTN and antihypertensive drug response, among treated hypertensive patients.We defined RHTN cases as patients with uncontrolled high BP despite the use of three or more antihypertensive drug classes, vs controls, who were defined as having controlled BP levels requiring the use of no more than three drug classes.BP-GRS were constructed for European ancestry patients from ASCOT for systolic (SBP), diastolic BP (DBP) and pulse pressure (PP). The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) recruited 19,342 hypertensive European patients between 40 and 79 years of age and randomised them to a beta-blocker (BB) or calcium channel blocker (CCB) arms. A total of 6,266 patients with available genetic date were included in ASCOT analyses.Change in BP response to treatment was considered within a sub-sample of ASCOT for patients on monotherapy treatment only (1,518 patients on BB, 1,780 on CCB). The BP drug response phenotype was calculated as the difference in their baseline vs on-treatment BP measurements. Methods BP-GRS were constructed in all ASCOT individuals with genetic data. Each BP-GRS comprised all 2,103 published BP variants, weighted by their independent effect estimates from UK Biobank GWAS data only, so that increasing BP-GRS scores corresponded to increasing BP levels.We tested BP-GRS for association with: (i) RHTN, adjusted for: sex, age, BMI, diabetes, randomisation treatment arm and left ventricular hypertrophy; and (ii) BP response to monotherapy treatment, adjusted for sex, age, baseline-BP, dose and baseline antihypertensive use. All the analyses performed for SBP-GRS, DBP-GRS, PP-GRS were adjusted for the top 10 genetic principal components (PCs) of ancestry. Results All three BP-GRS were significantly associated with RHTN (3,103 cases vs 3,163 controls): p=6.73 × 10-15 for SBP-GRS; p=2.86 × 10-4 for DBP-GRS; and p<10-16 for PP-GRS, with increased genetic risk of hypertension increasing odds of RHTN. Patients in the top 20% of SBP-GRS distribution had 1.78 × odds of RHTN compared with the lowest 20% (p=6.90 × 10-11).BP-GRS were also significantly associated with BP response to CCBs (n=1,780): eg, patients in the lowest 20% genetic risk group achieved better lowering response with a 3.79 mmHg mean difference between SBP pre and post treatment (p=4.9 × 10-4). However, results were non-significant for BB drug response. Conclusion Our results confirm genetic contributions to both RHTN and BP drug response. Results indicate that RHTN patients are likely to be those with highest genetic risk of hypertension, hence the greater clinical challenge. These findings could aid the management of patients with RHTN in clinical practice, since genetic risk profiling could identify earlier those at risk.Similarly, we show that patients with greater BP genetic risk respond less effectively to antihypertensive treatment, with less reduction of BP post-treatment.

BACKGROUND:The prediction of future cardiovascular events in those with risk factors is important for the appropriate optimisation of preventative therapies for those at greatest risk. The value of high sensitivity C-reactive Protein (hsCRP) has been questioned in this regard. The objectives of this post-hoc analysis of a randomised controlled trial were to investigate the usefulness of baseline serum hsCRP for predicting very long-term cardiovascular events in patients with hypertension in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Legacy Study. METHODS:The ASCOT Legacy Study reports events up to 20 years of follow-up of the UK participants in the Lipid Lowering Arm of the original ASCOT trial. We examined outcomes related to serum hsCRP levels measured using a commercial ELISA, in tertiles or continuously, adjusting for classical cardiovascular risk factors as well as treatment allocation within ASCOT. The primary outcome was non-fatal myocardial infarction (MI) and fatal coronary heart disease (CHD); whilst secondary outcomes were all-cause mortality, total coronary events and procedures, total cardiovascular events and stroke. FINDINGS:After excluding 3286 participants without hsCRP data, 5294 participants were included in the final cohort. The highest tertile of hsCRP was associated with the following outcomes compared to the lowest tertile: non-fatal myocardial infarction (MI) and fatal CHD (HR 1.32 [1.05-1.67]); total coronary events and procedures (HR 1.27 [1.09-1.47]); total cardiovascular events (HR 1.22 [1.08-1.37]); and all-cause mortality (HR 1.25 [1.10-1.42]). However, there was insufficient evidence regarding the association between hsCRP levels and stroke events. Addition of hsCRP in tertiles resulted in an improved net reclassification index for the prediction of non-fatal MI and fatal CHD at 20 years (9.68%, p < 0.0001). INTERPRETATION:Higher baseline serum hsCRP levels can independently predict cardiovascular events and all-cause mortality at long-term follow-up in stable patients with hypertension. FUNDING:British Heart Foundation Clinical Research Fellowship (FS/17/16/32560), Wellcome Trust Clinical Research Fellowship (220572/Z/20/Z), and Sansour Fund at Imperial Healthcare Charity. The substudy of ASCOT Biomarker Programme was supported by Pfizer, New York, NY, USA. Infrastructure support was provided by the NIHR Imperial Biomedical Research Centre as well as the Imperial British Heart Foundation Research Excellence Award (4) (RE/24/130023).

Background: Most BP guidelines suggest universal systolic BP (SBP) targets for reducing cardiovascular (CV) events. We hypothesised that the link between average mean SBP levels on treatment differs for CV events in different vascular territories, and this relationship is more pronounced in specific sub-groups. Using data from hypertensive patients in 3 trials (ASCOT, ALLHAT and SPRINT; n >50,000), we examined, separately, the relationship between cumulative mean SBP achieved after 1y of treatment (cum_avg_SBP1y) and the risk of 3 outcomes: Coronary heart disease (CHD), stroke and peripheral arterial disease (PAD) in those with/without previous CVD (example sub-group). Methods: For each trial and outcome, separate Cox models were used to model cum_avg_SBP1y using restricted cubic splines. HRs (95%CI) adjusted for other CV risk factors, treatment allocation and incident non-outcome events, were estimated with reference to the cum_avg_SBP1y of 120 mmHg. Relationships were categorised as potentially harmful when HR>1, lower CI≤1; and clearly harmful when HR>1, lower CI>1. Results: At 1y, cum_avg_SBP1y was 152mmHg (SD14) in ASCOT, 130mmHg (SD9.5) in SPRINT, and 140mmHg (SD13) in ALLHAT. Amongst CVD-free participants at 1y (N~14500 in ASCOT, 6500 in SPRINT, 19300 in ALLHAT): As per fig 1-3, for CHD outcome, potential harm appeared at cum_avg_SBP1y >120mmHg in ALLHAT and >160mmHg in ASCOT. For stroke events, potential harm was apparent at cum_avg_SBP1y > 120 mmHg in ALLHAT and ASCOT; clear harm only at SBP> 130 mmHg in ALLHAT, > 140 mmHg in SPRINT. For PAD event , cum_avg_SBP1y < 120 mmHg was potentially harmful in ALLHAT, with clear harm beyond ~145 mmHg in ASCOT and ALLHAT. Among participants with CVD (N~2900 in ASCOT, 1700 in SPRINT, 6000 in ALLHAT): For CHD , cum_avg_SBP1y <120mmHg was harmful in all 3 trials, while between 120–160mmHg was protective in ALLHAT. For stroke , cum_avg_SBP1y < 120 mmHg was clearly harmful in ASCOT and SPRINT. For PAD , cum_avg_SBP1y < 120 mmHg and > 130 mmHg were associated with potential harm in ALLHAT; potential harm was also apparent with cum_avg_SBP1y > 120 mmHg in ASCOT and SPRINT. Conclusion: Harmful levels of BP control (especially lower range ones) differ for different CV events and are influenced by participant characteristics, such as prior CVD history. These findings suggest that SBP targets for primary and secondary prevention of CVD may need to be personalised using existing comorbidities and vascular territories of concern.

Abstract Diabetes and hypertension are both risk factors for cardiovascular disease (CVD), and often co-exist. Over recent decades practice guidance and health policy efforts have been made to improve population wide blood pressure (BP) control, particularly amongst those with diabetes, to reduce CVD. However, the nationwide impact of these ongoing efforts is yet to be documented comprehensively in England. We used data from 11 serial nationally representative health surveys of England between 2003 and 2019 and compared BP control and presence of untreated hypertension amongst those with and without diabetes. These cross-sectional, randomly sampled surveys included 94,100 individuals cumulatively. We applied sample weights, accounting for oversampling and survey nonresponse, and transformations mitigating for survey equipment changes during this period. We used ‘period definitions’ to define those with diabetes and quantify BP control at the time of each coinciding survey, facilitating accurate comparison of trends over the sixteen-year period, while accounting for changes in understanding, variations in definitions, and shifts in medical practices. Python and STATA were used to conduct analyses and Join Point regression software was used to develop and compare trends. In England, from 2003-2019, the prevalence of hypertension amongst those with diabetes and without diabetes decreased from 74.4% to 66.5% and from 32.6% to 27.1% (7.9% vs. 5.5%), respectively. This corresponded to reductions in population-wide mean systolic (S) and diastolic (D) BPs: compared to those without diabetes, those with diabetes had greater reduction in both SBP (7.9mmHg vs. 4.8mmHg) and DBP (2.7mmHg vs. 1.9mmHg) (Figure1). Both groups showed similar temporal improvement in BP-control amongst those with diagnosed hypertension, with those with diabetes showing better improvement in BP control compared to those without diabetes (14% vs. 12%). There was a significant difference in proportions of those with undiagnosed (unaware) hypertension amongst those with and without diabetes (11.4% vs. 30.0% respectively) (Figure2). Notably, there was no change in proportion of those with hypertension unaware about the condition (i.e. detection rate for hypertension in either of the group did not show any improvement over time). These results suggest that we have been able to improve BP control over this period amongst those with and without diabetes, however, those without diabetes (more than 90% of population) have shown significantly poorer improvement. In addition, around one third of hypertensive patients amongst the no-diabetes group are unaware of the condition, and overall, the detection rates for hypertension in both groups have not improved in the last two decades. Lessons learnt from improving BP control amongst those with diabetes should be applied across the entire population, and newer strategies need to develop to improve detection of those with hypertension and are unaware.

Abstract Globally, raised blood pressure (BP) contributes to more than 10.8 million avoidable deaths from cardiovascular (CV) and renal disease. Understanding national BP control trends amongst hypertensive patients will help inform the effectiveness and gaps in existing pathways and policies. We used data from 13 nationally representative health surveys in England between 1994-2019 to compare nationwide trends in BP control and hypertension awareness over 25 years. We used ‘period’ definitions to define hypertension and BP control (i.e. using existing guidance at the time of the survey) to account for changes in BP targets and definitions. Analyses were also conducted using ‘current definitions’ (i.e. definition of hypertension and BP control targets as per NICE 2023), applied across the entire duration. Sample weights, accounting for oversampling and survey nonresponse, and other relevant transformations were applied. Python and STATA 18 were used to conduct analyses and Join Point regression software was used to compare trends. In England, between 1994-2019, the prevalence of hypertension initially increased sharply by 8% from 23.3% when the BP cut off was lowered in 1999. Thereafter for the next 12 years it remained static at 32-34%, and since 2011 has plateaued at 31-32%, showing only marginal improvement of 1.5% over this 25-year period (Figure 1). This is consistent with population-wide mean systolic (S) and diastolic (D) BPs, and amongst those with and without hypertension. Population-wide there was a reduction in SBP (8.5mmHg) and DBP (3.8mmHg) over the period. There was significantly greater reduction in SBP (11.9 vs 9.5mmHg) and DBP (4.1 vs 2.5mmHg) amongst those with diagnosed hypertension as compared to those without. Using the current target of below 140/90mmHg when evaluating BP control over this period suggests that we have improved. However, when we use ‘period definitions’ of BP targets at that time, it seems that over last 25 years there has been ‘no change’ in the proportion of diagnosed hypertensives with uncontrolled BPs (Figure 2). Additionally, although appearing to increase over the period, there has been no significant change in proportions of those with hypertension who are unaware of this condition since BP cut-offs were lowered in 1999. These findings indicate that in England, over last 25 years, whilst there have been some improvements in population wide mean SBP and DBP with slight reduction in hypertension prevalence, the proportions of those with known hypertension with uncontrolled BPs have remained static. This is despite improvement in medications and practice. Furthermore, there has been little progress in detection of those hypertensive patients who are unaware about and untreated for their condition. Clearly, these call in question the effectiveness of the current policies and clinical practice pathways and provide huge opportunity to improve population wide CV riskSytolic and Diastolic BP trendsTrends in the prevalence of BP control

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10-8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10-126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10-44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10-34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.

Clinical trials and observational studies have demonstrated that long-term systolic blood pressure variability derived from repeated measurements of visit-to-visit clinic blood pressure is an important predictor of cardiovascular outcomes, independent of average levels of systolic pressure. Even in patients with well-controlled blood pressure (<140/90 mmHg), high systolic blood pressure variability confers an increased risk of cardiovascular events. Systolic blood pressure variability is currently derived from several measurements of visit-to-visit clinic blood pressure and expressed as the standard deviation of systolic pressure. Values in excess of 12 are indicative of high systolic blood pressure variability. Ongoing studies aim to determine whether home blood pressure monitoring may be an alternative way of measuring blood pressure variability. Evidence from several clinical trials shows that long-acting calcium-channel blockers, such as amlodipine, and thiazide-like diuretics are the only antihypertensive drugs that reduce longterm systolic blood pressure variability, and should be used preferentially in patients with high variability.

Background and Aims Visit-to-visit systolic blood pressure variability (BPV) is an important predictor of cardiovascular (CV) outcomes. The long-term effect of a period of blood pressure (BP) control, but with differential BPV, is uncertain. Morbidity and mortality follow-up of UK participants in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure-Lowering Arm has been extended for up to 21 years to determine the CV impact of mean systolic blood pressure (SBP) control and BPV during the trial, and amongst those allocated to amlodipine-and atenolol-based treatment. Methods Eight thousand five hundred and eighty hypertensive participants (4305 assigned to amlodipine +/- perindopril-based and 4275 to atenolol +/- diuretic-based treatment during the in-trial period (median 5.5 years) were followed for up to 21 years (median 17.4 years), using linked hospital and mortality records. A subgroup of participants (n = 2156) was followed up 6 years after the trial closure with a self-administered questionnaire and a clinic visit. In-trial mean SBP and standard deviation of visit-to-visit SBP as a measure of BPV, were measured using >100 000 BP measurements. Cox proportional hazard models were used to estimate the risk [hazard ratios (HRs)], associated with (i) mean with SBP and BPV during the in-trial period, for the CV endpoints occurring after the end of the trial and (ii) randomly assigned treatment to events following randomization, for the first occurrence of pre-specified CV outcomes. Results Using BP data from the in-trial period, in the post-trial period, although mean SBP was a predictor of CV outcomes {HR per 10 mmHg, 1.14 [95% confidence interval (CI) 1.10-1.17], P < .001}, systolic BPV independent of mean SBP was a strong predictor of CV events [HR per 5 mmHg 1.22 (95% CI 1.18-1.26), P < .001] and predicted events even in participants with well-controlled BP. During 21-year follow-up, those on amlodipine-based compared with atenolol-based in-trial treatment had significantly reduced risk of stroke [HR 0.82 (95% CI 0.72-0.93), P = .003], total CV events [HR 0.93 (95% CI 0.88-0.98), P = .008], total coronary events [HR 0.92 (95% CI 0.86-0.99), P = .024], and atrial fibrillation [HR 0.91 (95% CI 0.83-0.99), P = .030], with weaker evidence of a difference in CV mortality [HR 0.91 (95% CI 0.82-1.01), P = .073]. There was no significant difference in the incidence of non -fatal myocardial infarction and fatal coronary heart disease, heart failure, and all-cause mortality. Conclusions Systolic BPV is a strong predictor of CV outcome, even in those with controlled SBP. The long -term benefits of amlodipinebased treatment compared with atenolol-based treatment in reducing CV events appear to be primarily mediated by an effect on systolic BPV during the trial period.

Additional file 5: Table S4. Frequency of lipid-related publications for the PoPS+ prioritized genes.

Rationale for the Study The prediction of future cardiovascular events in those with vascular risk factors is important to appropriately optimise preventative therapies in those at greatest risk. The value of high sensitivity C-reactive Protein (hsCRP) has been questioned in this regard, and recent studies have suggested the utility of this widely assessed biomarker for predicting future mortality in those presenting with suspected myocardial infarction (MI), however the relationship in stable patients is still debated. Therefore, we investigated the usefulness of baseline hsCRP for predicting incident cardiovascular events in hypertensive patients in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Legacy Study. Methodology The ASCOT Legacy Study reports events after 16 years of follow-up of the UK participants in the original ASCOT trial. ASCOT was a multicentre randomised trial, randomising patients with hypertension into amlodipine-based or atenolol-based blood pressure-lowering (BPL) treatment. Furthermore, those with total cholesterol £6.5 mmol/L and no previous lipid-lowering treatment, underwent further randomisation to either atorvastatin or placebo as part of the lipid-lowering (LL) arm of ASCOT. We examined outcomes related to hsCRP levels in the LL arm, dichotomously (< or 3 2mg/L), in tertiles or continuously, adjusting in Model 1 (age, sex, socio-economic status [years of education] and ethnicity) and Model 2 (Model 1 plus current smoker, body mass index, baseline systolic blood pressure, creatinine, diabetes, history of vascular diseases, history of antihypertensive medication and allocation to BPL and LL). All-cause mortality, non-fatal and fatal MI, total coronary events and procedures and total cardiovascular events were assessed. Results 5,294 participants were included in the final cohort, after exclusion of 3,286 participants in the LL arm (n=8,580) without hsCRP data. There were no substantial differences in baseline characteristics between treatment allocation arms (non-randomised, placebo or atorvastatin). The highest tertile of hsCRP (median [IQR], 6.41 [4.81-10.44]) strongly related to all-cause mortality, withstanding adjustment in both Model 1 (HR 95% CI, 1.38 [1.27-1.53]; p<0.001; p<0.001 for interaction) and Model 2 (HR 1.25 [1.10-1.42]; p<0.001; p<0.001 for interaction). Moreover, the highest hsCRP tertile also related to fatal and non-fatal MI (Model 2 ‘ HR 1.32 [1.05-1.67]; p=0.020; p=0.019 for interaction); total coronary events and procedures (Model 2 ‘ HR 1.27 [1.09-1.47]; p=0.002; p=0.003 for interaction); and total cardiovascular events (Model 2 ‘ HR 1.22 [1.08-1.37]; p=0.001; p=0.001 for interaction). These findings were confirmed in Kaplan-Meier analysis, with p<0.001 between tertiles for all outcomes. Conclusions This analysis of ASCOT Legacy Study demonstrates that higher baseline hsCRP levels independently predict cardiovascular events and all-cause mortality at long term follow-up in stable patients with hypertension. Conflict of Interest None

Introduction: We have previously shown that visit to visit systolic blood pressure variability (BPV) was the major predictor of cardiovascular outcomes in ASCOT, a trial in hypertensive participants randomised to amlodipine based or atenolol based treatment. Treatment differences in BPV accounted for the benefits of the amlodipine based regimen over the atenolol based regimen on cardiovascular (CV) events during the trial. We now report observations from the 20 yr follow up of UK participants to determine the long term impact of mean systolic blood pressure control during the trial and BPV on CV and renal outcomes. Methods: In the ASCOT Legacy Cohort, 7,092 hypertensive participants with hypertension, aged 40 to 79 years, with at least three other CV risk factors have been followed for up to 20 years. All available SBP visit records (n = 100,933) were included after excluding the first six months observations. The mean of SBP as a measure of BP control and the standard deviation (SD) of all SBPs as an estimate of visit to visit BPV were calculated for the five years of the trial. Participants were then followed for up to 15 years after the end of the trial using the UK National Health Service (NHS) electronic health records. CV and renal outcomes were measured using Cox proportional hazards model adjusted for confounding variables. Results: Although in trial mean SBP predicted long term CV and renal outcomes, SBP variability independent of mean SBP was a strong predictor of both CV and renal outcomes. (Table) Those originally assigned amlodipine based (vs. atenolol based) treatment had a significantly reduced long term risk of risk of stroke [0.82, 0.72 to 0.93, p = 0.003], total CV events and procedures [0.93, 0.88 to 0.98, p = 0.008], total coronary events [0.92, 0.86 to 0.99, p = 0.024] and atrial fibrillation [0.91, 95% CI, 0.83 to 0.99, p = 0.030]. There was no significant difference in the incidence of heart failure, non fatal myocardial infarction and fatal CHD or renal events. Conclusions: Amlodipine based treatment conferred long term advantages over atenolol based treatment on several CV outcomes. Both mean SBP and BPV are strong predictors of long term CV and renal outcomes, but BPV, independent of mean BP, confers a significant additional risk and should be considered for future preventive and therapeutic strategies.

Additional file 17: Table S9. PheWAS UKB-MVP meta-analysis results for each index lipid variant at Bonferroni threshold for multiple testing p<=3.5e-8)

Abstract Introduction The prediction of future cardiovascular events in those at greatest risk is essential to optimise preventative therapies appropriately and effectively. The value of high sensitivity C-reactive Protein (hsCRP) has been questioned in this regard, and recent studies have suggested the utility of this widely assessed biomarker for predicting future mortality in those presenting with suspected myocardial infarction (MI), however the relationship in stable patients is still debated. Purpose To investigate the role of baseline hsCRP for predicting long-term incident cardiovascular events in hypertensive patients in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), with follow-up extending to 20-years. Methods This ASCOT legacy study reports events after 20-years of the UK participants in the original ASCOT trial. ASCOT was a multicentre randomised trial, randomising patients with hypertension into amlodipine-based or atenolol-based blood pressure-lowering (BPL) treatment. In addition, those with total cholesterol <6.5 mmol/L and no previous lipid-lowering treatment underwent further randomisation to either atorvastatin or placebo as part of the lipid-lowering (LL) arm of ASCOT. We examined outcomes related to hsCRP levels in the LL arm, dichotomously (< or > 2mg/L), in tertiles or continuously, adjusting in Model 1 (age, sex, socio-economic status [years of education] and ethnicity) and Model 2 (Model 1 plus current smoker, body mass index, baseline systolic blood pressure, creatinine, diabetes, history of vascular diseases, history of antihypertensive medication and allocation to BPL and LL). All-cause mortality, non-fatal and fatal MI, total coronary events and procedures and total cardiovascular events were assessed. Results 5,294 participants were included in the final cohort, after exclusion of 3,286 participants in the LL arm (n=8,580) without hsCRP data. There were no substantial differences in baseline characteristics between treatment allocation arms (non-randomised, placebo or atorvastatin). The highest tertile of hsCRP (median [IQR], 6.41 [4.81-10.44]) strongly related to all-cause mortality, withstanding adjustment in both Model 1 (HR 95% CI, 1.38 [1.27-1.53]; p<0.001; p<0.001 for interaction) and Model 2 (HR 1.25 [1.10-1.42]; p<0.001; p<0.001 for interaction). Moreover, the highest hsCRP tertile also related to fatal and non-fatal MI (Model 2 – HR 1.32 [1.05-1.67]; p=0.020; p=0.019 for interaction); total coronary events and procedures (Model 2 – HR 1.27 [1.09-1.47]; p=0.002; p=0.003 for interaction); and total cardiovascular events (Model 2 – HR 1.22 [1.08-1.37]; p=0.001; p=0.001 for interaction). Conclusions This study demonstrates that one hsCRP reading at baseline independently predicts cardiovascular events and all-cause mortality at very long-term follow-up in patients at high-risk for these events, and may help stratify patients into higher risk categories for intensive preventative strategies.

Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P -value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

Background: We sought to identify protein biomarkers of new-onset heart failure (HF) in 3 independent cohorts (HOMAGE cohort [Heart Omics and Ageing], ARIC study [Atherosclerosis Risk in Communities], and FHS [Framingham Heart Study]) and assess if and to what extent they improve HF risk prediction compared to clinical risk factors alone. Methods: A nested case-control design was used with cases (incident HF) and controls (without HF) matched on age and sex within each cohort. Plasma concentrations of 276 proteins were measured at baseline in ARIC (250 cases/250 controls), FHS (191/191), and HOMAGE cohort (562/871). Results: In single protein analysis, after adjusting for matching variables and clinical risk factors (and correcting for multiple testing), 62 proteins were associated with incident HF in ARIC, 16 in FHS, and 116 in HOMAGE cohort. Proteins associated with incident HF in all cohorts were BNP (brain natriuretic peptide), NT-proBNP (N-terminal pro-B-type natriuretic peptide), eukaryotic translation initiation factor 4E-BP1 (4E-binding protein 1), hepatocyte growth factor (HGF), Gal-9 (galectin-9), TGF-alpha (transforming growth factor alpha), THBS2 (thrombospondin-2), and U-PAR (urokinase plasminogen activator surface receptor). The increment in C -index for incident HF based on a multiprotein biomarker approach, in addition to clinical risk factors and NT-proBNP, was 11.1% (7.5%–14.7%) in ARIC, 5.9% (2.6%–9.2%) in FHS, and 7.5% (5.4%–9.5%) in HOMAGE cohort, all P <0.001), each of which was a larger increase than that for NT-proBNP on top of clinical risk factors. Complex network analysis revealed a number of overrepresented pathways related to inflammation (eg, tumor necrosis factor and interleukin) and remodeling (eg, extracellular matrix and apoptosis). Conclusions: A multiprotein biomarker approach improves prediction of incident HF when added to natriuretic peptides and clinical risk factors.