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Here, we randomized 53 patients hospitalized with coronavirus disease 2019 (COVID-19) to hydroxychloroquine therapy (at a dose of 400 mg twice daily for seven days) in addition to standard care or standard care alone (ClinicalTrials.gov Identifier, NCT04316377). All severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive patients 18 years of age or older were eligible for study inclusion if they had moderately severe COVID-19 at admission. Treatment with hydroxychloroquine did not result in a significantly greater rate of decline in SARS-CoV-2 oropharyngeal viral load compared to standard care alone during the first five days. Our results suggest no important antiviral effect of hydroxychloroquine in humans infected with SARS-CoV-2. The use of hydroxychloroquine therapy for the treatment of Covid-19 is controversial. In this study, Lyngbakken and colleagues present a randomized controlled trial and show that the drug has no antiviral effects in humans infected with SARS-CoV-2.

Heart failure (HF) causes substantial morbidity and mortality but its pathobiology is incompletely understood. The proteome is a promising intermediate phenotype for discovery of novel mechanisms. We measured 4877 plasma proteins in 13,900 HF-free individuals across three analysis sets with diverse age, geography, and HF ascertainment to identify circulating proteins and protein networks associated with HF development. Parallel analyses in Atherosclerosis Risk in Communities study participants in mid-life and late-life and in Trøndelag Health Study participants identified 37 proteins consistently associated with incident HF independent of traditional risk factors. Mendelian randomization supported causal effects of 10 on HF, HF risk factors, or left ventricular size and function, including matricellular (e.g. SPON1, MFAP4), senescence-associated (FSTL3, IGFBP7), and inflammatory (SVEP1, CCL15, ITIH3) proteins. Protein co-regulation network analyses identified 5 modules associated with HF risk, two of which were influenced by genetic variants that implicated trans hotspots within the VTN and CFH genes. The pathobiology of heart failure (HF) is incompletely understood. The authors identify 37 circulating proteins and 5 protein modules associated with HF risk, with several demonstrating causal effects on HF, risk factors, or cardiac dysfunction by Mendelian randomization analysis.

To compare the performance of high-sensitivity cardiac troponin I and T (hs-cTnI; hs-cTnT) in diagnosing obstructive coronary artery disease (CAD 50 ) in patients with suspected chronic coronary syndrome (CCS). A total of 706 patients with suspected CCS, referred for Coronary Computed Tomography Angiography, were included. cTn concentrations were measured using the Singulex hs-cTnI (limit of detection [LoD] 0.08 ng/L) and Roche hs-cTnT (LoD 3 ng/L) assays. Obstructive coronary artery disease (CAD 50 ) was defined as ≥ 50% coronary stenosis. Cardiovascular risk was determined by the NORRISK2-score. Median age of the patients was 65 (range 28–87) years, 35% were women. All patients had hs-cTnI concentrations above the LoD (median 1.9 [Q1-3 1.2–3.6] ng/L), 72% had hs-cTnT above the LoD (median 5 [Q1-3 2–11] ng/L). There was a graded relationship between hs-cTn concentrations and coronary artery calcium. Only hs-cTnI remained associated with CAD 50 in adjusted analyses (OR 1.20 95% Confidence Interval [1.05–1.38]), p  = 0.009). The C-statistics for hs-cTnI and hs-cTnT were 0.65 (95% CI [0.60–0.69]) and 0.60 (0.56–0.64). The highest specificity and negative predictive values for CAD 50 were in the lowest NORRISK2-tertile. hs-cTn concentrations provide diagnostic information in patients with suspected CCS, with superior performance of hs-cTnI compared to hs-cTnT in regard to CAD 50 . The diagnostic performance appeared best in those with low cardiovascular risk.

Background Physical activity (PA) has been associated with a reduced risk of severe COVID-19 outcomes. However, the relationship between cardiorespiratory fitness (CRF) and the risk of SARS-CoV-2 infection and COVID-19 hospitalization has not been thoroughly investigated. We aimed to investigate the association of estimated CRF (eCRF) and leisure-time PA (LTPA) with risk of SARS-CoV-2 infection and COVID-19 related hospitalization in a general population of Norwegian adults. Methods This cohort study included 48,821 adults participating in the population based Trøndelag Health Study (the HUNT Study). Individual data on pre-pandemic (2017–2019) eCRF and LTPA were linked to COVID-19 registries from February 2020 through September 2022. eCRF was categorized into sex-and-age specific quintiles based on V̇O 2peak (mL/kg/min) and LTPA was categorized based on metabolic equivalent hours per week (MET h/wk): inactive (0-3.5 MET h/wk), insufficiently active (> 3.5 to 7.5 MET h/wk), and sufficiently active (> 7.5 MET h/wk). Poisson regression was used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for the association of eCRF and LTPA with SARS-CoV-2 infection and COVID-19 hospitalization. Results Age averaged 53.6 years (SD 16.8) and 53.9% were women. During 2.6 years of follow-up there were 5991 SARS-CoV-2 infections and 218 COVID-19 related hospitalizations. Fitness and LTPA categories did not associate with risk of infection. However, adults with the highest eCRF had significantly lower risk of hospitalization compared to adults with the lowest eCRF (IRR, 0.54, 95% CI, 0.34–0.86). Similarly, sufficiently active adults (> 7.5 MET h/wk) prior to the pandemic had significantly lower risk of being hospitalized compared to inactive adults (IRR, 0.60, 95% CI, 0.47–0.83). Conclusions Higher eCRF and LTPA were not associated with risk of SARS-CoV-2 infection. In contrast, adults with high eCRF and LTPA were associated with a lower risk of COVID-19 related hospitalization compared to adults with low fitness and inactive lifestyles.

Aerobic fitness, measured as maximal oxygen uptake (VO2max), is a good indicator of cardiovascular health, and a strong predictor of cardiovascular mortality. Biomarkers associated with low VO2max may therefore represent potential early markers of future cardiovascular disease (CVD). The aim of this study was to assess whether circulating microRNAs (miRs) are associated with VO2max-level in healthy individuals. In a screening study, 720 miRs were measured in serum samples from healthy individuals (40-45 yrs) with high (n = 12) or low (n = 12) VO2max matched for gender, age and physical activity. Candiate miRs were validated in a second cohort of subjects with high (n = 38) or low (n = 38) VO2max. miR-210 and miR-222 were found to be higher in the low VO2max-group (p<0.05). In addition, miR-21 was increased in male participants with low VO2max (p<0.05). There were no correlations between traditional risk factors for CVD (blood pressure, cholesterol, smoking habit, or obesity) and miR-21, miR-210 and miR-222. DIANA-mirPath identified 611 potential gene-targets of miR-21, miR-210 and miR-222, and pathway analysis indicated alterations in several important signaling systems in subjects with low VO2max. Potential bias involve that blood was collected from non-fasting individuals, and that 8 performed exercise within 24 h before sampling. In conclusion, we found that miR-210, miR-21, and miR-222 were increased in healthy subjects with low VO2max. The lack of association between these three miRs, and other fitness related variables as well as traditional CVD risk factors, suggests that these miRs may have a potential as new independent biomarkers of fitness level and future CVD.

The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment. In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol. Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48·7%] women; median age 51·0 years [IQR 40·7–59·7]). 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years (median 13·5 years, IQR 7·0–20·1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories (from 7·7% for non-HDL cholesterol <2·6 mmol/L to 33·7% for ≥5·7 mmol/L in women and from 12·8% to 43·6% in men; p<0·0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1·1, 95% CI 1·0–1·3 for non-HDL cholesterol 2·6 to <3·7 mmol/L to 1·9, 1·6–2·2 for ≥5·7 mmol/L in women and from 1·1, 1·0–1·3 to 2·3, 2·0–2·5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced. Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician–patient communication about primary prevention strategies. EU Framework Programme, UK Medical Research Council, and German Centre for Cardiovascular Research.

BackgroundThe 2024 European Society of Cardiology (ESC) Guidelines for hypertension introduced the ‘elevated BP’ (eBP) category (120–139/70–89 mm Hg). Individuals with persistent eBP (130–139/80–89 mm Hg), despite lifestyle intervention, may be recommended pharmacological treatment in case of concomitant elevated cardiovascular (CV) risk. We aimed to assess the impact of these updated recommendations on treatment eligibility at ages 40 and 62–65 and to examine the CV event rates over 30 years of follow-up, focusing on those with eBP (130–139/80–89 mm Hg) eligible for pharmacological treatment.MethodsData from individuals born in 1950 who participated in the Age 40 Programme and the Akershus Cardiac Examination 1950 Study was linked to national health registries. These data include BP measurements at age 40 (1990–1991) and 62–65 (2012–2015), assessment of elevated CV risk based on Systematic Coronary Risk Evaluation 2 (SCORE2) and outcomes of major adverse cardiovascular events (MACEs) tracked through 2022.ResultsAt age 40, 854 (32%) of 2688 individuals had eBP (130–139/80–89 mm Hg), but only 4 had elevated CV risk warranting pharmacological treatment. At age 62–65, 1657 (61%) were on BP-lowering medication or had a BP ≥140/90, while 64 (8%) out of 851 with eBP were eligible for drug treatment. Based on BP values at age 40, only 2 of the 93 MACEs in the eBP (130–139/80–89 mm Hg) category occurred among those eligible for pharmacological treatment.ConclusionsA single BP measurement at age 40 identified eBP (130–139/80–89 mm Hg) among one-third of the individuals, yet MACE cases within the eBP category occurred primarily in individuals who were not eligible for medical treatment.

Multiple circulating biomarkers have been associated with the incidence of cardiovascular events and proposed as potential tools for risk stratification in stable ischemic heart disease (IHD), yet current guidelines do not make any firm recommendations concerning the use of biomarkers for risk stratification in this setting. This state-of-the-art review provides an overview of biomarkers for risk stratification in stable IHD. Circulating biomarkers associated with the risk of cardiovascular events in patients with stable IHD reflect different pathophysiological processes, including myocardial injury, myocardial stress and remodeling, metabolic status, vascular inflammation, and oxidative stress. Compared to the primary prevention setting, biomarkers reflecting end-organ damage and future risk of heart failure development and cardiovascular death may play more important roles in the stable IHD setting. Accordingly, biomarkers that reflect chronic, low-grade myocardial injury, and stress, i.e., high-sensitivity cardiac troponins and natriuretic peptides, provide graded and incremental prognostic information to conventional risk markers. In contrast, in stable IHD patients the prognostic value of traditional metabolic biomarkers, including serum lipids, is limited. Among several novel biomarkers, growth-differentiation factor-15 may provide the most robust prognostic information, whereas most inflammatory markers provide limited incremental prognostic information to risk factor models that include conventional risk factors, natriuretic peptides, and high-sensitivity troponins. Circulating biomarkers hold promise as useful tools for risk stratification in stable IHD, but their future incorporation into clinically useful risk scores will depend on prospective, rigorously performed clinical trials that document enhanced risk prediction.

C-reactive protein and cardiac troponin I measured with high-sensitivity assays (high-sensitivity C-reactive protein [hs-CRP] and high-sensitivity troponin I [hs-TnI]) have been associated with risk of fatal and nonfatal cardiovascular events in the general population. The relative prognostic merits of hs-CRP and hs-TnI, and whether these markers of inflammation and subclinical myocardial injury provide incremental information to established cardiovascular risk prediction models, remain unclear. hs-CRP and hs-TnI were measured in 9,005 participants from the prospective observational Nord-Trøndelag Health (HUNT) study. All study subjects were free from known cardiovascular disease at baseline. During a median follow-up period of 13.9 years, 733 participants reached the composite end point of hospitalization for acute myocardial infarction or heart failure, or cardiovascular death. In adjusted models, increased hs-TnI concentrations (>10 ng/L for women and >12 ng/L for men) were associated with the incidence of the composite end point (hazard ratio 3.61, 95% confidence interval [CI] 2.89 to 4.51]), whereas the risk associated with increased hs-CRP concentrations (>3 mg/L for both genders) appeared to be weaker (HR 1.71, 95% CI 1.40 to 2.10). The addition of hs-TnI to established cardiovascular risk prediction models led to a net reclassification improvement of 0.35 (95% CI 0.27 to 0.42), superior to that of hs-CRP (0.21, 95% CI 0.13 to 0.28). The prognostic accuracy of hs-TnI, assessed by C-statistics, was significantly greater than that of hs-CRP (0.753, 95% CI 0.735 to 0.772, vs 0.644, 95% CI 0.625 to 0.663). In conclusion, in subjects from the general population without a history of cardiovascular disease, hs-TnI provides prognostic information superior to that provided by hs-CRP and may therefore be a preferred marker for targeted prevention.

Remarkable recent advances have revolutionized the field of heart failure. Survival has improved among individuals with heart failure and a reduced ejection fraction and for the first time, new therapies have been shown to improve outcomes across the entire ejection fraction spectrum of heart failure. Great strides have been taken in the treatment of specific cardiomyopathies such as cardiac amyloidosis and hypertrophic cardiomyopathy, whereby conditions once considered incurable can now be effectively managed with novel genetic and molecular approaches. Yet there remain substantial residual unmet needs in heart failure. The translation of successful clinical trials to improved patient outcomes is limited by large gaps in implementation of care, widespread lack of disease awareness and poor understanding of the socioeconomic determinants of outcomes and how to address disparities. Ongoing clinical trials, advances in phenotype segmentation for precision medicine and the rise in technology solutions all offer hope for the future. Recent years have seen major advances in heart failure treatment, but gaps in implementation and disparities in care remain; this Review outlines the current state of the field.