Blood Signature of Pre-Heart Failure: A Microarrays Study

International audienceBACKGROUND: The preclinical stage of systolic heart failure (HF), known as asymptomatic left ventricular dysfunction (ALVD), is diagnosed only by echocardiography, frequent in the general population and leads to a high risk of developing severe HF. Large scale screening for ALVD is a difficult task and represents a major unmet clinical challenge that requires the determination of ALVD biomarkers. METHODOLOGY/PRINCIPAL FINDINGS: 294 individuals were screened by echocardiography. We identified 9 ALVD cases out of 128 subjects with cardiovascular risk factors. White blood cell gene expression profiling was performed using pangenomic microarrays. Data were analyzed using principal component analysis (PCA) and Significant Analysis of Microarrays (SAM). To build an ALVD classifier model, we used the nearest centroid classification method (NCCM) with the ClaNC software package. Classification performance was determined using the leave-one-out cross-validation method. Blood transcriptome analysis provided a specific molecular signature for ALVD which defined a model based on 7 genes capable of discriminating ALVD cases. Analysis of an ALVD patients validation group demonstrated that these genes are accurate diagnostic predictors for ALVD with 87% accuracy and 100% precision. Furthermore, Receiver Operating Characteristic curves of expression levels confirmed that 6 out of 7 genes discriminate for left ventricular dysfunction classification. CONCLUSIONS/SIGNIFICANCE: These targets could serve to enhance the ability to efficiently detect ALVD by general care practitioners to facilitate preemptive initiation of medical treatment preventing the development of HF

Sex differences in cardiovascular complications and mortality in hospital patients with covid-19: registry based observational study

Objective To assess whether the risk of cardiovascular complications of covid-19 differ between the sexes and to determine whether any sex differences in risk are reduced in individuals with pre-existing cardiovascular disease. Design Registry based observational study. Setting 74 hospitals across 13 countries (eight European) participating in CAPACITY-COVID (Cardiac complicAtions in Patients With SARS Corona vIrus 2 regisTrY), from March 2020 to May 2021 Participants All adults (aged ≥18 years), predominantly European, admitted to hospital with highly suspected covid-19 disease or covid-19 disease confirmed by positive laboratory test results (n=11 167 patients). Main outcome measures Any cardiovascular complication during admission to hospital. Secondary outcomes were in-hospital mortality and individual cardiovascular complications with ≥20 events for each sex. Logistic regression was used to examine sex differences in the risk of cardiovascular outcomes, overall and grouped by pre-existing cardiovascular disease. Results Of 11 167 adults (median age 68 years, 40% female participants) included, 3423 (36% of whom were female participants) had pre-existing cardiovascular disease. In both sexes, the most common cardiovascular complications were supraventricular tachycardias (4% of female participants, 6% of male participants), pulmonary embolism (3% and 5%), and heart failure (decompensated or de novo) (2% in both sexes). After adjusting for age, ethnic group, pre-existing cardiovascular disease, and risk factors for cardiovascular disease, female individuals were less likely than male individuals to have a cardiovascular complication (odds ratio 0.72, 95% confidence interval 0.64 to 0.80) or die (0.65, 0.59 to 0.72). Differences between the sexes were not modified by pre-existing cardiovascular disease; for the primary outcome, the female-to-male ratio of the odds ratio in those without, compared with those with, pre-existing cardiovascular disease was 0.84 (0.67 to 1.07). Conclusions In patients admitted to hospital for covid-19, female participants were less likely than male participants to have a cardiovascular complication. The differences between the sexes could not be attributed to the lower prevalence of pre-existing cardiovascular disease in female individuals. The reasons for this advantage in female individuals requires further research

Nephroprotective effects of GLP-1 receptor agonists: where do we stand?

Glucagon-like peptide (GLP)-1 receptor agonists are the cornerstone in the treatment of hyperglycemia in many people suffering from type 2 diabetes (T2D). These drugs have potent glucose-lowering actions and, additionally, lower body weight through satiety induction while reducing blood pressure and dyslipidemia. Partly through these actions, GLP-1 receptor agonism was shown to reduce cardiovascular disease (CVD) in people with T2D with previous CVD or at high-risk thereof. In these cardiovascular safety trials, in secondary or exploratory analyses, GLP-1 receptor agonists were also shown to reduce macro-albuminuria, an accepted surrogate marker for diabetic kidney disease (DKD), a condition that still represents a major unmet medical need. In this review we will discuss the evidence which suggests renoprotection induced by GLP-1 receptor agonists and the potential mechanisms that may be involved. These include mitigation of hyperglycemia, overweight and insulin resistance, systemic and glomerular hypertension, dyslipidemia, sodium retention, inflammation and renal hypoxia. The recently initiated large-sized FLOW trial investigating the effects of semaglutide on hard renal outcomes in patients with DKD will provide clarity whether GLP-1 receptor agonists may reduce the burden of DKD in addition to their other beneficial metabolic and cardiovascular effects

Mechanisms underlying the blood pressure-lowering effects of empagliflozin, losartan and their combination in people with type 2 diabetes: A secondary analysis of a randomized crossover trial

Aim: To study the effects of the sodium-glucose co-transporter-2 (SGLT2) inhibitor empagliflozin, the angiotensin receptor blocker (ARB) losartan, and their combination on blood pressure, while studying the mechanisms potentially involved. Methods: A total of 24 people with type 2 diabetes (T2D) (age: 66 ± 6 years; body mass index: 31.0 ± 3 kg/m 2; estimated glomerular filtration rate: 90 ml/min/1.73m 2) received a 1-week treatment with empagliflozin 10 mg once daily, losartan 50 mg once daily, their combination, and placebo, in a randomized double-blind crossover design, with 4-week washout periods in between. Blood pressure, arterial stiffness, autonomic nervous system activity and plasma volume, extracellular fluid and serum albumin were assessed. Results: Versus placebo (139 mmHg), empagliflozin reduced systolic blood pressure (SBP) by 8 mmHg (P =.001), losartan by 12 mmHg (P =.001) and empagliflozin + losartan by 15 mmHg (P <.001). Combination therapy had a larger SBP-lowering effect versus empagliflozin monotherapy (-7 [95% CI -12; -2] mmHg) and numerically larger effects versus losartan monotherapy (-3 [-8; 2] mmHg). Empagliflozin reduced sympathetic nervous system (SNS) activity, arterial stiffness and extracellular fluid, while increasing serum albumin. Losartan reduced SNS activity and arterial stiffness. Combination therapy induced volume contraction variables, together with a reduction in SNS activity and arterial stiffness. Conclusion: In people with T2D, SGLT2 inhibition in combination with an ARB had a larger blood pressure-lowering effect versus placebo than either of the drugs alone. Our data further suggest that the mechanisms underlying these blood pressure reductions at least partially differ between these agents

Differences in Body Composition Convey a Similar Risk of Type 2 Diabetes Among Different Ethnic Groups With Disparate Cardiometabolic Risk-The HELIUS Study

OBJECTIVE: Studies have shown a disparate association between body composition and the risk of type 2 diabetes. We assessed whether associations between differences in body composition and type 2 diabetes vary among ethnic groups with disparate cardiometabolic risk. RESEARCH DESIGN AND METHODS: We used data from the Healthy Life in an Urban Setting (HELIUS) study, including individuals aged 18-70 years of African Surinamese (n = 3,997), South Asian Surinamese (n = 2,956), Turkish (n = 3,546), Moroccan (n = 3,850), Ghanaian (n = 2,271), and Dutch (n = 4,452) origin living in Amsterdam. Type 2 diabetes was defined using the World Health Organization criteria. Logistic regression was used to assess the relation between body composition and type 2 diabetes. Waist-to-hip ratio (WHR), waist circumference, BMI, and body fat percentage by bioelectrical impedance were used to estimate body composition. RESULTS: Per unit change in BMI, only Ghanaian (odds ratio [OR] 0.94 [95% CI 0.89-0.99]) and Moroccan (0.94 [0.89-0.99]) women had a smaller increase in type 2 diabetes compared with the Dutch population, whereas the ORs for body fat percentage were 0.94 (0.89-1.00) for Ghanaian, 0.93 (0.88-0.99) for Moroccan, and 0.95 (0.90-1.00) for South Asian Surinamese women. There was no interaction between WHR and ethnicity on the risk of type 2 diabetes, and there were no differences in men. WHR had the highest precision in predicting type 2 diabetes in both men (C statistic = 0.78) and women (C statistic = 0.81). CONCLUSIONS: The association between differences in body composition and type 2 diabetes is roughly the same in all ethnic groups. WHR seems the most reliable and consistent predictor of type 2 diabetes regardless of ethnic background

Ethnic disparities in the association between low-grade inflammation biomarkers and chronic kidney disease: The HELIUS Cohort Study

Aims: Ethnic differences exist in the prevalence and progression of chronic kidney disease (CKD). However, underlying mechanisms remain unclear. It has been proposed that chronic low-grade inflammation plays an important role in CKD pathogenesis. In the current analysis, we study the association between systemic inflammatory biomarkers and CKD prevalence in different ethnic groups. Methods: We examined cross-sectional associations between biomarkers of low-grade inflammation, including serum high-sensitive (hs)-CRP, fibrinogen, and D-dimer, and CKD prevalence in different ethnic groups residing in Amsterdam, the Netherlands. We included 5740 participants (similar-sized Dutch, African Surinamese, South-Asian Surinamese, Ghanaian, Turkish and Moroccan populations) aged 18 to 70 years of the Healthy Life in an Urban Setting study (HELIUS) cohort. Results: In the fully adjusted models, adjusted for ethnicity-specific cut-off values, elevated fibrinogen [odds ratio 2.50 (95 % confidence interval 1.10–5.78)] and D-dimer [2.99 (1.28–7.00)] were significantly associated with CKD in Dutch. In South-Asian Surinamese, a significant association with elevated D-dimer [2.66 (1.32–5.37)] was found. Conclusions: Our study shows that there are both differences in biomarker levels and the association with CKD across ethnic groups. Future research to identify potential drivers of the differential associations and susceptibility of CKD among ethnic groups to reduce the CKD burden is necessary

ASSOCIATIONS BETWEEN PLASMA METABOLOMICS AND BLOOD PRESSURE ACROSS ETHNICITIES: THE HELIUS STUDY

OBJECTIVE: Blood pressure (BP) is regulated by plasma metabolites from different neurohumoral and cardiometabolic systems. Since there are well-established differences in hypertension pathogenesis and treatment response between ethnicities, we hypothesized that plasma metabolites may be differently associated with BP across ethnic groups. DESIGN AND METHOD: From the HELIUS study, 369 subjects (mean age 52 ± 11 years, 51%F) of African and non-African descent were included. Office systolic and diastolic BP levels were recorded. Plasma metabolites were measured with untargeted LC-MS from fasting plasma samples. Associations between metabolite profiles and BP were assessed with machine learning prediction models. Associations between the resulting best predictors and BP were assessed with linear regression models while adjusting for age, sex, renal function and diabetes, and interactions with ethnicity were tested. RESULTS: Plasma metabolite profiles explained 14.1% of systolic BP variance and 10.6% of diastolic BP variance. Top predictors for both systolic and diastolic BP included N-formylmethionine, several acylcarnitines and polyunsaturated fatty acids such as hexadecadienoate. These metabolites were significantly associated with higher systolic BP with estimates ranging from 3.0-4.5 mmHg per 1 SD increase in the adjusted models. Associations with hexadecadienoate, dihomolinoleate and catecholamine metabolites, including vanillactate had significant interactions with ethnicity and were only significant in subjects of non-African descent. The top predictor N-formylmethionine was the most consistent predictor across ethnicities and sex. This metabolite was associated with higher levels of nitric oxide (NO)-related metabolites, including dimethylarginine (r = 0.42, p < 0.001) and citrulline (r = 0.24, p < 0.0001). CONCLUSIONS: Plasma metabolome composition explained a large proportion of BP variance, but best predicting metabolites were differently associated with BP across ethnicities. N-formylmethionine was the most consistent predictor for BP across ethnicities and sex. This metabolite was associated with metabolites in the NO-pathway. We hypothesize that formylmethionine affects BP through the inhibition of endothelial NO formation

ASSOCIATIONS BETWEEN PLASMA METABOLOMICS AND BLOOD PRESSURE ACROSS ETHNICITIES: THE HELIUS STUDY

OBJECTIVE: Blood pressure (BP) is regulated by plasma metabolites from different neurohumoral and cardiometabolic systems. Since there are well-established differences in hypertension pathogenesis and treatment response between ethnicities, we hypothesized that plasma metabolites may be differently associated with BP across ethnic groups. DESIGN AND METHOD: From the HELIUS study, 369 subjects (mean age 52 ± 11 years, 51%F) of African and non-African descent were included. Office systolic and diastolic BP levels were recorded. Plasma metabolites were measured with untargeted LC-MS from fasting plasma samples. Associations between metabolite profiles and BP were assessed with machine learning prediction models. Associations between the resulting best predictors and BP were assessed with linear regression models while adjusting for age, sex, renal function and diabetes, and interactions with ethnicity were tested. RESULTS: Plasma metabolite profiles explained 14.1% of systolic BP variance and 10.6% of diastolic BP variance. Top predictors for both systolic and diastolic BP included N-formylmethionine, several acylcarnitines and polyunsaturated fatty acids such as hexadecadienoate. These metabolites were significantly associated with higher systolic BP with estimates ranging from 3.0-4.5 mmHg per 1 SD increase in the adjusted models. Associations with hexadecadienoate, dihomolinoleate and catecholamine metabolites, including vanillactate had significant interactions with ethnicity and were only significant in subjects of non-African descent. The top predictor N-formylmethionine was the most consistent predictor across ethnicities and sex. This metabolite was associated with higher levels of nitric oxide (NO)-related metabolites, including dimethylarginine (r = 0.42, p < 0.001) and citrulline (r = 0.24, p < 0.0001). CONCLUSIONS: Plasma metabolome composition explained a large proportion of BP variance, but best predicting metabolites were differently associated with BP across ethnicities. N-formylmethionine was the most consistent predictor for BP across ethnicities and sex. This metabolite was associated with metabolites in the NO-pathway. We hypothesize that formylmethionine affects BP through the inhibition of endothelial NO formation

Ethnic disparities in the association between low-grade inflammation biomarkers and chronic kidney disease: The HELIUS Cohort Study

Aims: Ethnic differences exist in the prevalence and progression of chronic kidney disease (CKD). However, underlying mechanisms remain unclear. It has been proposed that chronic low-grade inflammation plays an important role in CKD pathogenesis. In the current analysis, we study the association between systemic inflammatory biomarkers and CKD prevalence in different ethnic groups. Methods: We examined cross-sectional associations between biomarkers of low-grade inflammation, including serum high-sensitive (hs)-CRP, fibrinogen, and D-dimer, and CKD prevalence in different ethnic groups residing in Amsterdam, the Netherlands. We included 5740 participants (similar-sized Dutch, African Surinamese, South-Asian Surinamese, Ghanaian, Turkish and Moroccan populations) aged 18 to 70 years of the Healthy Life in an Urban Setting study (HELIUS) cohort. Results: In the fully adjusted models, adjusted for ethnicity-specific cut-off values, elevated fibrinogen [odds ratio 2.50 (95 % confidence interval 1.10–5.78)] and D-dimer [2.99 (1.28–7.00)] were significantly associated with CKD in Dutch. In South-Asian Surinamese, a significant association with elevated D-dimer [2.66 (1.32–5.37)] was found. Conclusions: Our study shows that there are both differences in biomarker levels and the association with CKD across ethnic groups. Future research to identify potential drivers of the differential associations and susceptibility of CKD among ethnic groups to reduce the CKD burden is necessary