Showing papers by "Luis M. Ruilope published in 2021"

Finerenone and Cardiovascular Outcomes in Patients With Chronic Kidney Disease and Type 2 Diabetes.

Abstract: Background: The FIDELIO-DKD trial (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease) evaluated the effect of the nonsteroidal, selective mineralocorticoid re...

Lifestyle interventions for the prevention and treatment of hypertension

Abstract: Hypertension affects approximately one third of the world's adult population and is a major cause of premature death despite considerable advances in pharmacological treatments. Growing evidence supports the use of lifestyle interventions for the prevention and adjuvant treatment of hypertension. In this Review, we provide a summary of the epidemiological research supporting the preventive and antihypertensive effects of major lifestyle interventions (regular physical exercise, body weight management and healthy dietary patterns), as well as other less traditional recommendations such as stress management and the promotion of adequate sleep patterns coupled with circadian entrainment. We also discuss the physiological mechanisms underlying the beneficial effects of these lifestyle interventions on hypertension, which include not only the prevention of traditional risk factors (such as obesity and insulin resistance) and improvements in vascular health through an improved redox and inflammatory status, but also reduced sympathetic overactivation and non-traditional mechanisms such as increased secretion of myokines.

Finerenone Reduces Risk of Incident Heart Failure in Patients With Chronic Kidney Disease and Type 2 Diabetes: Analyses from the FIGARO-DKD Trial

Abstract: Background: Chronic kidney disease (CKD) and type 2 diabetes (T2D) are independently associated with heart failure (HF), a leading cause of morbidity and mortality. In the FIDELIO-DKD and FIGARO DK...

An Overview of FGF-23 as a Novel Candidate Biomarker of Cardiovascular Risk

Abstract: Fibroblast growth factor-23 (FGF)-23 is a phosphaturic hormone involved in mineral bone metabolism that helps control phosphate homeostasis and reduces 1,25-dihydroxyvitamin D synthesis. Recent data have highlighted the relevant direct FGF-23 effects on the myocardium, and high plasma levels of FGF-23 have been associated with adverse cardiovascular outcomes in humans, such as heart failure and arrhythmias. Therefore, FGF-23 has emerged as a novel biomarker of cardiovascular risk in the last decade. Indeed, experimental data suggest FGF-23 as a direct mediator of cardiac hypertrophy development, cardiac fibrosis and cardiac dysfunction via specific myocardial FGF receptor (FGFR) activation. Therefore, the FGF-23/FGFR pathway might be a suitable therapeutic target for reducing the deleterious effects of FGF-23 on the cardiovascular system. More research is needed to fully understand the intracellular FGF-23-dependent mechanisms, clarify the downstream pathways and identify which could be the most appropriate targets for better therapeutic intervention. This review updates the current knowledge on both clinical and experimental studies and highlights the evidence linking FGF-23 to cardiovascular events. The aim of this review is to establish the specific role of FGF-23 in the heart, its detrimental effects on cardiac tissue and the possible new therapeutic opportunities to block these effects.

Efficacy and safety of finerenone in patients with chronic kidney disease and type 2 diabetes by GLP-1RA treatment: A subgroup analysis from the FIDELIO-DKD trial.

Abstract: AIMS: Finerenone significantly reduced the risk of kidney and cardiovascular (CV) outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) in the FIDELIO-DKD trial (NCT02540993). This exploratory subgroup analysis investigates the effect of glucagon-like peptide-1 receptor agonist (GLP-1RA) use on the treatment effect of finerenone. MATERIALS AND METHODS: Patients with T2D, urine albumin-to-creatinine ratio (UACR) 30-5000 mg/g and estimated glomerular filtration rate (eGFR) 25-<75 mL/min per 1.73 m2 receiving optimized renin-angiotensin system blockade were randomized to finerenone or placebo. RESULTS: Of the 5674 patients analysed, overall, 394 (6.9%) received GLP-1RAs at baseline. A reduction in UACR with finerenone was observed with or without baseline GLP-1RA use; ratio of least-squares means 0.63 (95% confidence interval [CI] 0.56, 0.70) with GLP-1RA use and 0.69 (95% CI 0.67, 0.72) without GLP-1RA use (P value for interaction 0.20). Finerenone also significantly reduced the primary kidney (time to kidney failure, sustained decrease in eGFR ≥40% from baseline, or renal death) and key secondary CV outcomes (time to CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure) versus placebo, with no clear difference due to GLP-1RA use at baseline (P value for interaction 0.15 and 0.51 respectively) or any time during the trial. The safety profile of finerenone was similar between subgroups. CONCLUSIONS: This exploratory subgroup analysis suggests that finerenone reduces UACR in patients with or without GLP-1RA use at baseline, and the effects on kidney and CV outcomes are consistent irrespective of GLP-1RA use. This article is protected by copyright. All rights reserved.

Physical exercise and epicardial adipose tissue: A systematic review and meta‐analysis of randomized controlled trials

Abstract: We performed a meta-analysis of the effects of exercise on epicardial adipose tissue (EAT). A systematic search was conducted in PubMed and Scopus (since inception to 1 February 2020) of randomized controlled trials assessing the effects of exercise interventions alone (with no concomitant weight loss intervention) on EAT. The standardized mean difference (Hedges' g) and 95% confidence interval between interventions were computed using a random effects model. Ten studies (including 521 participants who had, on average, overweight/obesity) met all inclusion criteria. Interventions were supervised and lasted 2 to 16 weeks (≥3 sessions·per week). Exercise significantly reduced EAT (g = 0.82 [0.57-1.07]) irrespective of the duration of the intervention or the EAT imaging assessment method. Exercise benefits were separately confirmed for endurance (six studies, n = 287; g = 0.83 [0.52-1.15]) but not for resistance exercise training (due to insufficient data for quantitative synthesis). It was not possible to compare the effect of high-intensity interval training (HIIT) versus moderate-intensity continuous training (two studies, one reporting higher benefits with HIIT and the other no differences). Physical exercise interventions-particularly endurance training, with further evidence needed for other exercise modalities-appear as an effective strategy for reducing EAT in individuals with overweight/obesity, which supports their implementation for cardiovascular risk reduction.

Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes

Abstract: Background Finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, has favorable effects on cardiorenal outcomes in patients with predominantly stage 3 or 4 chronic kid...

Renal denervation in patients with versus without chronic kidney disease: results from the global SYMPLICITY Registry with follow-up data of 3 years.

Abstract: BACKGROUND Activity of the sympathetic nervous system is increased in patients with hypertension and chronic kidney disease (CKD). Here we compare short- and long-term blood pressure (BP) lowering effects of renal denervation (RDN) between hypertensive patients with or without CKD in the Global SYMPLICITY Registry. METHODS Office and 24-hour ambulatory BP (ABP) were assessed at pre-specified time-points after RDN. The presence of CKD was defined according to estimated glomerular filtration rate (eGFR), and enrolled patients were stratified based on the presence (N = 475, eGFR < 60 ml/min/1.73m2) or absence (N = 1505, eGFR ≥ 60ml/min/1.73m2) of CKD. RESULTS Patients with CKD were older (p < 0.001) and were prescribed more antihypertensive medications (p < 0.001). eGFR-decline/year was not significantly different between groups after the first year. Office and 24-hour ABP were significantly reduced from baseline at all timepoints after RDN in both groups (all p < 0.001). After adjusting for baseline data, patients without CKD had a greater reduction in office systolic BP (-17.3 ± 28.3 vs. -11.7 ± 29.9 mmHg, p = 0.009), but not diastolic BP at 36 months compared to those with CKD. Similar BP and eGFR-results were found when the analysis was limited to patients with both baseline and 36-month BP data available. There was no difference in the safety profile of the RDN-procedure between groups. CONCLUSIONS After adjusting for baseline data, 24-hour systolic and diastolic ABP reduction was similar in patients with and without CKD after RDN, whereas office systolic but not diastolic BP was reduced less in patients with CKD. We conclude that RDN emerged as an effective antihypertensive treatment option in CKD patients.

Prediction of fatal and non-fatal cardiovascular events in young and middle-aged healthy workers: The IberScore model:

Abstract: AimsOur primary objective was to improve risk assessment for fatal and non-fatal cardiovascular events in a working population, mostly young and healthy.MethodsWe conducted a prospective cohort stu...

Antihypertensive therapy and short-term blood pressure variability

Abstract: Background and aim Blood pressure variability (BPV) is recognized as a prognostic contributor in hypertension. We aimed to assess differences in short-term BPV in treated hypertensive patients depending on the number, classes, combinations and individual compounds of the antihypertensive treatment. Methods We selected 38 188 treated patients from the Spanish Ambulatory BP Monitoring (ABPM) Registry. SBP and DBP standard deviations (SD) from 24-h, daytime and night-time, weighted SD (WSD), and average real variability (ARV) were calculated through ABPM. They were compared (after adjustment for clinical confounders and BP) depending on the number of antihypertensive drugs, antihypertensive drug classes and compounds (in 13 765 patients on monotherapy), or combinations (in 12 716 patients treated with two drugs and 7888 treated with three drugs). Results Systolic and diastolic BPV significantly increased in patients treated with multiple drugs with respect to monotherapy. Among drug classes, calcium channel blockers, especially amlodipine, and diuretics were associated with lower systolic BPV, including daytime and night-time SD, WSD and ARV, compared with beta blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Likewise, in patients treated with two-drug and three-drug combinations, those which included a calcium channel blocker showed lower BPV in comparison to those without such drug class. Conclusion Treatment with calcium channel blockers, especially amlodipine, and with diuretics is associated with slight, but significant lower values of short-term BPV in comparison to other major drug classes, both in monotherapy and in combination. These results could be helpful when considering BPV reduction as an additional treatment target.

TCA Cycle and Fatty Acids Oxidation Reflect Early Cardiorenal Damage in Normoalbuminuric Subjects with Controlled Hypertension

Abstract: Moderately increased albuminuria, defined by an albumin to creatinine ratio (ACR) > 30 mg/g, is an indicator of subclinical organ damage associated with a higher risk of cardiovascular and renal disease. Normoalbuminuric subjects are considered at no cardiorenal risk in clinical practice, and molecular changes underlying early development are unclear. To decipher subjacent mechanisms, we stratified the normoalbuminuria condition. A total of 37 hypertensive patients under chronic renin-angiotensin system (RAS) suppression with ACR values in the normoalbuminuria range were included and classified as control (C) (ACR < 10 mg/g) and high-normal (HN) (ACR = 10-30 mg/g). Target metabolomic analysis was carried out by liquid chromatography and mass spectrometry to investigate the role of the cardiorenal risk urinary metabolites previously identified. Besides this, urinary free fatty acids (FFAs), fatty acid binding protein 1 (FABP1) and nephrin were analyzed by colorimetric and ELISA assays. A Mann-Whitney test was applied, ROC curves were calculated and Spearman correlation analysis was carried out. Nine metabolites showed significantly altered abundance in HN versus C, and urinary FFAs and FABP1 increased in HN group, pointing to dysregulation in the tricarboxylic acid cycle (TCA) cycle and fatty acids β-oxidation. We showed here how cardiorenal metabolites associate with albuminuria, already in the normoalbuminuric range, evidencing early renal damage at a tubular level and suggesting increased β-oxidation to potentially counteract fatty acids overload in the HN range.

Cardiovascular Risk Stratification Based on Oxidative Stress for Early Detection of Pathology

Abstract: Aims: Current cardiovascular (CV) risk prediction algorithms are able to quantify the individual risk of CV disease. However, CV risk in young adults is underestimated due to the high dependency of age in biomarker-based algorithms. Because oxidative stress is associated with CV disease, we sought to examine CV risk stratification in young adults based on oxidative stress to approach the discovery of new markers for early detection of pathology. Results: Young adults were stratified into (i) healthy controls, (ii) subjects with CV risk factors, and (iii) patients with a reported CV event. Plasma samples were analyzed using FASILOX, a novel approach to interrogate the dynamic thiol redox proteome. We also analyzed irreversible oxidation by targeted searches using the Uniprot database. Irreversible oxidation of cysteine (Cys) residues was greater in patients with reported CV events than in healthy subjects. These results also indicate that oxidation is progressive. Moreover, we found that glutathione reductase and glutaredoxin 1 proteins are differentially expressed between groups and are proteins involved in antioxidant response, which is in line with the impaired redox homeostasis in CV disease. Innovation: This study, for the first time, describes the oxidative stress (reversible and irreversible Cys oxidation) implication in human plasma according to CV risk stratification. Conclusion: The identification of redox targets and the quantification of protein and oxidative changes might help to better understand the role of oxidative stress in CV disease, and aid stratification for CV events beyond traditional prognostic and diagnostic markers. Antioxid. Redox Signal. 35, 602-617.

Acute Aerobic Exercise Induces Short-Term Reductions in Ambulatory Blood Pressure in Patients With Hypertension: A Systematic Review and Meta-Analysis

Abstract: Chronic exercise reduces clinic and ambulatory blood pressure (BP), but the short-term effects of an acute exercise bout on ambulatory BP have not been studied widely. We reviewed the literature re...

Early renal and vascular damage within the normoalbuminuria condition.

Abstract: OBJECTIVE A continuous association between albuminuria and cardiorenal risk exists further below moderately increased albuminuria ranges. If only based in albumin to creatinine ratio (ACR) higher than 30 mg/g, a significant percentage of individuals may be out of the scope for therapeutic management. Despite epidemiological outcomes, the identification of biochemical changes linked to early albuminuria is underexplored, and normoalbuminuric individuals are usually considered at no risk in clinical practice. Here, we aimed to identify early molecular alterations behind albuminuria development. METHODS Hypertensive patients under renin-angiotensin system (RAS) suppression were classified as control, (ACR < 10 mg/g) or high-normal (ACR = 10-30 mg/g). Urinary protein alterations were quantified and confirmed by untargeted and targeted mass spectrometry. Coordinated protein responses with biological significance in albuminuria development were investigated. Immunohistochemistry assays were performed in human kidney and arterial tissue to in situ evaluate the associated damage. RESULTS A total of 2663 identified proteins reflect inflammation, immune response, ion transport and lipids metabolism (P value ≤ 0.01). A1AT, VTDB and KNG1 varied in high-normal individuals (P value < 0.05), correlated with ACR and associated with the high-normal condition (odds ratio of 20.76, 6.00 and 7.04 were found, respectively (P value < 0.001)). After 12 months, protein variations persist and aggravate in progressors to moderately increased albuminuria. At tissue level, differential protein expression was found in kidney from individuals with moderately increased albuminuria and atherosclerotic aortas for the three proteins, confirming their capacity to reflect subclinical organ damage. CONCLUSION Early renal and vascular damage is molecularly evidenced within the normoalbuminuria condition.

TWEAK-Fn14 as a common pathway in the heart and the kidneys in cardiorenal syndrome.

Abstract: There is a complex relationship between cardiac and renal disease, often referred to as the cardiorenal syndrome. Heart failure adversely affects kidney function, and both acute and chronic kidney disease are associated with structural and functional changes to the myocardium. The pathological mechanisms and contributing interactions that surround this relationship remain poorly understood, limiting the opportunities for therapeutic intervention. The cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor, fibroblast growth factor-inducible 14 (Fn14), are abundantly expressed in injured kidneys and heart. The TWEAK-Fn14 axis promotes responses that drive tissue injury such as inflammation, proliferation, fibrosis, and apoptosis, while restraining the expression of tissue protective factors such as the anti-aging factor Klotho and the master regulator of mitochondrial biogenesis peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). High levels of TWEAK induce cardiac remodeling, and promote inflammation, tubular and podocyte injury and death, fibroblast proliferation, and, ultimately, renal fibrosis. Accordingly, targeting the TWEAK-Fn14 axis is protective in experimental kidney and heart disease. TWEAK has also emerged as a biomarker of kidney damage and cardiovascular outcomes and has been successfully targeted in clinical trials. In this review, we update our current knowledge of the roles of the TWEAK-Fn14 axis in cardiovascular and kidney disease and its potential contribution to the cardiorenal syndrome. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Analysis of Global Oxidative Status Using Multimarker Scores Reveals a Specific Association Between Renal Dysfunction and Diuretic Therapy in Older Adults.

Abstract: Aging and chronic kidney disease (CKD) are important interrelated cardiovascular risk (CVR) factors linked to oxidative stress, but this relationship has not been well studied in older adults. We assessed the global oxidative status in an older population with normal to severely impaired renal function. We determined the oxidative status of 93 older adults (mean age 85 years) using multimarker scores. OxyScore was computed as index of systemic oxidative damage by analyzing carbonyl groups, oxidized low-density lipoprotein, 8-hydroxy-2'-deoxyguanosine, and xanthine oxidase activity. AntioxyScore was computed as index of antioxidant defense by analyzing catalase and superoxide dismutase (SOD) activity and total antioxidant capacity. OxyScore and AntioxyScore were higher in subjects with estimated glomerular filtration rate (eGFR) 60 mL/min/1.73 m2, with protein carbonyls, catalase, and SOD activity as major drivers. Older adults with a recent cardiovascular event had similar OxyScore and AntioxyScore as peers with eGFR >60 mL/min/1.73 m2. Multivariate linear regression analysis revealed that both indices were associated with decreased eGFR independently of traditional CVR factors. Interestingly, AntioxyScore was also associated with diuretic treatment, and a more pronounced increase was seen in subjects receiving combination therapy. The associations of AntioxyScore with diuretic treatment and eGFR were mutually independent. In conclusion, eGFR is the major contributor to the imbalance in oxidative stress in this older population. Given the association between oxidative stress, CKD, and CVR, the inclusion of renal function parameters in CVR estimators for older populations, such as the SCORE-OP, might improve their modest performance.

Mineralocorticoid receptor antagonists for nephroprotection and cardioprotection in patients with diabetes mellitus and chronic kidney disease

Abstract: Diabetic kidney disease develops in about 40% of patients with diabetes and is the commonest cause of chronic kidney disease worldwide. Patients with chronic kidney disease, especially those with diabetes mellitus, are at high risk of both developing kidney failure and cardiovascular death. The use of renin-angiotensin system blockers to reduce the incidence of kidney failure in patients with diabetic kidney disease dates back to studies that are now 20 or more years old. During the last few years sodium-glucose co-transporter-2 inhibitors have shown beneficial renal effects in randomized trials. However, even in response to combined treatment with renin-angiotensin system blockers and sodium-glucose co-transporter-2 inhibitors, the renal residual risk remains high with kidney failure only deferred, but not avoided. The risk of cardiovascular death also remains high even with optimal current treatment. Steroidal mineralocorticoid receptor antagonists reduce albuminuria and surrogate markers of cardiovascular disease in patients already on optimal therapy. However, their use has been curtailed by the significant risk of hyperkalaemia. In The FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease (FIDELIO-DKD) study comparing the actions of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo, finerenone reduced the progression of diabetic kidney disease and the incidence of cardiovascular events with a relatively safe adverse event profile. This document presents in detail the available evidence on the cardioprotective and nephroprotective effects of mineralocorticoid receptor antagonists, analyses the potential mechanisms involved and discusses their potential future place in the treatment of patients with diabetic chronic kidney disease.

Fibroblast Growth Factor-23-Klotho Axis in Cardiorenal Syndrome: Mediators and Potential Therapeutic Targets

Abstract: Cardiorenal syndrome (CRS) is a complex disorder that refers to the category of acute or chronic kidney diseases that induce cardiovascular disease, and inversely, acute or chronic heart diseases that provoke kidney dysfunction. There is a close relationship between renal and cardiovascular disease, possibly due to the presence of common risk factors for both diseases. Thus, it is well known that renal diseases are associated with increased risk of developing cardiovascular disease, suffering cardiac events and even mortality, which is aggravated in those patients with end-stage renal disease or who are undergoing dialysis. Recent works have proposed mineral bone disorders (MBD) as the possible link between kidney dysfunction and the development of cardiovascular outcomes. Traditionally, increased serum phosphate levels have been proposed as one of the main factors responsible for cardiovascular damage in kidney patients. However, recent studies have focused on other MBD components such as the elevation of fibroblast growth factor (FGF)-23, a phosphaturic bone-derived hormone, and the decreased expression of the anti-aging factor Klotho in renal patients. It has been shown that increased FGF-23 levels induce cardiac hypertrophy and dysfunction and are associated with increased cardiovascular mortality in renal patients. Decreased Klotho expression occurs as renal function declines. Despite its expression being absent in myocardial tissue, several studies have demonstrated that this antiaging factor plays a cardioprotective role, especially under elevated FGF-23 levels. The present review aims to collect the recent knowledge about the FGF-23-Klotho axis in the connection between kidney and heart, focusing on their specific role as new therapeutic targets in CRS.

May Measurement Month 2019: an analysis of blood pressure screening results from Spain.

Abstract: The aim of the May Measurement Month (MMM) is devoted to better understanding the awareness, treatment, and control rates of hypertension in Spain. Presented here are the data corresponding to 2019 campaign. In 2019, a total of 4433 patients (61.5% males) with a mean age of 54.8 years were included. Of all, 96.0% were Caucasian, and 3294 were recruited in pharmacies. The mean values of systolic blood pressure (BP) were 125.6 and of diastolic 76.7 mmHg in the whole population. The most recent previous BP measurement took place more than 1 year before in 27.6% of participants. A total of 1883 were hypertensive (systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg or taking antihypertensive medication), of whom 77.2%/were aware and 71.1% were on medication. Of all, 64.9% of those on medication and 46.1% of all hypertensive participants had a BP controlled to <140/90 mmHg. These data from MMM 2019 continue to indicate the need for an improvement in the awareness, treatment, and control of hypertension in Spain.