Urinary extracellular vesicles as a monitoring tool for renal damage in patients not meeting criteria for chronic kidney disease.

Background: Current definition of chronic kidney disease (CKD) identifies only advanced stages, but effective management demands early detection. Urinary albumin-to-creatinine ratio (ACR) 30 mg/g is a cut-off point for CKD clinical diagnosis. Patients with lower values (normoalbuminuria) and eGFR > 60 mL/min/1.73 m2 are considered at no increased cardiorenal risk. However, higher incidence of renal function decline and cardiovascular events have been shown within the normoalbuminuria range. Novel subclinical indicators may help to identify higher-risk patients. Urinary extracellular vesicles (uEVs) are sentinels of renal function non-invasively. Here we aimed to approach the early assessment of cardiorenal risk by investigating the protein cargo of uEVs. Methods: Hypertensive patients were classified in control group (C) with ACR < 10 mg/g, and high-normal group (HN) with ACR 10-30 mg/g. Isolated uEVs were characterized by western blotting and electron microscopy and the protein cargo was analyzed by untargeted proteomics (LC-MS/MS) in a first discovery cohort. Protein confirmation was performed in a different cohort by ExoView. Immunohistochemistry of human kidney biopsies was also performed to evaluate the potential of uEVs to reflect renal damage. Results: HN albuminuria does not affect the uEVs concentration, size, or tetraspanin profile. Among >6200 uEVs proteins identified, 43 define a panel significantly altered in HN patients without variation in urine, mostly annotated in the tubule (39 out of 43). The tubular transporter long-chain fatty acid transport protein 2 (SLC27A2) and the apical membrane protein amnionless (AMN) confirmed their alteration in HN patients evidencing impaired tubular reabsorption. SLC27A2 showed tubular expression and significantly reduced levels in patients with diagnostic criteria for CKD. Conclusions: Alterations in the EV-mediated molecular profile are evident before pathological ACR levels are reached. Direct quantitation of SLC27A2 and AMN in uEVs helps identifying normoalbuminuric subjects with higher cardiorenal risk in early monitoring of CKD.

The Urinary Glycopeptide Profile Differentiates Early Cardiorenal Risk in Subjects Not Meeting Criteria for Chronic Kidney Disease.

Early diagnosis and treatment of chronic kidney disease (CKD) is a worldwide challenge. Subjects with albumin-to-creatinine ratio (ACR) ≥ 30 mg/g and preserved renal function are considered to be at no cardiorenal risk in clinical practice, but prospective clinical studies evidence increased risk, even at the high-normal (HN) ACR range (10-30 mg/g), supporting the need to identify other molecular indicators for early assessment of patients at higher risk. Following our previous studies, here we aim to stratify the normoalbuminuria range according to cardiorenal risk and identify the glycoproteins and N-glycosylation sites associated with kidney damage in subclinical CKD. Glycoproteins were analyzed in urine from hypertensive patients within the HN ACR range compared to control group (C; ACR < 10 mg/g) by mass spectrometry. A different cohort was analyzed for confirmation (ELISA) and sex perspective was evaluated. Patients' follow-up for 8 years since basal urine collection revealed higher renal function decline and ACR progression for HN patients. Differential N-glycopeptides and their N -glycosylation sites were also identified, together with their pathogenicity. N-glycosylation may condition pathological protein deregulation, and a panel of 62 glycoproteins evidenced alteration in normoalbuminuric subjects within the HN range. Haptoglobin-related protein, haptoglobin, afamin, transferrin, and immunoglobulin heavy constant gamma 1 (IGHG1) and 2 (IGHG2) showed increased levels in HN patients, pointing to disturbed iron metabolism and tubular reabsorption and supporting the tubule as a target of interest in the early progression of CKD. When analyzed separately, haptoglobin, afamin, transferrin, and IGHG2 remained significant in HN, in both women and men. At the peptide level, 172 N-glycopeptides showed differential abundance in HN patients, and 26 showed high pathogenicity, 10 of them belonging to glycoproteins that do not show variation between HN and C groups. This study highlights the value of glycosylation in subjects not meeting KDIGO criteria for CKD. The identified N-glycopeptides and glycosylation sites showed novel targets, for both the early assessment of individual cardiorenal risk and for intervention aimed at anticipating CKD progression.

Donor-Dependent Variations in Systemic Oxidative Stress and Their Association with One-Year Graft Outcomes in Kidney Transplantation.

INTRODUCTION: Oxidative stress has been implicated in complications after kidney transplantation (KT), including delayed graft function (DGF) and rejection. However, its role in long-term posttransplant outcomes remains unclear. METHODS: We investigated oxidative damage and antioxidant defense dynamics, and their impact on the graft outcomes, in 41 KT recipients categorized by type of donation over 12 months. Oxidative status was determined using OxyScore and AntioxyScore indexes, which comprise several circulating biomarkers of oxidative damage and antioxidant defense. Donor types included donation after brain death (DBD [61.0%]), donation after circulatory death (DCD [26.8%]), and living donation (LD [12.1%]). RESULTS: There was an overall increase in oxidative damage early after transplantation, which was significantly higher in DCD as compared to DBD and LD recipients. The multivariate adjustment confirmed the independent association of OxyScore and type of deceased donation with DGF, donor kidney function, and induction therapy with antithymocyte globulin. There were no differences in terms of antioxidant defense. Lower oxidative damage at day 7 predicted better graft function at 1-year posttransplant only in DBD recipients. CONCLUSION: DCD induced greater short-term oxidative damage after KT, whereas the early levels of oxidative damage were predictive of the graft function 1 year after KT among DBD recipients.

Artificial Intelligence-Derived Risk Prediction: A Novel Risk Calculator Using Office and Ambulatory Blood Pressure.

BACKGROUND: Quantification of total cardiovascular risk is essential for individualizing hypertension treatment. This study aimed to develop and validate a novel, machine-learning-derived model to predict cardiovascular mortality risk using office blood pressure (OBP) and ambulatory blood pressure (ABP). METHODS: The performance of the novel risk score was compared with existing risk scores, and the possibility of predicting ABP phenotypes utilizing clinical variables was assessed. Using data from 59 124 patients enrolled in the Spanish ABP Monitoring registry, machine-learning approaches (logistic regression, gradient-boosted decision trees, and deep neural networks) and stepwise forward feature selection were used. RESULTS: For the prediction of cardiovascular mortality, deep neural networks yielded the highest clinical performance. The novel mortality prediction models using OBP and ABP outperformed other risk scores. The area under the curve achieved by the novel approach, already when using OBP variables, was significantly higher when compared with the area under the curve of the Framingham risk score, Systemic Coronary Risk Estimation 2, and Atherosclerotic Cardiovascular Disease score. However, the prediction of cardiovascular mortality with ABP instead of OBP data significantly increased the area under the curve (0.870 versus 0.865; P=3.61×10-28), accuracy, and specificity, respectively. The prediction of ABP phenotypes (ie, white-coat, ambulatory, and masked hypertension) using clinical characteristics was limited. CONCLUSIONS: The receiver operating characteristic curves for cardiovascular mortality using ABP and OBP with deep neural network models outperformed all other risk metrics, indicating the potential for improving current risk scores by applying state-of-the-art machine learning approaches. The prediction of cardiovascular mortality using ABP data led to a significant increase in area under the curve and performance metrics.

Albumin Redox Modifications Promote Cell Calcification Reflecting the Impact of Oxidative Status on Aortic Valve Disease and Atherosclerosis.

Calcific aortic valve disease (CAVD) and coronary artery disease (CAD) are related cardiovascular diseases in which common mechanisms lead to tissue calcification. Oxidative stress plays a key role in these diseases and there is also evidence that the redox state of serum albumin exerts a significant influence on these conditions. To further explore this issue, we used multimarker scores (OxyScore and AntioxyScore) to assess the global oxidative status in patients with CAVD, with and without CAD, also evaluating their plasma thiol levels. In addition, valvular interstitial cells were treated with reduced, oxidized, and native albumin to study how this protein and its modifications affect cell calcification. The differences we found suggest that oxidative status is distinct in CAVD and CAD, with differences in redox markers and thiol levels. Importantly, the in vitro interstitial cell model revealed that modified albumin affects cell calcification, accelerating this process. Hence, we show here the importance of the redox system in the development of CAVD, emphasizing the relevance of multimarker scores, while also offering evidence of how the redox state of albumin influences vascular calcification. These data highlight the relevance of understanding the overall redox processes involved in these diseases, opening the door to new studies on antioxidants as potential therapies for these patients.

Targeting the TWEAK-Fn14 pathway prevents dysfunction in cardiac calcium handling after acute kidney injury.

Heart and kidney have a closely interrelated pathophysiology. Acute kidney injury (AKI) is associated with significantly increased rates of cardiovascular events, a relationship defined as cardiorenal syndrome type 3 (CRS3). The underlying mechanisms that trigger heart disease remain, however, unknown, particularly concerning the clinical impact of AKI on cardiac outcomes and overall mortality. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) are independently involved in the pathogenesis of both heart and kidney failure, and recent studies have proposed TWEAK as a possible therapeutic target; however, its specific role in cardiac damage associated with CRS3 remains to be clarified. Firstly, we demonstrated in a retrospective longitudinal clinical study that soluble TWEAK plasma levels were a predictive biomarker of mortality in patients with AKI. Furthermore, the exogenous application of TWEAK to native ventricular cardiomyocytes induced relevant calcium (Ca2+ ) handling alterations. Next, we investigated the role of the TWEAK-Fn14 axis in cardiomyocyte function following renal ischaemia-reperfusion (I/R) injury in mice. We observed that TWEAK-Fn14 signalling was activated in the hearts of AKI mice. Mice also showed significantly altered intra-cardiomyocyte Ca2+ handling and arrhythmogenic Ca2+ events through an impairment in sarcoplasmic reticulum Ca2+ -adenosine triphosphatase 2a pump (SERCA2a ) and ryanodine receptor (RyR2 ) function. Administration of anti-TWEAK antibody after reperfusion significantly improved alterations in Ca2+ cycling and arrhythmogenic events and prevented SERCA2a and RyR2 modifications. In conclusion, this study establishes the relevance of the TWEAK-Fn14 pathway in cardiac dysfunction linked to CRS3, both as a predictor of mortality in patients with AKI and as a Ca2+ mishandling inducer in cardiomyocytes, and highlights the cardioprotective benefits of TWEAK targeting in CRS3. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Cardiovascular and renal health: Preeclampsia as a risk marker.

BACKGROUND: Cardiovascular (CVD) and chronic kidney disease (CKD) in women have unique risk factors related to hormonal status and obstetric history that must be taken into account. Pregnancy complications, such as preeclampsia (PE), can reveal a subclinical predisposition for the development of future disease that may help identify women who could benefit from early CVD and CKD prevention strategies. MATERIALS AND METHODS: Review of PE and its association with future development of CVD and CKD. RESULTS: Multiple studies have established an association between PE and the development of ischemic heart disease, chronic hypertension, peripheral vascular disease, stroke and CKD. It has not been sufficiently clarified if this relation is a causal one or if it is mediated by common risk factors. Nevertheless, the presence of endothelial dysfunction and thrombotic microangiopathy during pregnancies complicated with PE makes us believe that PE may leave a long-term imprint. Early identification of women who have had a pregnancy complicated by PE becomes a window of opportunity to improve women's health through adequate follow-up and targeted preventive actions. Oxidative stress biomarkers and vascular ultrasound may play a key role in the early detection of this arterial damage. CONCLUSIONS: The implementation of preventive multidisciplinary targeted strategies can help slow down CVD and CKD's natural history in women at risk through lifestyle modifications and adequate blood pressure control. Therefore, we propose a series of recommendations to guide the prediction and prevention of CVD and CKD throughout life of women with a history of PE.

Chronic kidney disease promotes atrial fibrillation via inflammasome pathway activation.

Chronic kidney disease (CKD) is associated with a higher risk of atrial fibrillation (AF). The mechanistic link between CKD and AF remains elusive. IL-1ß, a main effector of NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation, is a key modulator of conditions associated with inflammation, such as AF and CKD. Circulating IL-1ß levels were elevated in patients with CKD who had AF (versus patients with CKD in sinus rhythm). Moreover, NLRP3 activity was enhanced in atria of patients with CKD. To elucidate the role of NLRP3/IL-1ß signaling in the pathogenesis of CKD-induced AF, Nlrp3-/- and WT mice were subjected to a 2-stage subtotal nephrectomy protocol to induce CKD. Four weeks after surgery, IL-1ß levels in serum and atrial tissue were increased in WT CKD (WT-CKD) mice versus sham-operated WT (WT-sham) mice. The increased susceptibility to pacing-induced AF and the longer AF duration in WT-CKD mice were associated with an abbreviated atrial effective refractory period, enlarged atria, and atrial fibrosis. Genetic inhibition of NLRP3 in Nlrp3-/- mice or neutralizing anti-IL-1ß antibodies effectively reduced IL-1ß levels, normalized left atrial dimensions, and reduced fibrosis and the incidence of AF. These data suggest that CKD creates a substrate for AF development by activating the NLRP3 inflammasome in atria, which is associated with structural and electrical remodeling. Neutralizing IL-1ß antibodies may be beneficial in preventing CKD-induced AF.

Salud cardiovascular y renal en la mujer: la preeclampsia como marcador de riesgo / Cardiovascular and renal health: Preeclampsia as a risk marker

Antecedentes: La enfermedad cardiovascular (ECV) y renal en la mujer presentan factores de riesgo propios relacionados con el estatus hormonal y los antecedentes obstétricos que deben tenerse en cuenta. Las complicaciones del embarazo, como la preeclampsia (PE), pueden revelar predisposiciones subclínicas a padecer enfermedades futuras que ayuden a identificar a aquellas mujeres que puedan beneficiarse de nuevas oportunidades para la prevención de la ECV y la enfermedad renal crónica. Materiales y métodos: Revisión sobre la PE y su asociación con el desarrollo de ECV y renal futuras. Resultados: Múltiples estudios han establecido una asociación entre PE y el desarrollo de cardiopatía isquémica, hipertensión crónica, enfermedad vascular periférica, accidente cerebrovascular y enfermedad renal. No se ha aclarado suficientemente si esta relación es de causalidad o está mediada por la presencia de factores de riesgo comunes. Sin embargo, la demostración de fenómenos de disfunción endotelial y microangiopatía trombótica en los embarazos que cursan con PE hace suponer que esta puede dejar una impronta a largo plazo. La identificación precoz de las mujeres que han padecido un embarazo complicado con PE es una ventana de oportunidad para mejorar la salud de la mujer, mediante su seguimiento y la adopción de medidas preventivas adecuadas. Los marcadores bioquímicos de daño oxidativo y la ecografía vascular pueden desempeñar un papel clave en la identificación precoz de este daño arterial. Conclusiones: La implantación de estrategias preventivas multidisciplinares y específicas puede ayudar a frenar la historia natural de la ECV y renal en las mujeres de riesgo, a través de la modificación de su estilo de vida y del adecuado control de la tensión arterial. Para ello, proponemos una serie de recomendaciones para guiar el estudio de la predicción y prevención de la ECV tras la PE a lo largo de la vida de la mujer. (AU)

Background: Cardiovascular (CVD) and chronic kidney disease (CKD) in women have unique risk factors related to hormonal status and obstetric history that must be taken into account. Pregnancy complications, such as preeclampsia (PE), can reveal a subclinical predisposition for the development of future disease that may help identify women who could benefit from early CVD and CKD prevention strategies. Materials and methods: Review of PE and its association with future development of CVD and CKD. Results: Multiple studies have established an association between PE and the development of ischemic heart disease, chronic hypertension, peripheral vascular disease, stroke and CKD. It has not been sufficiently clarified if this relation is a causal one or if it is mediated by common risk factors. Nevertheless, the presence of endothelial dysfunction and thrombotic microangiopathy during pregnancies complicated with PE makes us believe that PE may leave a long-term imprint. Early identification of women who have had a pregnancy complicated by PE becomes a window of opportunity to improve women's health through adequate follow-up and targeted preventive actions. Oxidative stress biomarkers and vascular ultrasound may play a key role in the early detection of this arterial damage. Conclusions: The implementation of preventive multidisciplinary targeted strategies can help slow down CVD and CKD's natural history in women at risk through lifestyle modifications and adequate blood pressure control. Therefore, we propose a series of recommendations to guide the prediction and prevention of CVD and CKD throughout life of women with a history of PE. (AU)

Global Oxidative Status Is Linked to Calcific Aortic Stenosis: The Differences Due to Diabetes Mellitus and the Effects of Metformin.

Calcific aortic stenosis (CAS) and type 2 diabetes mellitus (T2DM) are related and often concomitant pathologies, accompanied by common comorbidities such as hypertension or dyslipidemia. Oxidative stress is one of the mechanisms that trigger CAS, and it can drive the vascular complications in T2DM. Metformin can inhibit oxidative stress, yet its effects have not been studied in the context of CAS. Here, we assessed the global oxidative status in plasma from patients with CAS, both alone and with T2DM (and under treatment with metformin), using multimarker scores of systemic oxidative damage (OxyScore) and antioxidant defense (AntioxyScore). The OxyScore was determined by measuring carbonyls, oxidized LDL (oxLDL), 8-hydroxy-20-deoxyguanosine (8-OHdG), and xanthine oxidase (XOD) activity. In contrast, the AntioxyScore was determined through the catalase (CAT) and superoxide dismutase (SOD) activity, as well as the total antioxidant capacity (TAC). Patients with CAS displayed enhanced oxidative stress compared to control subjects, probably exceeding their antioxidant capacity. Interestingly, patients with CAS and T2DM displayed less oxidative stress, possibly due to the benefits of their pharmacological therapy (metformin). Thus, reducing oxidative stress or enhancing antioxidant capacity through specific therapies could be a good strategy to manage CAS, focusing on personalized medicine.

Relationship between clinic and ambulatory blood pressure and mortality: an observational cohort study in 59 124 patients.

BACKGROUND: Ambulatory blood pressure provides a more comprehensive assessment than clinic blood pressure, and has been reported to better predict health outcomes than clinic or home pressure. We aimed to examine associations of clinic and 24-h ambulatory blood pressure with all-cause and cardiovascular mortality in a large cohort of primary care patients referred for assessment of hypertension. METHODS: We did an observational cohort study using clinic and ambulatory blood pressure data obtained from March 1, 2004, to Dec 31, 2014, from the Spanish Ambulatory Blood Pressure Registry. This registry included patients from 223 primary care centres from the Spanish National Health System in all 17 regions of Spain. Mortality data (date and cause) were ascertained by a computerised search of the vital registry of the Spanish National Institute of Statistics. Complete data were available for age, sex, all blood pressure measures, and BMI. For each study participant, follow-up was from the date of their recruitment to the date of death or Dec 31, 2019, whichever occurred first. Cox models were used to estimate associations between usual clinic or ambulatory blood pressure and mortality, adjusted for confounders and additionally for alternative measures of blood pressure. For each measure of blood pressure, we created five groups (ie, fifths) defined by quintiles of that measure among those who subsequently died. FINDINGS: During a median follow-up of 9·7 years, 7174 (12·1%) of 59 124 patients died, including 2361 (4·0%) from cardiovascular causes. J-shaped associations were observed for several blood pressure measures. Among the top four baseline-defined fifths, 24-h systolic blood pressure was more strongly associated with all-cause death (hazard ratio [HR] 1·41 per 1 - SD increment [95% CI 1·36-1·47]) than clinic systolic blood pressure (1·18 [1·13-1·23]). After adjustment for clinic blood pressure, 24-h blood pressure remained strongly associated with all-cause deaths (HR 1·43 [95% CI 1·37-1·49]), but the association between clinic blood pressure and all-cause death was attenuated when adjusted for 24-h blood pressure (1·04 [1·00-1·09]). Compared with the informativeness of clinic systolic blood pressure (100%), night-time systolic blood pressure was most informative about risk of all-cause death (591%) and cardiovascular death (604%). Relative to blood pressure within the normal range, elevated all-cause mortality risks were observed for masked hypertension (HR 1·24 [95% CI 1·12-1·37]) and sustained hypertension (1·24 [1·15-1·32]), but not white-coat hypertension, and elevated cardiovascular mortality risks were observed for masked hypertension (1·37 [1·15-1·63]) and sustained hypertension (1·38 [1·22-1·55]), but not white-coat hypertension. INTERPRETATION: Ambulatory blood pressure, particularly night-time blood pressure, was more informative about the risk of all-cause death and cardiovascular death than clinic blood pressure. FUNDING: Spanish Society of Hypertension, Lacer Laboratories, UK Medical Research Council, Health Data Research UK, National Institute for Health and Care Research Biomedical Research Centres (Oxford and University College London Hospitals), and British Heart Foundation Centre for Research Excellence.

Partial Genetic Deletion of Klotho Aggravates Cardiac Calcium Mishandling in Acute Kidney Injury.

Acute kidney injury (AKI) is associated with an elevated risk of cardiovascular major events and mortality. The pathophysiological mechanisms underlying the complex cardiorenal network interaction remain unresolved. It is known that the presence of AKI and its evolution are significantly associated with an alteration in the anti-aging factor klotho expression. However, it is unknown whether a klotho deficiency might aggravate cardiac damage after AKI. We examined intracellular calcium (Ca2+) handling in native ventricular isolated cardiomyocytes from wild-type (+/+) and heterozygous hypomorphic mice for the klotho gene (+/kl) in which an overdose of folic acid was administered to induce AKI. Twenty-four hours after AKI induction, cardiomyocyte contraction was decreased in mice with the partial deletion of klotho expression (heterozygous hypomorphic klotho named +/kl). This was accompanied by alterations in Ca2+ transients during systole and an impairment of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) function in +/kl mice after AKI induction. Moreover, Ca2+ spark frequency and the incidence of Ca2+ pro-arrhythmic events were greater in cardiomyocytes from heterozygous hypomorphic klotho compared to wild-type mice after AKI. A decrease in klotho expression plays a role in cardiorenal damage aggravating cardiac Ca2+ mishandling after an AKI, providing the basis for future targeted approaches directed to control klotho expression as novel therapeutic strategies to reduce the cardiac burden that affects AKI patients.

Prevention of cardiorenal damage: importance of albuminuria.

Chronic kidney disease (CKD) is projected to become a leading global cause of death by 2040, and its early detection is critical for effective and timely management. The current definition of CKD identifies only advanced stages, when kidney injury has already destroyed >50% of functioning kidney mass as reflected by an estimated glomerular filtration rate <60 mL/min/1.73 m2 or a urinary albumin/creatinine ratio >six-fold higher than physiological levels (i.e. > 30 mg/g). An elevated urinary albumin-excretion rate is a known early predictor of future cardiovascular events. There is thus a 'blind spot' in the detection of CKD, when kidney injury is present but is undetectable by current diagnostic criteria, and no intervention is made before renal and cardiovascular damage occurs. The present review discusses the CKD 'blind spot' concept and how it may facilitate a holistic approach to CKD and cardiovascular disease prevention and implement the call for albuminuria screening implicit in current guidelines. Cardiorenal risk associated with albuminuria in the high-normal range, novel genetic and biochemical markers of elevated cardiorenal risk, and the role of heart and kidney protective drugs evaluated in recent clinical trials are also discussed. As albuminuria is a major risk factor for cardiovascular and renal disease, starting from levels not yet considered in the definition of CKD, the implementation of opportunistic or systematic albuminuria screening and therapy, possibly complemented with novel early biomarkers, has the potential to improve cardiorenal outcomes and mitigate the dismal 2040 projections for CKD and related cardiovascular burden.

Effect of finerenone on ambulatory blood pressure in chronic kidney disease in type 2 diabetes.

OBJECTIVE: Finerenone is a selective nonsteroidal mineralocorticoid receptor antagonist with a short half-life. Its effects on cardiorenal outcomes were thought to be mediated primarily via nonhemodynamic pathways, but office blood pressure (BP) measurements were insufficient to fully assess hemodynamic effects. This analysis assessed the effects of finerenone on 24-h ambulatory BP in patients with chronic kidney disease and type 2 diabetes. METHODS: ARTS-DN (NCT01874431) was a phase 2b trial that randomized 823 patients with type 2 diabetes and chronic kidney disease, with urine albumin-to-creatinine ratio ≥30 mg/g and estimated glomerular filtration rate of 30-90 ml/min per 1.73 m2 to placebo or finerenone (1.25-20 mg once daily in the morning) administered over 90 days. Ambulatory BP monitoring (ABPM) over 24 h was performed in a subset of 240 patients at screening, Day 60, and Day 90. RESULTS: Placebo-adjusted change in 24-h ABPM systolic BP (SBP) at Day 90 was -8.3 mmHg (95% confidence interval [CI], -16.6 to 0.1) for finerenone 10 mg (n = 27), -11.2 mmHg (95% CI, -18.8 to -3.6) for finerenone 15 mg (n = 34), and -9.9 mmHg (95% CI, -17.7 to -2.0) for finerenone 20 mg (n = 31). Mean daytime and night-time SBP recordings were similarly reduced and finerenone did not increase the incidence of SBP dipping. Finerenone produced a persistent reduction in SBP over the entire 24-h interval. CONCLUSIONS: Finerenone reduced 24-h, daytime, and night-time SBP. Despite a short half-life, changes in BP were persistent over 24 h with once-daily dosing in the morning.

Rationale and Protocol of the Multimodality Evaluation of Antibody-Mediated Injury in Heart Transplantation (LEONE-HT) Observational Cross-Sectional Study.

INTRODUCTION: Heart transplant (HT) survival has barely improved in the last decades, which is unsatisfactory for many HT recipients. The development of anti-human leukocyte antigen (anti-HLA) antibodies in HT patients is associated with a cardiac allograft dysfunction. The mechanisms leading to this damage are unclear. The Multimodality Evaluation Of Antibody-Mediated Injury In Heart Transplantation (LEONE-HT) study aimed to thoroughly describe the damage inflicted on the myocardium by anti-HLA antibodies. METHODS AND ANALYSIS: The LEONE-HT study is a cohort study with a cross-sectional approach in which HT patients with positive anti-HLA antibodies are compared with coetaneous HT patients with negative anti-HLA antibodies. All patients will undergo a state-of-the-art multimodal assessment, including imaging techniques, coronary anatomy and physiology evaluations and histological and immunological analyses. The individual and combined primary outcomes of structural graft injuries and longitudinal secondary outcomes are to be compared between the exposed and non-exposed groups with univariate and multivariable descriptive analyses. ETHICS AND DISSEMINATION: The LEONE-HT study is carried out in accordance with the principles set out in the Declaration of Helsinki and the International Conference on Harmonization guidelines for good clinical practice and following national laws and regulations. The study design, objectives and participant centers have been communicated to clinicaltrials.gov (NCT05184426). The LEONE-HT study counts on the support of patient associations to disseminate the objectives and results of the research. This study was funded by the Spanish Ministry of Science and Innovation and the Spanish Society of Cardiology.

Hypertension mediated kidney and cardiovascular damage and risk stratification: Redefining concepts / Daño renal y cardiovascular mediado por hipertensión y estratificación del riesgo: redefinición de conceptos

Hypertension mediated organ damage (HMOD) refers to structural or functional changes in arteries or target organs that can be present in long-standing hypertension, but it can be also found in naïve never treated patients. Traditionally, cardiovascular risk is stratified with charts or calculators that tend to underestimate the real cardiovascular risk. The diagnosis of HMOD automatically reclassifies patients to the highest level of cardiovascular risk. Subclinical HMOD can be present already at the diagnosis of hypertension and more than 25% of hypertensives are misclassified with the routine tests recommended by hypertension guidelines. Whether HMOD regression improves cardiovascular outcomes has never been investigated in randomized clinical trials and remains controversial. However, different drugs have been probed with promising results in high cardiovascular risk patients, such as the new antidiabetic or the novel non-steroid mineralocorticoid antagonists. Accordingly, trials have shown that lowering blood pressure reduces cardiovascular events. In this narrative review, we will discuss the role of HMOD in cardiovascular risk stratification, the different types of organ damage, and the evidence available to define whether HMOD can be used as a therapeutic target. (AU)

El daño orgánico mediado por hipertensión (HMOD) se refiere a cambios estructurales o funcionales de larga duración en las arterias u órganos diana de la hipertensión, pero también se puede encontrar en pacientes que nunca han recibido tratamiento antihipertensivo previo. Tradicionalmente, el riesgo cardiovascular se ha estratificado utilizando tablas, calculadoras o algoritmos que tienden a subestimar el riesgo cardiovascular real. El diagnóstico del HMOD reclasifica automáticamente a los pacientes al nivel más alto de riesgo cardiovascular. El HMOD subclínico ya puede estar presente en el momento del diagnóstico de hipertensión y más del 25% de los hipertensos están mal clasificados con las pruebas de rutina recomendadas por las guías de hipertensión. Sin embargo, si la regresión del HMOD mejora los resultados cardiovasculares no suele ser un objeto de investigación en ensayos clínicos aleatorizados y sigue siendo un aspecto controvertido. A pesar de ello, se han probado diferentes fármacos con resultados prometedores en pacientes de alto riesgo cardiovascular, como los nuevos antidiabéticos o los nuevos antagonistas de mineralocorticoides no esteroides. De hecho, diferentes estudios han demostrado que bajar la presión arterial reduce los eventos cardiovasculares. En esta revisión narrativa, se discutirá el papel del HMOD en la estratificación del riesgo cardiovascular, los diferentes tipos de daño orgánico y la evidencia disponible para definir si HMOD puede usarse como un objetivo terapéutico. (AU)

Klotho relieves inflammation and exerts a cardioprotective effect during renal ischemia/reperfusion-induced cardiorenal syndrome.

BACKGROUND: Renal ischemia and reperfusion injury (IRI) is the main cause of acute kidney injury (AKI). AKI induces the development of cardiac hypertrophy (CH) during cardiorenal syndrome (CRS), and cardiomyocyte calcium mishandling though systemic inflammation after 8 days of renal IRI. Klotho has recently been described as an anti-inflammatory component. Given this, Klotho treatment could prevent or attenuate the inflammation, thereby also preventing electrical cardiac outcomes incurred by CRS. The aim of this study was to investigate the therapeutic role of Klotho in CRS after unilateral renal IRI through its anti-inflammatory action. METHODS: We examined renal tissue structure and function, intracellular Ca2+ dynamics in adult ventricular cardiomyocytes and serum cytokine levels from C57BL/6 mice that suffered unilateral renal IRI by occluding the left pedicle for 60 min and reperfusion for 8 days. The animals were treated with recombinant Klotho protein starting from the day of the surgery, then daily for 8 days. RESULTS: After Klotho treatment for 8 days, the left renal tissue remained damaged, however the renal function was restored due to the right kidney tissue preservation. In parallel, Klotho also prevented an increase in serum interleukin (IL-) 6, IL-1ß, and tumor necrosis factor alpha (TNF-α) levels. CH and low cell contraction were also prevented, as well as a decrease in systolic Ca2+ transients and sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) activity measured as Ca2+ transient decay, an increase in spontaneous Ca2+ release and the incidence of pro-arrhythmic events. CONCLUSIONS: The Klotho treatment showed promise, playing an important role in the pathophysiology of CRS. We were unable to observe a total renoprotective role of the compound in the model; in turn, a cardioprotective role of Klotho was demonstrated through the prevention of hypertrophy and normalization of the Ca2+ cycle dysfunction of cardiomyocytes. We propose that Klotho acts in the cardiorenal syndrome by systematically preventing inflammation and increased FGF23, alleviating cardiac outcomes.

Specialized Proresolving Mediators Protect Against Experimental Autoimmune Myocarditis by Modulating Ca2+ Handling and NRF2 Activation.

Specialized proresolving mediators and, in particular, 5(S), (6)R, 7-trihydroxyheptanoic acid methyl ester (BML-111) emerge as new therapeutic tools to prevent cardiac dysfunction and deleterious cardiac damage associated with myocarditis progression. The cardioprotective role of BML-111 is mainly caused by the prevention of increased oxidative stress and nuclear factor erythroid-derived 2-like 2 (NRF2) down-regulation induced by myocarditis. At the molecular level, BML-111 activates NRF2 signaling, which prevents sarcoplasmic reticulum-adenosine triphosphatase 2A down-regulation and Ca2+ mishandling, and attenuates the cardiac dysfunction and tissue damage induced by myocarditis.