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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., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

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., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: The European Guidelines on Hypertension define an office pulse pressure (PP) at least 60 mmHg in the elderly patient as asymptomatic organ damage. Our objective was to estimate the cutoff point of 24-h PP that best predicts office PP associated with higher cardiovascular risk (≥60 mmHg) in hypertensive older patients., Methods: We studied all hypertensive patients at least 60 years with a first valid ambulatory blood pressure monitoring drawn from the Spanish ambulatory blood pressure monitoring registry. Receiver operating characteristic curves were used to estimate the best 24-h PP cutoff predictor of office PP at least 60 mmHg that maximized the sum of sensitivity and specificity., Results: We included 52 246 hypertensive patients [52.4%, female; mean age (SD) 69.0 (7.0) years]. From these, 34 530 (66.1%) patients had an office PP at least 60 mmHg. The value of 24-h PP that best predicts higher risk clinic PP is 54.9 mmHg [sensitivity: 69.2%; specificity: 70.3%; area under the receiver operating characteristic curve of 0.761 (95% confidence interval 0.756-0.765)]. Mean clinic and 24-h PPs were progressively higher as the study participants were classified at higher cardiovascular risk group. Some 20.5% of patients presented isolated office high PP and 10% a masked high 24-h PP., Conclusion: In a large clinical sample of older hypertensive patients, the cutoff point of 24-h PP that best predicts office PP at least 60 mmHg is 55 mmHg. In 30.5% of cases, there is a discrepancy between office PP and ambulatory 24-h PP.

Objective: Albuminuria has been recently described in hypertensive patients under chronic renin-angiotensin system (RAS) suppression. We investigated whether this fact could be related to an increase in oxidative stress., Methods: We examined normoalbuminuric and albuminuric patients in stage 2 chronic kidney disease, both with more than 2 years of RAS blockade. The relationship between albuminuria and circulating biomarkers for both oxidative damage, that is carbonyl and malondialdehyde, as well as antioxidant defense, that is reduced glutathione, thiol groups, uric acid, bilirubin, or catalase, and superoxide scavenging activity, was assessed., Results: We found that only patients with albuminuria showed an important increase in carbonyls (P < 0.001) and malondialdehyde (P < 0.05) compared to normoalbuminuric patients. This increase in oxidative damage was also accompanied by a rise in catalase activity (P < 0.05) and low-molecular-weight antioxidants only when they were measured as total antioxidant capacity (P < 0.01). In order to establish the specific oxidative status of each group, new indexes of oxidative damage and antioxidant defense were calculated with all these markers following a mathematical and statistical approach. Although both pro-oxidant and antioxidant indexes were significantly increased in patients with albuminuria, only the oxidative damage index positively correlated with the increase of albumin/creatinine ratio (P = 0.0024)., Conclusions: We conclude that albuminuria is accompanied by an amplified oxidative damage in patients in early stages of chronic kidney disease. These results indicate that chronic RAS protection must be directed to avoid development of albuminuria and oxidative damage.

Objective: The Munich Wistar Frömter (MWF) rat develops progressive spontaneous albuminuria largely attributable to quantitative trait loci on rat chromosome (RNO)6 and RNO8, respectively. We tested the hypothesis whether quantitative trait loci on these chromosomes are linked to both albuminuria and endothelial dysfunction., Methods: Experiments were performed in male 12-week-old MWF, Wistar Kyoto (WKY), spontaneously hypertensive rat (SHR) and consomic MWF-6 and MWF-8 rats, in which RNO6 or RNO8 was replaced by the respective SHR chromosome (n = 10 per strain). Vascular function was assessed in aorta and vascular superoxide anion production was determined by confocal microscopy., Results: Acetylcholine potency to induce relaxation was significantly reduced in MWF (6.2 ± 0.1) compared with WKY (7.1 ± 0.1) or SHR (7.3 ± 0.1; P < 0.01). N-nitro-L-arginine methyl ester abolished relaxation to acetylcholine in all three strains, whereas indomethacin exhibited no effect in WKY and MWF. Contractions to noradrenaline and superoxide production were significantly higher in MWF compared with SHR and WKY (P < 0.05, respectively). In consomic MWF-6 and MWF-8 rats albuminuria was markedly suppressed (-85 and -92%, P < 0.005 compared with MWF, respectively). Interestingly, relaxation to acetylcholine and contraction to noradrenaline were restored to normal WKY levels only in MWF-8, but not in MWF-6, due to an increase in stimulated and basal nitric oxide availability, respectively., Conclusion: These data demonstrate the partial genetic independence of albuminuria and endothelial dysfunction in this model. From two known albuminuria quantitative trait loci one locus affects both albuminuria and endothelial dysfunction. Whether this observation is based on a common genetic mechanism related to NO availability warrants further investigation.

Left ventricular hypertrophy (LVH) is regarded as a complication common to a number of cardiovascular diseases, including hypertension, myocardial infarction and ischaemia associated with coronary artery disease. Initially LVH is a compensatory mechanism, but in the long term cardiac hypertrophy predisposes individuals to heart failure, myocardial infarction and sudden death. Alteration of the nitric oxide (NO) pathway is believed to play an important role in the haemodynamically overloaded heart and pathological cardiac remodelling. Although re-establishment of the physiological NO pathway could be considered an important therapeutic target, the use of conventional nitrates is limited in the clinical setting by the development of tissue resistance and tolerance and by the shortage of large-scale clinical trials unequivocally confirming the beneficial impact of NO donors on cardiovascular morbidity and mortality. The aim of this review is to present current therapeutic options for dealing with changes in the L-arginine-NO pathway. The most promising therapeutic approach is represented by a new neutral sugar organic nitrate, LA-419, the thiol group of which seems to protect NO from degradation, thereby increasing its bioavailability. In a model of aortic stenosis-induced pressure overload, LA-419 has been found to restore the complete NO signalling cascade and reduce left ventricular remodelling, but without restoring the original pressure gradient, indicating a possible direct antiproliferative effect. Future studies are needed to confirm this therapeutic benefit in other animal models of hypertension and in the clinical setting.