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Aims Finerenone reduces the risk of cardiovascular events in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). We investigated the causes of mortality in the FIDELITY population. Methods and results The FIDELITY prespecified pooled data analysis from FIDELIO-DKD and FIGARO-DKD excluded patients with heart failure and reduced ejection fraction. Outcomes included intention-to-treat and prespecified on-treatment analyses of the risk of all-cause and cardiovascular mortality. Of 13 026 patients [mean age, 64.8 years; mean estimated glomerular filtration rate (eGFR), 57.6 mL/min/1.73 m2], 99.8% were on renin–angiotensin system inhibitors. Finerenone reduced the incidence of all-cause and cardiovascular mortality vs. placebo (8.5% vs. 9.4% and 4.9% vs. 5.6%, respectively) and demonstrated significant on-treatment reductions [hazard ratio (HR), 0.82; 95% confidence interval (CI), 0.70–0.96; P = 0.014 and HR, 0.82; 95% CI, 0.67–0.99; P = 0.040, respectively]. Cardiovascular-related mortality was most common, and finerenone lowered the incidence of sudden cardiac death vs. placebo [1.3% (incidence rate 0.44/100 patient-years) vs. 1.8% (0.58/100 patient-years), respectively; HR, 0.75; 95% CI, 0.57–0.996; P = 0.046]. The effects of finerenone on mortality were similar across all Kidney Disease: Improving Global Outcomes risk groups. Event probability with finerenone at 4 years was consistent irrespective of baseline urine albumin-to-creatinine ratio, but seemingly more pronounced in patients with higher baseline eGFR. Conclusion In FIDELITY, finerenone significantly reduced the risk of all-cause and cardiovascular mortality vs. placebo in patients with T2D across a broad spectrum of CKD stages while on treatment, as well as sudden cardiac death in the intention-to-treat population. Clinical trials registration FIDELIO-DKD and FIGARO-DKD are registered with ClinicalTrials.gov, numbers NCT02540993 and NCT02545049, respectively (funded by Bayer AG).

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 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.

Background Mineralocorticoid receptor antagonists (MRAs) reduce systolic blood pressure (SBP) and increase serum potassium concentration ([K+]). This indirect comparison investigated any differences in SBP-lowering and hyperkalemia risk between finerenone, a nonsteroidal MRA, and the steroidal MRA spironolactone ± a potassium binder. Methods In FIDELITY (a pooled analysis of FIDELIO-DKD and FIGARO-DKD), a subgroup of patients with treatment-resistant hypertension (TRH) and chronic kidney disease meeting eligibility criteria of the AMBER trial were identified (FIDELITY-TRH). The main outcomes were mean change in SBP, incidence of serum [K+] ≥5.5 mmol/L and hyperkalemia-associated treatment discontinuation. Results at ∼17 weeks were compared with 12 weeks from AMBER. Results In 624 FIDELITY-TRH patients and 295 AMBER patients, the least squares mean change in SBP (mmHg) from baseline was −7.1 for finerenone and −1.3 for placebo {between-group difference −5.74 [95% confidence interval (CI) −7.99 to −3.49], P Conclusions In patients with TRH and chronic kidney disease compared with spironolactone with or without patiromer, finerenone was associated with a lower SBP reduction and lower risk of hyperkalemia and treatment discontinuation. Trial Registration: AMBER (NCT03071263), FIDELIO-DKD (NCT02540993), FIGARO-DKD (NCT02545049)

Instituto de Salud Carlos III FIS/Fondos FEDER (PI17/01093, PI17/01193, CP15/00129, CPII20/00022, PI18/01366, PI19/00588, PI19/00815, PI20/00763, DTS18/00032) ERA-PerMedJTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071, ISCIII-RETIC REDinREN RD016/0009) Sociedad Española de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina (B2017/BMD-3686 CIFRA2- CM) 35.855 JCR (2021) Q1, 3/143 Cardiac & Cardiovascular Systems 4.118 SJR (2021) Q1, 9/356 Cardiology and Cardiovascular Medicine No data IDR 2021 UEM

AimsThe aim of this study was to determine whether arterial stiffness assessed with the biochemical parameter active matrix metalloproteinase (MMP)-9 and the clinical parameters pulse pressure (PP) and pulse wave velocity predicts the response to spironolactone in resistant hypertension (RH).Methods and resultsAmbulatory blood pressure (BP) and active MMP-9 (measured by zymography and ELISA) were measured at baseline, and patients were classified as having pseudo-RH or RH. Patients with RH received spironolactone and the response was determined after 8 weeks by ambulatory BP monitoring: those who achieved BP goals were considered controlled (CRH) and those who did not were considered uncontrolled (UCRH). Plasma active MMP-9 was significantly higher in patients with RH than with pseudo-RH, and correlated with 24 h systolic BP and PP. Receiver operating characteristic analysis indicated that active MMP-9 could predict the response to spironolactone, and its combination with 24 h PP and pulse wave velocity significantly improved this prediction. Moreover, plasma of patients with UCRH induced the MMP-9 expression pathway.ConclusionWe propose active MMP-9 as a useful biomarker to identify patients with RH who will not respond to spironolactone. Combining MMP-9 activity with classical arterial stiffness parameters improves the prediction of the clinical response to spironolactone and might contribute to guide the most appropriate therapeutic decisions for patients with RH.

Aims Our primary objective was to improve risk assessment for fatal and non-fatal cardiovascular events in a working population, mostly young and healthy. Methods We conducted a prospective cohort study to derive a survival model to predict fatal and non-fatal 10-year cardiovascular risk. We recruited 992,523 workers, free of diagnosed cardiovascular disease at entry, over six years, from 2004–2009. We divided the sample into two independent cohorts: a derivation one (626,515 workers; from 2004–2006) and a temporal validation one (366,008 workers; over 2007–2009). Then, we followed both cohorts over 10 years and registered all fatal and non-fatal cardiovascular events. We built a new risk calculator using an estimation of cardiovascular biological age as a predictor and named it IberScore. There were remarkable differences between this new model and Systematic Coronary Risk Evaluation (SCORE) (in both the specification and the equation). Results Over the 10-year follow-up, we found 3762 first cardiovascular events (6‰) in the derivation cohort. Most of them (80.3%) were non-fatal ischaemic events. If we had been able to use our model at the beginning of the study, we had classified in the ‘high-risk’ or ‘very high-risk’ groups 82% of those who suffered a cardiovascular event during the follow-up. All the post-estimation tests showed superior performance (true positive rate: 81.8% vs 11.8%), higher discrimination power and better clinical utility (standardised net benefit: 58% vs 13%) for IberScore when compared to SCORE. Conclusion Risk assessment of fatal and non-fatal cardiovascular events in young and healthy workers was improved when compared to the previously used model (SCORE). The latter was not reliable to predict cardiovascular risk in our sample. The new model showed superior clinical utility and provided four useful measures for risk assessment. We gained valuable insight into cardiovascular ageing and its predictors.

Resistant hypertension (RH) is a concept that currently goes beyond the classical definition of blood pressure ≥140/90 mmHg in subjects receiving three or more drugs of different classes at maximally tolerated doses. Here, we review the clinical relevance of RH and the different types of RH-associated phenotypes, namely refractory hypertension, controlled resistant hypertension, and masked uncontrolled hypertension. We also discuss current drug strategies and future treatments for these high-risk phenotypes. Sin financiación 6.617 JCR (2020) Q1, 22/142 Cardiac & Cardiovascular Systems 1.895 SJR (2020) Q1, 39/349 Cardiology and Cardiovascular Medicine No data IDR 2020 UEM

Background and Aims Finerenone is a novel, selective, nonsteroidal mineralocorticoid receptor antagonist (MRA) that significantly reduced the risk of adverse kidney and cardiovascular (CV) outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) in the FIDELIO-DKD trial. In phase II studies, finerenone had modest effects on office blood pressure (BP) compared with the steroidal MRA spironolactone. We report an analysis of the relationship between baseline and changes in office systolic BP (SBP) and outcomes with finerenone in the FIDELIO-DKD trial. Method In FIDELIO-DKD, 5734 patients were randomised 1:1 to oral finerenone or placebo. Patients with T2D, urine albumin-to-creatine ratio (UACR) ≥30– Results A total of 5669 patients with available baseline SBP data were analysed. At baseline, the mean SBP and diastolic BP were 138.0 and 75.8 mmHg, respectively. Patients treated for hypertension at baseline received an average of 3.3 antihypertensive therapies. The study population was stratified by quartiles (Q) of SBP at baseline: ≤128.7 mmHg (Q1); >128.7–≤138.3 mmHg (Q2); >138.3–≤148.0 mmHg (Q3); and >148.0 mmHg (Q4). Patients in higher SBP categories tended to be older, with higher median UACR, but similar mean eGFR at baseline. Effects of finerenone, estimated as hazard ratios (HRs), were consistent across the quartiles for the primary endpoint (HR [95% CI]: Q1, 0.87 [0.66–1.15]; Q2, 0.76 [0.59–0.98]; Q3, 0.81 [0.65–1.02]; Q4, 0.86 [0.70–1.07]; p-value for interaction=0.87) and the key secondary endpoint (HR [95% CI]: Q1, 0.95 [0.69–1.29]; Q2, 0.81 [0.60–1.10]; Q3, 0.79 [0.60–1.03]; Q4, 0.91 [0.70–1.18]; p-value for interaction=0.78) (Figure). Finerenone treatment resulted in a modest reduction in SBP; over the duration of the trial, overall mean difference in SBP between treatment groups was –2.7 mmHg. Maximum differences in SBP between finerenone and placebo were observed at month 4; the mean change in SBP from baseline to month 4 across SBP quartiles were: Q1: 4.99 and 9.01 mmHg; Q2: –0.85 and 2.43 mmHg; Q3: –5.63 and –2.40 mmHg; Q4: –11.76 and –6.44 mmHg, for finerenone and placebo, respectively. Adjusting for baseline SBP and SBP change to month 4 resulted in small changes in treatment effect for the primary endpoint and the key secondary endpoint, with only slightly increased HRs for treatment compared with the unadjusted primary analysis (primary endpoint: HR: 0.85 vs 0.82; key secondary endpoint: HR: 0.90 vs 0.86) and no strong indication of an interaction between treatment and SBP. Conclusion In FIDELIO-DKD, a small proportion of the effect of finerenone on cardiorenal outcomes can be attributed to BP. However, most of the effect appears to be via BP-independent mechanisms. (Funded by Bayer AG; FIDELIO-DKD ClinicalTrials.gov number, NCT02540993)

The interest in RDN for hypertension has fluctuated recently, with a flurry of initial enthusiasm followed by sudden loss of interest by researchers and device manufacturers, with an almost as sudden resurgence in clinical trials activity and device innovation more recently. There is widespread consensus that this therapeutic strategy can be effective, at least for some of the technologies available. Major uncertainties remain as to the clinical role of RDN, and whether any of the emerging technologies such as AV-anastomosis formation, carotid body ablation, carotid bulb expansion, or baroreflex stimulation will have a future as effective treatment options in patients with hypertension. In our first consensus report in 2015, the European Expert Group pointed to the major unmet need of standardization of measurements, trial design and procedural performance.6 With the large number of different technologies currently in the pipeline, this need has even increased. Only through high-quality, collaborative research and openness to new methods for recruitment, patient selection, and assessment of outcomes will it be possible to establish incontrovertibly whether device therapies for hypertension are effective and what are preferred patient populations. Once the proof of concept is established, further studies with a design relevant to clinical reality will be needed to establish the place of new devices in the treatment armoury. The clinical and research community has a large responsibility to prove or disprove the value of new therapies, in order to ensure that antihypertensive devices provide future patients with the greatest benefit and the smallest risk. copy; The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology.

Although cardiovascular disease is a major health burden for patients with chronic kidney disease, most cardiovascular outcome trials have excluded patients with advanced chronic kidney disease. Moreover, the major cardiovascular outcome trials that have been conducted in patients with end-stage renal disease have not demonstrated a treatment benefit. Thus, clinicians have limited evidence to guide the management of cardiovascular disease in patients with chronic kidney disease, particularly those on dialysis. Several factors contribute to both the paucity of trials and the apparent lack of observed treatment effect in completed studies. Challenges associated with conducting trials in this population include patient heterogeneity, complexity of renal pathophysiology and its interaction with cardiovascular disease, and competing risks for death. The Investigator Network Initiative Cardiovascular and Renal Clinical Trialists (INI-CRCT), an international organization of academic cardiovascular and renal clinical trialists, held a meeting of regulators and experts in nephrology, cardiology, and clinical trial methodology. The group identified several research priorities, summarized in this paper, that should be pursued to advance the field towards achieving improved cardiovascular outcomes for these patients. Cardiovascular and renal clinical trialists must partner to address the uncertainties in the field through collaborative research and design clinical trials that reflect the specific needs of the chronic and end-stage kidney disease populations, with the shared goal of generating robust evidence to guide the management of cardiovascular disease in patients with kidney disease. Sin financiación 22.673 JCR (2019) Q1, 2/138 Cardiac & Cardiovascular Systems 5.883 SJR (2019) Q1, 4/362 Cardiology and Cardiovascular Medicine No data IDR 2019 UEM

Purpose Cardiomyocytes progenitor cells (CMPCs) are a candidate cell source for cardiac regenerative therapy. To assess their full potential for cardiac regeneration, it is essential to know if and how CMPCs sense and respond to the three-dimensional (3D) environment and the mechanical stimuli provided by the beating heart. Therefore, we study the response to cyclic strain of undifferentiated and predifferentiated human CMPCs in a 2D environment, as well as CMPC responses to unidirectionally constrained versus stress-free (unconstrained) 3D environments. The latter responses were studied using a hydrogel system that allows for interaction of the cells with a simulated ‘host’ tissue. Methods To test mechanosensitivity of CMPCs in 2D and 3D environments, the response of L9TB CMPCs to uniaxial (cyclic) strain (10% with 0.5 Hz) was investigated. To represent the 3D environment, CMPCs were cultured in unidirectionally constrained and stress-free collagen/Matrigel hydrogels, where the constrainment provides a static strain to the cells. The cellular mechanoresponse to the applied (cyclic) strain was quantified by cellular re-orientation away from the strain direction (strain avoidance). Next to cellular re-orientation, the effect of strain on cell differentiation was analyzed. Results Our results indicate that while undifferentiated cells maintain their original orientation, upon early cardiomyogenic differentiation (predifferentiated) CMPCs exhibit a distinct strain avoidance response during 48hrs of cyclic straining in a 2D environment. In 3D unidirectionally constrained hydrogels, undifferentiated CMPCs retain their cardiomyogenic profile. CMPCs cultured in 3D collagen/Matrigel hydrogels respond to static mechanical strains as expected by cell alignment. Conclusions Our results suggest that CMPCs respond to the presence of mechanical stimuli, in this research mimicked by the application of uniaxial (cyclic) strain in 2D and 3D environments, suggesting that CMPCs are indeed mechanosensitive. Although in 2D environments, mechanosensitivity of the CMPCs is dependent on their differentiation status. Our findings provide the first understanding of the ability of human CMPCs to sense mechanical stimuli, which is the first initial step in mechanotransduction. Mechanotransduction is essential for optimal recruitment, migration, and mechanical integration of progenitor cells into the injured myocardium. Therefore, the presented results can contribute to enhance efficacy of current treatments of cardiac disease, as well as to develop novel endogenous regeneration strategies.

Heart failure guidelines suggest evaluating renal function as a routine work-up in every patient with heart failure. Specifically, it is advised to calculate glomerular filtration rate and determine blood urea nitrogen. The reason for this is that renal impairment and worsening renal function (WRF) are common in heart failure, and strongly associate with poor outcome. Renal function, however, consists of more than glomerular filtration alone, and includes tubulointerstitial damage and albuminuria. For each of these renal entities, different biomarkers exist that have been investigated in heart failure. Hypothetically, and in parallel to data in nephrology, these markers may aid in the diagnosis of renal dysfunction, or for risk stratification, or could help in therapeutic decision-making. However, as reviewed in the present manuscript, while these markers may carry prognostic information (although not always additive to established markers of renal function), their role in predicting WRF is limited at best. More importantly, none of these markers have been evaluated as a therapeutic target nor have their serial values been used to guide therapy. The evidence is most compelling for the oldest-serum creatinine (in combination with glomerular filtration rate)-but even for this biomarker, evidence to guide therapy to improve outcome is circumstantial at best. Although many new renal biomarkers have emerged at the horizon, they have only limited usefulness in clinical practice until thoroughly and prospectively studied. For now, routine measurement of (novel) renal biomarkers can help to determine cardiovascular risk, but there is no role for these biomarkers to change therapy to improve clinical outcome in heart failure.

Approximately 8–18% of all patients with high blood pressure (BP) are apparently resistant to drug treatment.1,2 In this situation, new strategies to help reduce BP are urgently needed but the complex pathophysiology of resistant hypertension makes this search difficult. Not surprisingly in this context, the latest non-drug treatment which triggered controversy is catheter-based renal denervation (RDN).3,4 The method uses radiofrequency energy, or alternatively ultrasound or chemical denervation, to disrupt renal nerves within the renal artery wall, thereby reducing sympathetic efferent and sensory afferent signalling to and from the kidneys.5,6 Various experimental models of hypertension strongly support this concept7,8 and available evidence also suggests that sympathetic nervous system activation contributes to the development and progression of hypertension and subsequently to target organ damage.7–11 Historical observations have shown that surgical sympathectomy can reduce BP as well as morbidity and mortality in patients with uncontrolled hypertension.12,13 However, the clinical evidence in support of RDN as an effective interventional technique in patients with resistant hypertension is conflicting. A number of observational studies and three randomized, controlled trials (Symplicity HTN-2, Prague-15, and DENERHTN) support both safety and efficacy of this new therapy14–22 but some smaller studies and the large, single-blind, randomized, sham-controlled symplicity HTN-3 trial failed to show superiority of RDN when compared with medical therapy alone.23–25 Whatever the shortcomings of individual trials may be, the possibility remains that the observed BP responses were due to placebo response, the Hawthorne effect, regression to the mean, unknown co-interventions or other bias.26 The design, conduct, and interpretation …

Blocking the renin-angiotensin-aldosterone system (RAAS) has widely shown to be good for the protection of both cardiovascular and renal systems. A large number of trials have demonstrated clear benefits of using angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) to treat patients with established cardiovascular and renal disease during the last decades. Even more, simultaneous protection of cardiovascular and renal system with RAAS blockade has also been shown. However, some caveats of this therapy as the effectiveness lack in long-term, hyperkalaemia risk in patients with chronic kidney disease or aldosterone and albuminuria breakthrough limit their use, lead that new therapeutic strategies are needed for the RAAS blockade. At this time, new horizons are opened to manage the RAAS blockade in the cardiorenal disease through using the positive combination of an ACEi or an ARB plus and aldosterone antagonist, renin inhibitors, or other forms of blockade using new members as LCZ696.

BACKGROUND: Both increased night blood pressure (BP) and nondipping are associated with worse cardiovascular risk and prognosis. However, as they are often related features, their relative importance has been difficult to assess separately. In this study we address separate associations of nocturnal hypertension and nondipping with cardiovascular risk profile in treated and untreated hypertensive patients. METHODS: A total of 37,096 untreated patients and 62,788 patients receiving antihypertensive treatment from the Spanish Ambulatory Blood Pressure Monitoring Registry were included. Each cohort was separated into 4 groups: group 1, night systolic blood pressure (SBP) 10%); group 2, night SBP

AIMS: We investigated the potential influence of a moderate-to-high cardiovascular (CV) risk (CVR) (defined as a Systematic COronary Risk Evaluation model, or SCORE ≥ 4%), in the absence of an established CV disease, on the duration and cost of CV and non-CV sick leave (SL) resulting from common and occupational accidents or diseases. METHODS AND RESULTS: We conducted a prospective cohort study on 690 135 workers with a 1-year follow-up and examined CV- and non-CV-related SL episodes. To obtain baseline values, CVR factors were initially assessed at the beginning of the year during routine medical examination. The CVR was calculated with the SCORE charts for all subjects. Moderate-to-high CVR was defined as SCORE ≥ 4%. A baseline SCORE ≥ 4% was associated with a higher risk for long-term CV and non-CV SL, as revealed by follow-up assessment. This translated into an increased cost, estimated at euro5 801 464.18 per year. Furthermore, pharmacological treatment for hypertension or hyperlipidaemia was significantly associated with longer SL duration. CONCLUSION: Moderate-to-high CVR in asymptomatic subjects was significantly associated with the duration and cost of CV and non-CV SL. These results constitute the first body of evidence that the SCORE charts can be used to identify people with a non-established CV disease, which might ultimately translate into more lost workdays and therefore increased cost for society.

This editorial refers to ‘Aliskiren alone or with other antihypertensives in the elderly with borderline and stage 1 hypertension: the APOLLO trial’[†][1], by K.K.Teo et al. , on page 1743 and ‘Renin–angiotensin system antagonists and clinical outcomes in stable coronary artery disease without heart failure’[‡][2], by E. Sorbets et al. , on page 1760. A series of randomized clinical trials demonstrated that when compared with placebo, angiotensin-converting enzyme (ACE) inhibitiors or angiotensin receptor blockers (ARBs) were drugs able to improve the prognosis of patients with heart failure accompanied by low ejection fraction, patients with a myocardial infarction (MI), and patients with chronic kidney disease (CKD; most notably demonstrated by ARBs in diabetic nephropathy), allowing the recognition by Guidelines that blockade of the renin–angiotensin system (RAS) must be used in all these situations. The use of ACE inhibitors and also of ARBs was later expanded to patients with an increased global cardiovascular (CV) risk, patients with stable coronary artery disease (CAD), diabetic patients independently of the presence of established CV or renal disease, and hypertensive patients if clustering of CV risk factors or target organ damage was present. Table 1 lists the different clinical situations where RAS blockade is indicated according to Guidelines that led to the wide use of ACE inhibitors and ARBs in clinical practice; as an example, either alone or in combination, these drugs are prescribed in > 30–40% of the hypertensive population.1 View this table: Table 1 Clinical situations where the use of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker has demonstrated positive effects Recently, the first orally active renin inhibitor was launched as an antihypertensive drug able theoretically to improve the degree … [1]: #fn-2 [2]: #fn-3

Background: Adiponectin is secreted by adipose tissue and may play a role in cardiovascular disease. We examined adiponectin levels in patients with type 2 diabetes who participated in the Telmisartan vs. Ramipril in Renal Endothelial Dysfunction (TRENDY) study. Methods A total of 87 patients were assessed at baseline and following 9 weeks treatment with the angiotensin-receptor blocker telmisartan (final dose, 80 mg; n = 45) or the angiotensin-converting enzyme inhibitor ramipril (final dose, 10 mg; n = 42). Adiponectin levels were measured in plasma by radioimmunoassay. Results: Adiponectin levels were inversely correlated with systolic (SBP; r = -0.240, P < 0.05) and diastolic (DBP; r = -0.227, P < 0.05) blood pressure at baseline and following treatment with telmisartan or ramipril (SBP: r = -0.228, P < 0.05; DBP: r = -0.286, P < 0.05). Changes in adiponectin levels were related to changes in SBP (r = -0.357, P < 0.01) and DBP (r = -0.286, P < 0.01). There was a significant increase in adiponectin levels in the telmisartan (0.68 (95% confidence interval (CI), 0.27 to 1.10) µg/ml, P < 0.01) but not in the ramipril group (0.17 (95% CI, -0.56 to 0.90) µg/ml, P = 0.67). Blood pressure reduction in the telmisartan group (DeltaSBP: -13.5 (95% CI, -17.0 to -10.0) mm Hg; ΔDBP: -7.6 (95% CI, -9.8 to -5.3) mm Hg, each P < 0.001) was significantly (P less than or equal to 0.01 for SBP and P < 0.01 for DBP) greater than in the ramipril group (ΔSBP: -6.1 (95% CI, -6.2 to -2.0) mm Hg; ΔDBP: -2.7 (95% CI, -5.0 to -0.5) mm Hg; P < 0.01 and P < 0.05, respectively). Conclusion: Adiponectin is correlated with blood pressure in patients with type 2 diabetes. Whether increased adiponectin contributes to the blood pressure–lowering effect of telmisartan needs further study.

This study examines the relationship between awareness, treatment and control of hypertension, and health-related quality of life (HRQL) among older adults in Spain.We conducted a cross-sectional study that included 3368 subjects representative of the Spanish populationor = 60 years of age. We assessed HRQL using the MOS 36-Item Short Form (SF-36) questionnaire, and blood pressure (BP) was measured under standardized conditions. Data were analyzed using linear regression, adjusted for HRQL predictors (age, educational level, tobacco use, alcohol consumption, body mass index, physical activity, number of chronic diseases, and social support).Neither hypertension nor antihypertensive drug treatment or control were associated with worse HRQL. These results were also observed for awareness of hypertension among men, but in women awareness of hypertension was associated with a statistically significant (P.01) and clinically relevant reduction (a 4- to 7-point lower score) in all HRQL dimensions. This association remained in evidence on many SF-36 scales, even after additional adjustment for medical advice to lose weight, reduce salt intake, increase physical activity, and moderate alcohol consumption. After further adjustment for prescription of antihypertensive drugs, however, the association between hypertension awareness and HRQL lost statistical significance, declining by30% on most SF-36 scales.Neither hypertension nor antihypertensive drug treatment or control appears to lower HRQL in the elderly Spanish population. Yet, among women, awareness of hypertension is associated with lower HRQL, irrespective of change of lifestyle recommended by the physician. The impact of hypertension labeling on HRQL might be attributable in part to prescription of antihypertensive drugs.

Background Most current clinical guidelines focus primarily on the management of individual cardiovascular risk factors, such as high blood pressure (BP), hypercholesterolemia, or diabetes. A more appropriate clinical approach to reducing cardiovascular disease risk would be based on a comprehensive evaluation of risk profile, and accurate stratification of global (absolute) risk in individual patients. We propose that global risk should be used as the main determinant of whom to treat, how to treat, and how much to treat. Methods In this article we use a series of case studies to demonstrate the implications of replacing the traditional “single risk factor-based” approach to managing hypertension by one based on global risk assessment. In some situations patients with mildly elevated BP levels would not be recommended for antihypertensive drug treatment whereas others with lower BP would be treated, depending upon the entire risk profile. Conclusion We propose to replace the single risk factor-based approach with the assessment of global cardiovascular risk, both in the clinical management of individual patients and in guidelines.

The aim of this study was to establish the prevalence of erectile dysfunction (ED) in hypertensive patients in specialized care hypertension units (SCHUs) and to assess the effectiveness and tolerability of sildenafil treatment.This was a multicenter, prospective, open, observational pharmacoepidemiology study conducted in 25 Spanish SCHUs. A total of 2130 men with essential hypertension under treatment were recruited. In a second phase, 291 subjects with a scoreor = 21 in the Sexual Health Inventory for Men (SHIM) received sildenafil (50 mg/day) as required 30 to 60 minutes before sexual activity, and were evaluated by the International Index of Erectile Function (IIEF).A total of 975 subjects (45.8%) had a scoreor = 21 in the SHIM. In the second phase, sildenafil improved the score in the erectile function domain in 232 patients (83.2%). Severity of ED significantly improved (P.001); severe (22.3% to 7.7%), moderate (23% to 5.6%), and mild impairment (36.3% to 44.8%). The IIEF was normalized in 39.1% of patients who completed post-treatment IIEF. In all, 33 subjects (11.8%) failed to complete the study: two (0.7%) because of lack of efficacy, two (0.7%) intercurrent disease, 10 (3.6%) failure to return to the visits, three (1.1%) fear of therapy, four (1.4%) adverse effects requiring treatment discontinuation, and 12 (4.3%) protocol violations. No statistically significant association was found between the prevalence of adverse effects and antihypertensive treatment with single drug or combination therapy.A high incidence of ED was found in hypertensive patients from Spanish SCHUs. Sildenafil showed an excellent response and safety profile.

The Omapatrilat in Persons with Enhanced Risk of Atherosclerotic events (OPERA) trial is a large clinical trial of omapatrilat, a vasopeptidase inhibitor, in patients with stage 1 isolated systolic hypertension (ISH). OPERA is the first study to examine whether effective antihypertensive treatment can provide survival and clinical end point benefits in older persons with this common condition. This 5-year multinational, randomized, double-blind, parallel-group, placebo-controlled, forced-titration study will be conducted in approximately 12,600 subjects randomized by approximately 1100 study centers worldwide over a recruitment period of approximately 2 years. The primary objective of OPERA is to determine whether treatment with once-daily omapatrilat (target dose 40 mg) will reduce cardiovascular (CV) morbidity and mortality in older (> or = 65 years) men and women with enhanced risk for atherosclerotic events due to stage 1 ISH plus other risk factors for which currently there is no evidence-based requirement for treatment. Blood pressure inclusion criteria are systolic blood pressure (SBP) 140 to 159 mm Hg (SBP 125 to 139 mm Hg in diabetic individuals) and diastolic blood pressure (DBP)

The central role of aldosterone in cardiovascular and renal disease forces the need to use aldosterone blockers in both processes. Spironolactone and eplerenone have been shown to control blood pressure, to improve the outcomes of patients with heart failure, post.MI and also in those with chronic kidney disease and proteinuria. These positive effects are counteracted by the potential development of hyperkalemia and other side-effects particularly gynecomastia in the case of spironolactone. An adequate estimation of the level of glomerular filtration rate has to performed to calculate the risk or even more the contraindication of the use of these drugs to avoid hyperkalemia.

Changes in renal function can be detected in patients suffering from essential hypertension and heart failure. Detection of an increased serum creatinine, a decreased creatinine clearance and of proteinuria or microalbuminuria in hypertensive patients; and the finding of a diminution in the value of estimated creatinine clearance in heart failure patients are very potent predictors for a worse outcome of the patient. The parameters commonly used to evaluate renal function have to be considered in any stratification of cardiovascular risk in hypertensive and heart failure patients.

Background. The aim of the present study was to determine the effect of losartan on transforming growth factor-β1 (TGF-β1) plasma levels and urinary albumin excretion (UAE) in patients with type 2 diabetes mellitus, mild hypertension and microalbuminuria. Methods. Fourteen patients (eight males, aged 55 ± 6 years) with type 2 diabetes mellitus, mild arterial hypertension and microalbuminuria, participating in an open, uncontrolled, pilot study were included. Patients were treated for 8 weeks with losartan. TGF-β1 plasma levels, UAE and 24-h blood pressure monitoring were determined at baseline and at 4 and 8 weeks. Results. At 4 and 8 weeks of treatment, a reduction was observed in TGF-β1 plasma levels (5.5 ± 4.5 vs 2.0 ± 0.6 and 2.6 ± 1.0 ng/ml, P

Background We compared the effects of a long-acting calcium-channel blocker with a thiazide-amiloride combination on cardiovascular mortality and morbidity in patients with additional cardiovascular risk factors. The primary objective was to demonstrate 25% superiority of nifedipine GITS. A secondary objective was to establish non-inferiority compared with co-amilozide. Methods A prospective, randomized, double-masked trial was carried out in Europe and Israel, involving 6321 patients of 55–80 years of age with hypertension (blood pressure \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \({\geq}\ {150}/{95}\) \end{document} mmHg or systolic ≥ 160 mmHg). Patients were also required to have at least one out of ten additional cardiovascular risk factors, such as diabetes or hypercholesterolaemia. Patients were assigned randomly to initial treatment with either nifedipine GITS (N), 30 mg, or co-amilozide (C) (hydrochlorothiazide, 25 mg, and amiloride, 2·5 mg), so that similar numbers of patients with each risk factor could be compared between the two drugs. Dose titration was principally by dose doubling, and addition of atenolol, 25–50 mg, or enalapril, 5–10 mg. Patients were followed for a mean period of 3 years. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, heart failure or stroke, Secondary outcome variables included death from any cause. Superiority analysis was of time to first event, by intention-to-treat. Non-inferiority analysis required the difference (Δ) in event-rate, and the 95% CI around Δ, to be

Obesity is a metabolic disorder in which multiple clinical and biochemical alterations coexist. However, the progression of these alterations in relation to weight gain has not been investigated in detail. Therefore, we studied the evolution of insulin resistance and associated risk factors in a model of experimental obesity in dogs. We also studied whether chronic exposure to these pathogenic factors could induce cardiac and vascular alterations. Twenty male age- and body weight-matched beagle dogs were divided into four groups (n = 5), according to diet and pharmacologic therapy received, and followed for 2 years. Control animals were maintained with a regular diet, while the 15 remaining animals were fed a high-fat diet. The Obese group of dogs received no therapy, whereas the Capto group received 25 mg/12 h captopril, and the Prava+Capto was treated with 10 mg/24 h pravastatin plus the same dose of captopril throughout the study. Periodical determinations of clinical and biochemical parameters were made, and the degree of insulin resistance was also estimated. After the 2-year follow-up, the dogs were killed and vascular thickening in the aorta and the coronary arteries was evaluated. In addition, cardiac hypertrophy was estimated by heart weight and free-wall left ventricular width. Chronic pravastatin plus captopril treatment, together with decreasing weight gain rate, ameliorated the progression of insulin resistance and associated risk factors (hyperinsulinemia, hypercholesterolemia) related to this severe model. In addition, this combined therapy showed cardioprotective action, as cardiac and vascular hypertrophy observed in the Obese group was prevented. These positive results seems to emerge from the synergistic effects of both drugs, as captopril as monotherapy induced only a slight benefit on these parameters.

Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) in the United States, and accounts for 35% of all the patients with ESRD entering a dialysis program; 63% of patients with diabetic nephropathy have type II diabetes mellitus. Hypertension is a major risk factor for renal disease and is common in people with diabetes mellitus. Strategies for preventing the progression of renal failure in patients with diabetes mellitus include glycemic control, and control of blood pressure. Blocking the renin-angiotensin system (RAS) slows the progression of established diabetic nephropathy in type I diabetes mellitus, and inhibiting angiotensin II formation retards or impedes the progression from microalbuminuria to established diabetic nephropathy (macroproteinuria) in people with type I diabetes mellitus. The situation could be the same for people with type II diabetes mellitus. The ability of RAS blockade using irbesartan, an AT 1 angiotensin II receptor antagonist, to slow the progression in renal failure has been compared with that of the calicum channel blocker amlodipine and placebo in a pilot study. The results suggest that blockade of the RAS, in this case with irbesartan, is at least equivalent to calcium channel blockers with respect to antihypertensive efficacy, but provides better renoprotective benefits.

Cyclosporin has been shown to facilitate renal vasoconstriction and to have an antinatriuretic effect. The existence of an interference of cyclosporin with the vasodilating properties of endothelium mediated by nitric oxide production could mediate these effects. On the other hand, the infusion of the nitric oxide precursor L-arginine has been shown to induce renal vasodilatation and to facilitate natriuresis in normal volunteers. We have investigated the renal effects of the administration of an infusion of L-arginine in renal transplant patients chronically treated with cyclosporin. To facilitate the analysis of the data the effects of the administration of a similar dose of cyclosporin on renal function during the infusion of a vehicle were also investigated during the administration of a vehicle of L-arginine.Ten male renal transplant patients, chronically treated with cyclosporin and with a stable renal function were studied during 2 consecutive days after the administration of the usual morning dose of cyclosporin. The first day they received an intravenous infusion of vehicle and the second the infusion of graded doses of L-arginine (50, 100, 150 mg/kg/h) during 3 consecutive h.The first day, after cyclosporin administration a significant fall (P0.01) was observed in natriuresis and kaliuresis in the absence of changes in renal plasma flow and glomerular filtration rate. After the administration of L-arginine significant (P0.01) increases of renal plasma flow, glomerular filtration rate, and natriuresis were seen. The increase in blood levels of cyclosporin after its administration did not differ between days 1 and 2.These results indicate that L-arginine facilitates renal vasodilatation and natriuresis in renal transplant patients. Furthermore, the observed increase in sodium excretion could indicate that L-arginine counteracts the antinatriuretic effect of cyclosporin.

To estimate the effects of UP269-6, a nonpeptide angiotensin II receptor antagonist, and captopril, a converting enzyme inhibitor, on the progression of nephropathy, 77 uninephrectomized diabetic rats were maintained for 8 months with plasma glucose levels from 300 to 500 mg/dL. Systemic and renal parameters were periodically measured, and, at the time of death, a histological evaluation of renal damage was performed. Control rats (no additional treatment but insulin) showed increased blood pressure and urinary albumin levels, together with prominent alterations in the kidney (renal and glomerular hypertrophies, tubular atrophy, and 19% of sclerotic glomeruli). Captopril (50 mg/kg/day) and UP269-6 (10 mg/kg/day) reduced blood pressure and albumin excretion levels, and improved histological renal preservation (lower renal and glomerular hypertrophies, tubular atrophy, and percentage of sclerotic glomeruli: 5% and 7%, respectively). Finally, a low dose of UP269-6 (1 mg/kg/day), which induced an intermediate level of blood pressure between control and the other treated groups, produced an equivalent degree of nephroprotection. Our data demonstrate the efficacy of this new angiotensin II receptor antagonist on the progression of diabetic renal damage. These results also reinforce the role attributed to angiotensin II in the development of renal derangement in this model, as UP269-6 is devoid of agonistic effect on the kinin system.

We have studied the effects of chronic therapy with cicaprost (a PGI2 analog), fosinopril (a converting enzyme inhibitor), and the combination of both drugs on the progression of experimental diabetic nephropathy. Uninephrectomized streptozotocin-induced diabetic rats were maintained for 8 months with plasma glucose between 13.7 and 22.0 mmol/L to hasten renal damage. Systemic and renal parameters were measured periodically, and at sacrifice structural and morphometrical renal studies were performed to evaluate diabetic injury. Control rats exhibited characteristic features of this model, such as high blood pressure and plasma creatinine and urinary albumin excretion, together with prominent alterations in the kidney (renal and glomerular hypertrophies, mesangial matrix expansion, and tubular alterations). The three therapies attenuated equivalently the progression of diabetic renal injury, as estimated by lower urinary albumin excretion, renal and glomerular hypertrophies, and a better renal architectural preservation. No synergistic action was appreciated with the combined therapy. However, renal preservation achieved with cicaprost was not linked to reductions in systemic blood pressure, whereas in the groups treated with fosinopril the hypotensive effect of this drug could have contributed to the positive outcome of the therapy. Therefore, nephroprotection exerted by this PGI2 analog in this model seems more related to the derangement of renal local mechanisms than to systemic blood pressure control. Finally, the possibility that an impaired prostacyclin synthesis or bioavailability is involved in the pathogenesis of the diabetic nephropathy in this model underlies our results.

Background. The true incidence of lead (Pb) overload as a cause of chronic renal failure (CRF) is unknown. Also, it is unclear if CRF per se could generate an increment in the body Pb burden. Most studies of chronic Pb intoxication have been performed on cohorts or patients with a past history of occupational exposure. Therefore we studied the body Pb burden in CRF of known aetiology versus those patients with CRF with gout and hypertension of unclear aetiology without a past history of Pb exposure. In addition we studied patients diagnosed with essential hypertension. Methods. We studied 296 patients lacking a past history of Pb exposure, who were subdivided into four groups : group I (n=30), normal control subjects ; group II (n=104), patients with 'essential' hypertension and normal renal function ; group III (n=132), patients with CRF of uncertain aetiology in association with hypertension and/or gout, and group IV (n=30), patients with CRF of known aetiology. The blood and urine Pb levels were assessed before and after an EDTA test. Results. No abnormal test results were obtained for patients in groups I and IV. The EDTA test was abnormal in 16 patients (15.4%) in group II and in 74 patients (56.1%) in group III. A positive correlation was observed between plasma creatinine levels and post-EDTA urinary Pb in group III, but not in group I. No correlation regarding plasma creatinine and the duration of hypertension or gout were demonstrated. The bone Pb levels, measured in 12 patients with pathological EDTA test results, were positively correlated to the plasma creatinine levels. Conclusions. A high percentage of patients with gout, hypertension, and CRF have an excessive Pb burden, and about 15% of the patients diagnosed as 'essential' hypertensives also show high Pb burdens. It is remarkable that a history of overt Pb exposure was lacking in the whole study population.

The kidney can be considered as both culprit and victim in the hypertensive process. Deranged renal function contributes to the development of arterial hypertension and of secondary vascular damage at the glomerular and arteriolar level and accounts for the development of progressive nephrosclerosis. The most common alteration of renal function observed in humans from the early stages of essential hypertension is the presence of renal vasoconstriction. This can be accompanied by hyperuricaemia and increased urinary excretion of enzymes such as N-acetyl-beta-glucosaminidase and proteins such as albumin and beta 2-microglobulin. Later, a progressive fall in glomerular filtration rate, sometimes accompanied by proteinuria, can be observed if high blood pressure persists.

Carvedilol is a new cardiovascular compound with the combined pharmacologic properties of nonselective beta-blockade and vasodilation. The aim of this study was to compare the safety and antihypertensive efficacy of 25 to 50 mg carvedilol once daily with 50 to 100 mg atenolol once daily in patients with mild to moderate essential hypertension. This was a multicenter study conducted in Europe. After a single-blind placebo run-in phase, 325 eligible patients with stable hypertension were randomized to receive 25 mg carvedilol once daily (161 patients) or 50 mg atenolol (164 patients) in a double-blind 8-week treatment phase. After 4 weeks, the dosage was doubled if there was inadequate response. The primary index of efficacy (response) was the reduction of mean sitting diastolic blood pressure to 90 mg Hg or less (normalized) or by at least 10 mm Hg from baseline. At each of three to six run-in phase visits and after 2, 4, and 8 weeks of treatment, sitting blood pressure and heart rate at trough were measured in triplicate, and body weight, adverse experiences, compliance, and use of concomitant medications were assessed. Laboratory tests, including fasting serum lipids, and electrocardiograms were also monitored during the trial. After 8 weeks of treatment, response rates in the carvedilol and atenolol treatment groups were 75% and 82%, respectively. Compared to baseline, the mean sitting blood pressure was significantly (P < .05) reduced by carvedilol from 165/104 mm Hg to 147/89 mm Hg. With atenolol, mean sitting blood pressure was significantly (P < .05) reduced from 167/104 mm Hg to 150/90 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)

Ten age-matched beagle dogs were kept on a high-fat diet and followed for 12 weeks. During this period the animals were divided into two groups (n = 5), either with or without oral captopril treatment. Dogs were tested periodically for biochemical and clinical parameters, and at the end of the study animals were killed and thoracic aorta samples were obtained for histologic evaluation. From the third week, the captopril group presented significantly lower values of mean arterial pressure, plasma norepinephrine, and fasting glucose and cholesterol levels than those attained in the nontreated group. Furthermore, aorta samples from untreated animals showed profuse staining for fat content at the intima and adventitia layers, while this reaction was restricted to the outer layer in treated dogs. These data suggest that the beneficial effects of captopril therapy in this obesity-induced hypertension model could be based on blood pressure control, together with reduction of serum glucose, cholesterol, and sympathetic activity levels. In addition, captopril treatment could play a role in the retardation of the early stages of vascular atherogenetic lesion.

The kidney facilitates the development of arterial hypertension and suffers its consequences. Once renal damage is clinically manifested, a clear increase in cardiovascular risk appears. The coincidence of renal and cardiovascular damage strengthens the need for therapies attempting the simultaneous protection of both the kidney and the cardiovascular system.

We have studied the renal effects of different calcium antagonists on: glomerular filtration rate and renal plasma flow; urinary sodium excretion; Renni-angiotensin-aldosterone system; prevention of the renal toxicity of radiographic contrast agents; reduction of Cyclosporin nephrotoxicity in renal transplantation

This editorial refers to ‘Adherence to antihypertensive therapy prior to the first presentation of stroke in hypertensive adults: population-based study’[†][1], by K. Herrtua et al. , on page 2933 Cardiovascular (CV) disease is the leading cause of death worldwide, accounting for 30% of all deaths, and arterial hypertension is the most important modifiable risk factor to diminish this burden.1 According to the latest Guidelines, daily compliance and long-term adherence to therapy are the most important aims for the adequate control of arterial hypertension.2 As can be seen in Figure 1 , the most relevant reasons for a poor or low compliance depend in the first place on a poor relationship between doctor and patient preventing the latter from attaining … [1]: #fn-2

Background: Cardiac structural adaptation develops early in hypertension and diabetes and is aggravated if both conditions coexist. Blockade of the angiotensin receptors may attenuate these cardiac processes and we tested the ability of olmesartan to prevent or delay left ventricular (LV) remodeling and hypertrophy in various subgroups of type-2 diabetes. Methods: In the ROADMAP study, a double blind, placebo controlled, multicenter, phase IIIb study on prevention of microalbuminuria in diabetic patients, comparing olmesartan 40mg vs. placebo (additional anti-hypertensive medication allowed, except ACEI & ARBs), also 12-lead ECGs have been conducted at baseline and in yearly intervals over the mean study duration of 3.2 years. All ECGs were centrally and independently evaluated by two investigators in a blinded fashion. Results: In 1.513 patients interpretable ECGs were available at baseline and at last examination (N=736 in the placebo and N=777 in the olmesartan group). 90% of the patients were hypertensive at baseline. Dividing the study population into 4 quartiles defined by the Cornell voltage QRS duration product at baseline, the prevalence of patients in the highest quartile (ie. ≥ 200 mV*msec) increased from 25% to 26.5% in the placebo but decreased from 25% to 22.3% in the olmesartan group (odds ratio 0.598 [95% CI: 0.440-0.813], p=0.001) demonstrating a reduced prevalence by 40% with olmesartan. When adjusted for potential confounders (incl. blood pressure), the odds ratio did not change. Subgroup analysis revealed that the prevalence of the Cornell voltage QRS duration product was significantly reduced in diabetic patients with BP 7,0% (RR 46.1%, p=0.0023) and with a duration of diabetes > 5 years (RR 37.7%, p=0.0039). There was a numerical trend with HbA1c < 7.0% (RR 31.0%, p=0.1378), or duration < 5 years (RR 60.8%, p=0.1022). A significant reduction was also seen in patients with or without cardiovascular (CV) complications (RR 82.4% and 34.5%, p=0.010 and 0.0044, respectively) or with or without coronary heart disease (CHD) (RR 34.5% and 35.1%, p=0.0177 and 0.01, respectively) at baseline. Conclusion: Olmesartan significantly decreased the process of ECG left ventricular remodeling. This was even more pronounced in type 2 diabetic patients with a longer duration of or less controlled diabetes and irrespective of blood pressure or concomitant CV disease.

P-264 Key Words: Fasting Plasma Glucose, Metabolic Syndrome, Arterial Compliance