Coronary Angiography After Out-of-Hospital Cardiac Arrest Without ST-Segment Elevation: One-Year Outcomes of a Randomized Clinical Trial.

Importance: Myocardial infarction is a frequent cause of out-of-hospital cardiac arrest (OHCA). The long-term effect of early coronary angiography on patients with OHCA with possible coronary trigger but no ST-segment elevation remains unclear. Objective: To compare the clinical outcomes of early unselective angiography with the clinical outcomes of a delayed or selective approach for successfully resuscitated patients with OHCA of presumed cardiac origin without ST-segment elevation at 1-year follow-up. Design, Setting, and Participants: The TOMAHAWK trial was a multicenter, international (Germany and Denmark), investigator-initiated, open-label, randomized clinical trial enrolling 554 patients between November 23, 2016, to September 20, 2019. Patients with stable return of spontaneous circulation after OHCA of presumed cardiac origin but without ST-segment elevation on the postresuscitation electrocardiogram were eligible for inclusion. A total of 554 patients were randomized to either immediate coronary angiography after hospital admission or an initial intensive care assessment with delayed or selective angiography after a minimum of 24 hours. All 554 patients were included in survival analyses during the follow-up period of 1 year. Secondary clinical outcomes were assessed only for participants alive at 1 year to account for the competing risk of death. Interventions: Early vs delayed or selective coronary angiography and revascularization if indicated. Main Outcomes and Measures: Evaluations in this secondary analysis included all-cause mortality after 1 year, as well as severe neurologic deficit, myocardial infarction, and rehospitalization for congestive heart failure in survivors at 1 year. Results: A total of 281 patients were randomized to the immediate angiography group and 273 to the delayed or selective group, with a median age of 70 years (IQR, 60-78 years). A total of 369 of 530 patients (69.6%) were male, and 268 of 483 patients (55.5%) had a shockable arrest rhythm. At 1 year, all-cause mortality was 60.8% (161 of 265) in the immediate angiography group and 54.3% (144 of 265) in the delayed or selective angiography group without significant difference between the treatment strategies, trending toward an increase in mortality with immediate angiography (hazard ratio, 1.25; 95% CI, 0.99-1.57; P = .05). For patients surviving until 1 year, the rates of severe neurologic deficit, myocardial infarction, and rehospitalization for congestive heart failure were similar between the groups. Conclusions and Relevance: This study found that a strategy of immediate coronary angiography does not provide clinical benefit compared with a delayed or selective invasive approach for patients 1 year after resuscitated OHCA of presumed coronary cause and without ST-segment elevation. Trial Registration: ClinicalTrials.gov Identifier: NCT02750462.

Soluble suppression of tumorigenesis-2 is a strong predictor of all-cause, cardiovascular and infection-related mortality risk in haemodialysis patients with diabetes mellitus.

Background: Soluble suppression of tumorigenesis-2 (sST2) is a strong prognostic biomarker of cardiovascular (CV) disease. End-stage kidney disease (ESKD) patients are at high risk of CV events and infections. Herein we investigated the utility of sST2 to predict all-cause and cause-specific mortality in haemodialysis (HD) patients with diabetes mellitus. Methods: sST2 concentrations were measured in plasma samples of 1196 participants of the German Diabetes and Dialysis (4D) study who had type 2 diabetes mellitus and received maintenance HD for ESKD. Hazard ratios (HRs) for prespecified, adjudicated endpoints were determined according to sST2 levels at baseline by multivariate Cox proportional hazards analysis. Results: Participants (mean age 66 years, 54% male) had a median sST2 concentration of 25 ng/mL and were followed up for 4 years. After adjustment for possible confounders, participants with sST2 concentrations in the highest (>32.6 ng/mL) compared with the lowest (<20.1 ng/mL) quartile exhibited a 2-fold higher all-cause mortality risk {[HR 2.06 95% confidence interval (CI) 1.61-2.61]; P < .001}. High sST concentrations (fourth versus first quartile) were strongly associated with the risk of cardiac death [HR 2.29 (95% CI 1.55-3.39); P < .001]. Analysis of individual components of cardiac causes of death showed an increased risk of sudden death [HR 2.24 (95% CI 1.33-3.77); P < .001], death due to myocardial infarction [HR 2.12 (95% CI 0.9-5.0); P = .087] and heart failure [HR 3.34 (95% CI 1.15-9.75); P = .027] in participants with sST2 levels in the highest compared with the lowest quartile. Likewise, participants with the highest sST2 levels had an increased risk of fatal stroke [HR 1.92 (95% CI 1.17-3.14); P = .009] and fatal infections [HR 2.01 (95% CI 1.2-3.37); P = .008]. In contrast to fatal CV events, sST2 was not associated with the risk of non-fatal myocardial infarction [HR 0.68 (95% CI 0.41-1.12); P = .132] or non-fatal stroke [HR 1.28 (95% CI 0.64-2.53); P = .485]. Conclusions: In HD patients with diabetes mellitus, high concentrations of sST2 were strongly and independently associated with an increased risk of all-cause mortality, CV mortality and death due to infection but not non-fatal CV events.

Lower Cardiorespiratory Fitness Is Associated With Right Ventricular Geometry and Function - The Sedentary's Heart: SHIP.

Background Lower cardiorespiratory fitness (CRF) is associated with an increased risk for cardiovascular disease. However, very little information is available about the association between lower CRF and right ventricular (RV) remodeling. We investigated the relationship between CRF and RV structure and function in a large, aging, and largely sedentary adult population-based cohort. Methods and Results We used cross-sectional data of 2844 subjects (1486 women; median age, 51 years; interquartile range, 40-62 years) from the population-based cohort SHIP (Study of Health in Pomerania) with echocardiography, of which 941 also had cardiac magnetic resonance imaging. We analyzed the associations of peak oxygen uptake with RV parameters determined by both imaging techniques using multivariable-adjusted linear regression models. In echocardiography, a 1 L/min lower peak oxygen uptake was associated with a 1.18 mm (95% CI, 0.66-1.71; P<0.001) smaller RV end-diastolic diameter and a 1.41 mm (95% CI, 0.90-1.92; P<0.001) narrower RV end-diastolic outflow tract diameter. Similarly, using cardiac magnetic resonance imaging measurements, a 1 L/min lower peak oxygen uptake was associated with a 23.5 mL (95% CI, 18.7-28.4; P<0.001) smaller RV end-diastolic volume, a 13.0 mL (95% CI, 9.81-16.2; P<0.001) lower RV end-systolic volume, and a 10.7 mL/beat (95% CI, 8.10-13.3; P<0.001) lower RV stroke volume. Conclusions Our results indicate a significant association between CRF and RV remodeling. Lower CRF was associated with smaller RV chamber and lower RV systolic function, stroke volume, and cardiac output.

Protective effects of spironolactone on vascular calcification in chronic kidney disease.

BACKGROUND: Vascular calcification is common in chronic kidney disease (CKD) and associated with increased cardiovascular mortality. Aldosterone has been implicated as an augmenting factor in the progression of vascular calcification. The present study further explored putative beneficial effects of aldosterone inhibition by the mineralocorticoid receptor antagonist spironolactone on vascular calcification in CKD. METHODS: Serum calcification propensity was determined in serum samples from the MiREnDa trial, a prospective, randomized controlled clinical trial to investigate efficacy and safety of spironolactone in maintenance hemodialysis patients. Experiments were conducted in mice with subtotal nephrectomy and cholecalciferol treatment, and in calcifying primary human aortic smooth muscle cells (HAoSMCs). RESULTS: Serum calcification propensity was improved by spironolactone treatment in patients on hemodialysis from the MiREnDa trial. In mouse models and HAoSMCs, spironolactone treatment ameliorated vascular calcification and expression of osteogenic markers. CONCLUSIONS: These observations support a putative benefit of spironolactone treatment in CKD-associated vascular calcification. Further research is required to investigate possible improvements in cardiovascular outcomes by spironolactone and whether the benefits outweigh the risks in patients with CKD.

Angiography after Out-of-Hospital Cardiac Arrest without ST-Segment Elevation.

BACKGROUND: Myocardial infarction is a frequent cause of out-of-hospital cardiac arrest. However, the benefits of early coronary angiography and revascularization in resuscitated patients without electrocardiographic evidence of ST-segment elevation are unclear. METHODS: In this multicenter trial, we randomly assigned 554 patients with successfully resuscitated out-of-hospital cardiac arrest of possible coronary origin to undergo either immediate coronary angiography (immediate-angiography group) or initial intensive care assessment with delayed or selective angiography (delayed-angiography group). All the patients had no evidence of ST-segment elevation on postresuscitation electrocardiography. The primary end point was death from any cause at 30 days. Secondary end points included a composite of death from any cause or severe neurologic deficit at 30 days. RESULTS: A total of 530 of 554 patients (95.7%) were included in the primary analysis. At 30 days, 143 of 265 patients (54.0%) in the immediate-angiography group and 122 of 265 patients (46.0%) in the delayed-angiography group had died (hazard ratio, 1.28; 95% confidence interval [CI], 1.00 to 1.63; P = 0.06). The composite of death or severe neurologic deficit occurred more frequently in the immediate-angiography group (in 164 of 255 patients [64.3%]) than in the delayed-angiography group (in 138 of 248 patients [55.6%]), for a relative risk of 1.16 (95% CI, 1.00 to 1.34). Values for peak troponin release and for the incidence of moderate or severe bleeding, stroke, and renal-replacement therapy were similar in the two groups. CONCLUSIONS: Among patients with resuscitated out-of-hospital cardiac arrest without ST-segment elevation, a strategy of performing immediate angiography provided no benefit over a delayed or selective strategy with respect to the 30-day risk of death from any cause. (Funded by the German Center for Cardiovascular Research; TOMAHAWK ClinicalTrials.gov number, NCT02750462.).

Acute myocardial infarction and arterial embolism in a patient with newly diagnosed renal mass: management dilemmas! A case report.

BACKGROUND: Cancer is often associated with a hypercoagulable state and new thrombosis is often the first clinical manifestation of cancer. Surgical treatment of the primary tumor is crucial since it provides the only curative approach in most cases, but management of patients is highly complex, especially in the presence of new antiplatelet drugs and/or anticoagulants. Paraneoplastic syndromes (PNS) represent a frequent complication of renal cell carcinomas (RCC) and include different hematological symptoms in patients, whilst occlusion of arterial blood vessels displays a rare form of PNS accompanying renal tumors. CASE PRESENTATION: We report the case of a 62-year old man who was initially hospitalized due to acute coronary syndrome. He subsequently underwent coronary angioplasty treatment including multiple stenting and treatment with ticagrelor and aspirin. Post-interventional, acute arterial thrombotic emboli of several limb arteries required thrombectomy. By computer tomography we identified a renal lesion suspicious for an RCC and suspected a PNS as underlying cause of the thrombotic complications. Triple anticoagulant therapy was maintained with therapeutic dose low molecular weight heparin (LMWH), aspirin, and clopidogrel, by which we replaced ticagrelor. Surgery was postponed for 4 weeks. We paused LMWH, aspirin and clopidogrel only at the day of surgery and perioperatively restored hemostasis by transfusion of two platelet concentrates. Laparoscopic nephrectomy was uneventful. Pathology confirmed a clear cell RCC. The patient fully recovered whilst slowly reducing anticoagulation dose. CONCLUSIONS: A multidisciplinary team approach of experts in urology, cardiology and hemostasis was key in managing this patient since a personalized thrombosis consult was needed to minimize the risk of reinfarction due to in-stent thrombosis. We report a therapeutic protocol that may be helpful for the management of similar cases. Furthermore, the finding of thrombotic arterial occlusions in larger blood vessels represents a novel complication of PNS in RCC and adds to the varied possible manifestations of this clinical chameleon.

Quantification of left ventricular mass by echocardiography compared to cardiac magnet resonance imaging in hemodialysis patients.

BACKGROUND: Left ventricular hypertrophy (LVH), defined by the left ventricular mass index (LVMI), is highly prevalent in hemodialysis patients and a strong independent predictor of cardiovascular events. Compared to cardiac magnetic resonance imaging (CMR), echocardiography tends to overestimate the LVMI. Here, we evaluate the diagnostic performance of transthoracic echocardiography (TTE) compared to CMR regarding the assessment of LVMI in hemodialysis patients. METHODS: TTR and CMR data for 95 hemodialysis patients who participated in the MiREnDa trial were analyzed. The LVMI was calculated by two-dimensional (2D) TTE-guided M-mode measurements employing the American Society of Echocardiography (ASE) and Teichholz (Th) formulas, which were compared to the reference method, CMR. RESULTS: LVH was present in 44% of patients based on LVMI measured by CMR. LVMI measured by echocardiography correlated moderately with CMR, ASE: r = 0.44 (0.34-0.62); Th: r = 0.44 (0.32-0.62). Compared to CMR, both echocardiographic formulas overestimated LVMI (mean ∆LVMI (ASE-CMR): 19.5 ± 19.48 g/m2, p < 0.001; mean ∆LVMI (Th-CMR): 15.9 ± 15.89 g/m2, p < 0.001). We found greater LVMI overestimation in patients with LVH using the ASE formula compared to the Th formula. Stratification of patients into CMR LVMI quartiles showed a continuous decrease in ∆LVMI with increasing CMR LVMI quartiles for the Th formula (p < 0.001) but not for the ASE formula (p = 0.772). Bland-Altman analysis showed that the Th formula had a constant bias independent of LVMI. Both methods had good discrimination ability for the detection of LVH (ROC-AUC: 0.819 (0.737-0.901) and 0.808 (0.723-0.892) for Th and ASE, respectively). CONCLUSIONS: The ASE and Th formulas overestimate LVMI in hemodialysis patients. However, the overestimation is less with the Th formula, particularly with increasing LVMI. The results suggest that the Th formula should be preferred for measurement of LVMI in chronic hemodialysis patients. TRIAL REGISTRATION: The data was derived from the following clinical trial: NCT01691053 , registered on 19 September 2012 before enrollment of the first participant.

Invasive Validation of Antares, a New Algorithm to Calculate Central Blood Pressure from Oscillometric Upper Arm Pulse Waves.

Background: Antares is an algorithm for pulse wave analysis (PWA) by oscillometric blood pressure (BP) monitors in order to estimate central (aortic) blood pressure (cBP). Antares aims to enable brachial cuff-based BP monitors to be type II-devices, determining absolute cBP values independently of potential peripheral BP inaccuracies. The present study is an invasive validation of the Antares algorithm in the custo screen 400. Methods: We followed entirely the 2017 ARTERY protocol for validation of non-invasive cBP devices, the 2013 American National Standards Institute, Inc./Association for the Advancement of Medical Instrumentation/International Organization for Standardization (ANSI/AAMI/ISO) 81060-2 and 2018 AAMI/European Society of Hypertension (ESH)/ISO validation standard protocols. In total, 191 patients undergoing cardiac catheterization were included, of which 145 patients entered analysis. Invasive cBP recordings were compared to simultaneous non-invasive cBP estimations using the Antares algorithm, integrated into an oscillometric BP monitor. Results: Mean difference between invasive and non-invasively estimated systolic cBP was 0.71 mmHg with standard deviation of 5.95 mmHg, fulfilling highest validation criteria. Conclusion: Antares is the first algorithm for estimation of cBP that entirely fulfills the 2017 ARTERY and AAMI/ESH/ISO validation protocols. The Antares algorithm turns the custo screen 400 BP monitor into a type II-device. Integration of Antares into commercially available BP monitors could make it possible to measure PWA parameters in virtually every practice in future.

A randomized controlled trial of the effect of spironolactone on left ventricular mass in hemodialysis patients.

Mineralocorticoid receptor antagonists have beneficial effects on left ventricular remodeling, cardiac fibrosis, and arrhythmia in heart failure, but efficacy and safety in dialysis patients is less clear. We evaluated the effect of spironolactone on left ventricular mass (LVM), an independent predictor of all-cause and cardiovascular mortality, in hemodialysis patients. In this placebo-controlled, parallel-group trial, 97 hemodialysis patients (23% female; mean age 60.3 years) were randomized to spironolactone 50 mg once daily (n=50) or placebo (n=47). The primary efficacy endpoint was change in LVM index (LVMi) from baseline to 40 weeks as determined by cardiac magnetic resonance imaging. Safety endpoints were development of hyperkalemia and change in residual renal function. There was no significant change in LVMi in participants randomized to spironolactone compared to placebo (-2.86±11.87 vs. 0.41±10.84 g/m2). There was also no difference in the secondary outcomes of mean 24-hour systolic or diastolic ambulatory blood pressure, left ventricular ejection fraction, 6-minute walk test distance, or New York Heart Association functional class. Moderate hyperkalemia (pre-dialysis potassium levels of 6.0-6.5 mmol/L) was more frequent with spironolactone treatment (155 vs. 80 events), but severe hyperkalemia (≥6.5 mmol/L) was not (14 vs. 24 events). Changes in residual urine volume and measured glomerular filtration rate did not differ between groups. There were no deaths in the spironolactone group and 4 deaths in the placebo group. Thus, treatment with 50 mg spironolactone did not change left ventricular mass index, cardiac function, or blood pressure in hemodialysis patients. Spironolactone increased the frequency of moderate hyperkalemia, but did not increase severe hyperkalemia.

Immediate unselected coronary angiography versus delayed triage in survivors of out-of-hospital cardiac arrest without ST-segment elevation: Design and rationale of the TOMAHAWK trial.

Patients experiencing out-of-hospital cardiac arrest (OHCA) without ST-segment elevation are a heterogenic group with a variety of underlying causes. Up to one-third of patients display a significant coronary lesion compatible with myocardial infarction as OHCA trigger. There are no randomized data on patient selection and timing of invasive coronary angiography after admission. METHODS AND RESULTS: The TOMAHAWK trial randomly assigns 558 patients with return of spontaneous circulation after OHCA with no obvious extracardiac origin of cardiac arrest and no ST-segment elevation/left bundle-branch block on postresuscitation electrocardiogram to either immediate coronary angiography or initial intensive care assessment with delayed/selective angiography in a 1:1 ratio. The primary end point is 30-day all-cause mortality. Secondary analyses will be performed with respect to initial rhythm, electrocardiographic patterns, myocardial infarction as underlying cause, neurological outcome, as well as clinical and laboratory markers. Clinical follow-up will be performed at 6 and 12 months. Safety end points include bleeding and stroke. CONCLUSION: The TOMAHAWK trial will address the unresolved issue of timing and general indication of angiography after OHCA without ST-segment elevation.

Increased myocardial sodium signal intensity in Conn's syndrome detected by 23Na magnetic resonance imaging.

AIMS: Sodium intake has been linked to left ventricular hypertrophy independently of blood pressure, but the underlying mechanisms remain unclear. Primary hyperaldosteronism (PHA), a condition characterized by tissue sodium overload due to aldosterone excess, causes accelerated left ventricular hypertrophy compared to blood pressure matched patients with essential hypertension. We therefore hypothesized that the myocardium constitutes a novel site capable of sodium storage explaining the missing link between sodium and left ventricular hypertrophy. METHODS AND RESULTS: Using 23Na magnetic resonance imaging, we investigated relative sodium signal intensities (rSSI) in the heart, calf muscle, and skin in 8 PHA patients (6 male, median age 55 years) and 12 normotensive healthy controls (HC) (8 male, median age 61 years). PHA patients had a higher mean systolic 24 h ambulatory blood pressure [152 (140; 163) vs. 125 (122; 130) mmHg, P < 0.001] and higher left ventricular mass index [71.0 (63.5; 106.8) vs. 55.0 (50.3; 66.8) g/m2, P = 0.037] than HC. Compared to HC, PHA patients exhibited significantly higher rSSI in the myocardium [0.31 (0.26; 0.34) vs. 0.24 (0.20; 0.27); P = 0.007], calf muscle [0.19 (0.16; 0.22) vs. 0.14 (0.13; 0.15); P = 0.001] and skin [0.28 (0.25; 0.33) vs. 0.19 (0.17; 0.26); P = 0.014], reflecting a difference of +27%, +38%, and +39%, respectively. Treatment of PHA resulted in significant reductions of the rSSI in the myocardium, calf muscle and skin by -13%, -27%, and -29%, respectively. CONCLUSION: Myocardial tissue rSSI is increased in PHA patients and treatment of aldosterone excess effectively reduces rSSI, thus establishing the myocardium as a novel site of sodium storage in addition to skeletal muscle and skin.

High evening salivary cortisol is an independent predictor of increased mortality risk in patients with systolic heart failure.

AIMS: Serum cortisol independently predicts mortality risk in patients with systolic heart failure. Salivary cortisol may provide advantages as it better reflects the biologically active free compound. Furthermore, sampling is non-invasive and may easily be performed in outpatients. We comparatively evaluated associations of morning (MSC) vs. evening salivary cortisol (ESC) and all-cause mortality risk. METHODS AND RESULTS: MSC (8 am) and ESC (9 pm) were determined in 229 patients with heart failure participating in the Interdisciplinary Network for Heart Failure program (66 ± 13 years; 21% female; 37% New York Heart Association (NYHA) class III/IV, median left ventricular ejection fraction 33%). The association of cortisol with mortality risk was determined by univariate and Cox multivariable regression analyses adjusting for age, sex, NYHA class, and N-terminal pro-hormone B-type natriuretic peptide. Compared to ESC, MSC was significantly higher and exhibited a higher variance: median 0.59 ng/ml (interquartile range 0.41-0.93) vs. 0.25 ng/ml (0.15-0.48), p<0.001. During 18 months of follow-up, 25 (11%) patients died. In univariate and multivariable models mortality risk was not increased in the highest MSC quartile: crude hazard ratio (HR) 1.81 (95% confidence interval 0.79-4.14, p=0.160), adjusted HR 1.26 (0.51-3.13, p=0.616). However, patients in the highest ESC quartile had a significantly increased mortality risk, suggesting that associations of high ESC and increased mortality were independent of disease severity: crude HR 3.33 (1.50-7.42, p=0.003), adjusted HR 2.49 (1.01-6.14, p=0.047). ESC alone proved the best predictor of mortality. CONCLUSION: High ESC but not MSC levels independently predict increased mortality risk in heart failure.

Prognostic value of aldosterone and cortisol in patients hospitalized for acutely decompensated chronic heart failure with and without mineralocorticoid receptor antagonism.

BACKGROUND: Serum aldosterone and cortisol independently predict an increased mortality risk in heart failure (HF), and mineralocorticoid receptor antagonism (MRA) improves survival. The prognostic relevance of aldosterone and cortisol with MRA is unclear. METHODS AND RESULTS: In this post hoc analysis of a prospective cohort, study serum levels of aldosterone and cortisol were measured at baseline in 842 patients with systolic HF. The mean age was 68 ± 12 years (27% female, 45% in New York Heart Association functional class III/IV, 43% with MRA; median follow-up 38 months [interquartile range 30-43 mo]). Crude mortality in the total cohort was 43% (patients with vs without MRA: 34% vs 41%; P = .052). In MRA-naïve patients, higher levels of both aldosterone and cortisol were predictive of increased mortality risk in multivariable Cox regression: hazard ratio (HR) with 95% confidence interval of highest vs lowest tertile for aldosterone: 1.51 [1.02-2.24] (P = .040); and for cortisol: 1.94 [1.28-2.93] (P = .002). In MRA-treated patients, aldosterone (highest vs lowest tertile: HR 1.65 [1.01-2.71]; P = .048) but not cortisol (HR 0.77 [0.44-1.27]; P = .33) was associated with all-cause mortality. Further subgroup analysis revealed that particularly patients with low cortisol and high aldosterone levels had the worst prognosis (HR 5.01 [2.22-11.3]; P < .001), compared with the reference of low cortisol and low aldosterone. Subjects with this profile had larger ventricles and more often coronary artery disease. CONCLUSIONS: In systolic HF, the prognostic value of aldosterone and cortisol levels differs in dependency of MRA intake. The pathophysiologic link between low cortisol, high aldosterone, and increased mortality risk in patients with MRA needs to be clarified.

Rationale and design of the Mineralocorticoid Receptor Antagonists in End-Stage Renal Disease Study (MiREnDa).

BACKGROUND: End-stage renal disease (ESRD) patients exhibit an extraordinarily high annual mortality secondary to cardiac and vascular causes, particularly sudden cardiac death (SCD). Left ventricular (LV) hypertrophy is a frequent finding and constitutes an independent predictor of mortality risk in these patients. Mineralocorticoid receptor antagonists (MRAs) are cardioprotective in heart failure patients and effectively reduce LV mass, but are considered inappropriate in patients with severe renal impairment, given their potential to cause hyperkalaemia. Recent data from small clinical studies suggest that MRAs may be safe in patients undergoing regular haemodialysis, but cardiovascular (CV) protection in these patients is unclear. We here review the literature on CV effects of MRA in dialysis patients and report the design of the Mineralocorticoid Receptor antagonists in End-stage renal Disease (MiREnDa) trial. METHODS: The MiREnDa trial is a prospective randomized, placebo-controlled, double-blind, parallel group, multi-centre, intervention study investigating the effects of spironolactone (50 mg daily) compared with placebo in maintenance haemodialysis patients. The change in LV mass index (LVMI) as assessed by cardiac magnet resonance imaging (CMR) constitutes the primary efficacy end point. Secondary end points include changes in LV geometry and function, office and 24-h ambulatory blood pressure, cardiac arrhythmias, vascular function parameters, measures of heart failure and quality of life. Pre-dialysis potassium levels and the incidence of threatening hyperkalaemia (pre-dialysis potassium ≥6.5 mmol/L) constitute safety end points. CONCLUSIONS: MiREnDa will investigate CV efficacy and safety of spironolactone in haemodialysis patients [clinical trials.gov NCT01691053].

Aldosterone and cortisol affect the risk of sudden cardiac death in haemodialysis patients.

BACKGROUND: Sudden cardiac death is common and accounts largely for the excess mortality of patients on maintenance dialysis. It is unknown whether aldosterone and cortisol increase the incidence of sudden cardiac death in dialysis patients. METHODS AND RESULTS: We analysed data from 1255 diabetic haemodialysis patients participating in the German Diabetes and Dialysis Study (4D Study). Categories of aldosterone and cortisol were determined at baseline and patients were followed for a median of 4 years. By Cox regression analyses, hazard ratios (HRs) were determined for the effect of aldosterone, cortisol, and their combination on sudden death and other adjudicated cardiovascular outcomes. The mean age of the patients was 66 ± 8 years (54% male). Median aldosterone was <15 pg/mL (detection limit) and cortisol 16.8 µg/dL. Patients with aldosterone levels >200 pg/mL had a significantly higher risk of sudden death (HR: 1.69; 95% CI: 1.06-2.69) compared with those with an aldosterone <15 pg/mL. The combined presence of high aldosterone (>200 pg/mL) and high cortisol (>21.1 µg/dL) levels increased the risk of sudden death in striking contrast to patients with low aldosterone (<15 pg/mL) and low cortisol (<13.2 µg/dL) levels (HR: 2.86, 95% CI: 1.32-6.21). Furthermore, all-cause mortality was significantly increased in the patients with high levels of both hormones (HR: 1.62, 95% CI: 1.01-2.62). CONCLUSIONS: The joint presence of high aldosterone and high cortisol levels is strongly associated with sudden cardiac death as well as all-cause mortality in haemodialysed type 2 diabetic patients. Whether a blockade of the mineralocorticoid receptor decreases the risk of sudden death in these patients must be examined in future trials.

The effect of spironolactone upon corticosteroid hormone metabolism in patients with early stage chronic kidney disease.

CONTEXT: Aldosterone has emerged as an important mediator of disease progression and mortality in patients with chronic heart and kidney disease (CKD). Despite the increasing use of mineralocorticoid receptor antagonists in these patients, little is known about the effects on corticosteroid hormone secretion and metabolism. OBJECTIVE: To assess corticosteroid hormone secretion and metabolism in patients with early stage CKD before and after spironolactone (Spiro). DESIGN: Randomized, double-blind, placebo-controlled interventional study. SETTING: Single tertiary referral centre. PATIENTS: A total of 112 patients with stable stage 2/3 CKD. INTERVENTIONS: Patients were randomized to receive either Spiro 25 mg once daily or placebo for 36 weeks. MAIN OUTCOME MEASURES: Plasma renin activity (PRA), angiotensin II (AngII) and steroid hormones were analysed by standard assays; urinary corticosteroid hormone metabolites (5α+5ß-tetrahydro-cortisol (5α+5ß-THF), TH-cortisone (THE), 3α5ß-TH-aldosterone (TH-Aldo), 5α+5ß-TH-deoxycorticosterone (5α+5ß-TH-DOC), TH-11-desoxycortisol (THS)) were analysed by gas chromatography/mass spectrometry. RESULTS: Plasma aldosterone concentration (PAC) was inversely correlated with eGFR (r = -0·331, P < 0·001). Urinary 24-h excretion of TH-Aldo was correlated with PAC (r = 0·214, P < 0·05) and diastolic blood pressure (BP) (r = 0·212, P = <0·05), whereas total 24-h urinary cortisol metabolite excretion was correlated with systolic BP (r = 0·316, P < 0·01). In addition, 11ß-hydroxysteroid dehydrogenase (11ß-HSD) type 1 activity (urinary 5α+5ß-THF)/THE) ratio) was correlated with PRA (r = 0·277, P < 0·01). Spiro treatment significantly reduced BP (123 ± 11/76 ± 7 vs 119 ± 11/73 ± 8 mmHg, P < 0·01) despite renin-angiotensin-aldosterone system induction, reflected by increased urinary 24-h TH-Aldo excretion (17·6 (12, 86) vs 26 (18, 80) µg/24 h, P < 0·05). By contrast, Spiro had no effect on total urinary cortisol metabolite excretion, 11ß-hydroxylase, 11ß-HSD type 1 and 2 activity. CONCLUSIONS: Aldo and cortisol are positively associated with BP suggesting that adrenal hyperactivity may in part explain the increased cardiovascular risk in patients with early end-stage CKD. Addition of Spiro had no effect on glucocorticoid metabolism or total 24-h corticosteroid production.

Cortisol metabolism in hypertension.

Corticosteroids are critically involved in blood pressure regulation. Lack of adrenal steroids in Addison's disease causes life-threatening hypotension, whereas glucocorticoid excess in Cushing's syndrome invariably results in high blood pressure. At a pre-receptor level, glucocorticoid action is modulated by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs). 11Beta-HSD1 activates cortisone to cortisol to facilitate glucocorticoid receptor (GR)-mediated action. By contrast, 11beta-HSD2 plays a pivotal role in aldosterone target tissues where it catalyses the opposite reaction (i.e. inactivation of cortisol to cortisone) to prevent activation of the mineralocorticoid receptor (MR) by cortisol. Mutations in the 11beta-HSD2 gene cause a rare form of inherited hypertension, the syndrome of apparent mineralocorticoid excess (AME), in which cortisol activates the MR resulting in severe hypertension and hypokalemia. Ingestion of competitive inhibitors of 11beta-HSD2 such as liquorice and carbenoxolone result in a similar but milder clinical phenotype. Epidemiological data suggests that polymorphic variability in the HSD11B2 gene determines salt sensitivity in the general population, which is a key predisposing factor to adult onset hypertension in some patients. Extrarenal sites of glucocorticoid action and metabolism that might impact on blood pressure include the vasculature and the central nervous system. Intriguingly, increased exposure to glucocorticoids during fetal life promotes high blood pressure in adulthood suggesting an early programming effect. Thus, metabolism and action in many peripheral tissues might contribute to the pathophysiology of human hypertension.

Dissociation of serum dehydroepiandrosterone and dehydroepiandrosterone sulfate in septic shock.

CONTEXT: Dehydroepiandrosterone (DHEA) replacement in sepsis has been advocated because of the sepsis-associated decrease in serum DHEA sulfate (DHEAS). However, experimental sepsis in rodents leads to down-regulation of DHEA sulfotransferase, which inactivates DHEA to DHEAS, theoretically resulting in higher DHEA levels. OBJECTIVE: The objective of the study was to test whether serum DHEA and DHEAS are dissociated in septic shock and to determine their association with circulating cortisol in the context of severity of disease and mortality. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study consisting of 181 patients with septic shock, 31 patients with acute trauma, and 60 healthy controls. MAIN OUTCOME MEASURES: Serum cortisol, DHEA, and DHEAS were measured before and 60 min after ACTH stimulation. RESULTS: Serum cortisol was increased and DHEAS was decreased in both septic shock and trauma patients (all P < 0.001). However, compared with healthy controls, DHEA was significantly increased in sepsis but decreased after trauma (all P < 0.001). In sepsis, neither cortisol nor DHEA increased significantly after ACTH. Most severely ill patients had higher cortisol (P = 0.069) and lower DHEA (P = 0.076) and a significantly higher cortisol to DHEA ratio (P = 0.004). Similarly, the cortisol to DHEA ratio was significantly increased in nonsurvivors of septic shock (P = 0.026), whereas survivors did not differ from controls (P = 0.322). CONCLUSIONS: The observed dissociation of DHEA and DHEAS in septic shock contradicts the previous concept of sepsis-associated DHEA deficiency. Increased DHEA levels may maintain the balance between glucocorticoid- and DHEA-mediated immune and vascular effects. However, most severe disease and mortality is associated with an increased cortisol to DHEA ratio, which may represent a novel prognostic marker in septic shock.

Sex steroid metabolism in human peripheral blood mononuclear cells changes with aging.

CONTEXT: Dehydroepiandrosterone (DHEA) mainly exerts indirect action via downstream conversion toward sex steroids within peripheral target cells including immune cells. In vitro DHEA has been shown to enhance IL-2 release from T lymphocytes, whereas it inhibits IL-6 secretion. Conversely, aging is associated with a decline in both DHEA and IL-2, whereas IL-6 increases. OBJECTIVE: The objective of the study was to investigate age-related differences in expression and functional activity of steroidogenic enzymes involved in downstream conversion of DHEA in peripheral blood mononuclear cells (PBMCs). DESIGN: This study was cross-sectional. PARTICIPANTS/SETTING: Healthy young men (n = 8; age range, 23-29 yr) and healthy middle-aged men (n = 8; age range, 52-66 yr) were studied in an academic setting. MEASURES: mRNA expression of steroidogenic enzymes in PBMCs was measured by qualitative and quantitative RT-PCR analysis and enzyme activity assays after incubation of PBMCs with radiolabeled DHEA, 4-androstene-3,17-dione (androstenedione), and testosterone. RESULTS: RT-PCR analysis showed expression of all enzymes required for DHEA conversion toward active androgens and to the immune-stimulatory metabolite androstenediol. Steroid conversion patterns indicated a particularly increased activity of 17beta-hydroxysteroid dehydrogenase type 5 (17beta-HSD5) in the older men, demonstrated by significantly higher conversion rates of DHEA to androstenediol and of androstenedione to testosterone (all P < 0.05). By contrast, conversion of DHEA to androstenedione via 3beta-HSD occurred at a similar rate. Quantitative RT-PCR analysis revealed increased expression of 17beta-HSD 5 mRNA in PBMCs from the older men. CONCLUSIONS: Our results provide evidence for significant changes in sex steroid metabolism by human PBMCs with aging, which may represent an endocrine link to immune senescence.