Mineralocorticoid Receptor Antagonists in High‐Risk Heart Failure Patients With Diabetes Mellitus and/or Chronic Kidney Disease

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142475/1/jah32899.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142475/2/jah32899_am.pd

Management of hyperkalemia in the acutely ill patient.

PURPOSE:To review the mechanisms of action, expected efficacy and side effects of strategies to control hyperkalemia in acutely ill patients. METHODS:We searched MEDLINE and EMBASE for relevant papers published in English between Jan 1, 1938, and July 1, 2018, in accordance with the PRISMA Statement using the following terms: "hyperkalemia," "intensive care," "acute kidney injury," "acute kidney failure," "hyperkalemia treatment," "renal replacement therapy," "dialysis," "sodium bicarbonate," "emergency," "acute." Reports from within the past 10 years were selected preferentially, together with highly relevant older publications. RESULTS:Hyperkalemia is a potentially life-threatening electrolyte abnormality and may cause cardiac electrophysiological disturbances in the acutely ill patient. Frequently used therapies for hyperkalemia may, however, also be associated with morbidity. Therapeutics may include the simultaneous administration of insulin and glucose (associated with frequent dysglycemic complications), β-2 agonists (associated with potential cardiac ischemia and arrhythmias), hypertonic sodium bicarbonate infusion in the acidotic patient (representing a large hypertonic sodium load) and renal replacement therapy (effective but invasive). Potassium-lowering drugs can cause rapid decrease in serum potassium level leading to cardiac hyperexcitability and rhythm disorders. CONCLUSIONS:Treatment of hyperkalemia should not only focus on the ability of specific therapies to lower serum potassium level but also on their potential side effects. Tailoring treatment to the patient condition and situation may limit the risks

Eplerenone in patients with myocardial infarction and "mid-range" ejection fraction: An analysis from the EPHESUS trial

BACKGROUND: Trials using mineralocorticoid receptor antagonists (MRAs) in myocardial infraction (MI) without heart failure (HF) or systolic impairment have been underpowered to assess morbidity-mortality benefit. In EPHESUS 6632 patients were included, of whom 11% had an ejection fraction (EF) of 40% and HF or diabetes. We aim to assess the potential benefit of MRAs in MI with EF of 40%. METHODS: Cox models with interaction term for EF. The primary outcome was a composite of cardiovascular death or hospitalization for cardiovascular reasons. HYPOTHESIS: Patients with an EF of 40% benefit similarly from MRA therapy to those with an EF <40%. RESULTS: In EPHESUS, 753 patients had an EF = 40% and 5864 an EF < 40%. Patients with an EF = 40% were younger (63 vs 64 years), had lower heart rate (73 vs 75 bpm), less atrial fibrillation (10% vs 14%), previous MI (21% vs 28%), HF hospitalization (5% vs 8%), and had more often reperfusion therapy and/or revascularization (55% vs 44%). The mean EF was 40.0 ± 0.3% in those with EF = 40% vs 32.2 ± 5.9% in those with EF < 40%. The primary outcome occurred in 13.3% (10 events per 100 py) of the patients with EF = 40% vs 22.9% (19 events per 100 py) in those with EF < 40%; adjusted HR for EF = 40% vs <40% = 0.65 (0.53-0.81). Eplerenone reduced the event-rate homogenously regardless of EF (interaction p EF = 40% vs EF < 40% = 0.21). Similar findings were observed for cardiovascular and all-cause death. CONCLUSION: Eplerenone reduces hospitalizations and mortality in patients with MI and EF = 40% similarly to patients with EF < 40%. These findings suggest that MI patients with EF in the "mid-range zone" may also benefit from MRA therapy which might help clinicians in their treatment decisions.SEC-CNIC CARDIOJOVEN; Contrat de Plan Etat Région Lorraine and FEDER IT2MP; French PIA project “Lorraine Université d'Excellence” GEENAGE, Grant/Award Number: ANR-15-IDEX-04-LUE; French National Research Agency Fighting Heart Failure, Grant/Award Number: ANR-15-RHU-0004S

Visit-to-visit blood pressure variation is associated with outcomes in a U-shaped fashion in patients with myocardial infarction complicated with systolic dysfunction and/or heart failure: findings from the EPHESUS and OPTIMAAL trials

Background: Visit-to-visit office blood pressure variation (BPV) has prognostic implications independent from mean BP across several populations in the cardiovascular field. The association of BPV with outcomes in patients with myocardial infarction (MI) with systolic dysfunction and/or heart failure is yet to be determined. Methods: Two independent cohorts were assessed: the EPHESUS and the OPTIMAAL trials with a total of more than 12 000 patients. The primary outcome was all-cause death. BPV was calculated as a coefficient of variation, that is, the ratio of the SD to the mean BP along the postbaseline follow-up. Cox regression models were used to determine the associations between BPV and events. Results: Compared with the middle and lower BPV tertiles, patients in the upper BPV tertile were older, more often women, hypertensive, diabetic, with peripheral artery disease, and had more frequent use of loop diuretics and ACEi/ARBs. They also had lower LVEF, hemoglobin, and eGFR (all P &lt; 0.001). BPV was independently associated with worse prognosis in a U-shaped manner. In the EPHESUS trial, both low and high BPV were associated with higher rates of death (and also cardiovascular death and the composite of cardiovascular death/ cardiovascular hospitalization): adjusted hazard ratio (95% CI) for the outcome of death is 1.99 (1.68–2.36) for high BPV and is 1.60 (1.35–1.90) for low BPV. Similar results were observed in the OPTIMAAL trial population. Conclusion: In two independent cohorts of MI patients with systolic dysfunction and/or heart failure, BPV was associated with worse prognosis in a U-shaped manner independently of the mean BP

Patiromer to Enable Spironolactone Use in the Treatment of Patients with Resistant Hypertension and Chronic Kidney Disease: Rationale and Design of the AMBER Study

BACKGROUND: While chronic kidney disease (CKD) is common in resistant hypertension (RHTN), prior studies -evaluating mineralocorticoid receptor antagonists excluded patients with reduced kidney function due to risk of hyperkalemia. AMBER (ClinicalTrials.gov identifier NCT03071263) will evaluate if the potassium-binding polymer patiromer used concomitantly with spironolactone in patients with RHTN and CKD prevents hyperkalemia and allows more persistent spironolactone use for hypertension management. METHODS: Randomized, double-blind, placebo-controlled parallel group 12-week study of patiromer and spironolactone versus placebo and spironolactone in patients with uncontrolled RHTN and CKD. RHTN is defined as unattended systolic automated office blood pressure (AOBP) of -135-160 mm Hg during screening despite taking ≥3 antihypertensives, including a diuretic, and an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker -(unless not tolerated or contraindicated). The CKD inclusion criterion is an estimated glomerular filtration rate (eGFR) of 25 to ≤45 mL/min/1.73 m2. Screening serum potassium must be 4.3-5.1 mEq/L. The primary efficacy endpoint is the between-group difference (spironolactone plus patiromer versus spironolactone plus placebo) in the proportion of patients remaining on spironolactone at Week 12. RESULTS: Baseline characteristics have been analyzed as of March 2018 for 146 (of a targeted 290) patients. Mean (SD) baseline age is 69.3 (10.9) years; 52.1% are male, 99.3% White, and 47.3% have diabetes. Mean (SD) baseline serum potassium is 4.68 (0.25) mEq/L, systolic AOBP is 144.3 (6.8) mm Hg, eGFR is 35.7 (7.7) mL/min/1.73 m2. CONCLUSION: AMBER will define the ability of patiromer to facilitate the use of spironolactone, an effective antihypertensive therapy for patients with RHTN and CKD

Telomere length tracking in children and their parents:Implications for adult onset diseases

Adults with comparatively short or long leukocyte telomere length (LTL) typically continue to display comparatively short or long LTL throughout life. This LTL tracking stems from the inability of person-to-person variation in age-dependent LTL shortening during adulthood to offset the wide interindividual LTL variation established prior to adult life. However, LTL tracking in children is unstudied. This study aimed to examine LTL shortening rates and tracking in children and their parents. Longitudinal study in children (n = 67) and their parents (n = 99), whose ages at baseline were 11.4 +/- 0.3 and 43.4 +/- 0.4 yr, respectively. LTL was measured by Southern blotting at baseline and similar to 14 yr thereafter. LTL displayed tracking in both children [intraclass correlation coefficient (ICC) = 0.905, P <0.001] and their parents (ICC = 0.856, P <0.001). The children's rate of LTL shortening was twice that of their parents (40.7 +/- 2.5 bp/yr; 20.3 +/- 2.1 bp/yr, respectively; P <0.0001). LTL tracking applies not only to adulthood but also to the second decade of life. Coupled with previous work showing that the interindividual variation in LTL across newborns is as wide as in their parents, these findings support the thesis that the LTL-adult disease connection is principally determined before the second decade of life, perhaps mainly at birth

Numerical investigations on acoustic propagation effects for highly integrated intake ducts

Aeroacoustic assessment of highly integrated propulsion systems is a challenging task at an early design stage and requires detailed physical understanding with validated numerical prediction capabilities. This work presents numerical studies of an UCAV configuration with a complex intake duct as a complementary analysis to measurements. The setup is based on the agile (unmanned) NATO air vehicle MULDICON UCAV (MULti-DIsciplinary CONfiguration) with an S-shaped intake duct to primarily shield the engine from radar. A laser-based sound source is modeled as monopole in the intake duct. The computation of the acoustic field is performed in the time domain with the Discontinuous Galerkin (DG) code DISCO++ developed by DLR. RANS mean flow fields are calculated with DLR’s TAU solver as background flow input for the aeroacoustic noise propagation. A parametric study is conducted for the monopole sound source. Dependencies of the noise propagation on the intake mass flow rate and the ambient flow velocity are investigated by directivities and spectral characteristics