Preservation of Glucagon-Like Peptide-1 Level Attenuates Angiotensin II-Induced Tissue Fibrosis by Altering AT1/AT 2 Receptor Expression and Angiotensin-Converting Enzyme 2 Activity in Rat Heart.

PURPOSE: The glucagon-like peptide-1 (GLP-1) has been shown to exert cardioprotective effects in animals and patients. This study tests the hypothesis that preservation of GLP-1 by the GLP-1 receptor agonist liraglutide or the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin is associated with a reduction of angiotensin (Ang) II-induced cardiac fibrosis. METHODS AND RESULTS: Sprague-Dawley rats were subjected to Ang II (500 ng/kg/min) infusion using osmotic minipumps for 4 weeks. Liraglutide (0.3 mg/kg) was subcutaneously injected twice daily or linagliptin (8 mg/kg) was administered via oral gavage daily during Ang II infusion. Relative to the control, liraglutide, but not linagliptin decreased MAP (124 ± 4 vs. 200 ± 7 mmHg in control, p < 0.003). Liraglutide and linagliptin comparatively reduced the protein level of the Ang II AT1 receptor and up-regulated the AT2 receptor as identified by a reduced AT1/AT2 ratio (0.4 ± 0.02 and 0.7 ± 0.01 vs. 1.4 ± 0.2 in control, p < 0.05), coincident with the less locally-expressed AT1 receptor and enhanced AT2 receptor in the myocardium and peri-coronary vessels. Both drugs significantly reduced the populations of macrophages (16 ± 6 and 19 ± 7 vs. 61 ± 29 number/HPF in control, p < 0.05) and α-SMA expressing myofibroblasts (17 ± 7 and 13 ± 4 vs. 66 ± 29 number/HPF in control, p < 0.05), consistent with the reduction in expression of TGFß1 and phospho-Smad2/3, and up-regulation of Smad7. Furthermore, ACE2 activity (334 ± 43 and 417 ± 51 vs. 288 ± 19 RFU/min/µg protein in control, p < 0.05) and GLP-1 receptor expression were significantly up-regulated. Along with these modulations, the synthesis of collagen I and tissue fibrosis were inhibited as determined by the smaller collagen-rich area and more viable myocardium. CONCLUSION: These results demonstrate for the first time that preservation of GLP-1 using liraglutide or linagliptin is effective in inhibiting Ang II-induced cardiac fibrosis, suggesting that these drugs could be selected as an adjunctive therapy to improve clinical outcomes in the fibrosis-derived heart failure patients with or without diabetes.

Comparison of coronary revascularization strategies in older adults presenting with acute coronary syndromes.

BACKGROUND: The optimal coronary revascularization strategy to maximize the patient-centered outcome of days alive and out of hospital (DAOH), in multimorbid older (≥65-years) adults after an acute coronary syndrome (ACS) is incompletely understood. METHODS: Using Kaiser Permanente Northern California Health Plan databases, we identified 3871 patients ≥65-years presenting with ACS between 1/1/2010-3/1/2018 who underwent coronary revascularization with either coronary artery bypass grafting (CABG, N = 1575) or multivessel percutaneous coronary intervention (PCI, N = 2296). Selection bias was accounted for through propensity score modeling techniques and inverse probability of treatment weighting. Cox proportional hazards models were fit to evaluate the association of revascularization type with outcomes. PRIMARY OUTCOMES: Absolute DAOH and the relative risk of achieving ≥90%DAOH during three time intervals. SECONDARY OUTCOMES: All-cause mortality, recurrent MI, stroke, rehospitalization, repeat revascularization, and dialysis initiation. RESULTS: CABG (compared to PCI) was associated with greater absolute number of DAOH, significant after the first year (mean difference at 1-year: +5.8 days, 95% confidence interval [CI], -1.6 to 13 days; 3-years: +56 days, 95%CI, +25 to +88 days; 5-years: + 131 days, 95%CI, +57 to +205 days). The relative risk of achieving ≥90% DAOH significantly favored CABG after the first year (1-year:1.02, 95%CI, 0.98-1.05; 3-years:1.06, 95%CI 1.002-1.11, 5-years:1.12, 95%CI, 1.03-1.22), and was related to lower incidences of all-cause mortality, repeat revascularization, rehospitalization, incident dialysis, and nonfatal MI with CABG. CONCLUSIONS: In older adults with multivessel or left main coronary artery disease who presented with ACS, CABG, after the first year, was associated with a greater absolute number of DAOH-a geriatric and patient-centered outcome, compared to PCI. CABG patients also had a higher probability of achieving ≥90%DAOH-with lower all-cause mortality, recurrent MI, repeat revascularization, new dialysis, and rehospitalization rates. Future randomized trials should study the impact of optimal revascularization strategies on the quality of life of older adults with multimorbidity.

Sodium bicarbonate vs sodium chloride for the prevention of contrast medium-induced nephropathy in patients undergoing coronary angiography: a randomized trial.

CONTEXT: Sodium bicarbonate has been suggested as a possible strategy for prevention of contrast medium-induced nephropathy, a common cause of renal failure associated with prolonged hospitalization, increased health care costs, and substantial morbidity and mortality. OBJECTIVE: To determine if sodium bicarbonate is superior to sodium chloride for preventing contrast medium-induced nephropathy in patients with moderate to severe chronic kidney dysfunction who are undergoing coronary angiography. DESIGN, SETTING, AND PATIENTS: Randomized, controlled, single-blind study conducted between January 2, 2006, and January 31, 2007, and enrolling 353 patients with stable renal disease who were undergoing coronary angiography at a single US center. Included patients were 18 years or older and had an estimated glomerular filtration rate of 60 mL/min per 1.73 m(2) or less and 1 or more of diabetes mellitus, history of congestive heart failure, hypertension, or age older than 75 years. INTERVENTIONS: Patients were randomized to receive either sodium chloride (n = 178) or sodium bicarbonate (n = 175) administered at the same rate (3 mL/kg for 1 hour before coronary angiography, decreased to 1.5 mL/kg per hour during the procedure and for 4 hours after the completion of the procedure). MAIN OUTCOME MEASURE: The primary end point was a 25% or greater decrease in the estimated glomerular filtration rate on days 1 through 4 after contrast exposure. RESULTS: Median patient age was 71 (interquartile range, 65-76) years, and 45% had diabetes mellitus. The groups were well matched for baseline characteristics. The primary end point was met in 13.3% of the sodium bicarbonate group and 14.6% of the sodium chloride group (relative risk, 0.94; 95% confidence interval, 0.55-1.60; P = .82). In patients randomized to receive sodium bicarbonate vs sodium chloride, the rates of death, dialysis, myocardial infarction, and cerebrovascular events did not differ significantly at 30 days (1.7% vs 1.7%, 0.6% vs 1.1%, 0.6% vs 0%, and 0% vs 2.2%, respectively) or at 30 days to 6 months (0.6% vs 2.3%, 0.6% vs 1.1%, 0.6% vs 2.3%, and 0.6% vs 1.7%, respectively) (P > .10 for all). CONCLUSION: The results of this study do not suggest that hydration with sodium bicarbonate is superior to hydration with sodium chloride for the prevention of contrast medium-induced nephropathy in patients with moderate to severe chronic kidney disease who are undergoing coronary angiography. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00312117.