We previously reported that exogenous angiotensin (Ang) 1–7 has adverse cardiac effects in experimental kidney failure due to its action to increase cardiac angiotensin converting enzyme (ACE) activity. This study investigated if the addition of an ACE inhibitor (ACEi) to Ang 1–7 infusion would unmask any beneficial effects of Ang 1–7 on the heart in experimental kidney failure. Male Sprague–Dawley rats underwent subtotal nephrectomy (STNx) and were treated with vehicle, the ACEi ramipril (oral 1mg/kg/day), Ang 1–7 (subcutaneous 24 μg/kg/h) or dual therapy (all groups, n = 12). A control group (n = 10) of sham-operated rats were also studied. STNx led to hypertension, renal impairment, cardiac hypertrophy and fibrosis, and increased both left ventricular ACE2 activity and ACE binding. STNx was not associated with changes in plasma levels of ACE, ACE2 or angiotensin peptides. Ramipril reduced blood pressure, improved cardiac hypertrophy and fibrosis and inhibited cardiac ACE. Ang 1–7 infusion increased blood pressure, cardiac interstitial fibrosis and cardiac ACE binding compared to untreated STNx rats. Although in STNx rats, the addition of ACEi to Ang 1–7 prevented any deleterious cardiac effects of Ang 1–7, a limitation of the study is that the large increase in plasma Ang 1–7 with ramipril may have masked any effect of infused Ang 1–7.
BackgroundLeft ventricular hypertrophy (LVH) increases the risk of death in chronic kidney disease (CKD). The transcription factor Kruppel-like factor 15 (KLF15) is expressed in the heart and regulates cardiac remodelling through inhibition of hypertrophy and fibrosis. It is unknown if KLF15 expression is changed in CKD induced LVH, or whether expression is modulated by blood pressure reduction using angiotensin converting enzyme (ACE) inhibition.MethodsCKD was induced in Sprague–Dawley rats by subtotal nephrectomy (STNx), and rats received vehicle (n = 10) or ACE inhibition (ramipril, 1 mg/kg/day, n = 10) for 4 weeks. Control, sham-operated rats (n = 9) received vehicle. Cardiac structure and function and expression of KLF15 were assessed.ResultsSTNx caused impaired kidney function (P < 0.001), hypertension (P < 0.01), LVH (P < 0.001) and fibrosis (P < 0.05). LVH was associated with increased gene expression of hypertrophic markers, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP, P < 0.01) and connective tissue growth factor (CTGF) (P < 0.05). Cardiac KLF15 mRNA and protein expression were reduced (P < 0.05) in STNx and levels of the transcription regulator, GATA binding protein 4 were increased (P < 0.05). Ramipril reduced blood pressure (P < 0.001), LVH (P < 0.001) and fibrosis (P < 0.05), and increased cardiac KLF15 gene (P < 0.05) and protein levels (P < 0.01). This was associated with reduced ANP, BNP and CTGF mRNA (all P < 0.05).ConclusionThis is the first evidence that loss of cardiac KLF15 in CKD induced LVH is associated with unchecked trophic and fibrotic signalling, and that ACE inhibition ameliorates loss of cardiac KLF15.
BackgroundPrevious large multi‐centre randomised controlled trials have not provided clear benefit with routine intracoronary thrombus aspiration (TA) as an adjunct to primary percutaneous coronary intervention (PCI) in patients with ST‐elevation myocardial infarction (STEMI).AimTo determine whether there is a difference in outcomes with the use of manual TA prior to PCI, compared with PCI alone in a cohort of patients with STEMI.MethodsWe analysed data from 6270 consecutive patients undergoing primary PCI for STEMI prospectively enrolled in the Melbourne Interventional Group registry between 2007 and 2018. Multivariable analysis was performed to determine predictors of 30‐day major adverse cardiovascular and cerebrovascular events (MACCE) and long‐term mortality.ResultsWe compared 1621 (26%) patients undergoing primary PCI with TA to 4649 (74%) patients undergoing PCI alone. Male gender (81% vs 78%; P < 0.01), younger age (61 vs 63 years; P = 0.03), GP‐IIb/IIIa use (76% vs 58%, P < 0.01), and current smoking (40% vs 36%; P < 0.01) were more common in the TA group. TA was more likely to be used in patients with complex lesions (83% vs 66%; P < 0.01) with TIMI 0 flow (77% vs 56%; P < 0.01). No significant difference in post‐procedural TIMI flow, stroke, 30‐day mortality, or long‐term mortality were identified. Multivariable analysis demonstrated a reduction in 30‐day MACCE (hazard ratio (HR) 0.75; confidence interval (CI) 0.63–0.89; P < 0.01) in the TA group, but was not associated with long‐term mortality (HR 0.98; CI 0.85–1.1; P = 0.73).ConclusionThe use of TA in patients undergoing primary PCI for STEMI was not associated with improved short or long‐term mortality when compared with PCI alone.
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