Abstract
The renin-angiotensin-aldosterone axis plays a key role in mediating cardiac and kidney injury. Mineralocorticoid receptor antagonism has beneficial effects on cardiac dysfunction, but effects are less well quantified in the cardiorenal syndrome. This study investigated cardiac and kidney pathophysiology following permanent surgical ligation to induce myocardial infarction (MI) in hypertensive animals with or without mineralocorticoid receptor antagonism. Hypertension was induced in adult male Cyp1a1Ren2 rats. Hypertensive animals underwent MI surgery (n = 6), and were then treated daily with spironolactone for 28 days with serial systolic blood pressure measurements, echocardiograms and collection of urine and serum biochemical data. They were compared to hypertensive animals (n = 4), hypertensive animals treated with spironolactone (n = 4), and hypertensive plus MI without spironolactone (n = 6). Cardiac and kidney tissue was examined for histological and immunohistochemical analysis. MI superimposed on hypertension resulted in an increase in interstitial cardiac fibrosis (p<0.001), renal cortical interstitial fibrosis (p<0.01) and glomerulosclerosis (p<0.01). Increased fibrosis was accompanied by myofibroblast and macrophage infiltration in the heart and the kidney. Spironolactone post-MI, diminished the progressive fibrosis (p<0.001) and inflammation (myofibroblasts (p<0.05); macrophages (p<0.01)) in both the heart and the kidney, despite persistently elevated SBP (182±19 mmHg). Despite the reduction in inflammation and fibrosis, spironolactone did not modify ejection fraction, proteinuria, or renal function when compared to untreated animals post MI. This model of progressive cardiorenal dysfunction more closely replicates the clinical setting. Mineralocorticoid receptor blockade at a clinically relevant dose, blunted progression of cardiac and kidney fibrosis with reduction in cardiac and kidney inflammatory myofibroblast and macrophage infiltration. Further studies are underway to investigate the combined actions of angiotensin blockade with mineralocorticoid receptor blockade.
Highlights
Hypertension is a leading cause of left ventricular hypertrophy and heart failure (HF) [1]
myocardial infarction (MI) superimposed on hypertension resulted in an increase in interstitial cardiac fibrosis (p
Increased fibrosis was accompanied by myofibroblast and macrophage infiltration in the heart and the kidney
Summary
Hypertension is a leading cause of left ventricular hypertrophy and heart failure (HF) [1]. The hypertrophied ventricle is initially able to compensate for the increased after-load but this is associated with progressive myocardial remodelling, including accumulation of fibroblasts and collagen formation. In time, this leads to a reduction in left ventricular (LV) compliance, diastolic dysfunction, and subsequent systolic dysfunction resulting in left ventricular decompensation and heart failure [2–5]. Hypertension is associated with atherosclerosis [6] further increasing the risk of myocardial infarction. Hypertension is associated with the development of chronic kidney disease (hypertensive nephrosclerosis). Chronic kidney disease is recognised as a major risk factor for cardiovascular disease [7]
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