Prevention of Cardiorenal Fibrosis and Suppression of Proteinuria and Aldosterone Activation Following Experimental Myocardial Infarction with the Novel Natriuretic Peptide CD-NP

Myocardial infarction (MI) decreases ejection fraction (EF), increases left ventricular (LV) mass and increases collagen content in the myocardium. In preliminary studies we observed renal cortical and medullary fibrosis together with proteinuria following experimental MI supporting an important heart-kidney connection. Importantly, natriuretic peptides (NP) are antifibrotic and possess antialdosterone properties. A novel designer NP, CD-NP, has anti-fibrotic and renal preserving properties without excessive hypotension. Importantly, CD-NP represents the only NP in clinical development that co-activates both cGMP activating NP receptors (NPR-A and NPR-B). We hypothesized that in a model of MI in rats CD-NP would prevent LV and renal fibrosis and hypertrophy as well as reduce proteinuria and suppress aldosterone. Methods: In coronary artery ligation induced MI, we compared CD-NP (n = 9) to control (n = 10, no treatment). The treatment group received CD-NP through an osmotic pump for 2 weeks following MI while the control group received vehicle. Cardiorenal function and structure were assessed 3 weeks after MI. Hearts and kidneys were harvested. Cardiac function was assessed by echocardiography. Results: 3 weeks after MI, aldosterone was lower in the CD-NP group vs control (MI:39.4 ± 10, CD-NP:15 ± 1.04 dl/ml, p = 0.036). Heart weight/body weight ratio was lower (p<0.0005) and echo confirmed a decrease in LV mass (MI: 1.35 ± 0.04, CD-NP:1.18 ± 0.04 g, p<0.0005) in the CD-NP group . Mean arterial pressure was higher in the CD-NP group (MI:92 ± 2, CD-NP:105 ± 3.6 mmHg, p = 0.0047). Importantly, collagen content was decreased in the LV (MI:5 ± 0.6, CD-NP:3.5 ± 0.4 %, p<0.05), and also in renal cortex and medulla (MI:3.5 ± 0.5, CD-NP:1.3 ± 0.3, p = 0.002 and MI:19 ± 5 vs CD-NP:1.2 ± 0.3 %, p = 0.0006). Proteinuria was markedly reduced by CD-NP treatment (MI: 9.6 ± 1.3 vs CD-NP: 2.5 ± 0.4 mg/day, p<0.0001) while renal blood flow was increased (MI: 4.8 ± 0.6 vs CD-NP: 7 ± 0.7 ml/min, p = 0.0443). EF, GFR, diuresis and natriuresis were similar between both groups. Conclusion: CD-NP in this MI model reduced cardiorenal fibrosis, reduced LV hypertrophy and suppressed aldosterone activation. Proteinuria, a robust prognostic cardiorenal biomarker, was decreased with CD-NP demonstrating favorable renoprotective properties. These studies support a novel NP based therapeutic strategy for cardiorenal protection post MI.