First-in-Human Study of MANP: A Novel ANP (Atrial Natriuretic Peptide) Analog in Human Hypertension

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Dataset for: Early Activation of Deleterious Molecular Pathways in the Kidney in Experimental Heart Failure with Atrial Remodeling

Heart failure (HF) is a major health problem with worsening outcomes when renal impairment is present. Therapeutics for early phase HF may be effective for cardiorenal protection, however the detailed characteristics of the kidney in early-stage HF (ES-HF), and therefore treatment for potential renal protection, are poorly defined. We sought to determine the gene and protein expression profiles of specific maladaptive pathways of ES-HF in the kidney and heart. Experimental canine ES-HF, characterized by de-novo HF with atrial remodeling but not ventricular fibrosis, was induced by right ventricular pacing for 10 days. Kidney cortex (KC), medulla (KM), left ventricle (LV), and left atrial (LA) tissues from ES-HF vs normal canines (n=4 of each) were analyzed using RT-PCR microarrays and protein assays to assess genes and proteins related to inflammation, renal injury, apoptosis, and fibrosis. ES-HF was characterized by increased circulating natriuretic peptides and components of the renin-angiotensin-aldosterone system and decreased sodium and water excretion with mild renal injury with up-regulation of CNP and renin genes in the kidney. Compared to normals, widespread genes, especially genes of the inflammatory pathways, were up-regulated in KC similar to increases seen in LA. Protein expressions related to inflammatory cytokines were also augmented in the KC. Gene and protein changes were less prominent in the LV and KM. The ES-HF displayed mild renal injury with widespread gene changes and increased inflammatory cytokines. These changes may provide important clues into the pathophysiology of ES-HF and for therapeutic molecular targets in the kidney of ES-HF

Aldosterone predicts cardiovascular, renal, and metabolic disease in the general community: A 4-year follow-up

Background-We recently reported that normal aldosterone levels are associated with cardiovascular, renal, and metabolic disease in a sample of the US general community (Visit 1). For the current analyses we used the same cohort in a new 4-year follow-up study (Visit 2). Methods and Results-We measured aldosterone at Visit 1 and analyzed its predictive role for new diseases at Visit 2 (n=1140). We measured aldosterone at Visit 2 and investigated its associations with disease at Visit 2 (n=1368). We analyzed aldosterone continuously and we also dichotomized the variable as whether subjects were in the third tertile versus second and first tertiles. As continuous variable at Visit 1, aldosterone predicted new onset hypertension (HTN) (OR=1.36, CI=1.13-1.63, P=0.001), central obesity (OR=1.36, CI=1.07-1.73, P=0.011), and use of lipid-lowering drugs (OR=1.25, CI=1.05-1.48, P=0.012) at Visit 2, after adjustment for age, sex, and body mass index. When in the third tertile (8.5-88.6 ng/dL), aldosterone predicted type 2 diabetes (T2DM, OR=1.96, CI=1.03-3.70, P=0.039). At Visit 2, aldosterone remained associated with HTN, obesity, and chronic kidney disease (CKD), as reported for Visit 1. However, aldosterone was not associated with heart failure (HF) at Visit 1 and 2, nor was aldosterone a predictor of HF between visits. Conclusions-Aldosterone predicts new HTN, central obesity, T2DM, and use of lipid-lowering drugs in the general community and remains associated with HTN, obesity, and CKD over 4 years. Aldosterone is not associated nor predicts HF. Further studies are warranted to evaluate aldosterone as therapeutic target in the general community