Citations

C-type natriuretic peptide (CNP) possesses well-established cardiovascular properties. Although present in the mammalian kidney, CNP production in human kidney and its modulation in human renal disease remain less defined. We investigated the presence of CNP in normal human kidney and in patients with nephrotic syndrome (NS). We also addressed whether or not a low-protein diet (LPD) alters plasma CNP and urinary CNP excretion in NS. In situ hybridization studies demonstrated CNP mRNA expression in tubular cells and glomeruli of normal human kidneys. CNP immunoreactivity was positive in proximal, distal, and medullary collecting duct tubular cells in both controls and patients with NS. The ratios of plasma CNP and urinary CNP to creatinine were significantly higher in patients with NS compared with controls. Urinary CNP, but not plasma CNP, was significantly lowered in patients with NS after an LPD. Similarly, the ratios of urinary protein to creatinine and urinary albumin to creatinine, but not urinary guanosine 3′,5′-cyclic monophosphate to creatinine, decreased significantly with an LPD. These data confirm and extend previous reports and demonstrate for the first time the presence of CNP in human kidney with NS. We also report increased plasma CNP concentration and urinary CNP excretion in NS patients and a significant reduction of CNP excretion with an LPD. Our findings demonstrate that CNP metabolism is altered in patients with NS and support the hypothesis that activation of renal CNP can be partially offset by an LPD. These results underscore that the beneficial effect of an LPD on protein excretion is paralleled by a substantial reduction in intrarenal CNP release.

Dendroaspis natriuretic peptide (DNP) is a recently discovered peptide with structural similarity to known natriuretic peptides. DNP has been shown to possess potent renal actions. Our objectives were to define the acute hemodynamic actions of DNP in normal anesthetized dogs and the acute effects of DNP on left ventricular (LV) function in conscious chronically instrumented dogs. In anesthetized dogs, DNP, but not placebo, decreased mean arterial pressure (141 ± 6 to 109 ± 7 mmHg, P < 0.05) and pulmonary capillary wedge pressure (5.8 ± 0.3 to 3.4 ± 0.2 mmHg, P < 0.05). Cardiac output decreased and systemic vascular resistance increased with DNP and placebo. DNP-like immunoreactivity and guanosine 3′,5′-cyclic monophosphate concentration increased without changes in other natriuretic peptides. In conscious dogs, DNP decreased LV end-systolic pressure (120 ± 7 to 102 ± 6 mmHg, P < 0.05) and volume (32 ± 6 to 28 ± 6 ml, P < 0.05) and LV end-diastolic volume (38 ± 5 to 31 ± 4 ml, P < 0.05) but not arterial elastance. LV end-systolic elastance increased (6.1 ± 0.7 to 7.4 ± 0.6 mmHg/ml, P < 0.05), and Tau decreased (31 ± 2 to 27 ± 1 ms, P < 0.05). The effects on hemodynamics, LV function, and second messenger generation suggest synthetic DNP may have a role as a cardiac unloading and lusitropic peptide.

Background In epidemiologic studies, obesity has been associated with reduced natriuretic peptide ( NP ) concentrations. Reduced NP production could impair the ability of obese individuals to respond to salt loads, increasing the risk of hypertension and other disorders. We hypothesized that weight loss enhances NP production before and after salt loading. Methods and Results We enrolled 15 obese individuals (mean BMI 45±5.4 kg/m 2 ) undergoing gastric bypass surgery. Before and 6 months after surgery, subjects were admitted to the clinical research center and administered a large‐volume intravenous saline challenge. Echocardiography and serial blood sampling were performed. From the pre‐operative visit to 6 months after surgery, subjects had a mean BMI decrease of 27%. At the 6‐month visit, N‐terminal pro‐atrial NP (Nt‐pro ANP ) levels were 40% higher before, during, and after the saline infusion, compared with levels measured at the same time points during the pre‐operative visit ( P <0.001). The rise in Nt‐pro‐ ANP induced by the saline infusion (≈50%) was similar both before and after surgery (saline, P <0.001; interaction, P =0.2). Similar results were obtained for BNP and Nt‐pro BNP ; resting concentrations increased by 50% and 31%, respectively, after gastric bypass surgery. The increase in NP concentrations after surgery was accompanied by significant decreases in mean arterial pressure ( P =0.004) and heart rate ( P <0.001), and an increase in mitral annular diastolic velocity ( P =0.02). Conclusion In obese individuals, weight loss is associated with a substantial increase in the “setpoint” of circulating NP concentrations. Higher NP concentrations could contribute to an enhanced ability to handle salt loads after weight loss.

Abstract Aims Aldosterone activation is central to the sodium–fluid retention that marks the progression of heart failure (HF). The actions of dietary sodium restriction, a mainstay in HF management, on cardiorenal and neuroendocrine adaptations during the progression of HF are poorly understood. The study aim was to assess the role of dietary sodium during the progression of experimental HF. Methods and results Experimental HF was produced in a canine model by rapid right ventricular pacing which evolves from early mild HF to overt, severe HF. Dogs were fed one of three diets: (i) high sodium [250 mEq (5.8 g) per day, n =6]; (ii) standard sodium [58 mEq (1.3 g) per day, n =6]; and (iii) sodium restriction [11 mEq (0.25 g) per day, n =6]. During the 38-day study, haemodynamics, renal function, plasma renin activity (PRA), and aldosterone were measured. Changes in haemodynamics at 38 days were similar in all three groups, as were changes in renal function. Aldosterone activation was demonstrated in all three groups; however, dietary sodium restriction, in contrast to high sodium, resulted in early (10 days) activation of PRA and aldosterone. High sodium demonstrated significant suppression of aldosterone activation over the course of HF progression. Conclusions Excessive dietary sodium restriction particularly in early stage HF results in early aldosterone activation, while normal and excess sodium intake are associated with delayed or suppressed activation. These findings warrant evaluation in humans to determine if dietary sodium manipulation, particularly during early stage HF, may have a significant impact on neuroendocrine disease progression.

Background— The goal of this study was to identify genetic determinants of plasma N-terminal proatrial natriuretic peptide (NT-proANP) in the general community by performing a large-scale genetic association study and to assess its functional significance in in vitro cell studies and on disease susceptibility. Methods and Results— Genotyping was performed across 16 000 genes in 893 randomly selected individuals, with replication in 891 subjects from the community. Plasma NT-proANP 1–98 concentrations were determined using a radioimmunoassay. Thirty-three genome-wide significant single-nucleotide polymorphisms were identified in the MTHFR-CLCN6-NPPA-NPPB locus and were all replicated. To assess the significance, in vitro functional genomic studies and clinical outcomes for carriers of a single-nucleotide polymorphism rs5063 (V32M) located in NPPA that represented the most significant variation in this genetic locus were assessed. The rs5063 variant allozyme in transfected HEK293 cells was decreased to 55±8% of wild-type protein ( P =0.01) as assessed by quantitative western blots. Carriers of rs5063 had lower NT-proANP levels (1427 versus 2291 pmol/L; P <0.001) and higher diastolic blood pressures (75 versus 73 mm Hg; P =0.009) and were at an increased risk of stroke when compared with wild-type subjects independent of age, sex, diabetes mellitus, hypertension, atrial fibrillation, and cholesterol levels (hazard ratio, 1.6; P =0.004). Conclusions— This is the first large-scale genetic association study of circulating NT-proANP levels performed with replication and functional assessment that identified genetic variants in the MTHFR-CLCN6-NPPA-NPPB cluster to be significantly associated with NT-proANP levels. The clinical significance of this variation is related to lower NT-proANP levels, higher blood pressures, and an increased risk of stroke in the general community.

We sought to investigate the role of aldosterone as a mediator of disease and its relationship with the counter-regulatory natriuretic peptide (NP) system. We measured plasma aldosterone (n=1674; aged≥45 years old) in a random sample of the general population from Olmsted County, MN. In a multivariate logistic regression model, aldosterone analyzed as a continuous variable was associated with hypertension (odds ratio [OR]=1.75; 95% confidence interval [CI]=1.57–1.96; P <0.0001), obesity (OR=1.34; 95% CI=1.21–1.48; P <0.0001), chronic kidney disease (OR=1.39; 95% CI=1.22–1.60; P <0.0001), central obesity (OR=1.47; 95% CI=1.32–1.63; P <0.0001), metabolic syndrome (OR=1.41; 95% CI=1.26–1.58; P <0.0001), high triglycerides (OR=1.23; 95% CI=1.11–1.36; P <0.0001), concentric left ventricular hypertrophy (OR=1.22; 95% CI=1.09–1.38; P =0.0007), and atrial fibrillation (OR=1.24; 95% CI=1.01–1.53; P =0.04), after adjusting for age and sex. The associations with hypertension, central obesity, metabolic syndrome, triglycerides, and concentric left ventricular hypertrophy remained significant after further adjustment for body mass index, NPs, and renal function. Furthermore, aldosterone in the highest tertile correlated with lower NP levels and increased mortality. Importantly, most of these associations remained significant even after excluding subjects with aldosterone levels above the normal range. In conclusion, we report that aldosterone is associated with hypertension, chronic kidney disease, obesity, metabolic syndrome, concentric left ventricular hypertrophy, and lower NPs in the general community. Our data suggest that aldosterone, even within the normal range, may be a biomarker of cardiorenal and metabolic disease. Further studies are warranted to evaluate a therapeutic and preventive strategy to delay the onset and progression of disease, using mineralocorticoid antagonists or chronic NP administration in high-risk subjects identified by plasma aldosterone.

Background— We have reported that pro–B-type natriuretic peptide (BNP)-1-108 circulates and is processed to mature BNP1-32 in human blood. Building on these findings, we sought to determine whether proBNP1-108 processed forms in normal circulation are biologically active and stimulate cGMP, and whether proBNP1-108 processing and activity are altered in human heart failure (HF) compared with normal. Because BNP1-32 is deficient whereas proBNP1-108 is abundant in HF, we hypothesize that proBNP1-108 processing and degradation are impaired in HF patients ex vivo. Methods and Results— We measured circulating molecular forms, including BNP1-32, proBNP1-108, and N-terminal-proBNP, and all were significantly higher in patients with HF when compared with that in normals. Fresh serum samples from normals or patients with HF were incubated with or without exogenous nonglycosylated proBNP1-108 tagged with 6 C-terminal Histidines to facilitate peptide isolation. His-tag proBNP1-108 was efficiently processed into BNP1-32/3-32 at 5 minutes in normal serum, persisted for 15 minutes, then disappeared. Delayed processing of proBNP1-108 was observed in HF samples, and the degradation pattern differed depending on left ventricular function. The 5-minute processed forms from both normal and HF serums were active and generated cGMP via guanylyl cyclase-A receptors; however, the 180-minute samples were not active. The proBNP1-108 processing enzyme corin and BNP-degrading enzyme dipeptidyl peptidase-4 were reduced in HF versus normal, perhaps contributing to differential BNP metabolism in HF. Conclusions— Exogenous proBNP1-108 is processed into active BNP1-32 and ultimately degraded in normal circulation. The processing and degradation of BNP molecular forms were altered but complete in HF, which may contribute to the pathophysiology of HF.

Abstract INTRODUCTION High-sensitivity cardiac troponin assays have potent prognostic value in stable cardiovascular disease cohorts. Our objective was to assess the prognostic utility of a novel cardiac troponin I (cTnI) high-sensitivity assay, independently and in combination with amino-terminal pro–B-type natriuretic peptide (NT-proBNP), for the future development of heart failure and mortality in the general community. METHODS A well-characterized community-based cohort of 2042 participants underwent clinical assessment and echocardiographic evaluation. Baseline measurements of cTnI with a high-sensitivity assay and NT-proBNP were obtained in 1843 individuals. Participants were followed for new-onset heart failure and mortality with median (25th, 75th percentile) follow-up of 10.7 (7.9, 11.6) and 12.1 (10.4, 13.0) years, respectively. RESULTS When measured with a high-sensitivity assay, cTnI greater than the sex-specific 80th percentile was independently predictive of heart failure [hazard ratio 2.56 (95% confidence interval 1.88–3.50), P &lt; 0.001] and mortality [1.91(1.49–2.46), P &lt; 0.001] beyond conventional risk factors in this community-based cohort, with significant increases in the net reclassification improvement for heart failure. The prognostic utility of cTnI measured with a high-sensitivity assay goes beyond NT-proBNP, yet our data suggest that these 2 assays are complementary and most beneficial when evaluated together in identifying at-risk individuals in the community. CONCLUSIONS Our findings lay the foundation for prospective studies aimed at identification of individuals at high risk by use of a multimarker approach, followed by aggressive prevention strategies to prevent subsequent heart failure.