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BACKGROUND B-type natriuretic peptide (BNP), which is activated in heart failure (HF), is processed to an active form by corin. The corin gene is expressed in the human heart and kidney, but corin protein expression in the heart, kidney, and circulation, along with whether proBNP is processed by circulating corin, remains unknown. METHODS We examined corin protein expression by immunostaining and Western blot in human heart and kidney, and we assessed the circulating corin concentration by ELISA. We examined histidine-tagged (His-tag) proBNP1–108 processing in serum and plasma by immunoprecipitation and Western blot and sequenced the processed form. RESULTS Normal human heart and kidney displayed the presence of corin, especially in cells around the vasculature. Both corin and proBNP1–108 were present in the plasma of healthy human subjects, with circulating corin significantly higher in men than women (P < 0.0001) and a positive correlation of corin to age (P = 0.0497, r = 0.27). In fresh normal plasma and serum, His-tag proBNP1–108 was processed to a lower molecular weight form confirmed to be BNP. Processed BNP was higher in men than women (P = 0.041) and was positively correlated to plasma corin concentrations (P = 0.041, r = 0.65). CONCLUSIONS Our results support the concept that proBNP1–108 may be processed outside of the heart in the circulation where the proprotein convertase is present. Moreover, sex may impact this process, since corin concentrations are higher in men. These findings may have important physiologic and pathophysiologic implications for the proBNP/corin system in the human.

Myocardial aging is characterized by LV fibrosis leading to diastolic and systolic dysfunction. Studies have established the potent anti-fibrotic and anti-proliferative properties of C-type natriuretic peptide (CNP), however the relationship between circulating CNP, LV fibrosis and associated changes in LV function with natural aging are undefined. Accordingly, we characterized the relationship of plasma CNP with LV fibrosis and function in 2, 11 and 20 month old male Fischer rats. Further in vitro, we establish the anti-proliferative actions of CNP and the participation of the clearance receptor using adult human cardiac fibroblasts. Here we establish for the first time that a progressive decline in circulating CNP characterizes natural aging and is strongly associated with a reciprocal increase in LV fibrosis which precedes impairment of diastolic and systolic function. Additionally we demonstrate in cultured adult human cardiac fibroblasts that the direct anti-proliferative actions of high dose CNP may involve a non-cGMP pathway via the clearance receptor. Taken together these studies provide new insights into myocardial aging and the relationship to the anti-fibrotic and anti-proliferative peptide CNP.

Objectives Our objective was to determine the prognostic value of plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) for death and cardiovascular events among subjects without risk factors for heart failure (HF), which we term healthy normal. Background Previous studies report that plasma NT-proBNP has prognostic value for cardiovascular events in the general population even in the absence of HF. It is unclear if NT-proBNP retains predictive value in healthy normal subjects. Methods We identified a community-based cohort of 2,042 subjects in Olmsted County, Minnesota. Subjects with symptomatic (stage C/D) HF were excluded. The remaining 1,991 subjects underwent echocardiography and NT-proBNP measurement. We further defined healthy normal (n = 703) and stage A/B HF (n = 1,288) subgroups. Healthy normal was defined as the absence of traditional clinical cardiovascular risk factors and echocardiographic structural cardiac abnormalities. Subjects were followed for death, HF, cerebrovascular accident, and myocardial infarction with median follow-up of 9.1, 8.7, 8.8, and 8.9 years, respectively. Results NT-proBNP was not predictive of death or cardiovascular events in the healthy normal subgroup. Similar to previous reports, in stage A/B HF, plasma NT-proBNP values greater than age-/sex-specific 80th percentiles were associated with increased risk of death, HF, cerebrovascular accident, and myocardial infarction (p < 0.001 for all) even after adjustment for clinical risk factors and structural cardiac abnormalities. Conclusions These findings do not support the use of NT-proBNP as a cardiovascular biomarker in healthy normal subjects and have important implications for NT-proBNP–based strategies for early detection and primary prevention of cardiovascular disease.

Objectives We sought to define the cardiometabolic phenotype associated with rs5068, a genetic variant of the atrial natriuretic peptide (ANP) gene. Background ANP and BNP play an important role in cardiorenal homeostasis but also exert metabolic actions. Methods We genotyped 1608 randomly selected residents from Olmsted County, Minnesota, USA. Subjects were well characterized. Results Genotype frequencies were: AA 89.9%, AG 9.7%, and GG 0.4%; all subsequent analyses were AA vs AG+GG. After adjustment for age and gender the G allele was associated with increased plasma levels of N-terminal-proANP (NT-proANP) (p=0.002). The minor allele was also associated with lower BMI (p=0.006), prevalence of obesity (p=0.002), waist circumference (p=0.021), lower levels of C-reactive protein (p=0.027) and higher values of HDL cholesterol (p=0.019). The AG+GG group had a lower systolic blood pressure (p=0.011) and lower prevalence of myocardial infarction (p=0.042). The minor allele was associated with a lower prevalence of metabolic syndrome (p=0.025). After adjusting for BMI the association between the G allele and HDL cholesterol, C – reactive protein values, myocardial infarction and metabolic syndrome was not significant; the association with systolic blood pressure, BMI, obesity, waist circumference remained significant even after adjusting for NT-proANP. Conclusions In a random sample of the general US population the minor allele of rs5068 is associated with a favorable cardiometabolic profile. These findings suggest that rs5068 or genetic loci in linkage disequilibrium may affect susceptibility for cardiometabolic diseases and support the possible protective role of natriuretic peptides by their favorable effects on metabolic function. Replication studies are needed to confirm our findings.

IMPORTANCE Heart failure (HF) with preserved ejection fraction (HFpEF) is common, is frequently associated with ventricular wall thickening, and has no effective therapy. Transthyretin amyloid cardiomyopathy (ATTR-CM) can cause the HFpEF clinical phenotype, has highly effective therapy, and is believed to be underrecognized. OBJECTIVE To examine the prevalence of ATTR-CM without and with systematic screening in patients with HFpEF and ventricular wall thickening. DESIGN, SETTING, AND PARTICIPANTS This population-based cohort study assessed ATTR-CM prevalence in 1235 consecutive patients in southeastern Minnesota with HFpEF both without (prospectively identified cohort study) and with (consenting subset of cohort study, n = 286) systematic screening. Key entry criteria included validated HF diagnosis, age of 60 years or older, ejection fraction of 40% or greater, and ventricular wall thickness of 12 mm or greater. In this community cohort of 1235 patients, 884 had no known ATTR-CM, contraindication to technetium Tc 99m pyrophosphate scanning, or other barriers to participation in the screening study. Of these 884 patients, 295 consented and 286 underwent scanning between October 5, 2017, and March 9, 2020 (community screening cohort). EXPOSURES Medical record review or technetium Tc 99m pyrophosphate scintigraphy and reflex testing for ATTR-CM diagnosis. MAIN OUTCOMES AND MEASURESThe ATTR-CM prevalence by strategy (clinical diagnosis or systematic screening), age, and sex.RESULTS A total of 1235 patients participated in the study, including a community cohort (median age, 80 years; interquartile range, 72-87 years; 630 [51%] male) and a community screening cohort (n = 286; median age, 78 years; interquartile range, 71-84 years; 149 [52%] male). In the 1235 patients in the community cohort without screening group, 16 patients (1.3%; 95% CI, 0.7%-2.1%) had clinically recognized ATTR-CM. The prevalence was 2.5% (95% CI, 1.4%-4.0%) in men and 0% (95% CI, 0.0%-0.6%) in women. In the 286 patients in the community screening cohort, 18 patients (6.3%; 95% CI, 3.8%-9.8%) had ATTR-CM. Prevalence increased with age from 0% in patients 60 to 69 years of age to 21% in patients 90 years and older (P < .001). Adjusting for age, ATTR-CM prevalence differed by sex, with 15 of 149 men (10.1%; 95% CI, 5.7%-16.1%) and 3 of 137 women (2.2%; 95% CI, 0.4%-6.3%) having ATTR-CM (P = .002). CONCLUSIONS AND RELEVANCEIn this cohort study based in a community-based setting, ATTR-CM was present in a substantial number of cases of HFpEF with ventricular wall thickening, particularly in older men. These results suggest that systematic evaluation can increase the diagnosis of ATTR-CM, thereby providing therapeutically relevant phenotyping of HFpEF.

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BACKGROUND: High-sensitivity cardiac troponin (hscTn) assays are now available that can detect measurable troponin in significantly more individuals in the general population than conventional assays. The clinical use of these hs-cTn assays depends on the development of proper reference values. Therefore, our objective was to define hs-cTnI reference values and determinants in the general community, in a healthy reference cohort, and in subsets with diseases.