Possible Enzymatic Downregulation of the Natriuretic Peptide System in Patients with Reduced Systolic Function and Heart Failure: A Pilot Study

Abstract

Background In patients with reduced systolic function, the natriuretic peptide system affects heart failure (HF) progression, but the expression of key activating (corin) and degrading enzymes (neprilysin) is not well understood. Methods and Results This pilot study (n=48) compared plasma levels of corin, neprilysin, ANP, BNP, and cGMP in control patients with normal ejection fractions (mean EF 63 ± 3%) versus patients with systolic dysfunction, with (EF 24 ± 8%) and without (EF 27 ± 7%) decompensated HF (dHF), as defined by Framingham and BNP criteria. Mean ages, use of beta blockers, and ACE-inhibitors-angiotensin receptor blockers were similar between the groups. Corin levels were depressed in systolic dysfunction patients (797 ± 346 pg/ml) versus controls (1188 ± 549, p<0.02), but levels were not affected by dHF (p=0.77). In contrast, levels of neprilysin (p<0.01), cGMP (p<0.001), and ANP (p<0.001) were higher in systolic dysfunction patients than controls and were the highest in patients with dHF. Conclusions Levels of neprilysin, ANP, BNP, and cGMP increased in patients with reduced systolic function and were the highest in dHF patients. Conversely, corin levels were low in patients with reduced EF with or without dHF. This pattern suggests possible enzymatic downregulation of natriuretic peptide activity in patients with reduced EF, which may have diagnostic and prognostic implications.

Cardiac-Specific Overexpression of Catalytically Inactive Corin Reduces Edema, Contractile Dysfunction, and Death in Mice with Dilated Cardiomyopathy

“…Converging lines of evidence from clinical and translational studies have shown that genetic abnormalities and reduction in corin cardiac expression level negatively affect DCM and HFrEF outcomes. Cardiac transcripts and circulating levels of corin are depressed in patients and translational animal models with DCM and HFrEF [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]35,36,51], and are pathologically modulated in DCM before the onset of edema and other clinical signs and symptoms of HFrEF [22,23]. In a translationally relevant mouse model of DCM-HFrEF with reduced cardiac and plasma corin levels, we reported that genetic restoration of cardiac-specific catalytically active, native corin improved systolic function, reduced myocardial fibrosis, decreased edema, and prolonged survival [16,17].…”

“…A growing body of evidence in humans and experimental models suggests that corin, a cardiac transmembrane II serine protease, plays diagnostic, prognostic, and protective roles in DCM and HFrEF development [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]. Cardiac corin is co-expressed with pro-atrial natriuretic peptide (pro-ANP) and localized on the cardiomyocyte surface [25,26], where it cleaves/activates secreted pro-ANP generating biologically active ANP peptides.…”

“…We reported that plasma corin levels are robustly reduced in patients with acute HFrEF leading to impaired pro-ANP activation, suggesting that reduced corin levels may contribute, in some individuals, to the sodium and water retention associated with HFrEF [11,14,15,19]. Our recent clinical and experimental published data show that corin cardiac expression and plasma levels may reflect the severity of cardiomyopathy, impaired systolic function, and may precede the development of HFrEF [22,23]. Importantly, we found that cardiac-specific expression of catalytically active corin delays the onset of symptomatic HFrEF associated with lung edema and extends life in experimental mouse model of DCM [16,17].…”

Increases in plasma corin levels following experimental myocardial infarction reflect the severity of ischemic injury

“…However, key questions remain unanswered to understand the physical meaning of these measurements in patients. In HF, levels of cardiac and circulating (plasma) corin, are consistently decreased [ 4 , 7 ] and the magnitude of corin reduction is correlated with the severity of heart dysfunction [ 9 , 39 ]. However, whether lower circulating corin was accompanied with decreased cardiac corin expression in case of stroke or preeclampsia is unknown.…”

The impact of chronic obstructive pulmonary disease and hypertension on the development and progression of atrial fibrillation

“…Неблагоприятным последствием легочной гипертензии, в контексте ее аритмогенной активности, будет расширение правых отделов сердца и изменение архитектоники их миокарда. Доказана связь между возрастанием диаметра правого желудочка у лиц с ХОБЛ и наличием у них ФП [30]. Следовательно, можно полагать, что размер правых камер сердца несет диагностическую значимость в качестве фактора возникновения ФП у больных ХОБЛ.…”