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      Conflicting relationship between age-dependent disorders, valvular heart disease and coronary artery disease by covariance structure analysis: Possible contribution of natriuretic peptide

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          Abstract

          Background

          It is conceivable that contemporary valvular heart disease (VHD) is affected largely by an age-dependent atherosclerotic process, which is similar to that observed in coronary artery disease (CAD). However, a comorbid condition of VHD and CAD has not been precisely examined. The first objective of this study was to examine a possible comorbid condition. Provided that there is no comorbidity, the second objective was to search for the possible reasons by using conventional risk factors and plasma B-type natriuretic peptide (BNP) because BNP has a potentiality to suppress atherosclerotic development.

          Methods

          The study population consisted of 3,457 patients consecutively admitted to our institution. The possible comorbid condition of VHD and CAD and the factors that influence the comorbidity were examined by covariance structure analysis and multivariate analysis.

          Results

          The distribution of the patients with VHD and those with CAD in the histograms showed that the incidence of VHD and the severity of CAD rose with seniority in appearance. The real statistical analysis was planned by covariance structure analysis. The current path model revealed that aging was associated with VHD and CAD severity ( P < 0.001 for each); however, as a notable result, there was an inverse association regarding the comorbid condition between VHD and CAD (Correlation coefficient [β]: -0.121, P < 0.001). As the second objective, to clarify the factors leading to this inverse association, the contribution of conventional risk factors, such as age, gender, hypertension, smoking, diabetes, obesity and dyslipidemia, to VHD and CAD were examined by multivariate analysis. However, these factors did not exert an opposing effect on VHD and CAD, and the inverse association defied explanation. Since different pathological mechanisms may contribute to the formation of VHD and CAD, a differentially proposed path model using plasma BNP revealed that an increase in plasma BNP being drawn by VHD suppressed the progression of CAD (β: -0.465, P < 0.001).

          Conclusions

          The incidence of VHD and CAD showed a significant conflicting relationship. This result supported the likely presence of unknown diverse mechanisms on top of the common cascade of atherosclerosis. Among them, the continuous elevation of plasma BNP due to VHD might be one of the explicable factors suppressing the progression of CAD.

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          Most cited references27

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          Brain natriuretic peptide as a novel cardiac hormone in humans. Evidence for an exquisite dual natriuretic peptide system, atrial natriuretic peptide and brain natriuretic peptide.

          Using a specific radioimmunoassay for human brain natriuretic peptide (hBNP) with a monoclonal antibody, we have investigated its synthesis, secretion, and clearance in comparison with those of atrial natriuretic peptide (ANP) in normal subjects and patients with congestive heart failure (CHF). Mean BNP-like immunoreactivity (-LI) levels in normal atrium and ventricle were 250 and 18 pmol/g, respectively. The plasma BNP-LI level in normal subjects was 0.90 +/- 0.07 fmol/ml, which was 16% of the ANP-LI level. In contrast, the plasma BNP-LI level markedly increased in patients with CHF in proportion to its severity, and surpassed the ANP-LI level in severe cases. There was a significant step-up of the plasma BNP-LI level in the coronary sinus (CS) compared with that in the aortic root (Ao) and the difference between these BNP-LI levels, delta(CS-Ao)BNP, also increased with the severity of CHF. In addition, the step-up of the BNP-LI level in the anterior interventricular vein [delta(AIV-Ao)BNP] was comparable to delta(CS-Ao)BNP, indicating that BNP is secreted mainly from the ventricle. Predominant BNP synthesis in the ventricle was also confirmed by Northern blot analysis. Catheterization and pharmacokinetic studies revealed that hBNP is cleared from the circulation more slowly than alpha-hANP; this was in part attributed to lower (about 7%) binding affinity of hBNP to clearance receptors than that of alpha-hANP. A predominant molecular form of BNP-LI in the heart and plasma was a 3-kD form corresponding to hBNP. These results indicate that BNP is a novel cardiac hormone secreted predominantly from the ventricle, and that the synthesis, secretion and clearance of BNP differ from those of ANP, suggesting discrete physiological and pathophysiological roles of BNP in a dual natriuretic peptide system.
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            Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure.

            B-type or brain natriuretic peptide (BNP) is a novel natriuretic peptide secreted from the heart that forms a peptide family with A-type or atrial natriuretic peptide (ANP), and its plasma level has been shown to be increased in patients with congestive heart failure. This study was designed to examine the sources and mechanisms of the secretion of BNP in comparison with those of ANP in control subjects and in patients with heart failure. We measured the plasma levels of BNP as well as ANP in 16 patients with dilated cardiomyopathy (11 men and 5 women; mean age, 59 years) and 18 control subjects (9 men and 9 women; mean age, 54 years) by sampling blood from the femoral vein, the aortic root, the anterior interventricular vein (AIV), and the coronary sinus using the newly developed immunoradiometric assay systems. In the control subjects, there was no significant difference in the plasma ANP level between the aortic root and the AIV (24.0 +/- 5.2 pg/mL versus 32.2 +/- 17.0 pg/mL), but there was a highly significant step-up of the level between the AIV and the coronary sinus (32.2 +/- 17.0 pg/mL versus 371.4 +/- 111.1 pg/mL, P < .001). In contrast, there was a significant step-up of the plasma BNP level between the aortic root and the AIV (8.6 +/- 6.4 pg/mL versus 19.0 +/- 11.5 pg/mL, P < .01) but not between the AIV and the coronary sinus (19.0 +/- 11.5 pg/mL versus 28.8 +/- 14.0 pg/mL). On the other hand, in patients with dilated cardiomyopathy, there was a significant step-up in the plasma ANP level between the aortic root and the AIV (280.6 +/- 183.7 pg/mL versus 612.3 +/- 431.6 pg/mL, P < .01) and between the AIV and the coronary sinus (612.3 +/- 431.6 pg/mL versus 1229.0 +/- 772.7 pg/mL, P < .01). There was a significant step-up in the plasma BNP level between the aortic root and the AIV (268.4 +/- 293.2 pg/mL versus 511.6 +/- 458.1 pg/mL, P < .01) but not between the AIV and the coronary sinus (511.6 +/- 458.1 pg/mL versus 529.7 +/- 455.3 pg/mL) in patients with dilated cardiomyopathy. The arteriovenous difference at the AIV of the plasma level of BNP had a significant positive correlation with left ventricular end-systolic volume index (r = 0.859, P < .001) and a significant negative correlation with left ventricular ejection fraction (r = -.735, P < .001). We conclude that (1) BNP is secreted mainly from the left ventricle in normal adult humans as well as in patients with left ventricular dysfunction, whereas ANP is secreted from atria in normal adult humans and also from the left ventricle in patients with left ventricular dysfunction; (2) secretion of BNP as well as ANP from the left ventricle increases in proportion to the severity of the left ventricular dysfunction, suggesting that the secretions of ANP and BNP from the left ventricle are regulated mainly by wall tension of the left ventricle; and (3) the peripheral plasma levels of ANP and BNP reflect the secretion rate of these hormones from the left ventricle and may be used as a marker of the degree of left ventricular dysfunction in patients with left ventricular dysfunction.
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              Natriuretic Peptides/cGMP/cGMP-Dependent Protein Kinase Cascades Promote Muscle Mitochondrial Biogenesis and Prevent Obesity

              OBJECTIVE Natriuretic peptides (NPs) have been characterized as vascular hormones that regulate vascular tone via guanylyl cyclase (GC), cyclic GMP (cGMP), and cGMP-dependent protein kinase (cGK). Recent clinical studies have shown that plasma NP levels were lower in subjects with the metabolic syndrome. The present study was conducted to elucidate the roles for NP/cGK cascades in energy metabolism. RESEARCH DESIGN AND METHODS We used three types of genetically engineered mice: brain NP (BNP) transgenic (BNP-Tg), cGK-Tg, and guanylyl cyclase-A (GCA) heterozygous knockout (GCA+/−) mice and analyzed the metabolic consequences of chronic activation of NP/cGK cascades in vivo. We also examined the effect of NPs in cultured myocytes. RESULTS BNP-Tg mice fed on high-fat diet were protected against diet-induced obesity and insulin resistance, and cGK-Tg mice had reduced body weight even on standard diet; surprisingly, giant mitochondria were densely packed in the skeletal muscle. Both mice showed an increase in muscle mitochondrial content and fat oxidation through upregulation of peroxisome proliferator–activated receptor (PPAR)-γ coactivator (PGC)-1α and PPARδ. The functional NP receptors, GCA and guanylyl cyclase-B, were downregulated by feeding a high-fat diet, while GCA+/− mice showed increases in body weight and glucose intolerance when fed a high-fat diet. NPs directly increased the expression of PGC-1α and PPARδ and mitochondrial content in cultured myocytes. CONCLUSIONS The findings together suggest that NP/cGK cascades can promote muscle mitochondrial biogenesis and fat oxidation, as to prevent obesity and glucose intolerance. The vascular hormone, NP, would contribute to coordinated regulation of oxygen supply and consumption.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: ResourcesRole: SoftwareRole: SupervisionRole: VisualizationRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: ResourcesRole: SoftwareRole: VisualizationRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: ResourcesRole: SoftwareRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: ResourcesRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: ResourcesRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: ResourcesRole: SoftwareRole: SupervisionRole: VisualizationRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                20 July 2017
                2017
                : 12
                : 7
                : e0181206
                Affiliations
                [001]Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
                Scuola Superiore Sant'Anna, ITALY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                ‡ These authors also contributed equally to this work.

                Author information
                http://orcid.org/0000-0002-0914-9376
                Article
                PONE-D-17-15597
                10.1371/journal.pone.0181206
                5519065
                28727835
                134d20ae-1f7f-409e-b043-7788d570f65f
                © 2017 Fukumoto et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 22 April 2017
                : 27 June 2017
                Page count
                Figures: 4, Tables: 6, Pages: 16
                Funding
                The authors received no specific funding for this work.
                Categories
                Research Article
                Medicine and Health Sciences
                Vascular Medicine
                Coronary Heart Disease
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                Medicine and Health Sciences
                Cardiology
                Valvular Diseases
                Biology and Life Sciences
                Biochemistry
                Hormones
                Peptide Hormones
                Natriuretic Peptide
                Medicine and Health Sciences
                Vascular Medicine
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