Plasma natriuretic peptide concentrations rise in response to either atrial or ventricular wall stretch and have been found to be useful in the diagnosis and assessment of patients with congestive cardiac failure. Although previous studies have suggested that plasma natriuretic peptides may offer some prognostic information in patients with valvular heart disease, it is unclear whether concentrations reflect disease severity and how plasma concentrations vary across different valve lesions. The aim of this research was to identify the factors that affect natriuretic peptide releases in valvular heart disease (VHD) and to investigate whether natriuretic peptides can be used in clinical practice to identify those patients who may benefit from early intervention. Plasma brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) concentrations were measured in patients with normal left ventricular (LV) systolic function and isolated VHD (mitral regurgitation, MR, n=33; aortic regurgitation, AR, n=39; aortic stenosis, AS, n=34; mitral stenosis, MS, n=30), and age and sex matched controls (n=39) immediately prior to exercise stress echocardiography. Peptide levels were compared against age and sex matched controls and against markers of severity for each valve lesions and across different valve lesions. Compared to controls, patients with all types of VHD had elevated plasma BNP concentrations [(MR median 35(inter quartile range 23-52), AR 34(22-45), AS 31(22-60), MS 58(34-90); controls 24(16-33) pg/mL; p < 0.01 for all]. LV end diastolic volume index varied by valve lesion; [MR (mean ± standard deviation 77±14), AR (91±28), AS (50±17), MS (43±11), controls (52±13) mL/m2; p < 0.0001]. There were no associations between LV volume and BNP. Left atrial (LA) area index varied [MR (18±4cm2/m2), AR (12±2), AS (11±3), MS (19±6), controls (11±2); p < 0.0001], but correlated with plasma BNP concentrations: MR (r=0.42,p=0.02), MS (r=0.86,p < 0.0001), AR (r=0.53,p=0.001), AS (r=0.52, p=0.002). Higher plasma BNP concentrations were associated with increased pulmonary artery pressure and reduced exercise capacity. Despite adverse cardiac remodelling, 81(60%) patients had a BNP concentration within the normal range. In patients with MS BNP was strongly associated with left atrial area index (r=0.86; p < 0.0001) and a BNP level of greater than 2 times the upper limit of normal identified patients who fulfilled guideline criteria for intervention (Area under the curve (AUC) 0.87 [0.74,0.99], p =0.006) and lower exercise capacity (AUC 0.82 [0.67,0.97]; p=0.004). In AR patients significant remodelling could occur whilst BNP remained within the normal range and in general BNP appeared less useful in assessing disease severity. However raised levels of BNP was associated with more severe AR as assessed by left ventricular outflow tract:AR Jet area ratio (r=0.43 p=0.0007). AR patients with an abnormal BNP had signs of early LV dysfunction on exercise with a lower LV longitudinal strain rate post exercise compared to AR patients with a normal BNP (0.68±0.31 vs. 1.06±0.45 1/sec; p=0.02). In MR patients, higher plasma BNP concentrations were associated with larger left atrial area index (r=0.42, p=0.02), higher pulmonary artery pressure (r=0.53, p=0.002) and a lower exercise time (r=-0.60, p=0.0002). BNP was not associated with any marker of left ventricular size or function in MR. These findings suggest that despite significant LV remodelling, plasma BNP concentrations are often normal in patients with VHD. Consequently, plasma BNP concentrations should be interpreted with caution when assessing patients with VHD. However natriuretic peptide levels offer complementary information to the standard assessment of patients with VHD and an unexplained finding of an elevated BNP in an otherwise asymptomatic patient should prompt further investigation.

In this study, both physiological and cellular effects are elicited by natriuretic peptides (NPs), a novel type of plant hormone. It was found that rat ANP (rANP) influenced stomatal opening movement in Tradescantia sp., where a significant increase in stomatal opening was observed in the presence of 1 µM rANP. Furthermore, this effect is mediated by cGMP, a (putative) second messenger of NPs. Two inhibitors of guanylyl cyclase, LY 83583 and methylene blue, inhibited rANP-induced stomatal opening. In contrast, stomatal opening is induced in a concentration dependent manner by the cell permeant cGMP analogue 8-Br-cGMP. In addition it was found, that like in animals, the secondary structure of rANP is essential for rANP responses. Linearised rANP is biologically inactive. Since ANP elicit plant responses, an attempt was made to isolate NP analogues from plants. A protocol for partially purifying NP from plants was developed. It was found that two fractions eluted from an immunoaffinity chromatography column (0.5 M KCI eluted fraction and 0.75 M KCI eluted fraction) were biologically active. The level of cGMP in response to NPs was also tested. It is suggested that the receptor of NP is specific since only 0.75 M KCI eluted fractions increased cGMP levels in Zea mays root stele tissue. rANP did not elicit an effect on cGMP levels in this tissue and LY 83583 did not affect this response. It is therefore argued that a plant specific biologically active NP system is present in the stele and it is predicted that NPs modulate solute movement in this tissue. NPs also influence K⁺, Na⁺ and H⁺ fluxes in Zea mays root stele. Increase in both K⁺ and Na+ uptake were observed after 30 min., while H⁺ flux shifted immediately toward influx in the presence of both 0.5 and 0.75 KCI eluted fractions. Finally, a model is proposed for the effect of NPs on solute movement and its signalling system in plants.

The natriuretic peptide system (NPS) is a hormonal system critical to mammalian cardiovascular homeostasis. The purpose of the present study was to investigate the role of ANP during early postnatal cardiac development by i) monitoring the development of cardiac hypertrophy during early postnatal development of the ANP-/- mice, and ii) comparing morphologic, morphometric and molecular differences in ANP+/+ mice compared to ANP-/- mice during this developmental period. Age matched male ANP+/+ and ANP-/- mice, aged day 1 and weeks 1 to 5, were evaluated. Body weight, organ weights and hematocrit were recorded. RNA was isolated and quantitative real-time RT-PCR was used to monitor cardiac gene expression. An additional cohort of animals was used for morphologic and morphometric analysis. Heart weight to body weight ratio (HW/BW) was dramatically higher in ANP-/- animals at all time points, indicating cardiac hypertrophy is established before the advent of adult blood pressure. Molecular analysis of gene expression revealed a compensatory response of the NPS in the ANP-/- mice. Specifically an up-regulation of BNP expression in ANP-/- mice was noted throughout postnatal development. Similarly, NPR-A and NPR-C demonstrated compensatory action for the lack of ANP, as expressional levels also varied throughout development. Morphological analysis of cardiac vasculature revealed striking structural differences between ANP+/+ and ANP-/- mice. Quantitative stereological analysis of LM images indicated a greater vessel volume in ANP-/- compared to ANP+/+ mice. This study demonstrates that alterations in early molecular events, such as changes in NPS expression, may be responsible for the maintenance and progression of cardiac hypertrophy during early postnatal development in the ANP-/- mice. The absence of ANP during this critical period of development has a profound impact on final cardiac structure leading to future pathological states. / Thesis (Master, Anatomy & Cell Biology) -- Queen's University, 2010-02-05 14:15:33.982

Thesis (M.S.)--Cornell University, May, 2008. / Vita. Includes bibliographical references (leaves 102-120).

Universiẗat, Diss., 2004--München.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20979号 / 医博第4325号 / 新制||医||1026(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 妻木 範行, 教授 戸口田 淳也, 教授 柳田 素子 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Sex dimorphism in the prevalence, onset, development and progression of cardiovascular disease (CVD) is well recognized. Sex-specific differences in adaptation to cardiac pathological progressions such as cardiac hypertrophy (CH), and the extent to which they are attributable to sex hormones requires further delineation. The objective of this dissertation was to determine which cardiac vasoactive systems are responsible for sex-specific differences in CH modulation using the atrial natriuretic peptide gene-disrupted (ANP-/-) mouse model. First, sex-specific differences in the expression of the cardiac natriuretic peptide (NP) and nitric oxide synthase (NOS) systems were evaluated. Next, the influence of 17β-Estradiol (E2) on the expression and signaling of the cardiac NP and NOS systems was determined in ovariectomized (OVX) female ANP+/+ and ANP-/- mice. Finally, sex-specific differences in cardiac adaptation to Angiotensin II (ANGII) pressure overload were elucidated in male and intact female ANP+/+ and ANP-/- mice. These studies revealed that males predominantly use the NP system and females predominantly use the NOS system. Sex-specific differences in the cardiac NOS system were further enhanced by E2 in OVX female ANP+/+ and ANP-/- mice. In the female ANP-/- mouse, E2 was found to signal through the NOS system to significantly increase plasma cGMP. Finally, male and female differences were demonstrated in the sex-specific patterns of cardiac vasoactive gene system expression and development of cardiac dysfunction in response to ANGII treatment. Sex dimorphism was observed in the expression of BNP and NPR-A in male and female ANP-/- mice treated with ANGII. Female ANP+/+ and ANP-/- ANGII-treated mice exhibited elevated E/E’ ratios that were not found to the same extent in genotype matched ANGII-treated male mice, demonstrating that female mice developed ANGII-mediated mild left ventricle diastolic dysfunction. Based on the results of this dissertation, we conclude that sex-specific differences do indeed exist in the cardiac adaptation to pathological stresses. These data support the understanding that a progression towards sex-specific CVD treatments is warranted, with a particular emphasis on the potential benefits of female-specific targeting of the cardiac NOS system. / Thesis (Ph.D, Anatomy & Cell Biology) -- Queen's University, 2013-08-23 14:21:45.324

C-type natriuretic peptide (CNP) is synthesised and released by the endothelium and plays a vital role in the maintenance of vascular homeostasis (Moyes et al., 2014). However, a similar regulatory role of endogenous CNP in the heart has yet to be elucidated. Therefore, I have used three unique mouse strains with endothelium (Tie2-Cre), cardiomyocyte (αMHC-Cre) and fibroblast (Col1α2-Cre)-restricted deletion of CNP to investigate if the peptide modulates coronary vascular reactivity and cardiac function. Methods: Langendorff isolated hearts were used to investigate the effect of CNP deletion on coronary vascular reactivity in response to the endothelium-dependent vasodilators bradykinin (10nmol) and acetylcholine (0.1-1nmol). Vasodilatation associated with reperfusion was investigated by transient cessation of flow (20-80 seconds). Ischaemia reperfusion (IR) injury (35 minutes ischaemia followed by 60 minutes reperfusion) was also investigated in cell-specific knockout (KO) animals. Isoprenaline (ISO; 20mg/kg/day, 7days)- and pressure overload (abdominal aortic constriction [AAC]; 6 weeks)-induced heart failure were used to study the effect of CNP deletion during cardiac stress, with cardiac function assessed by echocardiography. Cardiac fibrosis and hypertrophy were determined by picro-sirius red and wheat-germ agglutinin fluorescence staining, respectively. A subset of experiments was repeated in mice with global deletion of natriuretic peptide receptor-C (NPR-C) to delineate the signalling pathway triggered by CNP. Real time qPCR was used to determine hypertrophic and fibrotic gene expression in left ventricles isolated from mice subjected to AAC or sham. Neonatal cardiomyocytes were isolated to investigate angiotensin (Ang)II-induced hypertrophy. Results: Coronary endothelial reactivity was reduced in endothelial CNP (ecCNP) KO mice compared to wild type (WT) in response to bradykinin, acetylcholine and reperfusion-induced vasodilatation. These observations were paralleled in NPR-C KO animals. ecCNP KO did not exacerbate IR injury, whilst mice with cardiomyocyte-restricted deletion of CNP (cmCNP KO) and NPR-C KO animals exhibited a larger infarct size compared to WT. cmCNP KO mice also displayed greater cardiac dysfunction and fibrosis after ISO infusion or AAC compared to WT; similar results were observed in fbCNP KO and NPR-C KO animals. Infusion of CNP (0.2mg/kg/day; osmotic mini-pump, s.c.) in WT, but not NPR-C KO, animals rescued the decline in cardiac function. CNP (1μM) administration in isolated cardiomyocyte also blunted Ang II-induced hypertrophy. Pro-hypertrophic and pro-fibrotic gene expression (ANP, β-MHC and MMP-2) was augmented in cmCNP KO and NPR-C KO mice compared to littermate controls following AAC. Conclusions: Endothelial, cardiomyocyte and fibroblast-derived CNP have distinct, complementary roles in the heart, modulating cardiac function by influencing coronary vascular tone and protecting against heart failure and IR injury. These protective effects of CNP are mediated, at least in part, via NPR-C activation. Developing CNP mimetics or selective NPR-C agonists could be a novel therapeutic intervention in cardiovascular disease.

In dieser post-hoc Analyse der Deutschen Diabetes und Dialyse Studie wurde der Einfluss von NT-proBNP und Troponin T auf plötzlichen Herztod, Schlaganfall, Myokardinfarkt und die Gesamtmortalität während vierjähriger Studiendauer bei 1255 Patienten mit Diabetes mellitus Typ 2 an der Hämodialyse analysiert. Des Weiteren wurde die Bedeutung einer longitudinalen Messung der Biomarker nach 6 Monaten auf die Endpunkte untersucht. Patienten mit dem höchsten NT-proBNP respektive Troponin T wiesen die größte Ereignisrate für plötzlichen Herztod, Schlaganfall und die Gesamtmortalität auf. In der multivariaten Regressionsanalyse waren sowohl NT-proBNP als auch Troponin T jeweils starke unabhängige Prädiktoren für plötzlichen Herztod, Schlaganfall und die Gesamtmortalität. Eine Assoziation von NT-proBNP mit dem Auftreten von Myokardinfarkten wurde nicht gesehen. Nicht nur ein hoher Ausgangswert der Biomarker, sondern auch eine Zunahme von NT-proBNP und Troponin T nach 6 Monaten waren assoziiert mit einer schlechteren Langzeitprognose / This post-hoc analysis of the German Diabetes and Dialysis study examined the effect of baseline and change from baseline after 6 months of NT-proBNP and Troponin T on sudden death, stroke, myocardial infarction, and all-cause mortality in 1255 hemodialysis patients with type 2 diabetes mellitus with a median follow up of 4 years. Patients with increasing baseline NT-proBNP and Troponin T exhibited a higher risk of sudden death, stroke, and all-cause mortality. In multivariate regression analysis both, NT-proBNP and Troponin T, were independent predictors of sudden death, stroke, and all-cause mortality. Neither baseline nor change in NT-proBNP was significantly associated with myocardial infarction. Increased longitudinal levels of NT-proBNP and Troponin T during follow up were associated with higher risks of adverse cardiovascular outcomes and death.

It has been known that anthracycline-based chemotherapy has the potential to cause cardiac dysfunction in breast cancer patients; however, recently evidence has shown that the addition of trastuzumab increases this risk. The study objective was to compare the cost-effectiveness of monitoring for cardiotoxicity with B-type natriuretic peptide (BNP), multi-gated acquisition scanning (MUGA), echocardiography (ECHO) or no monitoring from a payer’s prospective. Cost-effectiveness was compared between alternatives using an incremental cost-effectiveness ratio with outcomes of 1) quality-adjusted life-years and 2) percentage of patients diagnosed with each monitoring strategy. Costs estimates (in 2010 U.S. Dollars) of each strategy (obtained from the Center for Medicare and Medicaid Services website [www.cms.gov]) included the cost of the test, cost of treating heart failure once discovered (which includes medications, routine office visits, medication management) and the cost of potential acute care (which includes emergency department visits and hospitalizations). Estimates for the probabilities of heart failure development, disease progression, need for acute care, and mortality, as well as utility estimates for all disease stages were obtained from published literature. A 15-year time-frame was used with a 3% discount rate for both costs and QALYs. In the base-case analysis, the average costs and QALYs for monitoring patients were $10,062/ 6.92 QALY, $13,627/4.22 QALY, $14,739/ 6.61 QALY and $15,656/ 6.49 QALY for BNP, No Monitoring, ECHO and MUGA respectively. When comparing all alternatives to BNP, the ICER values were negative, indicating that BNP was the dominant monitoring strategy. Percent detection was similar between the three monitoring methods [21-22 % for HER-2(-) and 30-31% for HER-2(+) patients]. Again BNP was dominant over the other monitoring strategies. Sensitivity analyses were robust to changes in discount rate, probability of patients testing HER-2 (+), probability of patients being diagnosed in an asymptomatic stage, incidence of cardiac dysfunction in patients receiving anthracycline therapy ± trastuzumab and estimate of disutility associated with additional testing. A probabilistic sensitivity analysis conducted via Monte Carlo simulation led to the same conclusion as the base-case analysis; BNP was the dominant strategy over all monitoring alternatives. / text