Nora E. Zois

Effect of Pancreatic Hormones on pro-Atrial Natriuretic Peptide in Humans

Plasma concentrations of pro-Atrial natriuretic peptide, proANP, are decreased in obesity and diabetes. Decreased proANP concentrations have also been noted after meal intake, and recently, a glucose-mediated regulation of ANP gene expression was reported. Hence, we evaluated the effects of insulin, glucagon and glucose on plasma proANP in a series of observational and experimental studies. Six healthy men underwent seven days of bed rest. Before and after the bed rest, hyperinsulinemic euglycemic clamps with serial plasma measurements of proANP were performed. Moreover, plasma proANP was quantified in 65 individuals with normal or impaired glucose regulation. Finally, the effects of infusion-induced hyperglucagonemia were examined in ten healthy men. Bed rest decreased insulin sensitivity and plasma proANP. The decrease in proANP was not associated with insulin sensitivity and the peptide concentrations remained constant during euglycemic hyperinsulinemia and hyperglycemic hyperglucagonemia. Impaired glucose regulation was not associated with decreased proANP concentrations. Bed rest per se induces a marked decrease in plasma proANP concentrations whereas insulin resistance and impaired glucose regulation was not associated with lower proANP concentrations. Neither acute hyperinsulinemia nor hyperglucagonemia seems to affect plasma proANP. Our findings thus suggest that decreased plasma proANP concentrations occur late in the development of insulin resistance.

Serotonin markers show altered transcription levels in an experimental pig model of mitral regurgitation.

Serotonin (5-hydroxytryptamine, 5-HT) signalling is implicated in the pathogenesis of myxomatous mitral valve disease (MMVD) through 5-HT1B receptor (R), 5-HT2AR and 5-HT2BR-induced myxomatous pathology. Based on increased tryptophan hydroxylase-1 (TPH-1) and decreased serotonin re-uptake transporter (SERT) in MMVD-affected valves, increased valvular 5-HT synthesis and decreased clearance have been suggested. It remains unknown how haemodynamic changes associated with mitral regurgitation (MR) affect 5-HT markers in the mitral valve, myocardium and circulation. Twenty-eight pigs underwent surgically induced MR or sham-operation, resulting in three MR groups: control (CON, n = 12), mild MR (mMR, n = 10) and severe MR (sMR, n = 6). The gene expression levels of 5-HT1BR, 5-HT2AR, 5-HT2BR, SERT and TPH-1 were analysed using quantitative PCR (qPCR) in the mitral valve (MV), anterior papillary muscle (AP) and left ventricle (LV). MV 5-HT2BR was also analysed with immunohistochemistry (IHC) in relation to histological lesions and valvular myofibroblasts. All 5-HTR mRNAs were up-regulated in MV compared to AP and LV (P <0.01). In contrast, SERT and TPH-1 were up-regulated in AP and LV compared to MV (P <0.05). In MV, mRNA levels were increased for 5-HT2BR (P = 0.02) and decreased for SERT (P = 0.03) in sMR vs. CON. There were no group differences in 5-HT2BR staining (IHC) but co-localisation was found with α-SMA-positive cells in 91% of all valves and with 33% of histological lesions. In LV, 5-HT1BR mRNA levels were increased in sMR vs. CON (P = 0.01). In conclusion, these data suggest that MR may affect mRNA expression of valvular 5-HT2BR and SERT, and left ventricular 5-HT1BR in some pigs.

Alpha-smooth muscle actin and serotonin receptors 2A and 2B in dogs with myxomatous mitral valve disease.

Canine Myxomatous mitral valve disease (MMVD) is an age-related disease. Serotonin (5-HT) is implicated in the pathogenesis as locally-produced or platelet-derived. Involvement of the 5-HT2A receptor (R) and 5-HT2BR in the induction of myxomatous-mediating valvular myofibroblasts (MF) has been suggested. In an age-matched population of dogs with non-clinical and clinical MMVD, the objectives were to investigate (1) gene expression of 5-HT2AR and 5-HT2BR, (2) protein expression and spatial relationship of 5-HT2AR, 5-HT2BR and MF in the mitral valve (MV) and the cardiac anterior papillary muscle (AP) and (3) serum 5-HT concentrations. Gene expression of 5-HT2BR was significantly higher in MV and AP among dogs with clinical MMVD. This was not found for 5-HT2BR protein expression, though association of 5-HT2BR with myxomatous pathology and co-localization of 5-HT2BR and MF in MV and AP support a functional relationship, perhaps perpetuation of clinical MMVD. 5-HT2AR-expression and serum 5-HT showed no differences between groups.

Matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs) and transforming growth factor-β (TGF-β) in advanced canine myxomatous mitral valve disease.

This study investigated mitral valve and myocardial protein and gene expression of matrix metalloproteinases (MMPs), their tissue inhibitors (TIMPs) and transforming growth factor-β (TGF-β) and plasma MMP and TGF-β concentrations in age-matched dog groups euthanized due to either advanced myxomatous mitral valve disease (MMVD) or other reasons. Furthermore, echocardiographic data and lumen/area ratio were correlated with tissue and plasma levels of MMPs, TIMPs and TGF-βs. Mitral valve and myocardial gene expression of MMP2, MMP14, TGF-β1 and TGF-β2 were increased and plasma MMP9 was decreased in advanced MMVD dogs. Myocardial gene expression of TIMP2 and TIMP3 were increased in advanced MMVD. All affected markers correlated to echocardiographic parameters. Significantly narrowed lumen/area ratio was associated with increased myocardial expression of MMP2, MMP14, TIMP2 and TIMP3. No differences in tissue protein expression were recorded. MMP2, MMP14, TIMP2, TIMP3, TGF-β1 and TGF-β2 appear to play a local role in the development of advanced MMVD.

Natriuretic peptides and cerebral hemodynamics.

Natriuretic peptides have emerged as important diagnostic and prognostic tools for cardiovascular disease. Plasma measurement of the bioactive peptides as well as precursor-derived fragments is a sensitive tool in assessing heart failure. In heart failure, the peptides are used as treatment in decompensated disease. In contrast, their biological effects on the cerebral hemodynamics are poorly understood. In this mini-review, we summarize the hemodynamic effects of the natriuretic peptides with a focus on the cerebral hemodynamics. In addition, we will discuss its potential implications in diseases where alteration of the cerebral hemodynamics plays a role such as migraine and acute brain injury including stroke. We conclude that a possible role of the peptides is feasible as evaluated from animal and in vitro studies, but more research is needed in humans to determine the precise response on cerebral vessels.

Coagulation profile in patients undergoing video-assisted thoracoscopic lobectomy: A randomized, controlled trial.

Background Knowledge about the impact of Low-Molecular-Weight Heparin (LMWH) on the coagulation system in patients undergoing minimal invasive lung cancer surgery is sparse. The aim of this study was to assess the effect of LMWH on the coagulation system in patients undergoing Video-Assisted Thoracoscopic Surgery (VATS) lobectomy for primary lung cancer. Methods Sixty-three patients diagnosed with primary lung cancer undergoing VATS lobectomy were randomized to either subcutaneous injection with dalteparin (Fragmin®) 5000 IE once daily or no intervention. Coagulation was assessed pre-, peri-, and the first two days postoperatively by standard coagulation blood test, thromboelastometry (ROTEM®) and thrombin generation. Results Patients undergoing potential curative surgery for lung cancer were not hypercoagulable preoperatively. There was no statistically significant difference in the majority of the assessed coagulation parameters after LMWH, except that the no intervention group had a higher peak thrombin and a shorter INTEM clotting time on the first postoperative day and a lower fibrinogen level on the second postoperative day. A lower level of fibrin d-dimer in the LMWH group was found on the 1. and 2.postoperative day, although not statistical significant. No differences were found between the two groups in the amount of bleeding or number of thromboembolic events. Conclusions Use of LMWH administered once daily as thromboprophylaxis did not alter the coagulation profile per se. As the present study primarily evaluated biochemical endpoints, further studies using clinical endpoints are needed in regards of an optimized thromboprophylaxis approach.

Strong association between activated valvular interstitial cells and histopathological lesions in porcine model of induced mitral regurgitation

Strong association between activated valvular interstitial cells and histopathological lesions in porcine model of induced mitral regurgitation☆ S.E. Cremer , N.E. Zois , S.G. Moesgaard , N. Ravn , S. Cirera , J.L. Honge , M.H. Smerup , J.M. Hasenkam , E. Sloth , P.S. Leifsson , T. Falk , M.A. Oyama , C. Orton , T. Martinussen , L.H. Olsen a,⁎,1 a Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg, Denmark b Department of Clinical Biochemistry, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark c Novo Nordisk A/S, Maaloev, Denmark d Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Aarhus, Denmark e Department of Veterinary Clinical and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark f Department of Anaesthesiology and Intensive Care Medicine, Aarhus University Hospital, Aarhus, Denmark g Department of Clinical Studies, University of Pennsylvania, Philadelphia, PA, USA h Department of Clinical Sciences, Colorado State University, Fort Collins, CO, USA i Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark

Cardiac natriuretic peptides in plasma: from prediction to precision medicine

www.thelancet.com/diabetes-endocrinology Vol 4 October 2016 803 kidney disease. A combined analysis from the PLANET studies showed that individuals randomly assigned to atorvastatin not only had lower levels of proteinuria at the end of the 12-month study but also had signifi cantly slower decline in kidney function. Findings of other studies have suggested that at least some statins might have benefi cial eff ects on kidney function. Although eff ects on kidney function were not assessed in the CTT Collaboration’s current meta-analysis, it is an important topic worthy of more detailed analysis, and ideally suited to the CTT Collaboration’s datasets, and perhaps studies of PCSK9 inhibitors. Although the results from this CTT Collaboration meta-analysis provide clear evidence of the role of statins in chronic kidney disease, they raise further questions about the eff ects of lipid-lowering in advanced disease and highlight the importance of new trials with highly eff ective agents in this population. By defi ning what we still do not know, this analysis will hopefully encourage further studies that improve outcomes for this high-risk patient group.

Development of left ventricular hypertrophy in a novel porcine model of mitral regurgitation

Abstract Objectives. We aimed to develop a porcine model for chronic nonischemic mitral regurgitation (MR) to investigate left ventricular (LV) enlargement and eccentric hypertrophy. Design. Nonischemic MR was induced in 30 pigs by open-chest immobilization of the posterior mitral leaflet by transannular traction sutures that where applied in transmyocardial fashion. A sham operated control group (n = 13) was included. Echocardiographic LV size and heart weight assessed at euthanasia were used to evaluate the development of LV enlargement and eccentric hypertrophy after 8 weeks follow-up. Results. Eight pigs died and seven were excluded due to mediastinal infection (n = 2) or failure to produce MR (n = 5). Thus, 28 pigs were included and were divided into three groups: controls (n = 12), mild MR (mMR; n = 10), and moderate to severe MR (sMR; n = 6). The change in LV internal diameter in diastole (LVIDd) from baseline to follow-up was significantly higher in the sMR group compared to that of the control group (P = 0.0017). Furthermore, LV weight was significantly increased in the mMR (P = 0.047) and the sMR (P = 0.0087) groups compared to that of the control group. Conclusions. A new model for chronic moderate to severe nonischemic MR with development of LV enlargement and eccentric hypertrophy within 8 weeks has been established in pigs.

Cardiac procholecystokinin expression during haemodynamic changes in the mammalian heart

&NA; Cardiac myocytes express the cholecystokinin gene (CCK) at propeptide level. We recently reported that cardiac CCK expression is acutely regulated by isoprenaline in a porcine model. The regulation of CCK expression after myocardial infarction, in exercise, and in severe heart failure is, however, unknown. Cardiac tissue was obtained from healthy new‐born and adolescent farm pigs. Myocardial infarction was induced by coronary artery occlusion in adult minipigs. Healthy male subjects performed a 3‐hour exercise test, and patients with severe heart failure referred for right heart catheterization were included. Extracts of porcine cardiac tissue and human plasma were analysed with specific proCCK radioimmunoassays. Cardiac proCCK expression shifted from the right atrium in new‐born piglets to include the left atrium in adolescent pigs. Regional proCCK expression in the adolescent pig heart was mainly confined to the atria without different expression in sinus node tissue. In adult minipigs with myocardial infarction, no changes in overall left ventricular function or proCCK expression were observed after 8 weeks. In healthy adults, proCCK in circulation increased markedly during exercise in parallel with pro‐B‐type natriuretic peptide. Finally, patients with severe heart failure displayed markedly increased proCCK – but not CCK – concentrations in plasma. Taken together, our data shows that regional proCCK expression reflects haemodynamic changes in the mammalian heart. The data supports the notion that cardiac CCK expression resembles that of cardiac natriuretic peptides in atria. The ventricular content of proCCK, however, differs from natriuretic peptides and suggests a distinct secretory pathway in ventricular cardiomyocytes. HighlightsCardiac expression of procholecystokinin (proCCK) reflects hemodynamic changes in mammalian hearts.Ventricular cardiomyocytes store proCCK, contrasting natriuretic peptides.Patients with severe systolic heart failure display markedly increased proCCK in plasma.ProCCK in plasma seems independent of cardiac index and pulmonary capillary pressure.