Publications by authors named "Paul Mulder"

264 Publications

Soluble Epoxide Hydrolase Inhibition Prevents Experimental Type 4 Cardiorenal Syndrome.

Front Mol Biosci 2020 11;7:604042. Epub 2021 Mar 11.

Normandie University, UNIROUEN, INSERM U1096, FHU REMOD-VHF, Rouen, France.

Cardiovascular diseases (CVD) remain the leading cause of morbimortality in patients with chronic kidney disease (CKD). The aim of this study was to assess the cardiovascular impact of the pharmacological inhibition of soluble epoxide hydrolase (sEH), which metabolizes the endothelium-derived vasodilatory and anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acid (DHETs), in the 5/6 nephrectomy (Nx) mouse model. Compared to sham-operated mice, there was decrease in EET-to-DHET ratio 3 months after surgery in vehicle-treated Nx mice but not in mice treated with the sEH inhibitor -AUCB. Nx induced an increase in plasma creatinine and in urine albumin-to-creatinine ratio as well as the development of kidney histological lesions, all of which were not modified by -AUCB. In addition, -AUCB did not oppose Nx-induced blood pressure increase. However, AUCB prevented the development of cardiac hypertrophy and fibrosis induced by Nx, as well as normalized the echocardiographic indices of diastolic and systolic function. Moreover, the reduction in endothelium-dependent flow-mediated dilatation of isolated mesenteric arteries induced by Nx was blunted by -AUCB without change in endothelium-independent dilatation to sodium nitroprusside. Inhibition of sEH reduces the cardiac remodelling, and the diastolic and systolic dysfunctions associated with CKD. These beneficial effects may be mediated by the prevention of endothelial dysfunction, independent from kidney preservation and antihypertensor effect. Thus, inhibition of sEH holds a therapeutic potential in preventing type 4 cardiorenal syndrome.
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http://dx.doi.org/10.3389/fmolb.2020.604042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991096PMC
March 2021

Mineralocorticoid receptor blockade with finerenone improves heart function and exercise capacity in ovariectomized mice.

ESC Heart Fail 2021 Mar 20. Epub 2021 Mar 20.

Inserm U1096 ENVI, Rouen Medical School, UNIROUEN, Normandy University, Rouen, France.

Aims: In post-menopausal women, incidence of heart failure with preserved ejection fraction is higher than in men. Hormonal replacement therapies did not demonstrate benefits. We tested whether the non-steroidal mineralocorticoid receptor antagonist finerenone limits the progression of heart failure in ovariectomized (OVX) mice with metabolic disorders.

Methods And Results: Ovariectomy was performed in 4-month-old mice, treated or not at 7 months old for 1 month with finerenone (Fine) 1 mg/kg/day. Left ventricular (LV) cardiac and coronary endothelial functions were assessed by echocardiography, catheterization, and myography. Blood pressure was measured by plethysmography. Insulin and glucose tolerance tests were performed. Exercise capacity and spontaneous activity were measured on treadmill and in combined indirect calorimetric cages equipped with voluntary running wheel. OVX mice presented LV diastolic dysfunction without modification of ejection fraction compared with controls (CTL), whereas finerenone improved LV filling pressure (LV end-diastolic pressure, mmHg: CTL 3.48 ± 0.41, OVX 6.17 ± 0.30**, OVX + Fine 3.65 ± 0.55 , **P < 0.01 vs. CTL, P < 0.05 vs. OVX) and compliance (LV end-diastolic pressure-volume relation, mmHg/RVU: CTL 1.65 ± 0.42, OVX 4.77 ± 0.37***, OVX + Fine 2.87 ± 0.26 , ***P < 0.001 vs. CTL, P < 0.01 vs. OVX). Acetylcholine-induced endothelial-dependent relaxation of coronary arteries was impaired in ovariectomized mice and improved by finerenone (relaxation, %: CTL 86 ± 8, OVX 38 ± 3**, OVX + Fine 83 ± 7 , **P < 0.01 vs. CTL, P < 0.01 vs. OVX). Finerenone improved decreased ATP production by subsarcolemmal mitochondria after ovariectomy. Weight gain, increased blood pressure, and decreased insulin and glucose tolerance in OVX mice were improved by finerenone. The exercise capacity at race was diminished in untreated OVX mice only. Spontaneous activity measurements in ovariectomized mice showed decreased horizontal movements, reduced time spent in a running wheel, and reduced VO and VCO , all parameters improved by finerenone.

Conclusions: Finerenone improved cardiovascular dysfunction and exercise capacity after ovariectomy-induced LV diastolic dysfunction with preserved ejection fraction.
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http://dx.doi.org/10.1002/ehf2.13219DOI Listing
March 2021

Antifibrotic effect of novel neutrophil gelatinase-associated lipocalin inhibitors in cardiac and renal disease models.

Sci Rep 2021 Jan 28;11(1):2591. Epub 2021 Jan 28.

INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, 15 rue de l'Ecole de Médecine, 75006, Paris, France.

Neutrophil gelatinase-associated lipocalin (NGAL) is involved in cardiovascular and renal diseases. Gene inactivation of NGAL blunts the pathophysiological consequences of cardiovascular and renal damage. We aimed to design chemical NGAL inhibitors and investigate its effects in experimental models of myocardial infarction (MI) and chronic kidney disease induced by 5/6 nephrectomy (CKD) on respectively 8-12 weeks old C57Bl6/j and FVB/N male mice. Among the 32 NGAL inhibitors tested, GPZ614741 and GPZ058225 fully blocked NGAL-induced inflammatory and profibrotic markers in human cardiac fibroblasts and primary mouse kidney fibroblasts. The administration of GPZ614741 (100 mg/kg/day) for three months, was able to improve cardiac function in MI mice and reduced myocardial fibrosis and inflammation. The administration of GPZ614741 (100 mg/kg/day) for two months resulting to no renal function improvement but prevented the increase in blood pressure, renal tubulointerstitial fibrosis and profibrotic marker expression in CKD mice. In conclusion, we have identified new compounds with potent inhibitory activity on NGAL-profibrotic and pro-inflammatory effects. GPZ614741 prevented interstitial fibrosis and dysfunction associated with MI, as well as tubulointerstitial fibrosis in a CKD model. These inhibitors could be used for other diseases that involve NGAL, such as cancer or metabolic diseases, creating new therapeutic options.
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http://dx.doi.org/10.1038/s41598-021-82279-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844219PMC
January 2021

Transient heart rate reduction improves acute decompensated heart failure-induced left ventricular and coronary dysfunction.

ESC Heart Fail 2021 Apr 20;8(2):1085-1095. Epub 2021 Jan 20.

Normandie Université, UNIROUEN, Inserm U1096 Endothelium, Valvulopathy and Heart Failure, Rouen, 76183, France.

Aims: Acute decompensated heart failure (ADHF), a live-threatening complication of heart failure (HF), associates a further decrease of the already by HF-impaired cardiac function with an increase in heart rate. We evaluated, using a new model of ADHF, whether heart rate reduction (HRR) opposes the acute decompensation-related aggravation of cardiovascular dysfunction.

Methods And Results: Cardiac output (echocardiography), cardiac tissue perfusion (magnetic resonance imaging), pulmonary wet weight, and in vitro coronary artery relaxation (Mulvany) were assessed 1 and 14 days after acute decompensation induced by salt-loading (1.8 g/kg, PO) in rats with well-established HF due to coronary ligation. HRR was induced by administration of the I current inhibitor S38844, 12 mg/kg PO twice daily for 2.5 days initiated 12 h or 6 days after salt-loading (early or delayed treatment, respectively). After 24 h, salt-loading resulted in acute decompensation, characterized by a reduction in cardiac output (HF: 130 ± 5 mL/min, ADHF: 105 ±  8 mL/min; P < 0.01), associated with a decreased myocardial perfusion (HF: 6.41 ± 0.53 mL/min/g, ADHF: 4.20 ± 0.11 mL/min/g; P < 0.01), a slight increase in pulmonary weight (HF: 1.68 ± 0.09 g, ADHF: 1.81 ± 0.15 g), and impaired coronary relaxation (HF: 55 ± 1% of pre-contraction at acetylcholine 4.5 10  M, ADHF: 27 ± 7 %; P < 0.01). Fourteen days after salt-loading, cardiac output only partially recovered (117 ± 5 mL/min; P < 0.05), while myocardial tissue perfusion (4.51 ± 0.44 mL/min; P < 0.01) and coronary relaxation (28 ± 4%; P < 0.01) remained impaired, but pulmonary weight further increased (2.06 ± 0.15 g, P < 0.05). Compared with untreated ADHF, HRR induced by S38844 improved cardiac output (125 ± 1 mL/min; P < 0.05), myocardial tissue perfusion (6.46 ± 0.42 mL/min/g; P < 0.01), and coronary relaxation (79 ± 2%; P < 0.01) as soon as 12 h after S38844 administration. These effects persisted beyond S38844 administration, illustrated by the improvements in cardiac output (130 ± 6 mL/min; P < 0.05), myocardial tissue perfusion (6.38 ± 0.48 mL/min/g; P < 0.01), and coronary relaxation (71 ± 4%; P < 0.01) at Day 14. S38844 did not modify pulmonary weight at Day 1 (1.78 ± 0.04 g) but tended to decrease pulmonary weight at Day 14 (1.80 ± 0.18 g). While delayed HRR induced by S38844 never improved cardiac function, early HRR rendered less prone to a second acute decompensation.

Conclusions: In a model mimicking human ADHF, early, but not delayed, transient HRR induced by the I current inhibitor S38844 opposes acute decompensation by preventing the decompensated-related aggravation of cardiovascular dysfunction as well as the development of pulmonary congestion, and these protective effects persist beyond the transient treatment. Whether early transient HRR induced by I current inhibitors or other bradycardic agents, i.e. beta-blockers, exerts beneficial effects in human ADHF warrants further investigation.
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http://dx.doi.org/10.1002/ehf2.13094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006644PMC
April 2021

Cardiopulmonary bypass increases endothelial dysfunction after pulmonary ischaemia-reperfusion in an animal model.

Eur J Cardiothorac Surg 2020 Dec 4. Epub 2020 Dec 4.

Normandie Univ, UNIVROUEN, INSERM U1096, Rouen, France.

Objectives: Endothelial dysfunction during ischaemia-reperfusion (IR) is a major cause of primary graft dysfunction during lung transplantation. The routine use of cardiopulmonary bypass (CPB) during lung transplantation remains controversial. However, the contribution of CPB to pulmonary endothelial dysfunction remains unclear. The objective was to investigate the impact of CPB on endothelial dysfunction in a lung IR rat model.

Methods: Rats were allocated to 4 groups: (i) Sham, (ii) IR, (iii) CPB and (iv) IR-CPB. The primary outcome was the study of pulmonary vascular reactivity by wire myograph. We also assessed glycocalyx degradation by enzyme-linked immunosorbent assay and electron microscopy and both systemic and pulmonary inflammation by enzyme-linked immunosorbent assay and immunohistochemistry. Rats were exposed to 45 min of CPB and IR. We used a CPB model allowing femoro-femoral support with left pulmonary hilum ischaemia for IR.

Results: Pulmonary endothelium-dependent relaxation to acetylcholine was markedly reduced in the IR-CPB group (10.7 ± 9.1%) compared to the IR group (50.5 ± 5.2%, P < 0.001), the CPB group (54.1 ± 4.7%, P < 0.001) and the sham group (80.8 ± 6.7%, P < 0.001), suggesting that the association of pulmonary IR and CPB increases endothelial dysfunction. In IR-CPB, IR and CPB groups, vasorelaxation was completely abolished when inhibiting nitric oxide synthase, suggesting that this relaxation process was mainly mediated by nitric oxide. We observed higher syndecan-1 plasma levels in the IR-CPB group in comparison with the other groups, reflecting an increased degradation of glycocalyx. We also observed higher systemic inflammation in the IR-CPB group as shown by the increased plasma levels of IL-1β, IL-10.

Conclusions: CPB significantly increased the IR-mediated effects on pulmonary endothelial dysfunction. Therefore, the use of CPB during lung transplantation could be deleterious, by increasing endothelial dysfunction.
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http://dx.doi.org/10.1093/ejcts/ezaa412DOI Listing
December 2020

The effect of different anaesthetics on echocardiographic evaluation of diastolic dysfunction in a heart failure with preserved ejection fraction model.

Sci Rep 2020 09 24;10(1):15701. Epub 2020 Sep 24.

Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Herestraat 49, Bus 911, 3000, Leuven, Belgium.

Heart failure with preserved ejection fraction (HFpEF) is currently untreated. Therapeutics development demands effective diagnosis of diastolic dysfunction in animal models mimicking human pathology, which requires appropriate anaesthetics. Here, we investigated which anaesthetic, ketamine/xylazine or isoflurane, could be used to reveal diastolic dysfunction in HFpEF-diseased obese ZSF1 rats by echocardiography. First, diastolic dysfunction was confirmed by pressure-volume loops in obese compared to lean control ZSF1 rats. In echocardiography, ketamine/xylazine, unlike isoflurane, was able to demonstrate impaired relaxation in obese ZSF1 rats, as reflected by impaired early (E) and late (A) filling peak velocities, decreased E/A ratio, and a prolonged deceleration and isovolumic relaxation time. Interestingly, ketamine/xylazine induced a wider separation of both tissue and pulsed wave Doppler-derived echocardiographic waves required for diastolic dysfunction diagnosis, potentially by reducing the heart rate (HR), while isoflurane resulted in merged waves. To assess whether HR-lowering alone explained the differences between the anaesthetics, echocardiography measurements under isoflurane with and without the HR-lowering drug ivabradine were compared. However, diastolic dysfunction could not be diagnosed in ivabradine-treated obese ZSF1 rats. In summary, ketamine/xylazine compared to isoflurane is the anaesthetic of choice to detect diastolic dysfunction by echocardiography in rodent HFpEF, which was only partly mediated by HR-lowering.
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http://dx.doi.org/10.1038/s41598-020-72924-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518268PMC
September 2020

Nitrogen Dioxide Inhalation Exposures Induce Cardiac Mitochondrial Reactive Oxygen Species Production, Impair Mitochondrial Function and Promote Coronary Endothelial Dysfunction.

Int J Environ Res Public Health 2020 07 30;17(15). Epub 2020 Jul 30.

Normandie Univ, UNIROUEN, UNICAEN ABTE, 14000 Caen et, 76 000 Rouen, France.

Traffic air pollution is a major health problem and is recognized as an important risk factor for cardiovascular (CV) diseases. In a previous experimental study, we showed that diesel exhaust (DE) exposures induced cardiac mitochondrial and CV dysfunctions associated with the gaseous phase. Here, we hypothesized that NO exposures to levels close to those found in DE induce a mitochondrial reactive oxygen species (ROS) production, which contribute to an endothelial dysfunction, an early indicator for numerous CV diseases. For this, we studied the effects of NO on ROS production and its impacts on the mitochondrial, coronary endothelial and cardiac functions, after acute (one single exposure) and repeated (three h/day, five days/week for three weeks) exposures in Wistar rats. Acute NO exposure induced an early but reversible mitochondrial ROS production. This event was isolated since neither mitochondrial function nor endothelial function were impaired, whereas cardiac function assessment showed a reversible left ventricular dysfunction. Conversely, after three weeks of exposure this alteration was accompanied by a cardiac mitochondrial dysfunction highlighted by an alteration of adenosine triphosphate (ATP) synthesis and oxidative phosphorylation and an increase in mitochondrial ROS production. Moreover, repeated NO exposures promoted endothelial dysfunction of the coronary arteries, as shown by reduced acetylcholine-induced vasodilatation, which was due, at least partially, to a superoxide-dependent decrease of nitric oxide (NO) bioavailability. This study shows that NO exposures impair cardiac mitochondrial function, which, in conjunction with coronary endothelial dysfunction, contributes to cardiac dysfunction. Together, these results clearly identify NO as a probable risk factor in ischemic heart diseases.
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http://dx.doi.org/10.3390/ijerph17155526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432061PMC
July 2020

Short-and long-term administration of imeglimin counters cardiorenal dysfunction in a rat model of metabolic syndrome.

Endocrinol Diabetes Metab 2020 Jul 16;3(3):e00128. Epub 2020 Apr 16.

UNIROUEN Inserm U1096 FHU-REMOD-VHF Normandie Univ Rouen France.

Introduction: Imeglimin, a glucose-lowering agent targeting mitochondrial bioenergetics, decreases reactive oxygen species (ROS) overproduction and improves glucose homeostasis. We investigated whether this is associated with protective effects on metabolic syndrome-related left ventricular (LV) and vascular dysfunctions.

Methods: We used Zucker rats to assess the effects on LV function, LV tissue perfusion, LV oxidative stress and vascular function induced by imeglimin administered orally for 9 or 90 days at a dose of 150 mg/kg twice daily.

Results: Compared to untreated animals, 9- and 90-day imeglimin treatment decreased LV end-diastolic pressure and LV end-diastolic pressure-volume relation, increased LV tissue perfusion and decreased LV ROS production. Simultaneously, imeglimin restored acetylcholine-mediated coronary relaxation and mesenteric flow-mediated dilation. One hour after imeglimin administration, when glucose plasma levels were not yet modified, imeglimin reduced LV mitochondrial ROS production and improved LV function. Ninety-day imeglimin treatment reduced related LV and kidney fibrosis and improved kidney function.

Conclusion: In a rat model, mimicking Human metabolic syndrome, imeglimin immediately countered metabolic syndrome-related cardiac diastolic and vascular dysfunction by reducing oxidative stress/increased NO bioavailability and improving myocardial perfusion and after 90-day treatment myocardial and kidney structure, effects that are, at least in part, independent from glucose control.
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http://dx.doi.org/10.1002/edm2.128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375119PMC
July 2020

Hypertonic sodium lactate improves microcirculation, cardiac function, and inflammation in a rat model of sepsis.

Crit Care 2020 06 16;24(1):354. Epub 2020 Jun 16.

Normandie Université, UNIROUEN, Inserm U1096, FHU-REMOD-VHF, 76000, Rouen, France.

Background: Hypertonic sodium lactate (HSL) may be of interest during inflammation. We aimed to evaluate its effects during experimental sepsis in rats (cecal ligation and puncture (CLP)).

Methods: Three groups were analyzed (n = 10/group): sham, CLP-NaCl 0.9%, and CLP-HSL (2.5 mL/kg/h of fluids for 18 h after CLP). Mesenteric microcirculation, echocardiography, cytokines, and biochemical parameters were evaluated. Two additional experiments were performed for capillary leakage (Evans blue, n = 5/group) and cardiac hemodynamics (n = 7/group).

Results: HSL improved mesenteric microcirculation (CLP-HSL 736 [407-879] vs. CLP-NaCl 241 [209-391] UI/pixel, p = 0.0006), cardiac output (0.34 [0.28-0.43] vs. 0.14 [0.10-0.18] mL/min/g, p < 0.0001), and left ventricular fractional shortening (55 [46-73] vs. 39 [33-52] %, p = 0.009). HSL also raised dP/dt slope (6.3 [3.3-12.1] vs. 2.7 [2.0-3.9] 10 mmHg/s, p = 0.04), lowered left ventricular end-diastolic pressure-volume relation (1.9 [1.1-2.3] vs. 3.0 [2.2-3.7] RVU/mmHg, p = 0.005), and reduced Evans blue diffusion in the gut (37 [31-43] vs. 113 [63-142], p = 0.03), the lung (108 [82-174] vs. 273 [222-445], p = 0.006), and the liver (24 [14-37] vs. 70 [50-89] ng EB/mg, p = 0.04). Lactate and 3-hydroxybutyrate were higher in CLP-HSL (6.03 [3.08-10.30] vs. 3.19 [2.42-5.11] mmol/L, p = 0.04; 400 [174-626] vs. 189 [130-301] μmol/L, p = 0.03). Plasma cytokines were reduced in HSL (IL-1β, 172 [119-446] vs. 928 [245-1470] pg/mL, p = 0.004; TNFα, 17.9 [12.5-50.3] vs. 53.9 [30.8-85.6] pg/mL, p = 0.005; IL-10, 352 [267-912] vs. 905 [723-1243] pg/mL) as well as plasma VEGF-A (198 [185-250] vs. 261 [250-269] pg/mL, p = 0.009).

Conclusions: Hypertonic sodium lactate fluid protects against cardiac dysfunction, mesenteric microcirculation alteration, and capillary leakage during sepsis and simultaneously reduces inflammation and enhances ketone bodies.
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http://dx.doi.org/10.1186/s13054-020-03083-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298868PMC
June 2020

Abdominal aortic aneurysm patients remain at risk for delirium on the surgical ward after intensive care unit dismissal.

Minerva Anestesiol 2020 Sep 12;86(9):930-938. Epub 2020 Jun 12.

Department of Surgery, Amphia Hospital, Breda, the Netherlands.

Background: The incidence of delirium following open abdominal aortic aneurysm (AAA) surgery is significant, with incidence rates ranging from 12% to 33%. However, it remains unclear on what level of care a delirium develops in AAA patients. The aim of this study was to investigate the incidence of delirium in the ICU and on the surgical ward after AAA surgery.

Methods: A single-center retrospective cohort study was conducted that included all patients treated electively for an open AAA repair and patients who underwent emergency treatment for a ruptured AAA between 2013 and 2018. The diagnosis of delirium was verified by a psychiatrist or geriatrician using the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) criteria. The incidence of delirium was calculated. Cox proportional hazards regression analyses were used to analyze 6- and 12-month survival.

Results: A total of 135 patients were included, 46 patients (34%) had a delirium during admission. Of these, 30 patients (65%) developed a delirium in the ICU and 16 patients (35%) on the surgical ward. There was no significant difference in six months and twelve months mortality between the ICU and ward delirium groups (HR=1.64, 95% CI: 0.33-8.13, and HR=1.12, 95% CI: 0.28-4.47, respectively).

Conclusions: Delirium frequently occurs in patients who undergo AAA surgery. This study demonstrated that patients on the surgical ward remain at risk of developing a delirium after ICU dismissal. Patients with ICU delirium differ in clinical characteristics and outcomes from patients with a delirium on the surgical ward.
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http://dx.doi.org/10.23736/S0375-9393.20.14281-0DOI Listing
September 2020

Microvascular and lymphatic dysfunction in HFpEF and its associated comorbidities.

Basic Res Cardiol 2020 05 25;115(4):39. Epub 2020 May 25.

Institut National de la Santé et de la Recherche Médicale (Inserm) UMR1096, Faculty of Medicine and Pharmacy, Normandy University, 22 Boulevard Gambetta, 76183, Rouen, France.

Heart failure with preserved ejection fraction (HFpEF) is a complex heterogeneous disease for which our pathophysiological understanding is still limited and specific prevention and treatment strategies are lacking. HFpEF is characterised by diastolic dysfunction and cardiac remodelling (fibrosis, inflammation, and hypertrophy). Recently, microvascular dysfunction and chronic low-grade inflammation have been proposed to participate in HFpEF development. Furthermore, several recent studies demonstrated the occurrence of generalized lymphatic dysfunction in experimental models of risk factors for HFpEF, including obesity, hypercholesterolaemia, type 2 diabetes mellitus (T2DM), hypertension, and aging. Here, we review the evidence for a combined role of coronary (micro)vascular dysfunction and lymphatic vessel alterations in mediating key pathological steps in HFpEF, including reduced cardiac perfusion, chronic low-grade inflammation, and myocardial oedema, and their impact on cardiac metabolic alterations (oxygen and nutrient supply/demand imbalance), fibrosis, and cardiomyocyte stiffness. We focus primarily on HFpEF caused by metabolic risk factors, such as obesity, T2DM, hypertension, and aging.
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http://dx.doi.org/10.1007/s00395-020-0798-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248044PMC
May 2020

Lymphatic and Immune Cell Cross-Talk Regulates Cardiac Recovery After Experimental Myocardial Infarction.

Arterioscler Thromb Vasc Biol 2020 07 14;40(7):1722-1737. Epub 2020 May 14.

From the Normandy University, UniRouen, Inserm (Institut National de la Santé et de la Recherche Médicale) UMR1096 (EnVI Laboratory), FHU REMOD-VHF, Rouen, France (H.M., A.D., V.T., I.B., J.P.H., S.R., J.R., S.F., V.R., P.M.).

Objective: Lymphatics play an essential pathophysiological role in promoting fluid and immune cell tissue clearance. Conversely, immune cells may influence lymphatic function and remodeling. Recently, cardiac lymphangiogenesis has been proposed as a therapeutic target to prevent heart failure after myocardial infarction (MI). We investigated the effects of gene therapy to modulate cardiac lymphangiogenesis post-MI in rodents. Second, we determined the impact of cardiac-infiltrating T cells on lymphatic remodeling in the heart. Approach and Results: Comparing adenoviral versus adeno-associated viral gene delivery in mice, we found that only sustained VEGF (vascular endothelial growth factor)-C therapy, achieved by adeno-associated viral vectors, increased cardiac lymphangiogenesis, and led to reduced cardiac inflammation and dysfunction by 3 weeks post-MI. Conversely, inhibition of VEGF-C/-D signaling, through adeno-associated viral delivery of soluble VEGFR3 (vascular endothelial growth factor receptor 3), limited infarct lymphangiogenesis. Unexpectedly, this treatment improved cardiac function post-MI in both mice and rats, linked to reduced infarct thinning due to acute suppression of T-cell infiltration. Finally, using pharmacological, genetic, and antibody-mediated prevention of cardiac T-cell recruitment in mice, we discovered that both CD4 and CD8 T cells potently suppress, in part through interferon-γ, cardiac lymphangiogenesis post-MI.

Conclusions: We show that resolution of cardiac inflammation after MI may be accelerated by therapeutic lymphangiogenesis based on adeno-associated viral gene delivery of VEGF-C. Conversely, our work uncovers a major negative role of cardiac-recruited T cells on lymphatic remodeling. Our results give new insight into the interconnection between immune cells and lymphatics in orchestration of cardiac repair after injury.
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http://dx.doi.org/10.1161/ATVBAHA.120.314370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310303PMC
July 2020

Delineation of phenotypes and genotypes related to cohesin structural protein RAD21.

Hum Genet 2020 May 19;139(5):575-592. Epub 2020 Mar 19.

Department of Pediatrics, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands.

RAD21 encodes a key component of the cohesin complex, and variants in RAD21 have been associated with Cornelia de Lange Syndrome (CdLS). Limited information on phenotypes attributable to RAD21 variants and genotype-phenotype relationships is currently published. We gathered a series of 49 individuals from 33 families with RAD21 alterations [24 different intragenic sequence variants (2 recurrent), 7 unique microdeletions], including 24 hitherto unpublished cases. We evaluated consequences of 12 intragenic variants by protein modelling and molecular dynamic studies. Full clinical information was available for 29 individuals. Their phenotype is an attenuated CdLS phenotype compared to that caused by variants in NIPBL or SMC1A for facial morphology, limb anomalies, and especially for cognition and behavior. In the 20 individuals with limited clinical information, additional phenotypes include Mungan syndrome (in patients with biallelic variants) and holoprosencephaly, with or without CdLS characteristics. We describe several additional cases with phenotypes including sclerocornea, in which involvement of the RAD21 variant is uncertain. Variants were frequently familial, and genotype-phenotype analyses demonstrated striking interfamilial and intrafamilial variability. Careful phenotyping is essential in interpreting consequences of RAD21 variants, and protein modeling and dynamics can be helpful in determining pathogenicity. The current study should be helpful when counseling families with a RAD21 variation.
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http://dx.doi.org/10.1007/s00439-020-02138-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170815PMC
May 2020

Major hepatectomy decreased tumor growth in an experimental model of bilobar liver metastasis.

HPB (Oxford) 2020 Oct 7;22(10):1480-1489. Epub 2020 Mar 7.

Department of Hepatobiliary and Liver Transplantation - Paul Brousse University Hospital, France.

Background/purpose: Two-stage hepatectomy (TSH), is associated with a risk of drop-out due to tumoral progression following portal vein occlusion (PVO). We explored the impact of majorhepatectomy on tumor growth by objective radiological measures comparing to PVO and minor hepatectomy, using a model of bilobar colorectal liver metastasis (CLM).

Methods: CLM were induced in 48 BDIX rats by injection of DHDK12-cells. 7 days after cells injection, animals were distributed into 4 groups of equal number (n = 12): portal vein ligation (PVL), sham laparotomy (sham), minor (30%Phx) and major (70%Phx) hepatectomy. MR imaging was used for in vivo analysis of tumor implantation, growth and volumes.

Results: At POD10, tumour volumes were homogeneously distributed among the 4 groups. Lower TV were significantly observed after 70%Phx comparing to PVL at POD17 (0.63 ± 0.14cm3 vs 0.9 ± 0.16cm3, p = 0.008) and to the 3 others groups at POD24: 1.78 ± 0.38cm3 vs 3.2 ± 0.62cm3 (PVL, p = 0.019), 2.41 ± 0.74cm3 (Sham, p = 0.024) and 2.32 ± 0.59cm3 (30%PHx, p = 0.019).

Conclusion: We confirmed in a reproducible model that contrary to PVO, a major hepatectomy decreases the growth of CLM in the remnant liver. This result leads to questioning the usual TSH and justifies exploring alternative strategies. The "major hepatectomy first-approach" should be an option to be evaluated.
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http://dx.doi.org/10.1016/j.hpb.2020.02.008DOI Listing
October 2020

5/6 nephrectomy induces different renal, cardiac and vascular consequences in 129/Sv and C57BL/6JRj mice.

Sci Rep 2020 01 30;10(1):1524. Epub 2020 Jan 30.

Normandie Univ, UNIROUEN, INSERM U1096, FHU REMOD-VHF, 76000, Rouen, France.

Experimental models of cardiovascular diseases largely depend on the genetic background. Subtotal 5/6 nephrectomy (5/6 Nx) is the most frequently used model of chronic kidney disease (CKD) in rodents. However, in mice, cardiovascular consequences of 5/6 Nx are rarely reported in details and comparative results between strains are scarce. The present study detailed and compared the outcomes of 5/6 Nx in the 2 main strains of mice used in cardiovascular and kidney research, 129/Sv and C57BL/6JRj. Twelve weeks after 5/6 Nx, CKD was demonstrated by a significant increase in plasma creatinine in both 129/Sv and C57BL/6JRj male mice. Polyuria and kidney histological lesions were more pronounced in 129/Sv than in C57BL/6JRj mice. Increase in albuminuria was significant in 129/Sv but not in C57BL/6JRj mice. Both strains exhibited an increase in systolic blood pressure after 8 weeks associated with decreases in cardiac systolic and diastolic function. Heart weight increased significantly only in 129/Sv mice. Endothelium-dependent mesenteric artery relaxation to acetylcholine was altered after 5/6 Nx in C57BL/6JRj mice. Marked reduction of endothelium-dependent vasodilation to increased intraluminal flow was demonstrated in both strains after 5/6 Nx. Cardiovascular and kidney consequences of 5/6 Nx were more pronounced in 129/Sv than in C57BL/6JRj mice.
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http://dx.doi.org/10.1038/s41598-020-58393-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992698PMC
January 2020

Incidence and Risk Factors for Delirium in Elderly Patients with Critical Limb Ischaemia.

Eur J Vasc Endovasc Surg 2020 04 20;59(4):598-605. Epub 2019 Dec 20.

Department of Surgery, Amphia Hospital Breda, The Netherlands; Department of Cardiovascular Sciences, KU Leuven, Belgium.

Objective: Delirium is associated with adverse outcomes, such as increased mortality and prolonged hospital stay. Information on the risk factors for delirium in elderly patients with critical limb ischaemia (CLI) is scarce. The aim of this study was to analyse the incidence of delirium and to identify risk factors for delirium in elderly patients undergoing surgical or endovascular treatment.

Methods: A retrospective cohort study was conducted including patients aged ≥ 65 years undergoing surgical or endovascular treatment for CLI between January 2013 and June 2018. Delirium was scored using the DOSS (Delirium Observation Screening Scale) and the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) criteria. Risk factors for delirium were analysed using logistic regression. The discriminative ability of the model was calculated using the area under the receiver operating characteristics (AUROC) curve.

Results: In total, 392 patients were included, of which 70 (17.9%) developed delirium. Factors associated with an increased risk of delirium were: age, odds ratio (OR) 1.05 (95% confidence interval (CI) 1.0-1.1), history of femoral endarterectomy, OR 4.7 (95% CI 1.5-15), physical impairment, OR 2.2 (95% CI 1.1-4.5), history of delirium, OR 2.7 (95% CI 1.4-5.3), general anaesthesia, OR 2.6 (95% CI 1.2-5.7) and pre-operative anaemia, OR 5.9 (95% CI 2.3-15). The AUROC was .82 (95% CI 0.76-0.87, p < .001). Delirium was associated with more respiratory, renal and surgical complications, as well as a prolonged hospital stay and a more frequent discharge to a nursing home.

Conclusion: Delirium occurs frequently in patients with critical limb ischaemia undergoing any type of invasive treatment. This study identified multiple risk factors for delirium that may be helpful to delineate patients susceptible to its development.
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http://dx.doi.org/10.1016/j.ejvs.2019.11.029DOI Listing
April 2020

Adverse Cardiac Events and Mortality in Patients with Critical Limb Ischemia.

Ann Vasc Surg 2020 Jul 9;66:486-492. Epub 2019 Nov 9.

Department of Surgery, Amphia Hospital, Breda, the Netherlands; Department of Cardiovascular Science, UZ Leuven, Leuven, Belgium.

Background: Both surgical and endovascular treatment in elderly patients with critical limb ischemia are associated with high mortality rates. Patients with critical limb ischemia are at increased risk of adverse cardiovascular events and subsequent cardiovascular death. Little is known about the incidence and consequences of these adverse events. The aim of this study was to investigate the effect of adverse cardiac events on mortality in patients with critical limb ischemia undergoing surgical or endovascular treatment.

Methods: A retrospective cohort study including all patients with critical limb ischemia aged ≥65 undergoing surgical or endovascular treatment for critical limb ischemia between January 2013 and June 2018 was conducted. Data on adverse cardiac events were collected from medical records. The effect of an adverse cardiac event on mortality during 6 months follow-up was analyzed with a multivariable cox proportional hazards model to adjust for confounders. Effects are displayed as hazard ratios (HR) with 95% confidence intervals (CI).

Results: A total number of 449 patients were included. Median age was 76 years, 52.8% of patients were male. In total, 51 patients (11%) developed an adverse cardiac event, 31 patients (10%) in the surgical group and 20 patients (14%) in the endovascular group. After adjustment for confounders, adverse cardiac events were associated with an increased risk of mortality (HR 3.5 95% CI 2.1-5.9).

Conclusions: This study showed that adverse cardiac events commonly occur in elderly patients with critical limb ischemia. Adverse cardiac events continue to occur even months after treatment and are associated with an increased mortality risk. These findings justify routine cardiac evaluation in both surgical and endovascular treatment. Additionally, frequent postdischarge cardiac follow-up in the outpatient clinic may be helpful in limiting the occurrence of adverse cardiac events.
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http://dx.doi.org/10.1016/j.avsg.2019.10.087DOI Listing
July 2020

A mortality prediction model for elderly patients with critical limb ischemia.

J Vasc Surg 2020 06 8;71(6):2065-2072.e2. Epub 2019 Nov 8.

Department of Surgery, Amphia Hospital Breda, Breda, The Netherlands; Department of Cardiovascular Science, UZ Leuven, Leuven, Belgium.

Objective: To aid physicians in the process of shared decision-making, many predictive models for critical limb ischemia (CLI) have been constructed. However, none of these models is in widespread use. Predicting survival outcomes for a specific individual may be used to guide treatment selection. The aim of this study was to construct a 6-month survival-predicting model representative of elderly patients with CLI undergoing surgical or endovascular treatment.

Methods: An observational cohort study including all patients with CLI aged ≥65 years who underwent surgical or endovascular treatment of CLI between January 2013 and June 2018 was conducted. The model to predict survival at 6 months was based on a multivariable Cox proportional hazards regression model and a penalized likelihood method. The performance of the model was judged by means of the area under the receiver operating characteristic curve.

Results: In total, 449 patients were included in the study population. The median age was 76 years (range, 65-97 years), and 52.8% of the population was male. Surgical treatment was performed in 303 patients (67.5%), and 146 underwent endovascular treatment (32.5%). The estimated 30-day survival was 92.7% (standard error [SE], 1.2%); 6-month survival, 80% (SE, 1.9%); and 12-month survival, 71% (SE, 2.1%). Variables with the strongest association with 6-month mortality were age, living in a nursing home, physical impairment, and American Society of Anesthesiologists class. The area under the receiver operating characteristic curve of the 6-month mortality model was 0.81 (95% confidence interval, 0.76-0.85; P < .001).

Conclusions: A prediction model constructed for 6-month mortality of elderly patients undergoing surgical or endovascular treatment of CLI showed that age, living in a nursing home, physical impairment, and American Society of Anesthesiologists class have the highest association with an increase in mortality. These factors may be used to identify patients at risk for mortality in shared decision-making.
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http://dx.doi.org/10.1016/j.jvs.2019.08.245DOI Listing
June 2020

Lebetin 2, a Snake Venom-Derived B-Type Natriuretic Peptide, Provides Immediate and Prolonged Protection against Myocardial Ischemia-Reperfusion Injury via Modulation of Post-Ischemic Inflammatory Response.

Toxins (Basel) 2019 09 10;11(9). Epub 2019 Sep 10.

Laboratoire des Venins et Biomolécules Thérapeutiques (LR11IPT08) et Plateforme de Physiologie et de Physiopathologie Cardiovasculaires (P2C), Institut Pasteur de Tunis, Université Tunis El Manar, 1068 Tunis, Tunisia.

Myocardial infarction (MI) followed by left ventricular (LV) remodeling is the most frequent cause of heart failure. Lebetin 2 (L2), a snake venom-derived natriuretic peptide, exerts cardioprotection during acute myocardial ischemia-reperfusion (IR) ex vivo. However, its effects on delayed consequences of IR injury, including post-MI inflammation and fibrosis have not been defined. Here, we determined whether a single L2 injection exerts cardioprotection in IR murine models in vivo, and whether inflammatory response to ischemic injury plays a role in L2-induced effects. We quantified infarct size (IS), fibrosis, inflammation, and both endothelial cell and cardiomyocyte densities in injured myocardium and compared these values with those induced by B-type natriuretic peptide (BNP). Both L2 and BNP reduced IS, fibrosis, and inflammatory response after IR, as evidenced by decreased leukocyte and proinflammatory M1 macrophage infiltrations in the infarcted area compared to untreated animals. However, only L2 increased anti-inflammatory M2-like macrophages. L2 also induced a higher density of endothelial cells and cardiomyocytes. Our data show that L2 has strong, acute, prolonged cardioprotective effects in post-MI that are mediated, at least in part, by the modulation of the post-ischemic inflammatory response and especially, by the enhancement of M2-like macrophages, thus reducing IR-induced necrotic and fibrotic effects.
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http://dx.doi.org/10.3390/toxins11090524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784001PMC
September 2019

Myocardial Injury After Ischemia/Reperfusion Is Attenuated By Pharmacological Galectin-3 Inhibition.

Sci Rep 2019 07 3;9(1):9607. Epub 2019 Jul 3.

Cardiovascular Translational Research. Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain.

Although optimal therapy for myocardial infarction includes reperfusion to restore blood flow to the ischemic region, ischemia/reperfusion (IR) also initiates an inflammatory response likely contributing to adverse left ventricular (LV) extracellular matrix (ECM) remodeling. Galectin-3 (Gal-3), a β-galactoside-binding-lectin, promotes cardiac remodeling and dysfunction. Our aim is to investigate whether Gal-3 pharmacological inhibition using modified citrus pectin (MCP) improves cardiac remodeling and functional changes associated with IR. Wistar rats were treated with MCP from 1 day before until 8 days after IR (coronary artery ligation) injury. Invasive hemodynamics revealed that both LV contractility and LV compliance were impaired in IR rats. LV compliance was improved by MCP treatment 8 days after IR. Cardiac magnetic resonance imaging showed decreased LV perfusion in IR rats, which was improved with MCP. There was no difference in LV hypertrophy in MCP-treated compared to untreated IR rats. However, MCP treatment decreased the ischemic area as well as Gal-3 expression. Gal-3 blockade paralleled lower myocardial inflammation and reduced fibrosis. These novel data showing the benefits of MCP in compliance and ECM remodeling in IR reinforces previously published data showing the therapeutic potential of Gal-3 inhibition.
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http://dx.doi.org/10.1038/s41598-019-46119-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610618PMC
July 2019

Evaluation of an in vitro model with a novel statistical approach to measure differences in bacterial survival of extended-spectrum -lactamase-producing on an inanimate surface.

Antimicrob Resist Infect Control 2019 18;8:106. Epub 2019 Jun 18.

1Department of Infection Control, Amphia Hospital, P.O. box 90158, 4800 AK Breda, The Netherlands.

Background: The role of environmental contamination in the transmission of Enterobacteriaceae is increasingly recognized. However, factors influencing the duration of survival in the environment have not yet been extensively studied. In this study, we developed and evaluated an in vitro model with a novel statistical approach to accurately measure differences in bacterial survival, that can be used to model the effects of multiple factors/conditions in future experiments.

Methods: Two extended-spectrum β-lactamase (ESBL)-producing () isolates were used for this in vitro experiment: a CTX-M-15-producing sequence type (ST) 131 and a CTX-M-1-producing ST10 isolate. Each strain was 1:1 diluted in sterile water, sterile saline or sheep blood. Cover glasses (18 × 18 mm) were inoculated with the dilution and subsequently kept at room temperature. Bacterial survival on the glasses was determined hourly during the first day, once daily during the following 6 days, and from day 7 on, once weekly up to 100 days. The experiment was repeated six times for each strain, per suspension fluid.

Results: Viable bacteria could be detected up to 70 days. A biphasic survival curve for all suspension fluids was observed, whereby there was a rapid decrease in the number of viable bacteria in the first 7 h, followed by a much slower decrease in the subsequent days.

Conclusions: We found a difference in survival probability between ST10 and ST131, with a higher proportion of viable bacteria remaining after 7 h for ST131, particularly in sheep blood.
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http://dx.doi.org/10.1186/s13756-019-0558-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582696PMC
June 2020

The importance of increased awareness for delirium in elderly patients with rib fractures after blunt chest wall trauma: a retrospective cohort study on risk factors and outcomes.

BMC Emerg Med 2019 06 13;19(1):34. Epub 2019 Jun 13.

Department of surgery, Amphia Hospital Breda, P.O. Box 90518, 4800 RK, Breda, The Netherlands.

Background: Rib fractures are common in ageing people after trauma and delirium is a complication often seen in acutely hospitalized elderly patients. For both conditions, elderly have an increased risk for institutionalization, morbidity, and mortality. This study is the first to investigate risk factors of delirium in elderly patients with rib fractures after trauma.

Methods: A retrospective chart review was performed on patients ≥65 years admitted with rib fractures after blunt chest wall trauma to the Amphia hospital Breda, the Netherlands, between July 2013 and June 2018. Baseline patient, trauma- and treatment-related characteristics were identified. The main objectives were identification of risk factors of delirium and investigation of the effect of delirium on outcomes after rib fractures. Outcomes were additional complications, length of hospital stay, need for institutionalization and mortality within six months.

Results: Forty-seven (24.6%) of 191 patients developed a delirium. Independent risk factors for delirium were increased age, physical impairment (lower KATZ-ADL score), nutritional impairment (higher SNAQ score) and the need for a urinary catheter, with odds ratios of 1.07, 0.78, 1.53 and 8.53 respectively. Overall, more complications were observed in patients with delirium. Median ICU and hospital length of stay were 4 and 7 days respectively, of which the latter was significantly longer for delirious patients (p < 0.001). Significantly more patients with delirium were discharged to a nursing home or rehabilitation institution (p < 0.001). The 6-month mortality in delirious patients was nearly twice as high as in non-delirious patients; however, differences did not reach statistical significance.

Conclusion: Delirium in elderly patients with rib fractures is a serious and common complication, with a longer hospital stay and a higher risk of institutionalization as a consequence. Increased awareness for delirium is imperative, most importantly in older patients, in physically or nutritionally impaired patients and in patients in need of a urinary catheter.
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http://dx.doi.org/10.1186/s12873-019-0248-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567595PMC
June 2019

Integrative System Biology Analyses Identify Seven MicroRNAs to Predict Heart Failure.

Noncoding RNA 2019 Mar 7;5(1). Epub 2019 Mar 7.

Inserm, Institut Pasteur de Lille, Université de Lille, FHU-REMOD-VHF, U1167-RID-AGE, F-59000 Lille, France.

Heart failure (HF) has several etiologies including myocardial infarction (MI) and left ventricular remodeling (LVR), but its progression remains difficult to predict in clinical practice. Systems biology analyses of LVR after MI provide molecular insights into this event such as modulation of microRNA (miRNA) that could be used as a signature of HF progression. To define a miRNA signature of LVR after MI, we use 2 systems biology approaches, integrating either proteomic data generated from LV of post-MI rat induced by left coronary artery ligation or multi-omics data (proteins and non-coding RNAs) generated from plasma of post-MI patients from the REVE-2 study. The first approach predicted that 13 miRNAs and 3 of these miRNAs would be validated to be associated with LVR in vivo: miR-21-5p, miR-23a-3p and miR-222-3p. The second approach predicted that 24 miRNAs among 1310 molecules and 6 of these miRNAs would be selected to be associated with LVR in silico: miR-17-5p, miR-21-5p, miR-26b-5p, miR-222-3p, miR-335-5p and miR-375. We identified a signature of 7 microRNAs associated with LVR after MI that support the interest of integrative systems biology analyses to define a miRNA signature of HF progression.
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http://dx.doi.org/10.3390/ncrna5010022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468490PMC
March 2019

Diagnosis and management in Pitt-Hopkins syndrome: First international consensus statement.

Clin Genet 2019 04 18;95(4):462-478. Epub 2019 Feb 18.

Department of Pediatrics, Academic Medical Centre, Amsterdam UMC, Amsterdam, The Netherlands.

Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder characterized by intellectual disability, specific facial features, and marked autonomic nervous system dysfunction, especially with disturbances of regulating respiration and intestinal mobility. It is caused by variants in the transcription factor TCF4. Heterogeneity in the clinical and molecular diagnostic criteria and care practices has prompted a group of international experts to establish guidelines for diagnostics and care. For issues, for which there was limited information available in international literature, we collaborated with national support groups and the participants of a syndrome specific international conference to obtain further information. Here, we discuss the resultant consensus, including the clinical definition of PTHS and a molecular diagnostic pathway. Recommendations for managing particular health problems such as dysregulated respiration are provided. We emphasize the need for integration of care for physical and behavioral issues. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimization of diagnostics and care.
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http://dx.doi.org/10.1111/cge.13506DOI Listing
April 2019

An integrated functional and transcriptomic analysis reveals that repeated exposure to diesel exhaust induces sustained mitochondrial and cardiac dysfunctions.

Environ Pollut 2019 Mar 17;246:518-526. Epub 2018 Dec 17.

Normandie Univ, UNIROUEN, UNICAEN, ABTE, 14000 Caen et 76 000 Rouen, France. Electronic address:

Diesel exhaust (DE) contributes to air pollution, an important risk factor for cardiovascular diseases. However, the mechanisms by which DE exposure induces cardiovascular dysfunction remain unknown and there is still debate on the contribution of the primary particulate matter (PM) fraction compared to the gaseous phase. Although the mitochondria play a key role in the events leading to cardiovascular diseases, their role in DE-induced cardiovascular effects has not been investigated. The aim of this study was to highlight cardiac and mitochondrial events that could be disrupted following acute and/or repeated DE exposures and the contribution of gaseous pollutants to these effects. To address this question, Wistar rats were exposed to DE generated under strictly controlled and characterized conditions and extracted upstream or downstream of the diesel particulate filter (DPF). Evaluation of the cardiac function after acute DE exposure showed a disturbance in echocardiographic parameters, which persisted and worsened after repeated exposures. The presence of the DPF did not modify the cardiovascular dysfunction revealing an important implication of the gas phase in this response. Surprisingly, redox parameters were not altered by DE exposures while an alteration in mitochondrial oxidative capacity was observed. Exploration of the mitochondrial function demonstrated a more specific alteration in complex I of the respiratory chain after repeated exposures, which was further confirmed by transcriptional analysis of left ventricular (LV) tissue. In conclusion, this work provides new insights into cardiovascular effects induced by DE, demonstrating a cardiac mitochondrial impairment associated with the gaseous phase. These effects suggest deleterious consequences in terms of cardiac function for vulnerable populations with underlying energy deficit such as patients with heart failure or the elderly.
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http://dx.doi.org/10.1016/j.envpol.2018.12.049DOI Listing
March 2019

Publisher Correction: MicroRNAs regulating superoxide dismutase 2 are new circulating biomarkers of heart failure.

Sci Rep 2018 Nov 29;8(1):17584. Epub 2018 Nov 29.

INSERM, U1167, FHU-REMOD-HF, Institut Pasteur de Lille, University Lille Nord de France, 59800, Lille, France.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-35955-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265253PMC
November 2018

Interplay Between Phosphorylation and O-GlcNAcylation of Sarcomeric Proteins in Ischemic Heart Failure.

Front Endocrinol (Lausanne) 2018 5;9:598. Epub 2018 Oct 5.

INSERM U1167 Unité d'Epidémiologie et de Santé Publique, Lille, France.

Post-translational modifications (PTMs) of sarcomeric proteins could participate to left ventricular (LV) remodeling and contractile dysfunction leading in advanced heart failure (HF) with altered ejection fraction. Using an experimental rat model of HF (ligation of left coronary artery) and phosphoproteomic analysis, we identified an increase of desmin phosphorylation and a decrease of desmin O-N-acetylglucosaminylation (O-GlcNAcylation). We aim to characterize interplay between phosphorylation and O-GlcNAcylation for desmin in primary cultures of cardiomyocyte by specific O-GlcNAcase (OGA) inhibition with thiamet G and silencing O-GlcNAc transferase (OGT) and, in perfused heart perfused with thiamet G in sham- and HF-rats. In each model, we found an efficiency of O-GlcNAcylation modulation characterized by the levels of O-GlcNAcylated proteins and OGT expression (for silencing experiments in cells). In perfused heart, we found an improvement of cardiac function under OGA inhibition. But none of the treatments either in or cardiac models, induced a modulation of desmin, phosphorylated and O-GlcNAcylated desmin expression, despite the presence of O-GlcNAc moities in cardiac desmin. Our data suggests no interplay between phosphorylation and O-GlcNAcylation of desmin in HF post-myocardial infarction. The future requires finding the targets in heart involved in cardiac improvement under thiamet G treatment.
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http://dx.doi.org/10.3389/fendo.2018.00598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182077PMC
October 2018

Development, behaviour and autism in individuals with SMC1A variants.

J Child Psychol Psychiatry 2019 03 8;60(3):305-313. Epub 2018 Oct 8.

Autism Team Northern-Netherlands, Jonx Department of Youth Mental Health and Autism, Lentis Psychiatric Institute, Groningen, the Netherlands.

Introduction: Development and behaviour in Cornelia de Lange Syndrome (CdLS), including autism characteristics, have been described infrequently stratified to genetic cause and only a few studies have considered behavioural characteristics in relation to developmental level. Here, we describe the behavioural phenotype in individuals with CdLS with SMC1A variants.

Methods: We performed an international, interdisciplinary study on 51 individuals with SMC1A variants. Results of questionnaire studies are compared to those in individuals with Down Syndrome and with Autism Spectrum Disorder. Results on cognition and self-injurious behaviour (SIB) are compared to those in individuals with CdLS caused by NIPBL variants. For Dutch participants with SMC1A variants we performed direct in-person assessments of cognition, autism, and added an interview and questionnaire on adaptive behaviour and sensory processing.

Results: Individuals with SMC1A variants show a higher cognitive level and less SIB than individuals with NIPBL variants. Individuals with SMC1A variants without classic CdLS phenotype but with a Rett-like phenotype show more severe intellectual disability and more SIB compared to those with a CdLS phenotype. Autism is less present if outcomes in direct in-person assessments are evaluated taking developmental level into account compared to results based on a questionnaire.

Conclusions: Behaviour in individuals with CdLS should be evaluated taking genetic cause into account. Detailed interdisciplinary approaches are of clinical importance to inform tailored care and may eventually improve quality of life of patients and families.
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http://dx.doi.org/10.1111/jcpp.12979DOI Listing
March 2019

Oriented Attachment and Nanorod Formation in Atomic Layer Deposition of TiO on Graphene Nanoplatelets.

J Phys Chem C Nanomater Interfaces 2018 Aug 2;122(34):19981-19991. Epub 2018 Aug 2.

Department of Chemical Engineering, Delft University of Technology, 2629 HZ Delft, The Netherlands.

Understanding the spontaneous organization of atoms on well-defined surfaces promises to enable control over the shape and size of supported nanostructures. Atomic layer deposition (ALD) boasts atomic-scale control in the synthesis of thin films and nanoparticles. Yet, the possibility to control the shape of ALD-grown nanostructures remains mostly unexplored. Here, we report on the bottom-up formation of both linear and V-shaped anatase TiO nanorods (NRs) on graphene nanoplatelets during TiCl/HO ALD carried out at 300 °C. NRs as large as 200 nm form after only five ALD cycles, indicating that diffusional processes rather than layer-by-layer growth are behind the NR formation. In particular, high-resolution transmission electron microscopy reveals that the TiO NRs and graphene nanoplatelets are in rotational alignment as a result of lattice matching. Crucially, we also show that individual nanocrystals can undergo in-plane oriented attachment.
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http://dx.doi.org/10.1021/acs.jpcc.8b05572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6120748PMC
August 2018

The IL-1β Antibody Gevokizumab Limits Cardiac Remodeling and Coronary Dysfunction in Rats With Heart Failure.

JACC Basic Transl Sci 2017 Aug 28;2(4):418-430. Epub 2017 Aug 28.

INSERM U1096, Rouen, France.

This study reports preclinical data showing that the interleukin (IL)-1β modulation is a new promising target in the pathophysiological context of heart failure. Indeed, in nondiabetic Wistar and diabetic Goto-Kakizaki rats with chronic heart failure induced by myocardial infarction, administration of the IL-1β antibody gevokizumab improves 'surrogate' markers of survival (i.e., left ventricular remodeling, hemodynamics, and function as well as coronary function). However, whether IL-1β modulation per se or in combination with standard treatments of heart failure improves long-term outcome in human heart failure remains to be determined.
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http://dx.doi.org/10.1016/j.jacbts.2017.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034492PMC
August 2017