Author Correction: Synergistic effect of human Bone Morphogenic Protein-2 and Mesenchymal Stromal Cells on chronic wounds through hypoxia-inducible factor-1 α induction.

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Synergistic effect of human Bone Morphogenic Protein-2 and Mesenchymal Stromal Cells on chronic wounds through hypoxia-inducible factor-1 α induction.

Chronic skin ulcers and burns require advanced treatments. Mesenchymal Stromal Cells (MSCs) are effective in treating these pathologies. Bone Morphogenic Protein-2 (BMP-2) is known to enhance angiogenesis. We investigated whether recombinant human hBMP-2 potentiates the effect of MSCs on wound healing. Severe ulceration was induced in rats by irradiation and treated by co-infusion of MSCs with hBMP-2 into the ulcerated area which accelerated wound healing. Potentiation of the effect of MSCs by hBMP-2 on endothelial repair improved skin healing. HBMP-2 and MSCs synergistically, in a supra additive or enhanced manner, renewed tissue structures, resulting in normalization of the epidermis, hair follicles, sebaceous glands, collagen fibre density, and blood vessels. Co-localization of MSCs with CD31 + cells suggests recruitment of endothelial cells at the site of injection. HBMP-2 and MSCs enhanced angiogenesis and induced micro-vessel formation in the dermis where hair follicles were regenerated. HBMP-2 acts by causing hypoxia-inducible factor-1 α (HIF-1α) expression which impacts endothelial tube formation and skin repair. This effect is abolished by siRNA. These results propose that new strategies adding cytokines to MSCs should be evaluated for treating radiation-induced dermatitis, burns, and chronic ulcers in humans.

USPIO size control through microwave nonaqueous sol-gel method for neoangiogenesis T2 MRI contrast agent.

AIM: Tunable size ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles from 3 to 9 nm coated with polyethylene glycol phosphonate moieties have been designed for neovascularization MRI. MATERIALS & METHODS: USPIO were synthesized using a nonaqueous sol-gel method. An ischemia-reperfusion rat model has been chosen for neo-angiogenesis and scanned on MRI after injection of different sized USPIO. Histological studies have been performed for USPIO localization within the tissue. RESULTS: The magnetic properties and consequently their MRI relaxivities are drastically dependent on the crystalline core size. In vivo MRI spots were observed specifically in the ischemic area. The best MRI contrast within neovascularization is generated by 6 nm nanoparticles proving that compromise between T2 relaxivity and physico-chemical properties is essential for the design of effective MRI contrast agent.

Decisional early interim (18)F-fluoro-2-deoxy-D-glucose positron emission tomography after two cycles of chemotherapy in de novo Hodgkin lymphoma.

BACKGROUND/AIMS: An early evaluation with positron emission tomography (FDG-PET) has been demonstrated to be a valuable tool in the prediction of Hodgkin lymphoma's outcome. Herein we report a retrospective study on the outcome of Hodgkin lymphoma treated in accordance with interim FDG-PET results. METHODS: 48 patients with de novo Hodgkin lymphoma were treated with 2 cycles of chemotherapy. According to the interim FDG-PET (PET2) evaluation, pre-established treatment was continued if PET2 was considered negative. Patients with a positive PET2 result underwent a salvage therapy. Progression-free survival (PFS) and overall survival (OS) were chosen as end points. RESULTS: PET2 scan results were negative for 37 patients and positive for 11 patients. After salvage therapy, 7/11 patients were in complete remission and 4 patients had stable disease and were considered for third-line therapy. After a median follow-up of 5.2 years, 46 patients were still alive. The 4-year PFS were 84.5 and 45.4% for PET2-negative and PET2-positive patients, respectively (p = 0.007). In multivariate analysis, PET2 scan and extranodal disease remained relevant on PFS (p = 0.001 and 0.009, respectively). No difference was seen in OS. CONCLUSION: Our retrospective study suggests that salvage therapy for non-responder Hodgkin lymphoma using interim FDG-PET could improve the PFS of this group of patients.

Fluorine 18 fluorodeoxyglucose PET/CT volume-based indices in locally advanced non-small cell lung cancer: prediction of residual viable tumor after induction chemotherapy.

PURPOSE: To study whether volume-based indices of fluorine 18 fluorodeoxyglucose positron emission tomographic (PET)/computed tomographic (CT) imaging is an accurate tool to predict the amount of residual viable tumor after induction chemotherapy in patients with locally advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: This study was approved by institutional review board with waivers of informed consent. Twenty-two patients with locally advanced NSCLC underwent surgery after induction chemotherapy. All had pre- and posttreatment FDG PET/CT scans. CT largest diameter, CT volume, maximum standardized uptake value (SUVmax), mean SUV (SUVmean), metabolic tumor volume (TV), and total lesion glycolysis of primary tumor were calculated. Changes in tumor measurements were determined by dividing follow-up by baseline measurement (ratio index). Amounts of residual viable tumor, necrosis, fibrous tissue, inflammatory infiltrate, and Ki-67 proliferative index were estimated on resected tumor. Correlations between imaging indices and histologic parameters were estimated by using Spearman correlation coefficients or Mann-Whitney tests. RESULTS: No baseline or posttreatment indices correlated with percentage of residual viable tumor. TV ratio was the only index that correlated with percentage of residual viable tumor (r = 0.61 [95% confidence interval: 0.24, 0.81]; P = .003). Conversely, SUVmax and SUVmean ratios were only indices correlated with Ki-67 (r = 0.62 [95% confidence interval: 0.24, 0.82]; P = .003; and r = 0.60 [95% confidence interval: 0.21, 0.81]; P = .004, respectively). Total lesion glycolysis ratio was moderately correlated with residual viable tumor (r = 0.53 [95% confidence interval: 0.13, 0.78]; P = .01) and with Ki-67 (r = 0.57 [95% confidence interval: 0.18, 0.80]; P = .006). No ratios were correlated with presence of inflammatory infiltrate or foamy macrophages. CONCLUSION: TV and total lesion glycolysis ratios were the only indices correlated with residual viable tumor after induction chemotherapy in locally advanced NSCLC.

Relationship between tumor heterogeneity measured on FDG-PET/CT and pathological prognostic factors in invasive breast cancer.

BACKGROUND: There is currently little support to understand which pathological factors led to differences in tumor texture as measured from FDG PET/CT images. We studied whether tumor heterogeneity measured using texture analysis in FDG-PET/CT images is correlated with pathological prognostic factors in invasive breast cancer. METHODS: Fifty-four patients with locally advanced breast cancer who had an initial FDG-PET/CT were retrospectively included. In addition to SUVmax, three robust textural indices extracted from 3D matrices: High-Gray-level Run Emphasis (HGRE), Entropy and Homogeneity were studied. Univariate and multivariate logistic regression was used to identify PET parameters associated with poor prognosis pathological factors: hormone receptor negativity, presence of HER-2 and triple negative phenotype. Receiver operating characteristic (ROC) curves and the (AUC) analysis, and reclassification measures, were performed in order to evaluate the performance of combining texture analysis and SUVmax for characterizing breast tumors. RESULTS: Tumor heterogeneity, measured with HGRE, was higher in negative estrogen receptor (p = 0.039) and negative progesterone receptor tumors (p = 0.036), and in Scarff-Bloom-Richardson grade 3 tumors (p = 0.047). None of the PET indices could identify HER-2 positive tumors. Only SUVmax was positively correlated with Ki-67 (p<0.0004). Triple negative breast cancer (TNBC) exhibited higher SUVmax (Odd Ratio = 1.22, 95%CI [1.06-1.39],p = 0.004), lower Homogeneity (OR = 3.57[0.98-12.5],p = 0.05) and higher HGRE (OR = 8.06[1.88-34.51],p = 0.005) than non-TNBC. Multivariate analysis showed that HGRE remained associated with TNBC (OR = 5.27[1.12-1.38],p = 0.03) after adjustment for SUVmax. Combining SUVmax and HGRE yielded in higher area under the ROC curves (AUC) than SUVmax for identifying TNBC: AUC =  0.83 and 0.77, respectively. Probability of correct classification also increased in 77% (10/13) of TNBC and 71% (29/41) of non-TNBC (p = 0.003), when combining SUVmax and HGRE. CONCLUSIONS: Tumor heterogeneity measured on FDG-PET/CT was higher in invasive breast cancer with poor prognosis pathological factors. Texture analysis might be used, in addition to SUVmax, as a new tool to assess invasive breast cancer aggressiveness.

FDG-PET/CT in patients with ANCA-associated vasculitis: case-series and literature review.

OBJECTIVES: We aimed to assess the clinical value of FDG-PET/CT in patients with ANCA-associated vasculitis. MATERIALS AND METHODS: We retrospectively included 16 patients with ANCA-associated vasculitis who underwent 21 FDG-PET/CT between 2009 and 2013, in 2 university hospitals from the Paris suburb area. All FDG-PET/CTs were retrospectively analyzed and compared to clinical, biological and conventional imaging data at baseline and during the follow-up. RESULTS: ANCA-associated vasculitis was granulomatosis with polyangiitis (GPA, n=10), microscopic polyangiitis (MPA, n=4), and eosinophilic GPA (EGPA, n=2). PET was performed at initial presentation in 14 cases and during the follow-up in 7 cases. At baseline, PET was positive in 100% of GPA patients (8/8) and in 50% (3/6) of patients with other ANCA-vasculitis (p=0.05). FDG uptake tended to be higher in patients with GPA in comparison to patients with MPA/EGPA (median SUVmax: 5 versus 2.5; p=0.08). Sinonasal, lung, cardio-vascular and kidney involvements were all accurately identified by PET, except in one MPA patient with glomerulonephritis. As expected, skin, joint, eye and peripheral nervous system impairments were not detected by PET. No occult site was detected by PET, except in 2 salivary gland FDG uptake without clinical abnormalities. Patients with GPA exhibited a higher number of positive sites on PET (2 [1.75-2.25] versus 0.5 [0-1], p=0.006) than patients with MPA/EGPA. In pooled data including our study and the literature data of GPA patients (n=31), SUVmax was associated with Birmingham Vasculitis Activity Score (BVAS) (r=0.49; p=0.03). CONCLUSION: FDG-PET/CT accurately identifies organ localizations in GPA, other than in nervous system, eye and skin, but do not bring additional benefit to the usual organ screening. The value of FDG-PET/CT in other ANCA-associated vasculitis need to be further addressed.

18F-fluorodeoxyglucose positron emission tomography/computer tomography as an objective tool for assessing disease activity in Sjögren's syndrome.

OBJECTIVE: This study aims to determine the value of FDG-PET/CT to assess disease activity in patients with Sjögren's syndrome (SS). METHODS: Thirty-two patients with SS who underwent PET/CT were retrospectively analyzed. PET/CT activity score was measured using a 6-point scale including the 6 following items (0/1: absence or presence of an item): lymphadenopathy on CT, high-resolution CT (HRCT) evidence of interstitial lung disease (ILD), parotid glands SUVmax >3, submandibular glands SUVmax >3, lymph node uptake, ILD uptake. Combined PET/CT score was correlated to ESSDAI (EULAR Sjögren's Syndrome Disease Activity Index) score and other parameters of SS activity. RESULTS: Pathological FDG uptake was observed in 75% of patients (24/32): lymph-nodes (n=19, 60%), salivary glands (n=17, 53%), lungs (n=9, 28%), and thyroid (n=2). Median ESSDAI and PET/CT activity scores were 9.5 [5-12] and 2 [0-3], respectively. PET/CT activity score correlated with ESSDAI (r=0.49, p=0.005), unlike SUVmax. Patients with a high ESSDAI score had a higher PET/CT activity score than patients with a low ESSDAI score (3 vs 1, p=0.004). PET was also correlated with gammaglobulin levels (r=0.43, p=0.02), but not with the presence of cryoglobulinemia, activated complement or beta-2 microglobulin levels. The FDG uptake in patients with lymphoma (n=4) was higher than in patients without lymphoma (SUVmax=5.4 vs. 3.2, p=0.05). CONCLUSION: We described a new PET/CT activity score, which correlates to ESSDAI and could help to assess disease activity in SS patients. PET can also help in the diagnosis of lymphoma, even if inflammatory lymph nodes can be frequently observed in SS patients.

Decreased vascular contractility induced by hemin is associated with a reduced rho-kinase activity.

OBJECTIVES: In this study, the role of rho-kinase activity in the modulation of vascular contractility induced by hemin, a heme oxygenase inducer, was investigated. METHODS: Aortic rings from Wistar rats were incubated in physiological saline solution (PSS) containing hemin at 10-(4) M for six hours then contracted with phenylephrine, and a dose-response curve was established. The effect of Y-27632, a rho-kinase inhibitor, on the relaxation of the pre-contracted aortic rings was then studied. RESULTS: Incubation of the aortic rings in hemin induced an increased expression of heme oxygenase 1 (HO-1). A reduction in the contractile force of aortic rings incubated in hemin was observed in response to phenylephrine. Y-27632 at a concentration of 10-(6) M induced a 36% relaxation of the control aortic rings but only a 20% relaxation in aortic rings treated with hemin. CONCLUSION: These data suggest that the decreased vascular contractility induced by hemin could, in part, result from an inhibition of rho-kinase activity.

Use of hybrid SPECT/CT for diagnosis of radiographic occult fractures of the wrist.

Wrist and hand traumas represent most traumatic lesions. Any delay in treatment involves complications compromising the functional prognosis. We report typical examples illustrating the incremental diagnosis value of hybrid SPECT/CT compared with planar scintigraphy with semiquantitative analysis in the diagnosis of radiographic occult fractures of the wrist. Hybrid imaging diagnoses much more of scaphoid lesions because bone disruptions cannot always be shown on CT, as well as carpal-associated lesions and differentiates chronic arthritis or ligament lesions. This noninvasive approach could lead to improved therapeutic strategies with a beneficial impact on prognosis.

Prognostic implications of volume-based measurements on FDG PET/CT in stage III non-small-cell lung cancer after induction chemotherapy.

PURPOSE: We sought to determine whether metabolic volume-based measurements on FDG PET/CT scans could provide additional information for predicting outcome in patients with stage III non-small-cell lung cancer (NSCLC) treated with induction chemotherapy. METHODS: Included in the study were 32 patients with stage III NSCLC who were treated with induction platinum-based chemotherapy followed in 21 by surgery. All patients had an FDG PET/CT scan before and after the induction chemotherapy. Tumours were delineated using adaptive threshold methods. The SUVmax, SUVpeak, SUVmean, tumour volume (TV), total lesion glycolysis (TLG), and volume and largest diameter on the CT images (CTV and CTD, respectively) were calculated. Index ratios of the primary tumour were calculated by dividing the follow-up measurements by the baseline measurements. The prognostic value of each parameter for event-free survival (EFS) was determined using Cox regression models. RESULTS: The median follow-up time was 19 months (range 6-43 months). Baseline PET and CT parameters were not significant prognostic factors. After induction therapy, only SUVmax, SUVpeak, SUVmean, TV, TLG and CTV were prognostic factors for EFS, in contrast to CTD. Of the index ratios, only TV and TLG ratios were prognostic factors for EFS. Patients with a TLG ratio <0.48 had a longer EFS than those with a TLG ratio >0.48 (13.9 vs. 9.2 months, p = 0.04). After adjustment for the effect of surgical treatment, all the parameters significantly correlated with EFS remained significant. CONCLUSION: SUV, metabolic volume-based indices, and CTV after induction chemotherapy give independent prognostic information in stage III NSCLC. However, changes in metabolic TV and TLG under induction treatment provide more accurate prognostic information than SUV alone, and CTD and CTV.

[Current applications of PET/CT]. / Indications de la tomographie par émission de positons: où en est-on?

Positron emission tomography/computed tomography (PET/CT) is a sensitive method for detecting, staging, and therapy monitoring of many malignancies. It has modified the management of cancer. PET/CT allows for a "whole body" assessment of a metabolic process, depending on the type of tracer, combined with a CT scan. In the present article we review the different PET tracers available today and the most effective applications of PET-CT in oncology, but also in inflammatory diseases, heart diseases and dementia.

The rim sign: FDG-PET/CT pattern of pulmonary infarction.

OBJECTIVE: We aimed to describe a pattern of rim uptake observed in lung infarction on FDG-PET/CT, called the "rim sign." It was defined as a continuous slight FDG uptake along the border of a subpleural consolidation without uptake within the consolidation. METHODS: We retrospectively reviewed the FDG-PET/CT studies of 400 patients referred for thoracic oncological workup from November 2010 to July 2011. The rim sign was observed in six patients who had confirmed pulmonary infarction (PI) on MDCT showing acute pulmonary embolism (n = 4) or tumoral arterial obstruction (n = 2). RESULTS: Eight PIs in the six patients exhibited the rim sign with slight uptake (median SUV(max): 3.6, 2.2-6.8) and median size of 48.5 mm (30-74). On MDCT, central lucencies, triangular shape and vessel sign were observed in 5/8, 4/8 and 1/8 cases, respectively. Two out of the eight PIs exhibited only the rim sign and none the suggestive MDCT sign. CONCLUSION: The rim sign is easily recognisable at FDG-PET/CT and is strongly suggestive of PI. This pattern can be observed even in the absence of suggestive findings on MDCT. Recognition of this sign should prompt investigations for pulmonary embolism. MAIN MESSAGES: • The rim sign is a slight FDG uptake around an area of subpleural consolidation • The rim sign is strongly suggestive of pulmonary infarction • Recognition of the rim sign should prompt investigations for pulmonary embolism.

Comparison of FDG-PET/CT and MR with diffusion-weighted imaging for assessing peritoneal carcinomatosis from gastrointestinal malignancy.

OBJECTIVES: To assess the accuracy of FDG-PET/CT and MR with diffusion-weighted imaging (MR-DWI) for diagnosing peritoneal carcinomatosis (PC) from gastrointestinal malignancies. METHODS: Thirty consecutive patients referred for staging of gastrointestinal malignancy underwent FDG-PET/CT and MR-DWI in this retrospective study. Extent of PC was characterised by dividing the peritoneal cavity into three sites in each patient: right and left supramesocolic areas and inframesocolic level (total 90 sites). Presence of PC was confirmed either by surgery (18/30) or by follow-up (12/30). RESULTS: PC was confirmed in 19 patients (19/30). At a total of 90 sites, 27 showed proven PC. On a patient-based analysis, sensitivity, specificity, PPV, NPV and accuracy were respectively 84%, 73%, 84%, 73% and 80% for PET/CT and 84%, 82%, 89%, 75% and 83% for MR-DWI. On a site-based analysis, overall sensitivity and specificity of PET/CT (63%, 90%) and MR-DWI (74%, 97%) were not statistically different (P = 0.27). In the supramesocolic area, MR-DWI detected more sites involved than PET/CT (7/9 vs. 4/9). The sensitivities of PET and MR were lower for subcentimetre tumour implants (42%, 50%). Interobserver agreement was very good for PET/CT and good for MR-DWI. CONCLUSIONS: FDG-PET/CT and MR-DWI showed similar high accuracy in diagnosing PC. Both techniques underestimated the real extent of PC because of decreased sensitivity for subcentimetre lesions. KEY POINTS: FDG-PET/CT and MR-DWI showed similar high accuracy for diagnosing peritoneal carcinomatosis. • In the supramesocolic area, MR-DWI could be more sensitive than PET/CT. • Both techniques showed lower sensitivity for subcentimetre lesions. • Interobserver agreement was very good for PET/CT and good for MR-DWI.

Regeneration of three layers vascular wall by using BMP2-treated MSC involving HIF-1α and Id1 expressions through JAK/STAT pathways.

Engineering living, multilayered blood vessels to form in vivo arteries is a promising alternative to peripheral artery bypass using acellular grafts restricted by thrombosis and occlusion at long term. Bone Morphogenetic Protein 2 (BMP2) is a growth factor determining in the early vascular embryonic development. The aim of the present study was evaluate the collaborative effect of recombinant human--BMP2 and Bone marrow--Mesenchymal stem cells (BM-MSCs) seeded on vascular patch to regenerate a vascular arterial wall in a rat model. BM-MSCs expressing green fluorescent protein (GFP) seeded on vascular patch were cultured in presence of recombinant human-BMP2 [100 ng/mL] during 1 week before their implantation on the abdominal aorta of Wistar rats. We observed after 2 weeks under physiological arterial flow a regeneration of a three layers adult-like arterial wall with a middle layer expressing smooth muscle proteins and a border layer expressing endothelial marker. In vitro study, using Matrigel assay and co-culture of BM-MSCs with endothelial cells demonstrated that rh-BMP2 promoted tube-like formation even at long term (90 days) allowing the organization of thick rails. We demonstrated using inhibitors and siRNAs that rh-BMP2 enhanced the expression of HIF-1α and Id1 through, at least in part, the stimulation of JAK2/STAT3/STAT5 signaling pathways. Rh-BMP2 by mimicking embryological conditions allowed vascular BM-MSCs differentiation.

Hemin decreases cardiac oxidative stress and fibrosis in a rat model of systemic hypertension via PI3K/Akt signalling.

AIMS: Angiotensin II induces cardiac myocyte apoptosis and hypertrophy, which contribute to heart failure, possibly through enhanced oxidative stress. The aim of this work was to assess the impact of hemin (heme oxygenase-1 inducer) on NADPH oxidase activation, cardiac oxidative stress, and development of fibrosis in a rat model of renovascular hypertensive cardiomyopathy in comparison to an anti-hypertensive reference treatment with losartan. METHODS AND RESULTS: A 3 week hemin treatment was tested in an angiotensin II-dependent hypertensive rat model and a cellular model of neonatal rat cardiomyocytes stimulated by angiotensin II. Our findings demonstrate that hemin prevented development of intercellular fibrosis, expression of collagen I, and disorganization of intracellular fibres. Oxidative stress and apoptosis evaluated in hypertensive myocardial tissue were decreased by hemin. The reference treatment with the angiotensin II receptor (AT(1)) antagonist (losartan) was less effective than hemin in prevention of fibrosis and oxidative stress, although it was more effective in reducing hypertension. Rac-1 activation and, subsequently, NADPH oxidase activity were further decreased with hemin than with losartan. Hemin enhanced the expression of phosphoinositide 3-kinase (PI3K) p85 regulatory subunit, in contrast to losartan. The PI3K/Akt signalling pathway activation by hemin was related to heme oxygenase-1 activation and an increase in biliverdin reductase, and its inhibition by LY294002 reversed the effects of hemin on collagen I and caspase-3 expression. Finally, hemin increased Akt activation, and concomitantly decreased RhoA and p38 mitogen-activated protein kinase activation. CONCLUSION: We confirmed a positive effect of hemin on oxidative cardiac damage, apoptosis, and fibrosis induced by hypertension by modulating the NADPH oxidase activation through enhanced expression of the PI3K p85 regulatory subunit.

Interventricular delay measurement using equilibrium radionuclide angiography before resynchronization therapy should be performed outside the area of segmental wall motion abnormalities.

BACKGROUND: The aim of this study was to demonstrate that only mechanical dyssynchrony outside the area of segmental wall motion abnormalities (WMA) can be reduced by cardiac resynchronization therapy (CRT). METHODS AND RESULTS: Included in the study were 28 consecutive patients with nonischaemic cardiomyopathy selected for CRT. Equilibrium radionuclide angiography (ERNA) was carried out before and after implantation of a multisite pacemaker. Patients were separated into two groups depending on the presence or absence of segmental WMA. RESULTS: A reduction in QRS duration was observed in all patients after CRT. The interventricular delay (IVD) decreased significantly after CRT only in patients without WMA (homogeneous contraction, HG group; IVD 44 ± 11.4° vs. 17 ± 3.1°, p = 0.04). In contrast, no significant decrease was observed in patients with WMA (WMA group; IVD 51 ± 6° vs. 38 ± 6°, p NS). However, when dyssynchrony was considered outside the WMA area, a significant reduction in IVD was obtained, in the same range as in the HG group (IVD 32 ± 3° vs. 19 ± 3°, p = 0.04). In 9 of 15 patients (60%) with a reduction in IVD after CRT, the left ventricle ejection fraction (LVEF) increased by about +10%. In contrast, in 13 of 13 patients (100%) with no reduction in IVD, no modification of LVEF was obtained. In the presence of segmental WMA without significant delays outside the WMA area, no reduction in IVD was observed and LVEF did not increase (IVD 34 ± 5° before CRT vs. 37 ± 7° after CRT; LVEF 19 ± 4% before CRT vs. 22 ± 3% after CRT, p NS). CONCLUSION: ERNA can be used to predict good mechanical resychronization (decrease in IVD) in patients after pacing. IVD has to be determined excluding the area of WMA in order to select patients who will show an increase in their left ventricle function after CRT.

New insights into sexual dimorphism during progression of heart failure and rhythm disorders.

Neurohormonal imbalance is a key determinant of the progression of heart failure (HF), which results in an elevated risk of mortality. A better understanding of mechanisms involved may influence treatment strategies. The incidence and prevalence of HF are lower in women. We explored sexual dimorphism in the progression of HF using a mice model of neurohormonal-dependent HF. Male and female mice overexpressing the human beta2-adrenergic receptor (TG4 strain) develop HF. We compared TG4 animals with age-matched wild-type controls. Cardiac function was studied in vivo by echocardiography and electrocardiography. Histological studies were performed. Conduction parameters were assessed by intracardiac electrophysiological exploration, as was the occurrence of spontaneous and inducible arrhythmias. The patch-clamp technique was used to determine the cellular electrophysiological profile. The role of hormonal status in HF progression was investigated by surgical gonadectomy. High mortality rate was observed in TG4 mice with a dramatic difference between males and females. Male TG4 mice exhibited intraventricular conduction abnormalities, as measured by infrahisian interval and QRS durations potentially determining reentrant circuits and increasing susceptibility to arrhythmia. The severity of HF was correlated with the degree of fibrosis, which was modulated by the gonadal hormones. Action potentials recorded from male and female left ventricular cardiomyocytes were indistinguishable, although both sexes exhibited delayed repolarization when compared with their wild-type counterparts. In conclusion, female TG4 mice were better protected than males against cardiac remodeling and rhythm disorders. A link between fibrosis, conduction time, and mortality was established in relation with sex hormones.

Hemin, a carbon monoxide donor, improves systemic vascular compliance by inhibiting the RhoA-Rhokinase pathway in spontaneous hypertensive rats.

Carbon monoxide donors have nitrite oxide vasorelaxant properties. We performed this study in order to determine the impact of Hemin on smooth muscle layer vasoreactivity in spontaneous hypertensive rats as compared to control Wistar rats. Twenty-one days of peritoneal administration of Hemin decreased the mean arterial blood pressure in spontaneous hypertensive rats (150+/-5 mmHg in spontaneous hypertensive rats treated with Hemin=30 vs. 166+/-6 mmHg in spontaneous control n=30, P<0.05). The passive relaxation of isolated aortic rings after the initial stretch was more important in spontaneous hypertensive treated with Hemin as compared to spontaneous hypertensive treated by Hemin and decreased the maximal contractile force induced by phenylephrine in Wistar aortic rings (C, n=10; H, n=10) although EC(50) values remained unchanged. In spontaneous hypertensive rats, contractile force was impaired in control rats and increased slightly with Hemin treatment. Global potassium channels were decreased in spontaneous hypertensive rats treated with Hemin and this decrease was predominant on Kv channels sensitive current attested by a patch clamp and confirmed by a reduced Kv 1.5 protein expression. On the other hand, the relaxation of the precontracted aortic ring induced by Y27632, an inhibitor of Rhokinase activity, was altered with Hemin. In Wistar rats, the magnitude of relaxation by Y27632 at 310(-7)M was 30% in Hemin-treated rats and 40% in control rats (P>0.05), when expressed as the amplitude of the 80 mM KCl-solution-induced contraction. At the same concentration, the relaxation induced by Y27632 was 115% in spontaneous hypertensive rats -C and 90% in spontaneous hypertensive rats -H (P<0.05). Moreover, western blotting showed that Hemin treatment decreased the amount of the active form of GTP-RhoA but the total RhoA remained unchanged.