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International audience; Diabetic cardiomyopathy (DCM) is a leading complication in type 2 diabetes patients. Recently, we have shown that the reticulum-mitochondria Ca2+ uncoupling is an early and reversible trigger of the cardiac dysfunction in a diet-induced mouse model of DCM. Metformin is a first-line antidiabetic drug with recognized cardioprotective effect in myocardial infarction. Whether metformin could prevent the progression of DCM remains not well understood. We therefore investigated the effect of a chronic 6-week metformin treatment on the reticulum-mitochondria Ca2+ coupling and the cardiac function in our high-fat high-sucrose diet (HFHSD) mouse model of DCM. Although metformin rescued the glycemic regulation in the HFHSD mice, it did not preserve the reticulum-mitochondria Ca2+ coupling either structurally or functionally. Metformin also did not prevent the progression towards cardiac dysfunction, i.e., cardiac hypertrophy and strain dysfunction. In summary, despite its cardioprotective role, metformin is not sufficient to delay the progression to early DCM.

Diabetic cardiomyopathy (DCM) is a leading complication in type 2 diabetes patients. Recently, we have shown that the reticulum-mitochondria Ca

International audience; Protein palmitoylation regulates many aspects of cell function and is carried out by acyl transferases that contain zf-DHHC motifs. The in vivo physiological function of protein palmitoylation is largely unknown. Here we generated mice deficient in the acyl transferase Aph2 (Ablphilin 2 or zf-DHHC16) and demonstrated an essential role for Aph2 in embryonic/postnatal survival, eye development, and heart development. Aph2(-/-) embryos and pups showed cardiomyopathy and cardiac defects including bradycardia. We identified phospholamban, a protein often associated with human cardiomyopathy, as an interacting partner and a substrate of Aph2. Aph2-mediated palmitoylation of phospholamban on cysteine 36 differentially alters its interaction with PKA and protein phosphatase 1 alpha, augmenting serine 16 phosphorylation, and regulates phospholamban pentamer formation. Aph2 deficiency results in phospholamban hypophosphorylation, a hyperinhibitory form. Ablation of phospholamban in Aph2(-/-) mice histologically and functionally alleviated the heart defects. These findings establish Aph2 as a critical in vivo regulator of cardiac function and reveal roles for protein palmitoylation in the development of other organs including eyes.

International audience; Alterations in endocrine functions and low-grade systemic inflammation represent fundamental characteristics of obesity. These biological systems have been repeatedly linked to fatigue symptoms. The aim of the study was to assess the relationship between fatigue dimensions and metabolic/inflammatory markers in a sample of non-diabetic obese children. The possibility that inflammation-induced alterations in tryptophan metabolism relates to specific dimensions of fatigue was also investigated in a subsample of patients. The study was conducted in 41 obese children, median aged 12 [9-15] years, recruited in a pediatric tertiary center. Three dimensions of fatigue (e.g., general fatigue, sleep/rest, cognitive fatigue) were assessed using the Pediatric Quality of Life Inventory Multidimentional Fatigue Scale. In addition, a principal component analysis was performed to identify fatigue dimensions that were specific to the population under study. This analysis extracted five relevant dimensions corresponding respectively to concentration, energy, self-perceived cognitive efficiency, 'sleep/rest and motivation/anhedonia. Blood samples were collected for the measurement of inflammatory and metabolic markers, including, high sensitivity C-reactive protein (hs-CRP), insulin, uricemia and glycaemia. Tryptophan, kynurenine and neopterin levels were also determined in a subsample of 17 patients. In the whole population under study, cognitive fatigue and reduced motivation/anhedonia were associated with BMI, independently of sex and age. The dimension of reduced motivation/anhedonia was associated with insulin resistance and inflammatory biomarkers. The association with insulin resistance persisted when the extent of fat mass (BMI-SDS) was taken into account. No association was found between tryptophan metabolism and specific dimensions of fatigue, but kynurenine and the kynurenine/tryptophan ratio correlated with insulin and HOMA-IR. These data indicate that insulin resistance in non diabetic obese children is associated with both cognitive fatigue and reduced motivation/anhedonia and with alterations in tryptophan metabolism. Further investigations are needed to determine whether inflammation-induced alterations in tryptophan metabolism is directly or indirectly implicated in insulin resistance and related fatigue.

Background Although multiple echocardiographic methods exist to calculate cardiac output (CO), they have not been validated in mice using a reference method. Methods Echocardiographic and flow probe measurements of CO were obtained in mice before and after albumin infusion and inferior vena cava occlusions. Echocardiography was also performed before and after endotoxin injection. Cardiac output was calculated using left ventricular volumes obtained from an M-mode or a two-dimensional view, left ventricular stroke volume calculated using the pulmonary flow, or estimated by the measurement of pulmonary velocity time integral (VTI). Results Close correlations were demonstrated between flow probe-measured CO and all echocardiographic measurements of CO. All echocardiographic-derived CO overestimated the flow probe-measured CO. Two-dimensional image-derived CO was associated with the smallest overestimation of CO. Interobserver variability was lowest for pulmonary VTI-derived CO. Conclusion In mice, CO calculated from two-dimensional parasternal long-axis images is most accurate when compared with flow probe measurements; however, pulmonary VTI-derived CO is subject to less variability.

Background— Genetically modified mice offer the unique opportunity to gain insight into the pathophysiology of pulmonary arterial hypertension. In mice, right heart catheterization is the only available technique to measure right ventricular systolic pressure (RVSP). However, it is a terminal procedure and does not allow for serial measurements. Our objective was to validate a noninvasive technique to assess RVSP in mice. Methods and Results— Right ventricle catheterization and echocardiography (30-MHz transducer) were simultaneously performed in mice with pulmonary hypertension induced acutely by infusion of a thromboxane analogue, U-46619, or chronically by lung-specific overexpression of interleukin-6. Pulmonary acceleration time (PAT) and ejection time (ET) were measured in the parasternal short-axis view by pulsed-wave Doppler of pulmonary artery flow. Infusion of U-46619 acutely increased RVSP, shortened PAT, and decreased PAT/ET. The pulmonary flow pattern changed from symmetrical at baseline to asymmetrical at higher RVSPs. In wild-type and interleukin-6–overexpressing mice, the PAT correlated linearly with RVSP ( r 2 =−0.67, P r 2 =−0.76, P 32 mm Hg) were 100% (7/7) and 86% (6/7), respectively, for both indices (cutoff values: PAT, Conclusions— Right ventricular systolic pressure can be estimated noninvasively in mice. Echocardiography is able to detect acute and chronic increases in RVSP with high sensitivity and specificity as well as to assess the effects of treatment on RVSP. This noninvasive technique may permit the characterization of the evolution of pulmonary arterial hypertension in genetically modified mice.

Altered cGMP signaling has been implicated in myocardial depression, morbidity, and mortality associated with sepsis. Previous studies, using inhibitors of soluble guanylate cyclase (sGC), suggested that cGMP generated by sGC contributed to the cardiac dysfunction and mortality associated with sepsis. We used sGCα1-deficient (sGCα1−/−) mice to unequivocally determine the role of sGCα1β1in the development of cardiac dysfunction and death associated with two models of inflammatory shock: endotoxin- and TNF-induced shock. At baseline, echocardiographic assessment and invasive hemodynamic measurements of left ventricular (LV) dimensions and function did not differ between wild-type (WT) mice and sGCα1−/−mice on the C57BL/6 background (sGCα1−/−B6mice). At 14 h after endotoxin challenge, cardiac dysfunction was more pronounced in sGCα1−/−B6than WT mice, as assessed using echocardiographic and hemodynamic indexes of LV function. Similarly, Ca2+handling and cell shortening were impaired to a greater extent in cardiomyocytes isolated from sGCα1−/−B6than WT mice after endotoxin challenge. Importantly, morbidity and mortality associated with inflammatory shock induced by endotoxin or TNF were increased in sGCα1−/−B6compared with WT mice. Together, these findings suggest that cGMP generated by sGCα1β1protects against cardiac dysfunction and mortality in murine inflammatory shock models.

Mice are increasingly used in cardiovascular research, and echocardiography is ideally suited to evaluate their cardiac phenotype. This review describes the current use of mice echocardiography and focuses on some of its applications in both basic and clinical science.

Cardiologia CROATICA Background: Systemic sclerosis (Ssc) leads to progressive myocardial fibrosis and subsequent alteration in function. Cardiac magnetic resonance (CMR) T1-mapping and speckle tracking echocardiography (STE) are two recent modalities able to quantify diffuse fibrosis and deformation, respectively. We aimed to determine whether these methods could detect left ventricular (LV) dysfunction at an early stage of SSc, and whether there was a relationship between myocardial alteration and plasma levels of C-terminal pro-endothelin-1 (CT-proET-1). Methods: 54 consecutive SSc patients with normal conventional echocardiography and no CMR late gadolinium enhancement, and 16 healthy controls underwent CMR T1mapping and STE. CT-proET-1 was measured in 35 patients. Results: As compared with the controls, SSc patients had shorter global (354 ±23 ms vs. 367 ±23, P=0.04) and basal inferoseptal LV post-contrast T1 values (336 ±22 ms vs. 353 ±24, P=0.01). In addition, basal inferoseptal segment in SSc patients showed decreased longitudinal peak systolic strain as compared with controls (-16.3 ±4% vs -19.6 ±4%, P=0.009). T1 value correlated with parameters of longitudinal function (P

Backgruond: Systemic sclerosis (SSc) is a connective disease characterized by fibrosis and vascular remodelling with poor long-term survival of patients who develop pulmonary arterial hypertension (PAH). Exercise echocardiography might improve the early diagnosis of PAH by unmasking exercise-induced PAH (ex-PAH) but is not feasible in all SSc patients. We sought therefore to investigate whether pulmonary artery enlargement and right ventricle (RV) dysfunction were parameters indicative of ex-PAH. Methods: 89 SSc patients with normal resting systolic pulmonary artery pressure (sPAP) and without severe pulmonary function abnormalities underwent exercise echocardiography and multislice computed tomography (MSCT). They were divided into two groups according to the presence of ex-PAH, defined by sPAP >45 mmHg. Right ventricular (RV) function was evaluated using 2D strain. The ratio of main pulmonary artery diameter (mPA) over the diameter of ascending aorta (Ao) was determined using MSCT. Results: As compared with non ex-PAP group, ex-PAH group was older (60 ±10 vs 50 ±13 years, p=0.001), had higher exercise sPAP (54 ±10 vs 34 ±6 mmHg, P 1 to identify exPAH was 80% and 81%, respectively. Multivariate analysis identified age, RV strain and mPa/Ao ratio as independent parameters indicative of ex-PAH. Conclusions: In SSc patients with normal resting sPAP, increase in mPa/Ao ratio and decreased RV strain are parameters that can indicate the presence of exercise PAH.

Cardiologia CROATICA Background: Early identification of myocardial dysfunction is challenging for many cardiovascular diseases and systemic sclerosis (SSc) is an unique model of progressive myocardial fibrosis. Cardiac magnetic resonance with late gadolinium enhancement (LGE) can detect fibrosis in advanced stages of SSc, but is limited in the early stage due to the diffuse nature of fibrotic changes. T1 mapping is able to quantify myocardial fibrosis and can be used to quantify myocardial extracellular volume fraction (EVF), which changes when collagen content increases. We aimed to determine whether EVF quantification could detect subclinical left ventricular (LV) abnormalities and to investigate the relationship between EVF and subtle diastolic and systolic dysfunction. Materials and Methods: T1 mapping and EVF quantification were prospectively performed in 33 consecutive SSc patients with normal echocardiography, no severe diastolic dysfunction, no pulmonary hypertension at rest and no LGE, as well as in 16 healthy controls. The study was approved by the local ethics committee and all subjects gave written informed consent. Results: SSc patients had significantly higher global EVF (P

Background Genetically modified mice offer the unique opportunity to gain insights into the pathophysiology of pulmonary arterial hypertension (PAH). In mice, right heart catheterization is the only available technique to measure right ventricular systolic pressure (RVSP). However, it is a terminal procedure and does not allow serial follow-up. Our objective was to validate a non-invasive technique to assess RVSP in mice. Methods Right ventricle catheterization and echocardiography were simultaneously performed in mice with pulmonary hypertension induced acutely by infusion of a thromboxane analogue, U-46619 or chronically by lung-specific over-expression of interleukin 6 (IL-6). In a subgroup of mice, echocardiography was performed using light anesthesia before catheterization. Pulsed-Doppler of pulmonary artery flow was recorded in the parasternal short axis view. Pulmonary acceleration time (PAT), and ejection time (ET) were measured. Results Infusion of U-46619 acutely increased RVSP, shortened PAT and decreased PAT/ET. The pulmonary flow pattern changed from symmetric at baseline to asymmetric at higher RVSPs. Transgenic IL-6 mice had high RVSP measured by catheter (39±7 mmHg), short PAT (17±4 ms) and low PAT/ET ratio (31±8%). The PAT correlated linearly with RVSP (r2=–0.67; p 32 mmHg) were 100% (7/7) and 86% (6/7), respectively, for both indexes (cutoff values: PAT Conclusion Pulmonary artery systolic pressure can be estimated noninvasively in mice. Echocardiography allows to monitor acute changes of RVSP and to detect pulmonary hypertension. This technique enables to follow PAH evolution easily and repeatedly in mice. Download : Download full-size image