Pierre-François Lesault

Trials on tissue contractility estimation from cardiac cine MRI using a biomechanical heart model

In this paper we apply specific data assimilation methods in order to estimate regional contractility parameters in a biomechanical heart model, using as measurements real Cine MR images obtained in an animal experiment. We assess the effectiveness of this estimation based on independent knowledge of the controlled infarcted condition, and on late enhancement images. Moreover, we show that the estimated contractility values can improve the model behavior in itself, and that they can serve as an indicator of the local heart function, namely, to assist medical diagnosis for the post-infarct detection of hypokinetic or akinetic regions in the myocardial tissue.

Human Mesenchymal Stem Cells Reprogram Adult Cardiomyocytes Toward a Progenitor-Like State Through Partial Cell Fusion and Mitochondria Transfer†‡§

Because stem cells are often found to improve repair tissue including heart without evidence of engraftment or differentiation, mechanisms underlying wound healing are still elusive. Several studies have reported that stem cells can fuse with cardiomyocytes either by permanent or partial cell fusion processes. However, the respective physiological impact of these two processes remains unknown in part because of the lack of knowledge of the resulting hybrid cells. To further characterize cell fusion, we cocultured mouse fully differentiated cardiomyocytes with human multipotent adipose‐derived stem (hMADS) cells as a model of adult stem cells. We found that heterologous cell fusion promoted cardiomyocyte reprogramming back to a progenitor‐like state. The resulting hybrid cells expressed early cardiac commitment and proliferation markers such as GATA‐4, myocyte enhancer factor 2C, Nkx2.5, and Ki67 and exhibited a mouse genotype. Interestingly, human bone marrow‐derived stem cells shared similar reprogramming properties than hMADS cells but not human fibroblasts, which suggests that these features might be common to multipotent cells. Furthermore, cardiac hybrid cells were preferentially generated by partial rather than permanent cell fusion and that intercellular structures composed of f‐actin and microtubule filaments were involved in the process. Finally, we showed that stem cell mitochondria were transferred into cardiomyocytes, persisted in hybrids and were required for somatic cell reprogramming. In conclusion, by providing new insights into previously reported cell fusion processes, our data might contribute to a better understanding of stem cell‐mediated regenerative mechanisms and thus, the development of more efficient stem cell‐based heart therapies. STEM CELLS 2011;29:812–824

Estimation of tissue contractility from cardiac cine-MRI using a biomechanical heart model

The objective of this paper is to propose and assess an estimation procedure—based on data assimilation principles—well suited to obtain some regional values of key biophysical parameters in a beating heart model, using actual Cine-MR images. The motivation is twofold: (1) to provide an automatic tool for personalizing the characteristics of a cardiac model in order to achieve predictivity in patient-specific modeling and (2) to obtain some useful information for diagnosis purposes in the estimated quantities themselves. In order to assess the global methodology, we specifically devised an animal experiment in which a controlled infarct was produced and data acquired before and after infarction, with an estimation of regional tissue contractility—a key parameter directly affected by the pathology—performed for every measured stage. After performing a preliminary assessment of our proposed methodology using synthetic data, we then demonstrate a full-scale application by first estimating contractility values associated with 6 regions based on the AHA subdivision, before running a more detailed estimation using the actual AHA segments. The estimation results are assessed by comparison with the medical knowledge of the specific infarct, and with late enhancement MR images. We discuss their accuracy at the various subdivision levels, in the light of the inherent modeling limitations and of the intrinsic information contents featured in the data.

Nanotubular crosstalk with distressed cardiomyocytes stimulates the paracrine repair function of mesenchymal stem cells.

Mesenchymal stem cells (MSC) are known to repair broken heart tissues primarily through a paracrine fashion while emerging evidence indicate that MSC can communicate with cardiomyocytes (CM) through tunneling nanotubes (TNT). Nevertheless, no link has been so far established between these two processes. Here, we addressed whether cell‐to‐cell communication processes between MSC and suffering cardiomyocytes and more particularly those involving TNT control the MSC paracrine regenerative function. In the attempt to mimic in vitro an injured heart microenvironment, we developed a species mismatch coculture system consisting of terminally differentiated CM from mouse in a distressed state and human multipotent adipose derived stem cells (hMADS). In this setting, we found that crosstalk between hMADS and CM through TNT altered the secretion by hMADS of cardioprotective soluble factors such as VEGF, HGF, SDF‐1α, and MCP‐3 and thereby maximized the capacity of stem cells to promote angiogenesis and chemotaxis of bone marrow multipotent cells. Additionally, engraftment experiments into mouse infarcted hearts revealed that in vitro preconditioning of hMADS with cardiomyocytes increased the cell therapy efficacy of naïve stem cells. In particular, in comparison with hearts treated with stem cells alone, those treated with cocultured ones exhibited greater cardiac function recovery associated with higher angiogenesis and homing of bone marrow progenitor cells at the infarction site. In conclusion, our findings established the first relationship between the paracrine regenerative action of MSC and the nanotubular crosstalk with CM and emphasize that ex vivo manipulation of these communication processes might be of interest for optimizing current cardiac cell therapies. Stem Cells 2014;32:216–230

Daily administration of the TP receptor antagonist terutroban improved endothelial function in high-cardiovascular-risk patients with atherosclerosis

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Terutroban is a selective TP receptor antagonist, i.e. a specific antagonist of the thromboxane A(2) and prostaglandin endoperoxide receptors, shown to improve endothelial function after a single administration in patients with coronary artery disease. WHAT THIS STUDY ADDS • This randomized, double-blind, placebo-controlled trial demonstrates that repeated-dose terutroban for 15 days improves endothelial function and inhibits thromboxane A(2) -induced platelet aggregation in high-cardiovascular-risk patients taking 300 mg of aspirin per day. Terutroban may prove useful for preventing cardiovascular events in such patients. AIMS The specific TP receptor antagonist terutroban improves endothelial function after a single dose in patients with coronary artery disease. Our aim was to evaluate the effects and dose dependency of repeated-dose terutroban on endothelial function and platelet aggregation in high-cardiovascular-risk patients with carotid atherosclerosis. METHODS We randomly allocated 48 patients taking 300 mg aspirin per day to placebo or to one of three terutroban dosages (2.5, 5 or 10 mg) for 15 days in a double-blind study. Flow-mediated vasodilatation was evaluated before and 2 h after the first oral dose on day 0 and 2 h after the last oral dose on day 14. RESULTS On day 0 and day 14, all three terutroban dosages improved flow-mediated vasodilatation and abolished platelet aggregation induced by the TP receptor agonist U46619, without changing the aggregation response to ADP or collagen. CONCLUSION Terutroban, by chronically improving endothelium-dependent vasodilatation and inhibiting platelet aggregation, may prove useful for preventing cardiovascular events in high-risk patients.

Ambulatory transradial percutaneous coronary intervention: a safe, effective, and cost-saving strategy.

Objectives: The aim of this prospective, multicenter study was to assess the safety, feasibility, acceptance, and cost of ambulatory transradial percutaneous coronary intervention (PCI) under the conditions of everyday practice. Background: Major advances in PCI techniques have considerably reduced the incidence of post‐procedure complications. However, overnight admission still constitutes the standard of care in most interventional cardiology centers. Methods: Eligibility for ambulatory management was assessed in 370 patients with stable angina referred to three high‐volume angioplasty centers. On the basis of pre‐specified clinical and PCI‐linked criteria, 220 patients were selected for ambulatory PCI. Results: The study population included a substantial proportion of patients with complex procedures: 115 (52.3%) patients with multivessel coronary artery disease, 50 (22.7%) patients with multilesion procedures, and 60 (21.5%) bifurcation lesions. After 4‐6 hr observation period, 213 of the 220 patients (96.8%) were cleared for discharge. The remaining seven (3.2%) patients were kept overnight for unstable angina (n = 1), atypical chest discomfort (n = 2), puncture site hematoma (n = 1), or non‐cardiovascular reasons (n = 3). Within 24 hr after discharge, no patients experienced readmission, stent occlusion, recurrent ischemia, or local complications. Furthermore, 99% of patients were satisfied with ambulatory management and 85% reported no anxiety. The average non‐procedural cost was lower for ambulatory PCI than conventional PCI (1,230 ± 98 Euros vs. 2,304 ± 1814 Euros, P < 10−6). Conclusions: Ambulatory PCI in patients with stable coronary artery disease is safe, effective, and well accepted by the patients. It may both significantly reduce costs and optimize hospital resource utilization.

Pulmonary hemodynamic responses to inhaled NO in chronic heart failure depend on PDE5 G(-1142)T polymorphism.

To evaluate the vasoconstrictor component of PH in CHF by investigating the hemodynamic response to inhaled nitric oxide (iNO) and to determine whether this response was influenced by the phosphodiesterase 5 gene (PDE5) G(1142)T polymorphism. CHF patients underwent right heart catheterization at rest and after 20 ppm of iNO and plasma cGMP and PDE5 G(1142)T polymorphism determinations. Of the 72 included CHF patients (mean age, 53±1 years; mean left ventricular ejection fraction, 29±1%; and mean pulmonary artery pressure, 25.5±1.3 mmHg), 54% had ischemic heart disease. Proportions of patients with the TT, GT, and GG genotypes were 39%, 42% and 19% respectively. Baseline hemodynamic characteristics were not significantly different across PDE5 genotype groups, although pulmonary capillary wedge pressure (PCWP) tended to be lower in the TT group (P=0.09). Baseline plasma cGMP levels were significantly lower in the TT than in the GG and GT patients. With iNO, PVR diminished in TT (-33%) but not GG (-1.6%) or GT (0%) patients (P=0.002); and PCWP increased more in TT than in GT (P<0.05) or GG (P<0.003) patients. The PDE5 G(-1142) polymorphism is therefore a major contributor to the iNO-induced PVR decrease in CHF.

163 Diagnostic value of Doppler transthoracic echocardiography in the estimation of left ventricular filling pressure in patients with severe symptomatic systolic heart failure

Methods: We studied 72 patients with a first AMI. Measurements of Doppler echocardiographic parameters from mitral inflow were performed during the first 48 hours after admission. Mitral annulus Doppler tissue velocities were measured from septal and lateral wall. E/Ea ratio was calculated. Tei index was obtained as: (a – b)/b, where (a) is the interval between the cessation and onset of mitral flow and (b) is the ejection time by aortic flow by pulsed Doppler echocardiography. Aortic Pre-ejectionel period (PEP) was measured and Aortic PEP/ET (ejection time) ratio were also calculated. The left ventricular diastolic pressure was measured during the coronary angiography.