Joffrey Pozzo

CD4+ T Cells Promote the Transition From Hypertrophy to Heart Failure During Chronic Pressure Overload

Background— The mechanisms by which the heart adapts to chronic pressure overload, producing compensated hypertrophy and eventually heart failure (HF), are still not well defined. We aimed to investigate the involvement of T cells in the progression to HF using a transverse aortic constriction (TAC) model. Methods and Results— Chronic HF was associated with accumulation of T lymphocytes and activated/effector CD4+ T cells within cardiac tissue. After TAC, enlarged heart mediastinal draining lymph nodes showed a high density of both CD4+ and CD8+ T-cell subsets. To investigate the role of T cells in HF, TAC was performed on mice deficient for recombination activating gene 2 expression (RAG2KO) lacking B and T lymphocytes. Compared with wild-type TAC mice, RAG2KO mice did not develop cardiac dilation and showed improved contractile function and blunted adverse remodeling. Reconstitution of the T-cell compartment into RAG2KO mice before TAC enhanced contractile dysfunction, fibrosis, collagen accumulation, and cross-linking. To determine the involvement of a specific T-cell subset, we performed TAC on mice lacking CD4+ (MHCIIKO) and CD8+ T-cell subsets (CD8KO). In contrast to CD8KO mice, MHCIIKO mice did not develop ventricular dilation and dysfunction. MHCIIKO mice also displayed very low fibrosis, collagen accumulation, and cross-linking within cardiac tissue. Interestingly, mice with transgenic CD4+ T-cell receptor specific for ovalbumin failed to develop HF and adverse remodeling. Conclusions— These results demonstrate for the first time a crucial role of CD4+ T cells and specific antigen recognition in the progression from compensated cardiac hypertrophy to HF.

LEOPARD syndrome-associated SHP2 mutation confers leanness and protection from diet-induced obesity

Significance LEOPARD syndrome (multiple Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, sensorineural Deafness; LS) is a rare genetic disease associating various developmental defects mainly caused by inactivating mutations of the tyrosine phosphatase SHP2 (Src-homology 2 domain-containing phosphatase 2). SHP2 is a key regulator of essential signaling pathways (MAPK, PI3K), which confer on SHP2 major roles in development and metabolism control. However, nothing is known about the metabolic status of LS. We thus performed an extensive metabolic exploration of an original LS mouse model. These mice display a lean phenotype (reduced adiposity, improved carbohydrate metabolism), translating into resistance to obesity and associated disorders upon obesogenic diet. This phenotype correlated with defective adipogenesis, better insulin signaling, and enhanced energy expenditure and was partially corrected by MAPK inhibition. Preliminary data in LS patients are in agreement with these findings. LEOPARD syndrome (multiple Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, sensorineural Deafness; LS), also called Noonan syndrome with multiple lentigines (NSML), is a rare autosomal dominant disorder associating various developmental defects, notably cardiopathies, dysmorphism, and short stature. It is mainly caused by mutations of the PTPN11 gene that catalytically inactivate the tyrosine phosphatase SHP2 (Src-homology 2 domain-containing phosphatase 2). Besides its pleiotropic roles during development, SHP2 plays key functions in energetic metabolism regulation. However, the metabolic outcomes of LS mutations have never been examined. Therefore, we performed an extensive metabolic exploration of an original LS mouse model, expressing the T468M mutation of SHP2, frequently borne by LS patients. Our results reveal that, besides expected symptoms, LS animals display a strong reduction of adiposity and resistance to diet-induced obesity, associated with overall better metabolic profile. We provide evidence that LS mutant expression impairs adipogenesis, triggers energy expenditure, and enhances insulin signaling, three features that can contribute to the lean phenotype of LS mice. Interestingly, chronic treatment of LS mice with low doses of MEK inhibitor, but not rapamycin, resulted in weight and adiposity gains. Importantly, preliminary data in a French cohort of LS patients suggests that most of them have lower-than-average body mass index, associated, for tested patients, with reduced adiposity. Altogether, these findings unravel previously unidentified characteristics for LS, which could represent a metabolic benefit for patients, but may also participate to the development or worsening of some traits of the disease. Beyond LS, they also highlight a protective role of SHP2 global LS-mimicking modulation toward the development of obesity and associated disorders.

Obesity Paradox: Origin and best way to assess severity in patients with systolic HF

Obesity in patients with heart failure (HF) is a factor of better prognosis, supposedly partly because of the particular epidemiology of HF in this population. This study expected to compare the parameters of severity and mortality in patients with and without obesity, to better understand the origin of this paradox.

Local production of tenascin-C acts as a trigger for monocyte/macrophage recruitment that provokes cardiac dysfunction

Aims Tenascin-C (TNC) is an endogenous danger signal molecule strongly associated with inflammatory diseases and with poor outcome in patients with cardiomyopathies. Its function within pathological cardiac tissue during pressure overload remains poorly understood. Methods and results We showed that TNC accumulates after 1 week of transverse aortic constriction (TAC) in the heart of 12-week-old male mice. By cross bone marrow transplantation experiments, we determined that TNC deposition relied on cardiac cells and not on haematopoietic cells. The expression of TNC induced by TAC, or by administration of a recombinant lentivector coding for TNC, triggered a pro-inflammatory cardiac microenvironment, monocyte/macrophage (MO/MΦ) accumulation, and systolic dysfunction. TNC modified macrophage polarization towards the pro-inflammatory phenotype and stimulated RhoA/Rho-associated protein kinase (ROCK) pathways to promote mesenchymal to amoeboid transition that enhanced macrophage migration into fibrillar collagen matrices. The amplification of inflammation and MO/MΦ recruitment by TNC was abrogated by genetic invalidation of TNC in knockout mice. These mice showed less ventricular remodelling and an improved cardiac function after TAC as compared with wild-type mice. Conclusions By promoting a pro-inflammatory microenvironment and macrophage migration, TNC appears to be a key factor to enable the MO/MΦ accumulation within fibrotic hearts leading to cardiac dysfunction. As TNC is highly expressed during inflammation and sparsely during the steady state, its inhibition could be a promising therapeutic strategy to control inflammation and immune cell infiltration in heart disease.

Absolute iron deficiency without anaemia in patients with chronic systolic heart failure is associated with poorer functional capacity

BACKGROUND Functional status is one of the main concerns in the management of heart failure (HF). Recently, the FAIR-HF and CONFIRM-HF trials showed that correcting anaemia using intravenous iron supplementation improved functional variables in patients with absolute or relative iron deficiency. Relative iron deficiency is supposed to be a marker of HF severity, as ferritin concentration increases with advanced stages of HF, but little is known about the impact of absolute iron deficiency (AID). AIMS To study the impact of AID on functional variables and survival in patients with chronic systolic HF. METHODS One hundred and thirty-eight non-anaemic patients with chronic systolic HF were included retrospectively. Patients were divided into two groups according to iron status: the AID group, defined by a ferritin concentration<100μg/L and the non-AID group, defined by a ferritin concentration≥100μg/L. Functional, morphological and biological variables were collected, and survival was assessed. RESULTS Patients in the AID group had a poorer 6-minute walking test (342 vs. 387m; P=0.03) and poorer peak exercise oxygen consumption (13.8 vs. 16.0mL/min/kg; P=0.01). By multivariable analysis, ferritin<100μg/L was associated with impaired capacity of effort, assessed by peak exercise oxygen consumption. By multivariable analysis, there was no difference in total mortality between groups, with a mean follow-up of 5.1±1.1 years. CONCLUSIONS The poorer functional evaluations in iron-deficient patients previously reported are not caused by the merging of two different populations (i.e. patients with absolute or relative iron deficiency). Our study has confirmed that non-anaemic HF patients with AID have poorer peak oxygen consumption. However, AID has no impact on the survival of these patients.

0148: Intramyocardial transplantation of mesenchymal stromal cells for chronic myocardial ischemia and decreased left ventricular function: 1-year results of the MESAMI phase I clinical trial

Our aim was to investigate the safety and feasibility of transendocardial injections guided by 3-dimensional NogaStar XP mapping of autologous bone marrow-derived mesenchymal stromal cells (MSC) in patients with chronic myocardial ischemia and left ventricular dysfunction. The MESAMI 1 trial is a bicentric phase 1 study, including 10 patients with chronic myocardial ischemia. The inclusion criteria were: NYHA Class II-IV and/or angina pectoris CCS Class III or IV, chronic ischemic cardiomyopathy with LVEF ≤35%, optimal medical and revascularization therapies, and reversible perfusion defect by SPECT. Bone marrow was obtained by aspiration from the iliac crest and MSC were expanded in culture for 17 days. Transendocardial injections (n=14-16) of autologous bone marrow MSC were made into viable muscle in border zones of left ventricular scar. Bone marrow volume was 16.8±2.0ml, and patients received 61.5* 10 6 MSC. After 1-month follow-up (FU), the primary end-point of safety and feasibility was met since all patients tolerated the procedure with no adverse events due to the procedure and the cell therapy product. Secondary endpoints between baseline and 3-month FU showed a significant decreased of summed stress score measured by SPECT from 34.1±8 to 25.3±9.5(p 2 peak, and Quality of life (Qol) showed a trend toward improvement at 3 months compared to baseline and up to 12 months except for Qol. We demonstrated the safety and the feasibility of this innovative treatment. A randomized, double blind, multicenter, placebo-controlled clinical trial (MESAMI 2) will evaluate the efficiency of this procedure in a larger population.Clinical Trial Registration: NCT01076920

Coronary Perforation and Pericardial Effusion Complicating Coronary Radiation–Induced Angiosarcoma: Findings from Echocardiography, Cardiac Magnetic Resonance, Angiography, and Pathology

Graphical abstract