Rossignol, P.(Patrick)
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- Absence of cardiotrophin 1 is associated with decreased age-dependent arterial stiffness and increased longevity in mice(2013) Benetos, A.(Athanase); Lacolley, P. (Patrick); Calvier, L. (Laurent); Diez-Martinez, J. (Javier); Fay, R. (Reynaud); Zannad, F. (Faiez); Lopez-Andres, N. (Natalia); Rossignol, P.(Patrick); Labat, C. (Carlos)Cardiotrophin 1 (CT-1), an interleukin 6 family member, promotes fibrosis and arterial stiffness. We hypothesized that the absence of CT-1 influences arterial fibrosis and stiffness, senescence, and life span. In senescent 29-month- old mice, vascular function was analyzed by echotracking device. Arterial histomorphology, senescence, metabolic, inflammatory, and oxidative stress parameters were measured by immunohistochemistry, reverse transcription polymerase chain reaction, Western blot, and ELISA. Survival rate of wild-type and CT-1–null mice was studied. Vascular smooth muscle cells were treated with CT-1 (10 −9 mol/L) for 15 days to analyze senescence. The wall stress-incremental elastic modulus curve of old CT-1–null mice was shifted rightward as compared with wild-type mice, indicating decreased arterial stiffness. Media thickness and wall fibrosis were lower in CT-1–null mice. CT-1–null mice showed decreased levels of inflammatory, apoptotic, and senescence pathways, whereas telomere-linked proteins, DNA repair proteins, and antioxidant enzyme activities were increased. CT-1–null mice displayed a 5-month increased median longevity compared with wild-type mice. In vascular smooth muscle cells, chronic CT-1 stimulation upregulated apoptotic and senescence markers and downregulated telomere-linked proteins. The absence of CT-1 is associated with decreased arterial fibrosis, stiffness, and senescence and increased longevity in mice likely through downregulating apoptotic, senescence, and inflammatory pathways. CT-1 may be a major regulator of arterial stiffness with a major impact on the aging process
- Cardiotrophin 1 is involved in cardiac, vascular, and renal fibrosis and dysfunction(2012) Lacolley, P. (Patrick); Calvier, L. (Laurent); Diez-Martinez, J. (Javier); Rousseau, A.(Amélie); Zhao, X.(Xuegen); Cruickshank, K.(Kennedy); Akhtar, R.(Riaz); Zannad, F. (Faiez); Lopez-Andres, N. (Natalia); Rossignol, P.(Patrick); Labat, C. (Carlos); Iñigo, C. (Carmen)Cardiotrophin 1 (CT-1), a cytokine belonging to the interleukin 6 family, is increased in hypertension and in heart failure. We aimed to study the precise role of CT-1 on cardiac, vascular, and renal function; morphology; and remodeling in early stages without hypertension. CT-1 (20 g/kg per day) or vehicle was administrated to Wistar rats for 6 weeks. Cardiac and vascular functions were analyzed in vivo using M-mode echocardiography, Doppler, and echo tracking device and ex vivo using a scanning acoustic microscopy method. Cardiovascular and renal histomorphology were measured by immunohistochemistry, RT-PCR, and Western blot. Kidney functional properties were assessed by serum creatinine and neutrophile gelatinase-associated lipocalin and microalbuminuria/creatininuria ratio. Without alterations in blood pressure levels, CT-1 treatment increased left ventricular volumes, reduced fractional shortening and ejection fraction, and induced myocardial dilatation and myocardial fibrosis. In the carotid artery of CT-1–treated rats, the circumferential wall stress-incremental elastic modulus curve was shifted leftward, and the acoustic speed of sound in the aorta was augmented, indicating increased arterial stiffness. Vascular media thickness, collagen, and fibronectin content were increased by CT-1 treatment. CT-1–treated rats presented unaltered serum creatinine concentrations but increased urinary and serum neutrophile gelatinase-associated lipocalin and microalbuminuria/creatininuria ratio. This paralleled a glomerular and tubulointerstitial fibrosis accompanied by renal epithelial-mesenchymal transition. CT-1 is a new potent fibrotic agent in heart, vessels, and kidney able to induce cardiovascular-renal dysfunction independent from blood pressure. Thus, CT-1 could be a new target simultaneously integrating alterations of heart, vessels, and kidney in early stages of heart failure.
- Rationale of the FIBROTARGETS study designed to identify novel biomarkers of myocardial fibrosis(Wiley, 2018) Gyöngyösi, M. (Mariann); Pizard, A. (Anne); Thum, T. (Thomas); Jaisser, F. (Frederic); Machu, J.L. (Jean-Loup); Ferreira, J.P. (João Pedro); McDonald, K. (Kenneth); Firat, H. (Hueseyin); Heymans, S. (Stephane); Butler, J. (Javed); Zannad, F. (Faiez); Gonzalez, A. (Arantxa); Girerd, N. (Nicolas); Rossignol, P.(Patrick); Diez, J. (Javier)Aims Myocardial fibrosis alters the cardiac architecture favouring the development of cardiac dysfunction, including arrhythmias and heart failure. Reducing myocardial fibrosis may improve outcomes through the targeted diagnosis and treatment of emerging fibrotic pathways. The European-Commission-funded ‘FIBROTARGETS’ is a multinational academic and industrial consortium with the main aims of (i) characterizing novel key mechanistic pathways involved in the metabolism of fibrillary collagen that may serve as biotargets, (ii) evaluating the potential anti-fibrotic properties of novel or repurposed molecules interfering with the newly identified biotargets, and (iii) characterizing bioprofiles based on distinct mechanistic phenotypes involving the aforementioned biotargets. These pathways will be explored by performing a systematic and collaborative search for mechanisms and targets of myocardial fibrosis. These mechanisms will then be translated into individualized diagnostic tools and specific therapeutic pharmacological options for heart failure. Methods and results The FIBROTARGETS consortium has merged data from 12 patient cohorts in a common database available to individual consortium partners. The database consists of >12 000 patients with a large spectrum of cardiovascular clinical phenotypes. It integrates community-based population cohorts, cardiovascular risk cohorts, and heart failure cohorts. Conclusions The FIBROTARGETS biomarker programme is aimed at exploring fibrotic pathways allowing the bioprofiling of patients into specific ‘fibrotic’ phenotypes and identifying new therapeutic targets that will potentially enable the development of novel and tailored anti-fibrotic therapies for heart failure.
- Heart failure and diabetes: metabolic alterations and therapeutic interventions: a state-of-the-art review from the Translational Research Committee of the Heart Failure Association-European Society of Cardiology(European Society of Cardiology, 2018) Staels, B. (Bart); Heinzel, F.R. (Frank R.); Rosano, G. (Giuseppe); Huelsmann, M. (Martin); Hulot, J.S. (Jean-Sebastien); Ruschitzka, F. (Frank); Lyon, A.R. (Alexander R.); Laake, L.W. (Linda W.) van; Maack, C. (Christoph); Cosentino, F. (Francesco); Brutsaert, D. (Dirk); Rena, G. (Graham); Bauersachs, J. (Johann); Farmakis, D. (Dimitrios); Boer, R.A. (Rudolf A.) de; Keulenaer, G. (Gilles) de; Taegtmeyer, H. (Heinrich); Lunde, I.G. (Ida G.); Iaccarino, G. (Guido); Dei-Cas, A. (Alessandra); Clarke, K. (Kieran); Heymans, S. (Stephane); Pollesello, P. (Piero); Gonzalez, A. (Arantxa); Seferovic, P. (Petar); Paulus, W.J. (Walter J.); Wanner, C. (Christoph); Backs, J. (Johannes); Bugger, H. (Heiko); Riksen, N.P. (Niels P.); Lehrke, M. (Michael); Filippatos, G. (Gerasimos); Marx, N. (Nikolaus); Rossignol, P.(Patrick); Bayes-Genis, A. (Antoni)Heart failure (HF) is growing to a modern epidemic and despite advances in therapy, it still carries an ominous prognosis and a significant socioeconomic burden. Many novel agents that emerged as promising HF drugs failed to improve residual morbidity and mortality.2,3 Since developing and testing new agents has become increasingly costly,4 the concept of repurposing existing drugs for new indications has gained considerable importance. Conceptually, comorbidities such as type 2 diabetes mellitus (T2DM), obesity or chronic kidney disease, all highly prevalent in HF populations, have shifted from being innocent bystanders to drivers of HF. This applies especially to HF with preserved ejection fraction (HFpEF), a phenotype that accounts for more than 50% of HF patients and for which no effective therapy exists thus far.5,6 In particular, the prevalence of T2DM, thereby its combination with HF is rapidly increasing, mainly due to the obesity epidemic. Cardiovascular (CV) outcomes are addressed by an increasing number of clinical studies in T2DM, mainly as safety endpoints for anti-diabetic agents. Some of those drugs have beneficial CV effects independent of their glucose-lowering action. Consequently, antidiabetic agents have gained interest for their potential repurposing in HF treatment. In this context, the Translational Research Committee of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) organized a workshop on HF and T2DM, focusing on the pathophysiological and therapeutic aspects of this relationship. Here, we summarize the main points raised during this workshop, providing an overview of current evidence and open issues.