This study examined right-ventricular-pulmonary arterial (RV-PA) coupling and pulmonary vascular mechanics during acute exercise in 12 middle-aged men with a long-standing history of endurance training. Subjects underwent simultaneous right-heart catheterization and echocardiography, with measures obtained at steady state heart rates of 100, 130 and 150 beats/min. Subjects were highly trained and displayed RV remodeling of endurance-trained athletes. During exercise at 100 beats/min, systolic, diastolic, and mean pulmonary artery pressure increased significantly from rest, as did pulmonary capillary wedge pressure. The slope of pooled mean pulmonary pressure indexed to cardiac output was 1.436 mmHg⋅min-1⋅L-1 with a distensibility index of 0.112 ± 0.048 mmHg-1. The pulmonary arterial elastance-RV end-systolic elastance ratio (Ea:Ees) decreased from rest to exercise at 130 beats/min (P < 0.01). These results suggest that Ea:Ees becomes favourable for RV function during exercise, indicative of a pulmonary vasculature that is highly distensible and well matched to RV output.

This study examined right-ventricular-pulmonary arterial (RV-PA) coupling and pulmonary vascular mechanics during acute exercise in 12 middle-aged men with a long-standing history of endurance training. Subjects underwent simultaneous right-heart catheterization and echocardiography, with measures obtained at steady state heart rates of 100, 130 and 150 beats/min. Subjects were highly trained and displayed RV remodeling of endurance-trained athletes. During exercise at 100 beats/min, systolic, diastolic, and mean pulmonary artery pressure increased significantly from rest, as did pulmonary capillary wedge pressure. The slope of pooled mean pulmonary pressure indexed to cardiac output was 1.436 mmHg⋅min-1⋅L-1 with a distensibility index of 0.112 ± 0.048 mmHg-1. The pulmonary arterial elastance-RV end-systolic elastance ratio (Ea:Ees) decreased from rest to exercise at 130 beats/min (P < 0.01). These results suggest that Ea:Ees becomes favourable for RV function during exercise, indicative of a pulmonary vasculature that is highly distensible and well matched to RV output.

La fonction du ventricule droit est un déterminant majeur de la capacité fonctionnelle et du pronostic dans l’hypertension pulmonaire. La survenue dans ce contexte d’une insuffisance cardiaque droite requérant un support inotrope est associée à un taux de mortalité supérieur à 40%. Les déterminants cellulaires et moléculaires du découplage entre le coeur droit et la circulation artérielle pulmonaire sont méconnus, d’autant qu’il existe une grande hétérogénéité fonctionnelle parmi les patients soumis au même niveau de résistances vasculaires pulmonaires.Dans une première étude expérimentale, nous avons mis évidence à partir d’un modèle porcin d’hypertension pulmonaire chronique que les indices fonctionnels systoliques du ventricule droit mesurés en échocardiographie sont davantage corrélés au couplage ventriculo-artériel qu’à la performance contractile propre du ventricule droit. La réponse du ventricule droit à l’exercice ou à un stress pharmacologique a été peu documentée jusqu’à présent dans l’hypertension pulmonaire. Apartir de notre modèle porcin, nous avons montré que l’altération de la réserve contractile du ventricule droit est fortement associée au découplage ventriculo-artériel. La réserve contractile pourrait être un marqueur sensible et précoce de dysfonction ventriculaire droite. Dans une troisième étude, nous montrons la relation forte entre le couplage ventriculo-artériel et la plasticitéhémodynamique, fonctionnelle et moléculaire du ventricule droit dans un contexte de surcharge de pression chronique. Les variations d’expression de l’isoforme β de la chaîne légère de la myosine cardiaque pourraient déterminer l’efficacité du travail cardiaque droit. Nous avons par ailleurs constaté expérimentalement chez le rat que le remodelage géométrique et fonctionnel du ventricule droit en condition de surcharge barométrique chronique est associé à une infiltration macrophagique dumuscle cardiaque droit.Nos résultats physiopathologiques pourraient permettre une meilleure stratification des patients souffrant d’hypertension pulmonaire chronique. Ces mécanismes pourraient par ailleurs constituer autant de cibles thérapeutiques pour optimiser la fonction cardiaque droite lorsque la postcharge du ventricule droit n’est pas complètement corrigée, d’autant que les thérapies vaso-actives pulmonaires usuelles auraient des effets directs controversés sur le remodelage du ventricule droit. / Right ventricular function is a major determinant of functional capacity and prognosis in pulmonary hypertension. Right heart failure related to pulmonary hypertension is associated with a mortality rate up to 40% when inotrope support is necessary. Cellular and molecular determinants of right ventricular-pulmonary arterial coupling are misunderstood, while a wide functional range is remarkable among patients sharing the same degree of pulmonary vascular resistance.In a first experimental study, we showed from a porcine model of chronic pulmonary hypertension that usual non-invasive indices of right ventricular function are rather associated with ventricular-arterial coupling than with contractility. Right ventricular response to exercise or to pharmacological stress has been poorly reported in pulmonary hypertension. In our piglet model, we showed that impairment of right ventricular contractile reserve is strongly associated with ventricular-arterial uncoupling. Rightventricular reserve might be a sensitive marker of early ventricular dysfunction. In a third study, we highlighted that a strong relationship between ventricular-arterial coupling and functional and molecular plasticity of the pressure overloaded right ventricle. Gene expression of the beta-myosin heavy chain may be related to right heart efficiency. We also oberved experimentally in rats that structural and functional remodeling of the pressure overloaded right ventricle is associated withmacrophagic infiltration in the myocardium.Our pathophysiologic results could improve patient’s stratification in chronic pulmonary hypertension.These mechanisms may represent innovative targeted therapies to improve right ventricular function despite persistent elevated afterload.

Background: Stem cell therapy can facilitate cardiac repair after healed myocardial infarction but the optimal cell type remains uncertain. Aims: To investigate the pathophysiology of heart failure in a canine model of healed myocardial infarction and to compare the efficacy and the safety of autologous bone marrow mononuclear cell (BMNC) transfer and mesenchymal stem cell (MSC) transfer in this model. It was a blind, randomized and placebo control study. Methods: Eleven weeks after coronary ligation, 24 dogs received intramyocardial injections of BMNC, MSC or Placebo (n = 8 per groups). Echocardiography, conductance method, magnetic resonance imaging, serum neurohormones, holter monitoring, macromorphometry, histology and real time quantitative polymerase chain reaction were used to assess cardiac performance, safety and remodelling in healthy animals, before cell transplantation and up to 16 weeks’ follow-up. Results: The model was characterized by decreased left ventricular end-systolic elastance and ventricular-arterial uncoupling without alteration of compliance. Four months after BMNC transfer, the regional systolic function measured at echocardiographic showed a sustained improvement. This improvement was associated with an improved left ventricular end-systolic elastance and a decreased infarct size. Although the left ventricular ejection fraction stayed unchanged, the serum level of N-terminal B-type natriuretic propeptide level decreased. Mononuclear cell transfer was also associated with increased left ventricular relative wall area, increased vascular density, intramyocardial vascular remodelling and upregulation of angiogenic factors gene expression. Mesenchymal stem cell transfer only improved lately and moderately the regional systolic function, without improvement of cardiac contractility or decreased infarct size. Conclusions: In a canine model of chronic myocardial infarction, BMNC transfer is superior to MSC transfer in improvement of cardiac contractility and regional systolic function, and to reduce the infarct size and plasma N-terminal B-type natriuretic propeptide level. Functional improvement is associated with a favourable angiogenic environment and neovascularization.

<p>Background: Stem cell therapy can facilitate cardiac repair after healed myocardial infarction but the optimal cell type remains uncertain. <p>Aims: To investigate the pathophysiology of heart failure in a canine model of healed myocardial infarction and to compare the efficacy and the safety of autologous bone marrow mononuclear cell (BMNC) transfer and mesenchymal stem cell (MSC) transfer in this model. It was a blind, randomized and placebo control study.<p>Methods: Eleven weeks after coronary ligation, 24 dogs received intramyocardial injections of BMNC, MSC or Placebo (n = 8 per groups). Echocardiography, conductance method, magnetic resonance imaging, serum neurohormones, holter monitoring, macromorphometry, histology and real time quantitative polymerase chain reaction were used to assess cardiac performance, safety and remodelling in healthy animals, before cell transplantation and up to 16 weeks’ follow-up. <p>Results: The model was characterized by decreased left ventricular end-systolic elastance and ventricular-arterial uncoupling without alteration of compliance. <p>Four months after BMNC transfer, the regional systolic function measured at echocardiographic showed a sustained improvement. This improvement was associated with an improved left ventricular end-systolic elastance and a decreased infarct size. Although the left ventricular ejection fraction stayed unchanged, the serum level of N-terminal B-type natriuretic propeptide level decreased. Mononuclear cell transfer was also associated with increased left ventricular relative wall area, increased vascular density, intramyocardial vascular remodelling and upregulation of angiogenic factors gene expression. Mesenchymal stem cell transfer only improved lately and moderately the regional systolic function, without improvement of cardiac contractility or decreased infarct size. <p>Conclusions: In a canine model of chronic myocardial infarction, BMNC transfer is superior to MSC transfer in improvement of cardiac contractility and regional systolic function, and to reduce the infarct size and plasma N-terminal B-type natriuretic propeptide level. Functional improvement is associated with a favourable angiogenic environment and neovascularization. <p> / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished