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Older adults, defined as individuals older than 65 years, are vulnerable to drug-induced adverse effects due to age-related physiological changes, such as decreased renal and hepatic function, increased body fat, [...]

With the surgical improvement of congenital heart disease, Fontan operation has been applied to many complicated patients in recent years. This is the first report of a child with panhypopituitarism who underwent Fontan operation. A 5-year-old boy was scheduled for Fontan operation. He previously underwent Blalock-Taussig shunt and bidirectional Glenn operations for univentricular heart with double-outlet right ventricle and pulmonary atresia. He was receiving hydrocortisone and 1-desamino-8-D-arginine vasopressin (DDAVP) for panhypopituitarism secondary to removal of craniopharyngioma performed at the age of three years. Although urine output and serum sodium concentration were adequately controlled by adjustment of vasopressin infusion rate during surgery, massive pleural effusions and ascites developed postoperatively, which required several days for control by adjusting the dose of oral DDAVP and normalize the serum sodium level. Intraoperative management of Fontan operation for a patient with panhypopituitarism was controllable by appropriate hormone replacement. However, postoperative fluid management was complicated by the clinical features of panhypopituitarism and Fontan physiology., Author(s): Kohei Sunoki [sup.1], Yoji Otsuka [sup.1], Hidetaka Iwai [sup.1], Tatsuya Nagano [sup.1], Naoyuki Taga [sup.1], Masaaki Kawada [sup.2], Mamoru Takeuchi [sup.1] [sup.3] Author Affiliations: (1) grid.410804.9, 0000000123090000, Department of [...]

Metabolic, inflammatory, and autonomic nervous system (ANS) dysfunction are present in patients with heart failure. However, whether these changes are due to left ventricular dysfunction or heart failure etiology is unknown. We evaluated metabolism and inflammatory activity in patients with idiopathic dilated cardiomyopathy (IDC) and Chagas cardiomyopathy (CHG) and their correlation with the ANS. Forty-six patients were divided into 3 groups: IDC, CHG, and control. We evaluated adiponectin, leptin, insulin, interleukin-6, and tumor necrosis factor-alpha. ANS were analyzed by heart rate variability in time and frequency domains on a 24-hour Holter monitor. Levels of glucose, cholesterol, leptin, and adiponectin did not show differences between groups. Insulin levels were lower in CHG group (5.4 [+ or -] 3.3 [micro]U/mL) when compared with control (8.0 [+ or -] 4.9 [micro]U/mL) and IDC (9.9 [+ or -] 5.0 [micro]U/mL) groups (p = 0.007). Insulin was positively associated with LFr/HFr ratio (r = 0.562; p = 0.029) and with the LFr component (r = 0.562; p = 0.029) and negatively associated with adiponectin (r = -0.603; p = 0.017) in CHG group. The addition of an adiponectin unit reduced average insulin by 0.332 [micro]g/mL. Insulin levels were decreased in the CHG group when compared with the IDC group and were associated with ANS indexes and adiponectin levels.Key words: adipocytokine, insulin levels, Chagas heart disease.Les systemes metabolique, inflammatoire et nerveux autonome presentent des dysfonctionnements chez les patients atteints d'insuffisance cardiaque. Cependant, on ne sait pas si l'etiologie de ces modifications est liee au dysfonctionnement du ventricule gauche ou a l'insuffisance cardiaque. Nous avons evalue le metabolisme et l'activite inflammatoire chez des patients atteints de cardiomyopathie dilatee idiopathique (CDI) ou de cardiomyopathie de Chagas (CCH), ainsi que leur correlation avec le systeme nerveux autonome (SNA). Nous avons reparti 46 patients dans 3 groupes : CDI, CCH et temoin (GT). Nous avons evalue les taux d'adiponectine, de leptine, d'insuline, d'interleukine 6 et du facteur de necrose tumorale alpha. Le SNA a ete evalue par la variabilite de la frequence cardiaque dans le temps et les domaines de frequence a l'aide d'une surveillance de 24 heures par Holter. Les taux de glucose, de cholesterol, de leptine et d'adiponectine ne se sont pas reveles differents entre les groupes. Les taux d'insuline etaient moins eleves dans le groupe CCH (5,4 [+ or -] 3,3 [micro]U/mL) que dans les groupes GT (8,0 [+ or -] 4,9 [micro]U/mL) et CDI (9,9 [+ or -] 5,0 [micro]U/mL) (p = 0,007). Dans le groupe CCH, les taux d'insuline etaient directement proportionnels au ratio LFr/HFr (basses frequences sur hautes frequences; r = 0,562; p = 0,029) et a la composante LFr (r = 0,562; p = 0,029), ainsi qu'inversement proportionnels aux taux d'adiponectine (r = -0,603; p = 0,017). L'ajout d'une unite d'adiponectine entrainait une diminution des taux d'insuline moyens de 0,332 [micro]g/mL. Les taux d'insuline etaient plus bas dans le groupe CCH que dans le groupe CDI et associes aux indices du SNA et aux taux d'adiponectine. [Traduit par la Redaction]Mots-cles : adipocytokine, taux d'insuline, maladie cardiaque de Chagas., IntroductionChagas disease occurs from the southern United States to Patagonia and affects around 8 million people in Latin America and is the main cause of cardiomyopathy in these endemic areas [...]

Author(s): Hans Flaatten [sup.1] [sup.2], Elisabeth Skaar [sup.3] [sup.4], Gavin M. Joynt [sup.5] Author Affiliations: (1) 0000 0000 9753 1393, grid.412008.f, Department of Anaesthesia and Intensive Care, Haukeland University Hospital, [...]

Radiotherapy is the most commonly used methodology to treat oncological disease, one of the most widespread causes of death worldwide. Oncological patients cured by radiotherapy applied to the mediastinal area have been shown to suffer from cardiovascular disease. The increase in the prevalence of radiation- induced heart disease has emphasized the need to seek new therapeutic targets to mitigate the negative impact of radiation on the heart. In this regard, microRNAs (miRNAs) have received considerable interest. miRNAs regulate post- transcriptional gene expression by their ability to target various mRNA sequences because of their imperfect pairing with mRNAs. It has been recognized that miRNAs modulate a diverse spectrum of cardiac functions with developmental, pathophysiological, and clinical implications. This makes them promising potential targets for diagnosis and treatment. This review summarizes the recent findings about the possible involvement of miRNAs in radiation-induced heart disease and their potential use as diagnostic or treatment targets in this respect. Key words: free radicals, inflammation, microRNA, oxidative stress, radiation- induced heart disease. La radiotherapie constitue la modalite la plus courante pour traiter le cancer, l'une des causes les plus repandues de deces a l'echelle mondiale. On a montre que les patients cancereux gueris par la radiotherapie appliquee a la region mediastinale souffrent de maladies cardiovasculaires. L'augmentation de la prevalence de la maladie cardiaque entrainee par la radiotherapie a mis de l'emphase sur la necessite de chercher de nouvelles cibles therapeutiques pour mitiger l'incidence negative des rayonnements sur le creur. A cet egard, les microARN (miARN) ont recu une attention considerable. Les miARN assurent la regulation de l'expression post-transcriptionnelle des genes, par leur capacite de cibler diverses sequences d'ARNm en raison de leur appariement imparfait avec les ARNm. On s'est rendu compte que les miARN assurent la modulation d'un spectre diversifie de fonctions cardiaques, avec des implications sur le plan du developpement, de la physiopathologie et de la clinique. Cela en fait des cibles potentielles prometteuses en vue du diagnostic et du traitement. Cet article de synthese resume les resultats recents quant a la participation eventuelle des miARN dans la maladie cardiaque entrainee par les rayonnements et leur utilisation potentielle comme cibles de diagnostic et de traitement dans ce contexte. [Traduit par la Redaction] Mots-cles: radicaux libres, inflammation, microARN, stress oxydatif, maladie cardiaque entrainee par des rayonnements., Introduction MicroRNAs (miRNAs) represent small (22-24 nucleotides long) non-coding RNA molecules that regulate the expression of various target genes by hybridization to 3' untranslated region (3'UTR) of target mRNA (Small [...]

Endocardial endothelial cells (EECs) constitute an important component of the heart. These cells form a monolayer that covers the cavities of the right (EECRs) and left (EECLs) ventricles. They play an important role in cardiac excitation-contraction coupling via their secretion of cardioactive factors such as neuropeptide Y (NPY). They also contribute to cardiac pathology such as arrhythmia, hypertrophy, and heart failure. Differences between EECRs and EECLs contribute to tuning of circulating factors at the entry and exit of the ventricles. NPY, via activation of its receptors, modulates the excitation-secretion coupling of EECs, thus, indirectly modulating cardiac function and remodeling. Key words: NPY, NPY receptors, endocardial endothelial cells, ET-1, calcium. Les cellules endotheliales endocardiques (CEE) constituent une composante importante du creur. Ces cellules forment une monocouche qui tapisse les cavites des ventricules droit (CEED) et gauche (CEEG). Elles jouent un role important dans le couplage excitation-contraction du creur par l'intermediaire de la secretion de facteurs cardioactifs comme le neuropeptide Y (NPY). Elles contribuent aussi a des pathologies cardiaques comme les arythmies ainsi que l'hypertrophie et l'insuffisance cardiaques. Les differences entre les CEED et les CEEG contribuent a l'ajustement de facteurs circulants a l'entree et a la sortie des ventricules. Le NPY, par l'intermediaire de l'activation de ses recepteurs, assure la modulation du couplage excitationsecretion des CEE, et par consequent la modulation de la fonction cardiaque et du remodelage du creur. [Traduit par la Redaction] Mots-cles: NPY, recepteurs du NPY, cellules endotheliales endocardiques, ET-1, calcium., Introduction Our knowledge about cardiac function has evolved greatly over the years, so now the heart is recognized as a pluricellular, multifunctional organ in which the endothelium, and more particularly [...]

Irradiation of normal tissues leads to acute increase in reactive oxygen/nitrogen species that serve as intra- and inter-cellular signaling to alter cell and tissue function. In the case of chest irradiation, it can affect the heart, blood vessels, and lungs, with consequent tissue remodelation and adverse side effects and symptoms. This complex process is orchestrated by a large number of interacting molecular signals, including cytokines, chemokines, and growth factors. Inflammation, endothelial cell dysfunction, thrombogenesis, organ dysfunction, and ultimate failing of the heart occur as a pathological entity--'radiation-induced heart disease' (RIHD) that is major source of morbidity and mortality. The purpose of this review is to bring insights into the basic mechanisms of RIHD that may lead to the identification of targets for intervention in the radiotherapy side effect. Studies of authors also provide knowledge about how to select targeted drugs or biological molecules to modify the progression of radiation damage in the heart. New prospective studies are needed to validate that assessed factors and changes are useful as early markers of cardiac damage. Key words: radiation induced heart disease, ischemia, apoptosis, adaptation, markers. L'irradiation de tissus normaux mene a une augmentation aigue de la formation de derives reactifs de l'oxygene ou de l'azote, qui agissent en tant que voies de signalisation intra-et extra-cellulaires pour modifier le fonctionnement des cellules et des tissus. Dans le cas de l'irradiation du thorax, cela peut affecter le coeur, les vaisseaux sanguins et les poumons, avec un remodelage consecutif des tissus ainsi que des effets indesirables et des symptomes. Ce processus complexe est orchestre par l'interaction d'un grand nombre de signaux moleculaires, y compris des cytokines, des chimiokines et des facteurs de croissance. L'inflammation, le dysfonctionnement des cellules endotheliales, la thrombogenese, le dysfonctionnement des organes et enfin l'insuffisance cardiaque peuvent survenir comme une entite, la << cardiopathie post-radique >> (CPR), source majeure de morbidite et de mortalite. L'article de synthese a pour objectif d'apporter des perspectives pour les modes d'action a la base de la CPR qui pourraient mener a l'etablissement de cibles pour des interventions contre les effets indesirables de la radiotherapie. Les etudes d'auteurs permettent aussi d'obtenir des connaissances sur la maniere de selectionner des medicaments ou des molecules biologiques cibles en vue de modifier l'evolution des dommages cardiaques causes par les rayonnements. De nouvelles etudes prospectives sont necessaires pour valider que les facteurs et les changements evalues sont utiles comme marqueurs precoces de dommages cardiaques. [Traduit par la Redaction] Mots-cles: cardiopathie post-radique, ischemie, apoptose, adaptation, marqueurs., Introduction Treatment of oncological patients often requires radiation therapy (RT). Despite modern radiotherapy techniques, in some cases irradiation of tumors inevitably involves also exposure of normal tissues that causes undesired [...]

Diabetes mellitus, besides having deleterious effects, induces cardiac adaptation that may reduce the heart's susceptibility to ischemia-reperfusion (IR) injury. This study aimed to investigate whether changes in mitochondrial properties are involved in the mechanisms of increased resistance of the diabetic heart to IR. Adult male Wistar rats were made diabetic by a single dose of streptozotocin (65 mg-[kg.sup.-1], i.p.), and on the day 8, Langendorff-perfused hearts were subjected to 30 min global ischemia and 40 min reperfusion. Baseline preischemic parameters in the diabetic hearts did not differ markedly from those in the nondiabetic controls, except for lower left ventricular developed pressure, higher mitochondrial membrane fluidity, and protein levels of manganese superoxide dismutase. On the other hand, diabetic hearts showed significantly better post-IR functional restoration and reduced arrhythmogenesis associated with lower reactive oxygen species production as compared with healthy controls. IR decreased membrane fluidity in both experimental groups; however, it led to a complete recovery of mitochondrial [Mg.sup.2+]-ATPase activity in diabetics in contrast to its reduction in nondiabetics. These findings indicate that the heart may become adapted to diabetes-induced alterations that might increase its tolerance to an ischemic insult. Preserved mitochondrial function might play a role in the mechanisms of the heart's resistance to IR injury in diabetics. Key words: streptozotocin-induced diabetes, ischemia-reperfusion, adaptation, membrane fluidity, mitochondrial [Mg.sup.2+]-ATPase. Qu'outre ses effets deleteres, le diabete sucre entraine une adaptation du creur qui pourrait permettre de reduire sa susceptibilite aux lesions d'ischemie-reperfusion (IR). Ces travaux visaient a etudier si les proprietes des mitochondries jouent un role dans les modes d'action de l'augmentation de la resistance des creurs de patients diabetiques a l'IR. Chez des rats Wistar males adultes, nous avons provoque un diabete a l'aide d'une dose unique de streptozotocine (65 mg-[kg.sup.-1], i.p.), et au jour 8, nous avons perfuse les creurs en Langendorff et provoque une ischemie globale de 30 min, avec une reperfusion de 40 min. Avant l'ischemie, les parametres initiaux des creurs de rats diabetiques n'etaient pas differents de facon notable de ceux des rats temoins non-diabetiques, a l'exception d'un abaissement de la pression ventriculaire developpee, d'une augmentation de la fluidite des membranes mitochondriales et d'une augmentation des taux proteiques de superoxyde dismutase au manganese. Comparativement aux temoins en bonne sante, le retablissement du fonctionnement des creurs de rats diabetiques etait par ailleurs nettement superieur apres l'IR, avec une diminution de l'arythmogenese associee a une diminution de la production de derives reactifs de l'oxygene. L'IR entrainait une diminution de la de la fluidite des membranes mitochondriales dans les deux groupes a l'etude, mais nous avons observe un retablissement complet de l'activite de la [Mg.sup.2+]-ATPase mitochondriale chez les rats diabetiques, contrairement a sa diminution chez les rats non diabetiques. Ces resultats montrent que le creur peut s'adapter aux modifications provoquees par le diabete, ce qui pourrait entrainer une augmentation de sa tolerance a une agression ischemique. En somme, la preservation de la fonction mitochondriale pourrait jouer un role dans les modes d'action de la resistance aux lesions d'IR chez les patients diabetiques. [Traduit par la Redaction] Mots-cles : diabete provoque par la streptozotocine, ischemie-reperfusion, adaptation, fluidite membranaire, [Mg.sup.2+]-ATPase mitochondriale., Introduction Diabetes mellitus and ischemic heart disease belong to a broad range of civilization diseases that share a common feature, namely the presence of tissue hypoxia. However, unlike the ischemic [...]

We aimed to explore whether myocardial intercellular channel protein connexin-43 (Cx43) along with PKC[epsilon] and MMP-2 might be implicated in responses to acute cardiac injury induced by 2 distinct sublethal interventions in Wistar rats. Animals underwent either single chest irradiation at dose of 25 Gy or subcutaneous injection of isoproterenol (ISO, 120 mg/kg) and were compared with untreated controls. Forty-two days post-interventions, the hearts were excised and left ventricles were used for analysis. The findings showed an increase of total as well as phosphorylated forms of myocardial Cx43 regardless of the type of interventions. Enhanced phosphorylation of Cx43 coincided with increased PKC[epsilon] expression in both models. Elevation of Cx43 was associated with its enhanced distribution on lateral surfaces of the cardiomyocytes in response to both interventions, while focal areas of fibrosis without Cx43 were found in post-ISO but not post-irradiated rat hearts. In parallel, MMP-2 activity was decreased in the former while increased in the latter. Cardiac function was maintained and the susceptibility of the hearts to ischemia or malignant arrhythmias was not deteriorated 42 days after interventions when compared with controls. Altogether, the findings indicate that myocardial Cx43 is most likely implicated in potentially salutary responses to acute heart injury. Key words: acute heart injury, connexin-43, PKC[epsilon], MMP-2. Nous visions a evaluer si la connexine 43 (Cx43), une proteine canalaire intercardiomyocytes, ainsi que la PKC[epsilon] et la MMP-2 pourraient jouer un role dans les lesions cardiaques aigues provoquees par deux interventions subletales distinctes chez le rat Wistar. Les animaux ont subi une irradiation unique du thorax a 25 Gy ou l'injection sous-cutanee d'isoproterenol (ISO, a 120 mg/kg), et nous les avons compares a des temoins non traites. Quarante-deux jours apres les interventions, nous avons preleve les creurs et procede a une analyse des ventricules gauches. Les resultats ont montre une augmentation des taux de Cx43 myocardique totaux et des formes phosphorylees, sans egard au type d'intervention. Dans les deux modeles, l'augmentation de la phosphorylation de la Cx43 coincidait avec l'augmentation de l'expression de la PKC[epsilon]. La hausse des taux de Cx43 etait associee a une accentuation de sa distribution sur les surfaces laterales des cardiomyocytes en reaction aux deux interventions, alors que nous avons observe dans les creurs de rat des regions de fibrose sans Cx43 apres l'administration d'ISO, mais pas apres l'irradiation. En parallele, nous avons observe une diminution de l'activite de la MMP-2 dans le premier cas, mais une augmentation dans le second. Comparativement aux temoins, la fonction cardiaque se maintenait et la susceptibilite des creurs a l'ischemie ou aux arythmies malignes ne se deteriorait pas 42 jours apres les interventions. Dans l'ensemble, les resultats montrent que la Cx43 myocardique joue tres probablement un role dans des reactions a l'ischemie aigue cardiaque qui seraient potentiellement salutaires. [Traduit par la Redaction] Mots-cles: lesion cardiaque aigue, connexine 43, PKC[epsilon], MMP-2., Introduction Intercellular coupling at gap junction connexin channels plays a fundamental role in mediating communication for establishment and maintenance of coordinated heart function. Moreover, intercellular communication regulates adaptive functions of [...]

Given the importance of the aggregation of advanced glycation end products (AGEs) and cardiac inflammation in the onset and progression of diabetic cardiomyopathy (DCM), our objective in this study was to demonstrate the cardioprotective effect of mangiferin, an antidiabetic and anti-inflammatory agent, on diabetic rat model. The DCM model was established by a high-fat diet and a low dose of streptozotocin. DCM rats were treated orally with mangiferin (20 mg/kg) for 16 weeks. Serum and left ventricular myocardium were collected for determination of inflammatory cytokines. AGEs mRNA and protein expression of nuclear factor kappa B (NF-κB) and receptor for AGEs (RAGE) in myocardium were assayed by real-time PCR and Western blot. ROS levels were measured by dihydroethidium fluorescence staining. NF-κB binding activity was assayed by TransAM NF-κB p65 ELISA kit. Chronic treatment with mangiferin decreased the levels of myocardial enzymes (CK-MB, LDH) and inflammatory mediators (TNF-α, IL-1β). Meanwhile, NF-κB is inhibited by the reduction of nuclear translocation of p65 subunit, and mangiferin reduced AGE production and decreased the mRNA and protein expression of RAGE in DCM rats. Our data indicated that mangiferin could significantly ameliorate DCM by preventing the release of inflammatory cytokines, and inhibiting ROS accumulation, AGE/RAGE production, and NF-κB nuclear translocation, suggesting that mangiferin treatment might be beneficial in DCM. Key words: advanced glycation end products, diabetic cardiomyopathy, inflammatory cytokines, NF-κB, mangiferin. Etant donne l'importance du role de l'agregation des produits finaux de glycation avancee (AGE) et de l'inflammation du muscle cardiaque dans l'apparition et revolution de la cardiomyopathie diabetique (CMD), la presente etude avait pour objectif de montrer l'effet cardioprotecteur de la mangiferine, un agent antidiabetique et anti-inflammatoire, dans un modele de rat diabetique. Le modele de CMD etait obtenu en administrant un regime a haute teneur en matieres grasses et de la streptozotocine a faible dose. Nous avons traite les rats atteints de CMD en administrant de la mangiferine (20 mg/kg) par voie orale pendant 16 semaines. Nous avons ensuite preleve du tissu myocardique du ventricule gauche et du serum en vue de doser certaines cytokines inflammatoires. A l'aide des techniques d'amplification en chaine par polymerase (PCR) en temps et reel et d'electrobuvardage de Western, nous avons mesure l'expression des AGE (ARNm et proteines) induite par l'activation du facteur nucleaire kappa (NF-κB) et les taux de recepteurs des AGE (RAGE) dans le tissu myocardique. Nous avons aussi quantifie les taux de derives reactifs de l'oxygene (ROS) a l'aide de la technique de coloration fluorescente par le dihydroethidium et mesure l'activite de la liaison du NF-κB a l'aide du kit ELISA (essai immuno- enzymatique) TransAM NF-κB p65. Nous avons observe que l'administration chronique de mangiferine permettait d'abaisser les taux d'enzymes myocardiques (CK-MB et LDH) et de mediateurs inflammatoires (TNF-α et IL-1β). Tandis que l'effet du NF- κB etait inhibe par la diminution de la translocation nucleaire de la sous-unite p65, et l'administration de mangiferine permettait de diminuer la production des AGE ainsi que l'expression des RAGE (ARNm et proteines) chez les rats atteints de CMD. En somme, nos resultats laissent entendre que la mangiferine pourrait permettre de contrecarrer la CMD de facon appreciable par les mecanismes suivants : inhibition de la liberation de cytokines inflammatoires, reduction de l'accumulation de ROS, reduction de la production d'AGE et de RAGE et reduction de la translocation nucleaire du NF-κB. Il est donc possible que l'administration de mangiferine puisse etre utile dans le traitement de la CMD. [Traduit par la Redaction] Mots-cles: produits finaux de glycation avancee, cardiomyopathie diabetique, cytokines inflammatoires, NF-κB, mangiferine., Introduction Diabetic cardiomyopathy (DCM), as an early complication of diabetes, is considered a risk factor for acute myocardial infarction and death due to coronary artery disease. It carries increased mortality [...]

Regulated necrosis (necroptosis) and apoptosis are crucially involved in severe cardiac pathological conditions, including myocardial infarction, ischemia-reperfusion injury and heart failure. Whereas apoptotic signaling is well defined, the mechanisms that underlie cardiomyocyte necroptosis remain elusive. Here we show that receptor-interacting protein 3 (RIP3) triggers myocardial necroptosis, in addition to apoptosis and inflammation, through activation of [Ca.sup.2+]-calmodulin-dependent protein kinase (CaMKII) rather than through the well-established RIP3 partners RIP1 and MLKL. In mice, RIP3 deficiency or CaMKII inhibition ameliorates myocardial necroptosis and heart failure induced by ischemia-reperfusion or by doxorubicin treatment. RIP3-induced activation of CaMKII, via phosphorylation or oxidation or both, triggers opening of the mitochondrial permeability transition pore and myocardial necroptosis. These findings identify CaMKII as a new RIP3 substrate and delineate a RIP3CaMKII-mPTP myocardial necroptosis pathway, a promising target for the treatment of ischemia- and oxidative stress-induced myocardial damage and heart failure., Cell death is a fundamental process involved in development, aging and demise and has been classified into distinct forms, including necrosis, apoptosis and autophagy (1,2). Whereas apoptosis is understood to [...]

Using the UM-X7.1 hereditary cardiomyopathic and muscular dystrophy hamsters (HCMH), we tested the effects of lifelong preventive or curative treatments during the heart failure phase with the NHE-1 inhibitor EMD 87580 (EMD) or with the angiotensin-converting enzyme inhibitor cilazapril on the intracellular [Na.sup.+] and [Ca.sup.2+] overloads, elevated level of NHE-1, necrosis, hypertrophy, heart failure, and early death. Our results showed that 310-day pretreatment of 30-day-old HCMHs with EMD significantly prevented cardiac necrosis, cardiomyocyte hypertrophy, and reduced the heart to body mass ratio. This treatment significantly prevented [Na.sup.+] and [Ca.sup.2+] overloads and the increase in NHE-1 protein level observed in HCMHs. Importantly, this lifelong preventive treatment significantly decreased the levels of creatine kinase and prevented early death of HCMHs. Curative 0treatment of hypertrophic 275-day-old HCMHs for 85 days with EMD significantly prevented hypertrophy and early death of HCMHs. However, treatments with cilazapril did not have any significant effects on the cardiac parameters studied or on early death of HCMHs. Our results suggest that the increase in the NHE-1 level and the consequent [Na.sup.+] and [Ca.sup.2+] overloads are implicated in the pathological process leading to heart failure and early death in HCMHs, and treatment with the NHE-1 inhibitor is promising for preventing early death in hereditary cardiomyopathy. Key words: cardiomyopathy, early death, heart failure, NHE-1, NHE-1 inhibitor EMD 87580, ACE inhibitor. A l'aide d'un modele de hamster atteint de cardiomyopathie et de dystrophie musculaire hereditaires (souche UM-X7.1), nous avons etudie les effets de traitements preventifs a vie et de traitements curatifs pendant la phase d'insuffisance cardiaque par l'administration de l'EMD 87580, un inhibiteur de la NHE-1 (isoforme 1 de la proteine echangeuse d'ions sodium-proton), ou de cilazapril, un IECA (inhibiteur de l'enzyme de conversion de l'angiotensine), sur l'etablissement de surcharges intracellulaires en [Na.sup.+] et en [Ca.sup.2+], l'augmentation des taux de NHE-1, la necrose, l'hypertrophie, l'insuffisance cardiaque et la mort prematuree. Nos resultats ont montre qu'un pretraitement des hamsters UM-X7.1 par l'EMD 87580 pendant 310 jours permettait manifestement de prevenir la necrose cardiaque, l'hypertrophie des cardiomyocytes et l'augmentation du rapport entre le poids du creur et le poids corporel total. Ce traitement permettait de prevenir l'etablissement de surcharges en [Na.sup.+] et en [Ca.sup.2+] et d'augmenter les taux de proteine NHE-1 observes dans ce modele. Mais avant tout, administre a vie de maniere preventive, ce traitement permettait de diminuer les taux de creatine kinase et de prevenir la mort prematuree de maniere importante chez les hamsters UM-X7.1. Un traitement curatif par l'EMD 87580 pendant 85 jours administre a des hamsters UM-X7.1ages de 275 jours permettait de prevenir l'hypertrophie et la mort prematuree dans ce modele. Cependant, les traitements par le cilazapril n'avaient aucun effet notable sur les parametres cardiaques etudies ni sur la mort prematuree chez les hamsters UM-X7.1. Nos resultats indiquent que l'augmentation des taux de NHE-1 et les surcharges en [Na.sup.+] et en [Ca.sup.2+] qui en decoulent joueraient un role dans les processus pathologiques entrainant l'insuffisance cardiaque et la mort prematuree chez les hamsters UM-X7.1. En fait, l'administration d'inhibiteurs de la NHE-1 pourrait etre une avenue therapeutique prometteuse pour la prevention de la mort prematuree en cas de cardiomyopathie hereditaire. [Traduit par la Redaction] Mots-cles: cardiomyopathie, mort prematuree, insuffisance cardiaque, NHE-1, inhibiteur de la NHE-1 EMD 87580, IECA., Introduction An important characteristic of several types of hypertrophy and congestive heart failure (HF) is a disturbed intracellular calcium ([[[Ca.sup.2+]].sub.i]) handling in heart muscles (Jasmin and Proschek 1984, 1994; Bkaily [...]

Activation and accumulation of cardiac fibroblasts, which result in excessive extracellular matrix deposition and consequent mechanical stiffness, myocyte uncoupling, and ischemia, are key contributors to heart failure progression. Recently, endothelial-to-mesenchymal transition (EndoMT) and the recruitment of circulating hematopoietic progenitors to the heart have been reported to generate substantial numbers of cardiac fibroblasts in response to pressure overload-induced injury; therefore, these processes are widely considered to be promising therapeutic targets. Here, using multiple independent murine Cre lines and a collagenlal-GF-P fusion reporter, which specifically labels fibroblasts, we found that following pressure overload, fibroblasts were not derived from hematopoietic cells, EndoMT, or epicardial epithelial-to- mesenchymal transition. Instead, pressure overload promoted comparable proliferation and activation of two resident fibroblast lineages, including a previously described epicardial population and a population of endothelial origin. Together, these data present a paradigm for the origins of cardiac fibroblasts during development and in fibrosis. Furthermore, these data indicate that therapeutic strategies for reducing pathogenic cardiac fibroblasts should shift from targeting presumptive EndoMT or infiltrating hematopoietically derived fibroblasts, toward common pathways upregulated in two endogenous fibroblast populations., Introduction Heart failure is the primary cause of adult mortality in the developed world (1, 2). A key component of heart failure is excessive extracellular matrix deposition by cardiac fibroblasts [...]