endothelin-1 and Ventricular-Dysfunction

Despite the accumulating genetic and molecular investigations into hypertrophic cardiomyopathy (HCM), it remains unclear how this condition develops and worsens pathologically and clinically in terms of the genetic-environmental interactions. Establishing a human disease model for HCM would help to elucidate these disease mechanisms; however, cardiomyocytes from patients are not easily obtained for basic research. Patient-specific induced pluripotent stem cells (iPSCs) potentially hold much promise for deciphering the pathogenesis of HCM. The purpose of this study is to elucidate the interactions between genetic backgrounds and environmental factors involved in the disease progression of HCM.. We generated iPSCs from 3 patients with HCM and 3 healthy control subjects, and cardiomyocytes were differentiated. The HCM pathological phenotypes were characterized based on morphological properties and high-speed video imaging. The differences between control and HCM iPSC-derived cardiomyocytes were mild under baseline conditions in pathological features. To identify candidate disease-promoting environmental factors, the cardiomyocytes were stimulated by several cardiomyocyte hypertrophy-promoting factors. Interestingly, endothelin-1 strongly induced pathological phenotypes such as cardiomyocyte hypertrophy and intracellular myofibrillar disarray in the HCM iPSC-derived cardiomyocytes. We then reproduced these phenotypes in neonatal cardiomyocytes from the heterozygous Mybpc3-targeted knock in mice. High-speed video imaging with motion vector prediction depicted physiological contractile dynamics in the iPSC-derived cardiomyocytes, which revealed that self-beating HCM iPSC-derived single cardiomyocytes stimulated by endothelin-1 showed variable contractile directions.. Interactions between the patient's genetic backgrounds and the environmental factor endothelin-1 promote the HCM pathological phenotype and contractile variability in the HCM iPSC-derived cardiomyocytes.

Topics: Animals; Biomechanical Phenomena; Cardiomegaly; Cardiomyopathy, Hypertrophic; Carrier Proteins; Case-Control Studies; Cell Differentiation; Cells, Cultured; Dose-Response Relationship, Drug; Endothelin-1; Gene-Environment Interaction; Genotype; Humans; Induced Pluripotent Stem Cells; Mice, Inbred NOD; Mice, SCID; Mice, Transgenic; Myocardial Contraction; Myocytes, Cardiac; Myofibrils; Phenotype; Risk Factors; Signal Transduction; Time Factors; Transfection; Ventricular Dysfunction; Video Recording

The aim of this study was to evaluate echocardiography-based indices of myocardial function and markers of vascular inflammation and endothelial dysfunction in the early phases of severe sepsis.. Forty-five adult patients (67% women; age 51 ± 18 years; Acute Physiology and Chronic Health Disease Classification System II score, 23 ± 7) admitted to the intensive care unit up to 24 hours after fulfilling criteria for severe sepsis or septic shock were studied. Clinical, laboratorial (endothelin 1 [ET1], vascular cellular adhesion molecule 1), and echocardiographic data were collected within the first 24 hours and again 72 hours and 7 days after admission.. Intrahospital mortality was 33% (15 deaths). Left ventricular (LV) dysfunction (LV ejection fraction <55%) was identified in 15 (33%) patients, whereas right ventricular (RV) dysfunction (RV tissue Doppler peak systolic velocity [RV-Sm] <12 cm/s) was present in 14 (30%) patients. LogET1 was increased in patients with LV dysfunction (2.3 ± 0.6 vs 1.8 ± 0.4 pg/mL; P = .01) and RV dysfunction (2.5 ± 0.5 vs 1.8 ± 0.4 pg/mL; P < .001) and had negative correlations with LV ejection fraction (r = -0.50; P = .002) and RV-Sm (r = -0.67; P < .001). Left ventricular end-diastolic diameter, RV-Sm, and diastolic dysfunction were able to discriminate survivors from nonsurvivors, and the combination of these parameters identified groups of very low and high risk.. Both LV and RV systolic dysfunctions are prevalent in severe sepsis, being directly associated with markers of endothelial dysfunction. Left ventricular nondilation, RV dysfunction, and diastolic dysfunction seem related to poor prognosis in this scenario.

Topics: Biomarkers; Brazil; Cardiomyopathy, Dilated; Echocardiography; Endothelin-1; Endothelium, Vascular; Female; Humans; Intercellular Adhesion Molecule-1; Male; Middle Aged; Prognosis; Sepsis; Shock, Septic; Survival Rate; Ventricular Dysfunction

Reoxygenation of hypoxic myocardium during repair of congenital heart defects results in poor ventricular function and cellular injury. Endothelin-1 (ET-1), a potent vasoconstrictor that increases during hypoxia, may suppress myocardial function and activate leukocytes. The objective was to determine whether administration of an endothelin receptor antagonist could improve ventricular function and decrease cardiac injury after hypoxia and reoxygenation.. Fourteen piglets underwent 90 minutes of ventilator hypoxia, 1 hour of reoxygenation on cardiopulmonary bypass, and 2 hours of recovery (controls). Nine additional animals received an infusion of Bosentan, an ET(A/B) receptor antagonist, (5 mg/kg per hour) during hypoxia and reoxygenation.. Right and left ventricular dP/dt in controls decreased to 78% and 52% of baseline, respectively, after recovery (p < 0.05). In contrast, Bosentan-treated animals had complete preservation of RV dP/dt and less depression of LV dP/dt. Bosentan reduced the hypoxia and reoxygenation-induced elevation of ET-1 and iNOS mRNA at the end of recovery (p < 0.05). Bosentan-treated animals had diminished myocardial myeloperoxidase activity and lipid peroxidation compared with controls (p < 0.05). Myocardial apoptotic index, elevated by hypoxia and reoxygenation, was lower in the Bosentan-treated animals (p < 0.05).. Endothelin-1 receptor antagonism improved functional recovery and decreased leukocyte-mediated injury after reoxygenation. The reduction in cardiac cell death might also improve long-term outcome after reoxygenation injury.

Topics: Animals; Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Endothelin-1; Gene Expression; Infusions, Intravenous; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide Synthase; Receptors, Endothelin; RNA, Messenger; Sulfonamides; Swine; Ventricular Dysfunction

To analyze three-dimensional activation patterns of ventricular arrhythmias induced by endothelin-1 in comparison with ischemia-induced tachycardias.. Following AV node ablation, sixty pin electrodes containing four bipoles each were inserted into both ventricles of ten foxhounds. Using a computerized mapping system, this would allow to simultaneously record 240 endo-, epi- and midmyocardial electrograms for reconstruction of the three-dimensional activation pattern. In five dogs, endothelin-1 was infused into the LAD at 60 pmol/min. In another five animals, the LAD was ligated. During the following 40 min, all ventricular arrhythmias were recorded for subsequent analysis. Furthermore, left ventricular conduction times during constant pacing and local effective refractory periods at eight left ventricular sites were determined before and after either intervention.. Endothelin-1 had no significant effect on conduction time and refractoriness, whereas ligation prolonged both parameters significantly. Endothelin-1 as well as ligation induced multiple mono- and polymorphic nonsustained ventricular tachycardias. Endothelin-1-induced arrhythmias were exclusively based on focal mechanisms, whereas during ligation, macroreentrant mechanisms were involved in the maintenance of tachycardias in 29% of episodes.. The differences in the effects of endothelin-1 and LAD ligation on electrophysiologic properties and the difference in the mechanism of induced ventricular tachycardias support the hypothesis that, apart from vasoconstrictive properties, endothelin-1 exerts an intrinsic arrhythmogenic effect.

Topics: Animals; Body Surface Potential Mapping; Dogs; Endothelin-1; Heart Block; Myocardial Ischemia; Ventricular Dysfunction