Örökletes szívbetegségek klinikai és experimentális vizsgálata: genetikai analízis különböző eredetű szívizombetegségekben = Clinical and experimental examinations in inherited cardiac disorders: genetic analysis of heart muscle diseases of various origin

Munkatervünkben az örökletes szívbetegségek klinikai és experimentális vizsgálatát tűztük ki célul. Munkánk során, Magyarországon elsőként, sikerrel azonosítottunk kóroki mutációkat fenti betegcsoportokban. Hosszú QT szindrómában öt kóroki mutációt mutattunk ki (KCNQ1 gén: Tyr315His ill. Arg259Cys, KCNH2 gén: Thr162+6X inzerció ill. Trp568Cys, KCNE1 gén: Val109Ile). Megállapítottuk az érintett betegek családtagjainak klinikai és genetikai hordozó státuszát, vizsgáltuk a fenotípus-genotípus összefüggéseket, valamint a hordozó betegek EKG-jának repolarizációs paramétereit. Hypertrophiás cardiomyopathiában (HCM) a béta myozin nehéz lánc génben három kóroki mutációt azonosítottunk (Arg719Gln, Val606Met, Arg249Gln), míg a troponin T és troponin I génekben kóroki mutációt nem találtunk. Dilatatív cardiomyopathiában (DCM) a dystrophin gén hosszú delécióját igazoltuk vázizom dystrophiával társult DCM egy esetében, míg a béta myozin nehéz lánc génben kóroki mutációt nem észleltünk. Klinikai vizsgálataink során igazoltuk, hogy myopathiás vázizom eltéréssel nem rendelkező HCM betegcsoportban magasabb a hirtelen szívhalál familiáris előfordulása. Kimutattuk, hogy DCM-ben a tumor nekrózis faktor-alfa és az interleukin-6 (IL-6) szintje jelentősen megemelkedett, míg HCM-ben csak az IL-6 és a szolubilis IL-6 receptor szintje volt jelentősen magasabb. Igazoltuk, hogy HCM-ben myogén eredetű hallászavar jóval gyakoribb, mint DCM-ben ill. egészséges kontrollokban. | We aimed to investigate the clinical and experimental basis of inherited cardiac diseases. During the project we successfully identified disease casing mutations, for the first time in Hungary, in the above diseases. In the long QT syndrome we found five mutations (KCNQ1 gene: Tyr315His ill. Arg259Cys, KCNH2 gene: Thr162+6X insertion ill. Trp568Cys, KCNE1 gene: Val109Ile). We delineated the clinical and genetic carrier status of the family members and analysed repolarisation parameters in the carriers. In hypertrophic cardiomyopathy (HCM) we identified 3 disease causing mutations in the beta myosin heavy chain gene (Arg719Gln, Val606Met, Arg249Gln), while found no mutations in the troponin T and I genes. In dilated cardiomyopathy (DCM) we described a long deletion of the dystrophin gene in DCM associated with skeletal myopathy, while found no mutation in the beta myosin heavy chain gene. Our clinical investigations proved that familial sudden cardiac death was more frequent in a HCM cohort which exhibits no myopathic changes in the skeletal muscle. We also described that serum levels of tumor necrosis alpha and interlekin-6 (IL-6) were raised in DCM, while in HCM only IL-6 and soluble IL-6 receptor levels were raised. We also proved the myogenic hearing disturbances were more frequent in HCM than in DCM and healthy controls

Thromboangitis obliterans agyi manifesztációja

Thromboangiits obliterans (Buerger's disease) is a non-atherosclerotic, segmental inflammatory and obliterative disease affecting small and medium sized arteries and veins. The etiology is still unknown, but it is in close relationship with tobacco use. Symptoms begin under the age of 45 years and the undulating course is typical. Patients usually present with acute and chronic ischemic or infectious acral lesions. Diagnosis is usually based on clinical and angiographic criteria and it is important to exclude autoimmune disease, thrombophilia, diabetes, and proximal embolic sources. Even though Buerger's disease most commonly involves the arteries of the extremities, the pathologic findings sometimes affect the cerebral, coronary and internal thoracic, renal and mesenteric arteries as well. The authors present the history of a patient with known Buerger's disease and acute ischemic stroke. Brain imaging detected acute and chronic ischemic lesions caused by middle cerebral non-atherosclerotic arteriopathy on the symptomatic side. Other etiology was excluded by detailed investigations. Orv. Hetil., 2016, 157(30), 1207-1211

The cardioprotective potential of hydrogen sulfide in myocardial ischemia/reperfusion injury (Review)

Myocardial infarction is responsible for the majority of cardiovascular mortality and the pathogenesis of myocardial damage during and after the infarction involves reactive oxygen species. Serious efforts are under way to modulate the developing ischemia/reperfusion injury and recently the use of hydrogen sulfide (H2S) emerged as a new possibility. H2S has been best known for decades as a pungent toxic gas in contaminated environmental atmosphere, but it has now been recognized as a novel gasotransmitter in the central nervous and cardiovascular systems, similarly to nitric oxide (NO) and carbon monoxide (CO). This finding prompted the investigation of the potential of H2S as a cardioprotective agent and various in vitro and in vivo results demonstrate that H2S may be of value in cytoprotection during the evolution of myocardial infarction. Although several questions remain to be elucidated about the properties of this new gasotransmitter, increased H2S levels may have therapeutic potential in clinical settings in which ischemia/reperfusion injury is encountered. This review article overviews the current understanding of the effects of this exciting molecule in the setting of myocardial ischemia/reperfusion

The mechanism of action and role of hydrogen sulfide in the control of vascular tone

Our knowledge about hydrogen sulfide (H2S) significantly changed over the last two decades. Today it is considered as not only a toxic gas but also as a gasotransmitter with diverse roles in different physiological and pathophysiological processes. H2S has pleiotropic effects and its possible mechanisms of action involve (1) a reversible protein sulfhydration which can alter the function of the modified proteins similar to nitrosylation or phosphorylation; (2) direct antioxidant effects and (3) interaction with metalloproteins. Its effects on the human cardiovascular system are especially important due to the high prevalence of hypertension and myocardial infarction. The exact molecular targets that affect the vascular tone include the KATP channel, the endothelial nitric oxide synthase, the phosphodiesterase of the vascular smooth muscle cell and the cytochrome c oxidase among others and the combination of all these effects lead to the final result on the vascular tone. The relative role of each effect depends immensely on the used concentration and also on the used donor molecules but several other factors and experimental conditions could alter the final effect. The aim of the current review is to give a comprehensive summary of the current understanding on the mechanism of action and role of H2S in the regulation of vascular tone and to outline the obstacles that hinder the better understanding of its effects

H2S preconditioning of human adipose tissue-derived stem cells increases their efficacy in an in vitro model of cell therapy for simulated ischemia

Aims: A major limitation of cell-based therapies for ischemia – reperfusion injury is the excessive loss of adminis- tered cells. We investigated whether H 2 S can improve the survival and ef fi cacy of therapeutic cells in an in vitro model of cell-based therapy for simulated ischemia. Main methods: H9c2 rat cardiomyoblasts were exposed to oxygen – glucose deprivation and NaHS (3 – 30 μ M) pretreated human adipose tissue derived stem cells (hASCs) were added after reoxygenization. Viability of both cell lines was assessed with fl ow cytometry after 24 h. The effects of H 2 S on antioxidant defense, prolifera- tion, AKT and ERK1/2 phosphorylation and mitochondrial activity were analyzed in hASCs. Proliferation was evaluated using propargylglycine, an inhibitor of endogenous H 2 S synthesis. Key fi ndings: NaHS pretreatment decreased the ratio of necrotic therapeutic cells by 41.8% in case of 3 μ M NaHS and by 34.3% with 30 μ M NaHS. The ratio of necrotic postischemic cardiomyocytes decreased by 35%, but only with the use of 3 μ M NaHS. Antioxidant defense mechanisms and ERK-phosphorylation were enhanced after 3 μ M NaHS treatment while AKT-phosphorylation was suppressed. NaHS dose-dependently increased the prolif- eration of hASCs while pretreatment with propargylglycine decreased it. Signi fi cance: NaHS pretreatment can increase the survival of therapeutically used human adipose tissue-derived stemcells viaincreased antioxidant defense andimproves the postischemic cardiac derived cells' survival aswell. Proliferation ofhuman adiposetissue-derivedstemcells is enhanced by H 2 S.The underlying mechanisms involve enhanced ERK-phosphorylation and decreased AKT-phosphorylation. Pretreatment with NaHS may represent a simple pharmacological step that may enhance the ef fi cacy of cell-based therapies