Reactive oxygen and nitrogen species are overproduced in the cardiovascular system in response to the exposure to doxorubicin, a cardiotoxic anticancer compound. Oxidant-induced cell injury involves the activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) and pharmacological inhibition of PARP has recently been shown to improve myocardial contractility in doxorubicin-induced heart failure models. The current investigation, by utilizing an isolated perfused heart system capable of beat-to-beat intracellular calcium recording, addressed the following questions: (1) is intracellular calcium handling altered in hearts of rats after 6-week doxorubicin treatment, under baseline conditions, and in response to oxidative stress induced by hydrogen peroxide exposure in vitro; and (2) does pharmacological inhibition of PARP with the phenanthridinone-based PARP inhibitor PJ34 affect the changes in myocardial mechanical performance and calcium handling in doxorubicin-treated hearts under normal conditions and in response to oxidative stress. The results showed a marked elevation in intracellular calcium in the doxorubicin-treated hearts which was normalized by pharmacological inhibition of PARP. PARP inhibition also prevented the myocardial contractile disturbances and calcium overload that developed in response to hydrogen peroxide in the doxorubicin-treated hearts. We conclude that PARP activation contributes to the development of the disturbances in cellular calcium handling that develop in the myocardium in response to prolonged doxorubicin exposure.

The main objective of the present study was to determine alterations of calcium handling in the diabetic rat heart during the transition from adaptive to maladaptive phase of cardiomyopathy. By inhibiting the nuclear enzyme poly(ADP-ribose) polymerase (PARP), we also investigated the possible role of this enzyme in the sequence of pathological events. Six weeks after induction of type I diabetes by injection of streptozotocin in rats, the hearts were perfused according to Langendorff. Intracellular-free calcium (Ca 2+ i) levels were measured by surface fluorometry using Indo-1 AM. Cyclic changes in Ca 2+ i concentrations and hemodynamic parameters were measured simultaneously. The hearts were challenged by infusion of isoproterenol. Six weeks of diabetes resulted in reduced inotropy and lusitropy. The diabetic hearts (DM) expressed a significantly elevated end-diastolic Ca 2+ i level (control, 111±20 vs DM, 221±35 nM). The maximal transport capacity of SERCA2a and conductance of RyR2 were reduced. These changes were not accompanied by major alterations in the tissue content of SERCA2a, RyR2, phospholamban and Na + /Ca 2+ exchanger. In response to ß-adrenergic activation, SERCA2a transport capacity and RyR2 conductance were stunted in the DM hearts. Inhibition of PARP induced minor changes in the mechanical function and calcium handling of the DM hearts. In conclusion, the observed changes in contractility and in Ca 2+ i handling are most likely attributable to functional disturbances of SERCA2a and RyR2 in this transitional phase of diabetes. At this stage of diabetes, PARP does not appear to play a significant pathogenetic role in the alterations in contractile function and calcium handling.

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Bevezetés: Az egyes európai országokban a prevenciós tevékenységnek köszönhető morbiditáscsökkenést Magyarországon még nem sikerült elérni. A hatékony prevenció alapfeltétele a lakosság egészségi állapotának, a kockázati tényezők jelenlétének pontos ismerete. Célkitűzés: A szerzők célja volt, hogy egy közép-magyarországi longitudinális lakossági vizsgálattal információt nyerjenek a magyar lakosság egészségi állapotáról, cardiovascularis kockázati státu-sáról, ami lehetővé teszi új rizikóbecslést befolyásoló tényezők azonosítását. Módszer: A Budakalász Vizsgálat a felnőtt lakosságot célzó (>20 év, ~8000 fő), átfogó, önkéntes alapú cardiovascularis szűrőprogram, amely egészségkérdőív-ből, noninvazív tesztekből (antropometriai mérések, szívultrahang, carotisultrahang, vérnyomásmérés, boka-kar index mérése), illetve vénás vérvételből és laborvizsgálatokból áll. Eredmények: 2014. januárig 2420 fő (a lakosság 30%-a, 41,2% férfi , átlagéletkor 54,8 év) kérdőíves, fi zikális vizsgálata és cardiovascularis kockázatbecslése történt meg. A résztvevők cardiovascularis morbiditása a korábbi országos felméréshez viszonyítva magasabb volt, illetve a cardiovascularis kockázati faktorok száma és a becsült 10 éves kockázat is emelkedettnek bizonyult a lakosok körében. Következtetések: Az eredmények felhívják a fi gyelmet a szűrések és a hatékony terápia fontosságára. Orv. Hetil., 2014, 155(34), 1344-1352. Kulcsszavak: cardiovascularis, morbiditás, kockázatbecslés, szűrővizsgálat Cardiovascular screening programme in the Central Hungarian region The Budakalász StudyIntroduction: The reduction in mortality due to prevention programmes observed in some European countries is not currently reached in Hungary. Effective prevention is based on the screening of risk factors and health state of the population. Aim: The goal of this study was to develop a longitudinal, population-based screening programme in the Central Hungarian region in order to collect information on the health state and cardiovascular risk profi le of the citizens and discover new potential cardiovascular risk factors. Method: The Budakalász Study is a self-voluntary programme involving the adult population (>20 yrs, approx. 8000 persons), and it consists of questionnaires, noninvasive tests (anthropometry, cardiac echo, carotid duplex scan, blood pressure measurement, ankle-brachial index), venous blood sample collection and laboratory tests. Results: Until January, 2014, 2420 persons (30% of the population, male: 41.2%, average age 54.8 years) participated in the programme. Cardiovascular morbidity was higher in contrast to a former national survey. The number of risk factors and, therefore, 10-year cardiovascular risk were also elevated in this population. Conclusions: These fi ndings underline the importance of screening programmes and effective therapies.

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Heat shock (HS) pretreatment of the heart is effective in mitigating the deleterious effects of ischaemia/reperfusion. The main objective of this study was to determine whether the beneficial effect of HS is associated with the preservation of intracellular Ca2+ handling in the ischaemic/reperfused, isolated rat heart. Twenty-four hours after raising body core temperature to 42 degrees C for 15 min, rat hearts were perfused according to Langendorff and subjected to 30 min ischaemia followed by 20 min reperfusion. Cyclic changes of cytoplasmic calcium ion [Ca2+i] levels were measured by surface fluorometry using Indo-1 AM. Reperfused HS hearts showed improved recovery of contractile function compared with control hearts: end-diastolic pressure: 45+/-11 vs. 64+/-22 mmHg; developed pressure: 72+/-12 vs. 41+/-20 mmHg; maximum rate of pressure increase (+dP/dtmax): 1,513+/-305 vs. 938+/-500 mmHg/s; maximum rate of pressure decrease (-dP/dtmax): -1,354+/-304 vs. -806+/-403 mmHg/s. HS hearts displayed a significantly lower end-diastolic cytosolic [Ca2+] ([Ca2+]i) after reinstallation of flow. The dynamic parameters of the Ca2+i transients, i.e. the maximum rate of increase/decrease (+/-dCa2+i/dtmax) and amplitude, did not differ between reperfused control and HS hearts. The novel finding of this study is that improved performance of the HS-preconditioned heart after an ischaemic insult is associated with a reduced end-diastolic Ca2+i load, and most likely, preserved Ca2+ sensitivity of the myocardial contractile machinery.

Despite the well-known importance of left atrial (LA) mechanics in diastolic function, data are scarce regarding the prognostic power of LA longitudinal strain and its potential added value in the risk stratification of an elderly population. Accordingly, our aim was to determine the long-term prognostic importance of 2D speckle-tracking echocardiography-derived peak atrial longitudinal strain (PALS) in a community-based screening sample. Three hundred and fourteen volunteers were retrospectively identified from a population-based screening program (mean age 62 ± 11 years; 58% female) with a median follow-up of 9.5 years. All subjects who participated in the screening program underwent 2D echocardiography to measure left ventricular (LV) ejection fraction (EF), global longitudinal strain (GLS), and PALS, as well as low-dose cardiac CT to determine the Agatston score. The primary endpoint was all-cause mortality. Thirty-nine subjects (12.4%) met the primary endpoint. Subjects with adverse outcomes had significantly lower LV GLS (dead vs. alive; − 19.2 ± 4.3 vs. − 20.6 ± 3.5%, p < 0.05) and PALS (32.3 ± 12.0 vs. 41.8 ± 14.2%, p < 0.001), whereas LV EF did not show a difference between the two groups (51.1 ± 7.0 vs. 52.1 ± 6.2, %, p = NS). By multivariable Cox regression analysis, PALS was found to be a significant predictor of adverse outcomes independent of LV GLS, and Agatston and Framingham scores. In subjects with PALS values below the standard cut-off of 39%, the risk of all-cause mortality was almost 2.5 times higher (hazard ratio: 2.499 [95% confidence interval: 1.334–4.682], p < 0.05). Beyond the assessment of LV EF and LV GLS, PALS offers incremental value in cardiovascular risk stratification in a community-based elderly cohort. PALS was found to be a significant and independent predictor of long-term mortality among other classical cardiovascular risk estimators.