Systemic iron deficiency does not affect the cardiac iron content and progression of heart failure.

Chronic heart failure (HF) is often accompanied by systemic iron deficiency (ID). However, effects of ID on cardiac iron status and progression of HF are unknown. To investigate these effects rats underwent LAD ligation to induce post-myocardial infarction HF or sham operation. After 3 weeks the animals from both groups were randomized into three subgroups: control, moderate ID and severe ID+anemia (IDA) by a combination of phlebotomy and low iron diet for 5 weeks. Serum and hepatic iron content were reduced by 55% and 70% (ID) and by 80% and 77% (IDA), respectively, while cardiac iron content was unchanged in HF rats. Changes in expression of all cardiomyocyte iron handling proteins indicating preserved cardiomyocytes iron status in HF and ID/IDA. Contractile function of LV cardiomyocytes, Ca2+ transient amplitude, sarcoplasmic reticulum Ca2+ release and SERCA2a function was augmented by ID and IDA and it was accompanied by an increase in serum catecholamines. Neither ID nor IDA affected left ventricular (LV) systolic or diastolic function or dimensions. To sum up, systemic ID does not result in cardiac ID and does not affect progression of HF and even improves contractile function and Ca2+ handling of isolated LV cardiomyocytes, however, at the cost of increased catecholamine level. This suggests that intravenous iron therapy should be considered as an additional therapeutic option in HF, preventing the increase of catecholaminergic drive with its well-known long-term adverse effects.

Treatment of hypoxia-dependent cardiovascular diseases by myo-inositol trispyrophosphate (ITPP)-enhancement of oxygen delivery by red blood cells.

Heart failure is a consequence of progression hypoxia-dependent tissue damages. Therapeutic approaches to restore and/or protect the healthy cardiac tissue have largely failed and remain a major challenge of regenerative medicine. The myo-inositol trispyrophosphate (ITPP) is a modifier of haemoglobin which enters the red blood cells and modifies the haemoglobin properties, allowing for easier and better delivery of oxygen by the blood. Here, we show that this treatment approach in an in vivo model of myocardial infarction (MI) results in an efficient protection from heart failure, and we demonstrate the recovery effect on post-MI left ventricular remodelling in the rat model. Cultured cardiomyocytes used to study the molecular mechanism of action of ITPP in vitro displayed the fast stimulation of HIF-1 upon hypoxic conditions. HIF-1 overexpression was prevented by ITPP when incorporated into red blood cells applied in a model of blood-perfused cardiomyocytes coupling the dynamic shear stress effect to the enhanced O2 supply by modification of haemoglobin ability to release O2 in hypoxia. ITPP treatment appears a breakthrough strategy for the efficient and safe treatment of hypoxia- or ischaemia-induced injury of cardiac tissue.

Iron and the heart: A paradigm shift from systemic to cardiomyocyte abnormalities.

Iron is a key micronutrient for the human body and participates in biological processes, such as oxygen transport, storage, and utilization. Iron homeostasis plays a crucial role in the function of the heart and both iron deficiency and iron overload are harmful to the heart, which is partly mediated by increased oxidative stress. Iron enters the cardiomyocyte through the classic pathway, by binding to the transferrin 1 receptor (TfR1), but also through other routes: T-type calcium channel (TTCC), divalent metal transporter 1 (DMT1), L-type calcium channel (LTCC), Zrt-, Irt-like Proteins (ZIP) 8 and 14. Only one protein, ferroportin (FPN), extrudes iron from cardiomyocytes. Intracellular iron is utilized, stored bound to cytoplasmic ferritin or imported by mitochondria. This cardiomyocyte iron homeostasis is controlled by iron regulatory proteins (IRP). When the cellular iron level is low, expression of IRPs increases and they reduce expression of FPN, inhibiting iron efflux, reduce ferritin expression, inhibiting iron storage and augment expression of TfR1, increasing cellular iron availability. Such cellular iron homeostasis explains why the heart is very susceptible to iron overload: while cardiomyocytes possess redundant iron importing mechanisms, they are equipped with only one iron exporting protein, ferroportin. Furthermore, abnormalities of iron homeostasis have been found in heart failure and coronary artery disease, however, no clear picture is emerging yet in this area. If we better understand iron homeostasis in the cardiomyocyte, we may be able to develop better therapies for a variety of heart diseases to which abnormalities of iron homeostasis may contribute.

Omega-3 Fatty Acids Do Not Protect Against Arrhythmias in Acute Nonreperfused Myocardial Infarction Despite Some Antiarrhythmic Effects.

Ventricular arrhythmias are an important cause of mortality in the acute myocardial infarction (MI). To elucidate the effect of the omega-3 polyunsaturated fatty acids (PUFAs) on ventricular arrhythmias in acute nonreperfused MI, rats were fed with normal or eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA)-enriched diet for 3 weeks. Subsequently the rats were subjected to either MI induction or sham operation. ECG was recorded for 6 h after the operation and episodes of ventricular tachycardia/fibrillation (VT/VF) were identified. Six hours after MI epicardial monophasic action potentials (MAPs) were recorded, cardiomyocyte Ca(2+) handling was assessed and expression of proteins involved in Ca(2+) turnover was studied separately in non-infarcted left ventricle wall and infarct borderzone. EPA and DHA had no effect on occurrence of post-MI ventricular arrhythmias or mortality. Nevertheless, DHA but not EPA prevented Ca(2+) overload in LV cardiomiocytes and improved rate of Ca(2+) transient decay, protecting PMCA and SERCA function. Moreover, both EPA and DHA prevented MI-induced hyperphosphorylation of ryanodine receptors (RyRs) as well as dispersion of action potential duration (APD) in the left ventricular wall. In conclusion, EPA and DHA have no antiarrhythmic effect in the non-reperfused myocardial infarction in the rat, although these omega-3 PUFAs and DHA in particular exhibit several potential antiarrhythmic effects at the subcellular and tissue level, that is, prevent MI-induced abnormalities in Ca(2+) handling and APD dispersion. In this context further studies are needed to see if these potential antiarrhythmic effects could be utilized in the clinical setting. J. Cell. Biochem. 117: 2570-2582, 2016. © 2016 Wiley Periodicals, Inc.

Ivabradine protects against ventricular arrhythmias in acute myocardial infarction in the rat.

Ventricular arrhythmias are an important cause of mortality in the acute myocardial infarction (MI). To elucidate effect of ivabradine, pure heart rate (HR) reducing drug, on ventricular arrhythmias within 24 h after non-reperfused MI in the rat. ECG was recorded for 24 h after MI in untreated and ivabradine treated rats and episodes of ventricular tachycardia/fibrillation (VT/VF) were identified. Forty-five minutes and twenty-four hours after MI epicardial monophasic action potentials (MAPs) were recorded, cardiomyocyte Ca(2+) handling was assessed and expression and function of ion channels were studied. Ivabradine reduced average HR by 17%. Combined VT/VF incidence and arrhythmic mortality were higher in MI versus MI + Ivabradine rats. MI resulted in (1) increase of Ca(2+) sensitivity of ryanodine receptors 24 h after MI; (2) increase of HCN4 expression in the left ventricle (LV) and funny current (IF) in LV cardiomyocytes 24 h after MI, and (3) dispersion of MAP duration both 45 min and 24 h after MI. Ivabradine partially prevented all these three potential proarrhythmic effects of MI. Ivabradine is antiarrhythmic in the acute MI in the rat. Potential mechanisms include prevention of: diastolic Ca(2+)-leak from sarcoplasmic reticulum, upregulation of IF current in LV and dispersion of cardiac repolarization. Ivabradine could be an attractive antiarrhythmic agent in the setting of acute MI.

Sex- and age-dependent susceptibility to ventricular arrhythmias in the rat heart ex vivo.

The incidence of life-threatening ventricular arrhythmias, the most common cause of sudden cardiac death (SCD), depends largely on the arrhythmic substrate that develops in the myocardium during the aging process. There is a large deficit of comparative studies on the development of this substrate in both sexes, with a particular paucity of studies in females. To identify the substrates of arrhythmia, fibrosis, cardiomyocyte hypertrophy, mitochondrial density, oxidative stress, antioxidant defense and intracellular Ca2+ signaling in isolated cardiomyocytes were measured in the hearts of 3- and 24-month-old female and male rats. Arrhythmia susceptibility was assessed in ex vivo perfused hearts after exposure to isoproterenol (ISO) and hydrogen peroxide (H2O2). The number of ventricular premature beats (PVBs), ventricular tachycardia (VT) and ventricular fibrillation (VF) episodes, as well as intrinsic heart rate, QRS and QT duration, were measured in ECG signals recorded from the surfaces of the beating hearts. After ISO administration, VT/VFs were formed only in the hearts of males, mainly older ones. In contrast, H2O2 led to VT/VF formation in the hearts of rats of both sexes but much more frequently in older males. We identified several components of the arrhythmia substrate that develop in the myocardium during the aging process, including high spontaneous ryanodine receptor activity in cardiomyocytes, fibrosis of varying severity in different layers of the myocardium (nonheterogenic fibrosis), and high levels of oxidative stress as measured by nitrated tyrosine levels. All of these elements appeared at a much greater intensity in male individuals during the aging process. On the other hand, in aging females, antioxidant defense at the level of H2O2 detoxification, measured as glutathione peroxidase expression, was weaker than that in males of the same age. We showed that sex has a significant effect on the development of an arrhythmic substrate during aging. This substrate determines the incidence of life-threatening ventricular arrhythmias in the presence of additional stimuli with proarrhythmic potential, such as catecholamine stimulation or oxidative stress, which are constant elements in the pathomechanism of most cardiovascular diseases.

Role of Oxygen Starvation in Right Ventricular Decompensation and Failure in Pulmonary Arterial Hypertension.

Right ventricular (RV) function and eventually failure determine outcome in patients with pulmonary arterial hypertension (PAH). Initially, RV responds to an increased load caused by PAH with adaptive hypertrophy; however, eventually RV failure ensues. Unfortunately, it is unclear what causes the transition from compensated RV hypertrophy to decompensated RV failure. Moreover, at present, there are no therapies for RV failure; those for left ventricular (LV) failure are ineffective, and no therapies specifically targeting RV are available. Thus there is a clear need for understanding the biology of RV failure and differences in physiology and pathophysiology between RV and LV that can ultimately lead to development of such therapies. In this paper, we discuss RV adaptation and maladaptation in PAH, with a particular focus of oxygen delivery and hypoxia as the principal drivers of RV hypertrophy and failure, and attempt to pinpoint potential sites for therapy.

Arginase Inhibition Mitigates Bortezomib-Exacerbated Cardiotoxicity in Multiple Myeloma.

BACKGROUND: Multiple myeloma (MM) is associated with increased cardiovascular morbidity and mortality, while MM therapies also result in adverse cardiac effects. Endothelial dysfunction and impaired nitric oxide (NO) pathway is their possible mediator. OBJECTIVE: Since MM is associated with increased arginase expression, resulting in the consumption of ʟ-arginine, precursor for NO synthesis, our aim was to test if cardiotoxicity mediated by MM and MM therapeutic, bortezomib (a proteasome inhibitor), can be ameliorated by an arginase inhibitor through improved endothelial function. METHODS: We used a mouse Vĸ*MYC model of non-light chain MM. Cardiac function was assessed by echocardiography. RESULTS: MM resulted in progressive left ventricular (LV) systolic dysfunction, and bortezomib exacerbated this effect, leading to significant impairment of LV performance. An arginase inhibitor, OAT-1746, protected the heart against bortezomib- or MM-induced toxicity but did not completely prevent the effects of the MM+bortezomib combination. MM was associated with improved endothelial function (assessed as NO production) vs. healthy controls, while bortezomib did not affect it. OAT-1746 improved endothelial function only in healthy mice. NO plasma concentration was increased by OAT-1746 but was not affected by MM or bortezomib. CONCLUSIONS: Bortezomib exacerbates MM-mediated LV systolic dysfunction in a mouse model of MM, while an arginase inhibitor partially prevents it. Endothelium does not mediate either these adverse or beneficial effects. This suggests that proteasome inhibitors should be used with caution in patients with advanced myeloma, where the summation of cardiotoxicity could be expected. Therapies aimed at the NO pathway, in particular arginase inhibitors, could offer promise in the prevention/treatment of cardiotoxicity in MM.

Preserved cardiomyocyte function and altered desmin pattern in transgenic mouse model of dilated cardiomyopathy.

Taking advantage of the unique model of slowly developing dilated cardiomyopathy in mice with cardiomyocyte-specific transgenic overexpression of activated Gαq protein (Tgαq*44 mice) we analyzed the contribution of the cardiomyocyte malfunction, fibrosis and cytoskeleton remodeling to the development of heart failure in this model. Left ventricular (LV) in vivo function, myocardial fibrosis, cytoskeletal proteins expression and distribution, Ca(2+) handling and contractile function of isolated cardiomyocytes were evaluated at the stages of the early, compensated, and late, decompensated heart failure in 4-, 12- and 14-month-old Tgαq*44 mice, respectively, and compared to age-matched wild-type FVB mice. In the 4-month-old Tgαq*44 mice significant myocardial fibrosis, moderate myocyte hypertrophy and increased expression of regularly arranged and homogenously distributed desmin accompanied by increased phosphorylation of desmin chaperone protein, αB-crystallin, were found. Cardiomyocyte shortening, Ca(2+) handling and LV function were not altered. At 12 and 14 months of age, Tgαq*44 mice displayed progressive deterioration of the LV function. The contractile performance of isolated myocytes was still preserved, and the amplitude of Ca(2+) transients was even increased probably due to impairment of Na(+)/Ca(2+) exchanger function, while fibrosis was more extensive than in younger mice. Moreover, substantial disarrangement of desmin distribution accompanied by decreasing phosphorylation of αB-crystallin appeared. In Tgαq*44 mice disarrangement of desmin, at least partly related to inadequate phosphorylation of αB-crystallin seems to be importantly involved in the progressive deterioration of contractile heart function.

Ventricular arrhythmias in acute myocardial ischaemia-Focus on the ageing and sex.

Annually, approximately 17 million people die from cardiovascular diseases worldwide, half of them suddenly. The most common direct cause of sudden cardiac death is ventricular arrhythmia triggered by an acute coronary syndrome (ACS). The study summarizes the knowledge of the mechanisms of arrhythmia onset during ACS in humans and in animal models and factors that may influence the susceptibility to life-threatening arrhythmias during ACS with particular focus on the age and sex. The real impact of age and sex on the arrhythmic susceptibility within the setting of acute ischaemia is masked by the fact that ACSs result from coronary artery disease appearing with age much earlier among men than among women. However, results of researches show that in ageing process changes with potential pro-arrhythmic significance, such as increased fibrosis, cardiomyocyte hypertrophy, decrease number of gap junction channels, disturbances of the intracellular Ca2+ signalling or changes in electrophysiological parameters, occur independently of the development of cardiovascular diseases and are more severe in male individuals. A review of the literature also indicates a marked paucity of research in this area in female and elderly individuals. Greater awareness of sex differences in the aging process could help in the development of personalized prevention methods targeting potential pro-arrhythmic factors in patients of both sexes to reduce mortality during the acute phase of myocardial infarction. This is especially important in an era of aging populations in which women will predominate due to their longer lifespan.

Right Ventricle Remodelling in Left-Sided Heart Failure in Rats: The Role of Calcium Signalling.

Right ventricular dysfunction (RVD) can follow primary pulmonary diseases, but the most common cause of its development is left-sided heart failure (HF). RVD is associated with HF progression, increased risk of death and hospitalisation. The mechanism of right ventricle (RV) remodelling leading to RVD due to left-sided HF is not fully elucidated. Rats underwent LAD ligation to induce extensive left ventricle (LV) myocardial infarction (MI) and subsequent left-sided HF. Sham-operated animals served as controls. After 8 weeks of follow-up, the animals underwent LV and RV catheterisation, and systolic function and intracellular Ca2+ signalling were assessed in cardiomyocytes isolated from both ventricles. We demonstrated that rats with LV failure induced by extensive LV myocardial infarction also develop RV failure, leading to symptomatic biventricular HF, despite only mildly increased RV afterload. The contractility of RV cardiomyocytes was significantly increased, which could be related to increased amplitude of Ca2+ transient, preserved SERCA2a activity and reduced Ca2+ efflux via NCX1 and PMCA. Our study indicates that RV failure associated with post-MI LV failure in a rat model cannot be explained by a decline in cardiomyocyte function. This indicates that other factors may play a role here, pointing to the need for further research to better understand the biology of RV failure in order to ultimately develop therapies targeting the RV.

New potential treatment for cardiovascular disease through modulation of hemoglobin oxygen binding curve: Myo-inositol trispyrophosphate (ITPP), from cancer to cardiovascular disease.

The human body is a highly aerobic organism, which needs large amount of oxygen, especially in tissues characterized by high metabolic demand, such as the heart. Inadequate oxygen delivery underlies cardiovascular diseases, such as coronary artery disease, heart failure and pulmonary hypertension. Hemoglobin, the oxygen-transport metalloprotein in the red blood cells, gives the blood enormous oxygen carrying capacity; thus oxygen binding to hemoglobin in the lungs and oxygen dissociation in the target tissues are crucial points for oxygen delivery as well as potential targets for intervention. Myo-inositol trispyrophosphate (ITPP) acts as an effector of hemoglobin, shifting the oxygen dissociation curve to the right and increasing oxygen release in the target tissues, especially under hypoxic conditions. ITPP has been successfully used in cancer studies, demonstrating anti-cancer properties due to prevention of tumor hypoxia. Currently it is being tested in phase 2 clinical trials in humans with various tumors. First preclinical evidence also indicates that it can successfully alleviate myocardial hypoxia and prevent adverse left ventricular and right ventricular remodeling in post-myocardial infarction heart failure and pulmonary hypertension. The aim of the article is to summarize the current knowledge on ITTP, as well as to determine the prospects for its potential use in the treatment of many cardiovascular disorders.

Targeting arginase-1 exerts antitumor effects in multiple myeloma and mitigates bortezomib-induced cardiotoxicity.

Multiple myeloma (MM) remains an incurable malignancy of plasma cells despite constantly evolving therapeutic approaches including various types of immunotherapy. Increased arginase activity has been associated with potent suppression of T-cell immune responses in different types of cancer. Here, we investigated the role of arginase 1 (ARG1) in Vκ*MYC model of MM in mice. ARG1 expression in myeloid cells correlated with tumor progression and was accompanied by a systemic drop in ʟ-arginine levels. In MM-bearing mice antigen-induced proliferation of adoptively transferred T-cells was strongly suppressed and T-cell proliferation was restored by pharmacological arginase inhibition. Progression of Vκ*MYC tumors was significantly delayed in mice with myeloid-specific ARG1 deletion. Arginase inhibition effectively inhibited tumor progression although it failed to augment anti-myeloma effects of bortezomib. However, arginase inhibitor completely prevented development of bortezomib-induced cardiotoxicity in mice. Altogether, these findings indicate that arginase inhibitors could be further tested as a complementary strategy in multiple myeloma to mitigate adverse cardiac events without compromising antitumor efficacy of proteasome inhibitors.

Cardiotoxicity of the anticancer therapeutic agent bortezomib.

Recent case reports provided alarming signals that treatment with bortezomib might be associated with cardiac events. In all reported cases, patients experiencing cardiac problems were previously or concomitantly treated with other chemotherapeutics including cardiotoxic anthracyclines. Therefore, it is difficult to distinguish which components of the therapeutic regimens contribute to cardiotoxicity. Here, we addressed the influence of bortezomib on cardiac function in rats that were not treated with other drugs. Rats were treated with bortezomib at a dose of 0.2 mg/kg thrice weekly. Echocardiography, histopathology, and electron microscopy were used to evaluate cardiac function and structural changes. Respiration of the rat heart mitochondria was measured polarographically. Cell culture experiments were used to determine the influence of bortezomib on cardiomyocyte survival, contractility, Ca(2+) fluxes, induction of endoplasmic reticulum stress, and autophagy. Our findings indicate that bortezomib treatment leads to left ventricular contractile dysfunction manifested by a significant drop in left ventricle ejection fraction. Dramatic ultrastructural abnormalities of cardiomyocytes, especially within mitochondria, were accompanied by decreased ATP synthesis and decreased cardiomyocyte contractility. Monitoring of cardiac function in bortezomib-treated patients should be implemented to evaluate how frequently cardiotoxicity develops especially in patients with pre-existing cardiac conditions, as well as when using additional cardiotoxic drugs.

Ageing-dependent remodelling of ion channel and Ca2+ clock genes underlying sino-atrial node pacemaking.

The function of the sino-atrial node (SAN), the pacemaker of the heart, is known to decline with age, resulting in pacemaker disease in the elderly. The aim of the study was to investigate the effects of ageing on the SAN by characterizing electrophysiological changes and determining whether changes in gene expression are involved. In young and old rats, SAN function was characterized in the anaesthetized animal, isolated heart and isolated right atrium using ECG and action potential recordings; gene expression was characterized using quantitative PCR. The SAN function declined with age as follows: the intrinsic heart rate declined by 18 ± 3%; the corrected SAN recovery time increased by 43 ± 13%; and the SAN action potential duration increased by 11 ± 3% (at 75% repolarization). Gene expression in the SAN changed considerably with age, e.g. there was an age-dependent decrease in the Ca(2+) clock gene, RYR2, and changes in many ion channels (e.g. increases in Na(v)1.5, Na(v)ß1 and Ca(v)1.2 and decreases in K(v)1.5 and HCN1). In conclusion, with age, there are changes in the expression of ion channel and Ca(2+) clock genes in the SAN, and the changes may provide a partial explanation for the age-dependent decline in pacemaker function.

Effect of Ivabradine on Cardiac Ventricular Arrhythmias: Friend or Foe?

Life-threatening ventricular arrhythmias, such as ventricular tachycardia and ventricular fibrillation remain an ongoing clinical problem and their prevention and treatment require optimization. Conventional antiarrhythmic drugs are associated with significant proarrhythmic effects that often outweigh their benefits. Another option, the implantable cardioverter defibrillator, though clearly the primary therapy for patients at high risk of ventricular arrhythmias, is costly, invasive, and requires regular monitoring. Thus there is a clear need for new antiarrhythmic treatment strategies. Ivabradine, a heartrate-reducing agent, an inhibitor of HCN channels, may be one of such options. In this review we discuss emerging data from experimental studies that indicate new mechanism of action of this drug and further areas of investigation and potential use of ivabradine as an antiarrhythmic agent. However, clinical evidence is limited, and the jury is still out on effects of ivabradine on cardiac ventricular arrhythmias in the clinical setting.

Effect of ivabradine on cardiac arrhythmias: Antiarrhythmic or proarrhythmic?

Cardiac arrhythmias are a major source of mortality and morbidity. Unfortunately, their treatment remains suboptimal. Major classes of antiarrhythmic drugs pose a significant risk of proarrhythmia, and their side effects often outweigh their benefits. Therefore, implantable devices remain the only truly effective antiarrhythmic therapy, and new strategies of antiarrhythmic treatment are required. Ivabradine is a selective heart rate-reducing agent, an inhibitor of hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, currently approved for treatment of coronary artery disease and chronic heart failure. In this review, we focus on the clinical and basic science evidence for the antiarrhythmic and proarrhythmic effects of ivabradine. We attempt to dissect the mechanisms behind the effects of ivabradine and indicate the focus of future studies.

Intravenous ferric carboxymaltose does not provide benefits in reperfused acute myocardial infarction in the rat with normal iron status.

BACKGROUND: Iron deficiency has been implicated in the pathophysiology of heart failure and myocardial ischemia and reperfusion injury. Moreover, reperfused heart seems to lose iron, thus even subjects with normal iron status could benefit from iron therapy. Impaired mitochondrial respiration and energy starvation may be among possible consequences of myocardial iron deficiency. So far no attempts have been made to treat acute coronary syndromes with iron. Thus our aim was to verify the hypothesis that intravenous iron therapy given during reperfusion of an acute myocardial infarction will reduce left ventricular remodeling and hemodynamic abnormalities in a 2-month follow-up as well as early mitochondrial dysfunction and mortality, in the rat with normal iron status. METHODS AND RESULTS: A single dose of ferric carboxymaltose was administered intravenously at 30 min of reperfusion following 30 min of ischemia in the rat model of myocardial infarction. Ventricular arrhythmias were monitored using a telemetric system, activity of mitochondrial enzymes was assessed using spectrophotometry, serum markers of oxidative stress and inflammation were determined and left ventricular function and remodeling were monitored using echocardiography and pressure-volume loops. Intravenous iron therapy did not affect post-myocardial infarction mortality, left ventricular size or function, ventricular arrhythmias, activity of mitochondrial respiratory chain, oxidative stress or markers of inflammation, but was not associated with any adverse effects. CONCLUSIONS: Although ferric carboxymaltose given at reperfusion was safe, it was ineffective in this model of reperfused myocardial infarction in the rat with normal iron status.

Effect of age and sex on the incidence of ventricular arrhythmia in a rat model of acute ischemia.

BACKGROUND: The impact of sex and age on the arrhythmic susceptibility within the setting of acute ischemia is masked by the fact that acute coronary events result from coronary artery disease appearing with age much earlier among men than among women. METHODS AND RESULTS: LAD ligation or sham operations were performed in rats of both sexes at the age 3 and 24 months. An ECG was recorded continuously for 6 h after the operation. The number of early and late premature ventricular beats (PVBs), episodes of ventricular tachycardia (VT) and fibrillation (VF), heart rate, QRS, QT and Tpeak-Tend duration were analysed. Epicardial action potentials were recorded in vivo, Ca2+ signaling was evaluated in isolated cardiomyocytes, fibrosis and connexin-43 expression and localization were measured in the septum. PVBs, VT and VF episodes are much more common in older males than in young males and females independently from their age. Fibrosis with varying intensity in different muscle layers, hypertrophy of cardiomyocytes, reduced number of gap junctions and their appearance on the lateral myocyte membrane, QT prolongation, increase transmural dispersion of repolarisation and a decreased function of SERCA2a may increase the propensity to arrhythmia within the setting of acute ischemia. CONCLUSION: We show that the male sex, especially in case of older individuals is a strong predictor of increased arrhythmic susceptibility within the acute ischemia setting regardless of its impact on the occurrence of cardiovascular diseases. A personalized sex-dependent prevention treatment is needed to reduce the mortality in acute phases of myocardial infarction.

Right ventricular myocardial oxygen tension is reduced in monocrotaline-induced pulmonary hypertension in the rat and restored by myo-inositol trispyrophosphate.

Pulmonary hypertension (PH) initially results in compensatory right ventricular (RV) hypertrophy, but eventually in RV failure. This transition is poorly understood, but may be triggered by hypoxia. Measurements of RV oxygen tension (pO2) in PH are lacking. We hypothesized that RV hypoxia occurs in monocrotaline-induced PH in rats and that myo-inositol trispyrophosphate (ITPP), facilitating oxygen dissociation from hemoglobin, can relieve it. Rats received monocrotaline (PH) or saline (control) and 24 days later echocardiograms, pressure-volume loops were obtained and myocardial pO2 was measured using a fluorescent probe. In PH mean pulmonary artery pressure more than doubled (35 ± 5 vs. 15 ± 2 in control), RV was hypertrophied, though its contractility was augmented. RV and LV pO2 was 32 ± 5 and 15 ± 8 mmHg, respectively, in control rats. In PH RV pO2 was reduced to 18 ± 9 mmHg, while LV pO2 was unchanged. RV pO2 correlated with RV diastolic wall stress (negatively) and LV systolic pressure (positively). Acute ITPP administration did not affect RV or LV pO2 in control animals, but increased RV pO2 to 26 ± 5 mmHg without affecting LV pO2 in PH. RV oxygen balance is impaired in PH and as such can be an important target for PH therapy. ITPP may be one of such potential therapies.