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.
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.
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.
•Age and sex influence arrhythmia risk regardless of cardiovascular comorbidities.•Older age and male sex predispose to arrhythmias in acute myocardial ischaemia.•The pro-arrhythmic substrate in the heart muscle appears in ageing especially in males.•Personalized prevention strategies may reduce mortality in acute myocardial ischaemia.
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.
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•Myo-inositol trispyrophosphate (ITPP) increases tissue O2 release acting on Hb.•ITPP reduces cancer progression through alleviation of hypoxia.•ITPP increases myocardial pO2 in cardiovascular diseases.•It prevents cardiac remodeling and improves exercise capacity in heart failure.•It is a promising drug candidate for right and left heart failure.
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.
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.
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•Systemic iron deficiency does not result in cardiac iron deficiency.•Iron deficiency in HF is accompanied by an increase of serum catecholamine level.•Iron deficiency temporarily improve cardiomyocyte contractile function.•Iron therapy may prevent the increase of catecholaminergic drive in HF.•Iron therapy should be considered as an additional therapeutic option in HF.
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.
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.
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.
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•Older age and male sex predispose to arrhythmias in acute myocardial ischemia.•Age and sex influence arrhythmia risk regardless of cardiovascular comorbidities.•QT and Tpeak-Tend prolongation and low SERCA2a function increase arrhythmia risk.•Non-heterogeneous fibrosis and decreased Cx43 expression are pro-arrhythmic.•Personalized prevention strategies may reduce mortality in acute myocardial ischemia.
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•2-week dopamine infusion ↓ hemodynamics and ↑ arrhythmias in the rat heart failure.•A heart rate reducing agent, ivabradine, prevents these changes.•Failing rat & human hearts ...exhibit ↑ HCN4, a channel blocked by ivabradine.•HCN4 downregulation by ivabradine does not mediate its effects in the rat.•HCN4 in human hearts is unrelated to severity of heart failure.
Exacerbations of chronic heart failure (CHF) are often treated with catecholamines to provide short term inotropic support, but this strategy is associated with long-term detrimental hemodynamic effects and increased ventricular arrhythmias (VA), possibly related to increased heart rate (HR). We hypothesized that ivabradine may prevent adverse effects of short-term dopamine treatment in CHF.
Rats with post-myocardial infarction CHF received 2-week infusion of saline, dopamine(D), ivabradine(I) or D&I; cardiac function was assessed using echocardiography and pressure-volume loops while VA were assessed using telemetric ECG recording. Expression of HCN4, a potentially proarrhythmic channel blocked by ivabradine, was assessed in left ventricular (LV) myocardium. HCN4 expression was also assessed in human explanted normal and failing hearts and correlated with VA.
Dopamine infusion had detrimental effects on hemodynamic parameters and LV remodeling and induced VA in CHF rats, while ivabradine completely prevented these effects. CHF rats demonstrated HCN4 overexpression in LV myocardium, and ivabradine and, unexpectedly, dopamine prevented this. Failing human hearts also exhibited HCN4 overexpression in LV myocardium that was unrelated to patient’s sex, CHF etiology, VA severity or plasma NT-proBNP.
HR reduction offered by ivabradine may be a feasible strategy to extract benefits of inotropic support in CHF exacerbations, avoiding detrimental effects on CHF biology or VA. Ivabradine may offer additional beneficial effects in this setting, going beyond pure HR reduction, however prevention of ventricular HCN4 overexpression is unlikely to play a major role.
Aims β-Blockers reduce mortality and morbidity in heart failure. Many of their benefits can be explained solely by heart rate reduction (HRR). We aimed to verify whether the β-blocker, metoprolol, ...and the pure heart-rate-reducing agent, ivabradine, have the same effects on haemodynamic function, ventricular remodeling, and Ca2+ handling in post-myocardial infarction (MI) heart failure in rat. Methods and results Metoprolol (250 mg/kg/day) or ivabradine (10 mg/kg/day), offering similar HRR, or no treatment, was started 24 h after an induction of MI or sham surgery in rat. Eight weeks post-MI metoprolol and ivabradine similarly partially prevented deterioration of left ventricular (LV) ejection fraction and reduced post-MI LV wall stress. However, metoprolol partially prevented LV dilation, whereas ivabradine potentiated LV hypertrophy. Metoprolol, but not ivabradine, partially prevented post-MI chronotropic incompetence. Metoprolol markedly, whereas ivabradine mildly, increased the amplitude of the Ca2+ transient in post-MI cardiomyocytes. Ivabradine, but not metoprolol, partially prevented the MI-induced depression of sarcoplasmic reticulum Ca2+-ATPase (SERCA) activity, while metoprolol, but not ivabradine, suppressed Na+/Ca2+ exchanger (NCX) overactivity and normalized Ca2+ sensitivity of ryanodine receptors. Conclusion Although both metoprolol and ivabradine comparably prevented post-MI deterioration of haemodynamic function in the rat, metoprolol had additional potentially beneficial effects; it prevented LV dilation and hypertrophy, chronotropic incompetence, strongly increased contractility of isolated cardiomyocytes, and prevented the potentially proarrhythmic increase in NCX activity. This indicates that pure HRR does not account for effects of β-blockade in the post-MI setting. Metoprolol and ivabradine similarly improve LV function, although differently affect LV morphology and cellular Ca2+ handling in the post-infarction rat heart.
The arrhythmogenic role of epicardial adipose tissue (EAT) in atrial arrhythmias is well established, but its effect on ventricular arrhythmias has been significantly less investigated. Since ...ventricular arrhythmias are thought to cause 75%-80% of cases of sudden cardiac death, this is not a trivial issue. We provide an overview of clinical data as well as experimental and molecular data linking EAT to ventricular arrhythmias, attempting to dissect possible mechanisms and indicate future directions of research and possible clinical implications. However, despite a wealth of data indicating the role of epicardial and intramyocardial fat in the induction and propagation of ventricular arrhythmias, unfortunately there is currently no direct evidence that indeed EAT triggers arrhythmia or can be a target for antiarrhythmic strategies.
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