Introduction:
Iron is a vital mineral that contributes to many biological activities. Enzyme activity, mitochondrial function, and oxygen transport and storage depend on iron. Numerous cardiovascular diseases (CVDs) are correlated with adequate iron overload or shortage. Heart failure may result from iron deficiency's detrimental effects on the energy supplement and mitochondrial activity of cardiomyocytes. On the other hand, because too much iron can cause oxidative damage and reactive oxygen species (ROS) production, it can also be cardiotoxic. Moreover, it has recently been discovered that iron-mediated cell death, or ferroptosis, causes damage to cardiomyocytes and is crucial in cardiovascular diseases.
What Is Iron Homeostasis and Iron Metabolism?
The body regulates iron metabolism through a network of proteins that balance absorption and use.
Intestinal Absorption - For the body to sustain iron homeostasis, the processes of iron absorption, transit, usage, and storage are essential. Iron's physiological status may be disturbed by conditions that interfere with these functions. Iron is absorbed in the digestive tract and is influenced by the kind of food eaten as well as the individual's iron levels. Heme and non-heme iron are the two types available; the latter is usually taken orally. Dietary iron is predominantly absorbed by enterocytes located in the duodenum and upper jejunum of the small intestine. Hepcidin controls iron absorption according to systemic iron levels by attaching to ferroproteins. Enteral iron absorption is essential for preserving the iron balance in the body because humans do not have an effective system for excreting iron from the body.
Transferrin - While the body's tissues require absorbed iron for vital biological functions, excess iron concentrates in particular tissues, such as the heart muscle, adrenal glands, and exocrine glands. The majority of iron in the blood is firmly attached to transferrin, a liver-derived protein. Iron is more easily transported into cells that express transferrin receptors, such as macrophages and erythroblasts when transferrin is present.
Cellular Iron Metabolism - Because iron is necessary for several biochemical activities, cellular iron usage includes processes like heme production and cellular metabolism. Fe2+ (ferrous) is the major type of iron found within cells, whereas Fe3+ (ferric) is the primary form found outside of cells. This difference aids in maintaining the physiological integrity of the cell compartments since the external environment often has less reducing circumstances than the cytosol. Hemostarin contains the majority of iron, and the liver is the primary organ for storing iron. The body uses ferritin, which is mostly found in tissues like the spleen, to meet its needs. The primary iron storage protein is ferritin. Cells employ numerous strategies to react to iron restriction, such as upregulating iron import proteins and downregulating iron export and storage mechanisms. Consequently, there are fewer illnesses brought on by low cellular iron, and cellular iron shortage is less common.
Iron Overload - Humans do not have a system in place to regulate their excretion of iron, which makes them particularly susceptible to intracellular iron accumulation. Numerous illnesses are linked to iron overload, both cellular and systemic. Furthermore, iron overload at the cellular level, as opposed to the systemic level, is a characteristic of numerous illnesses. Alterations in these systems may lead to disorders characterized by an excess or shortage of iron, which may have an impact on the emergence of cardiovascular conditions.
What Is the Role of Iron in Various Cardiovascular Diseases?
1. Atherosclerotic Cardiovascular Disease:
Iron's catalytically active state, which produces ROS (reactive oxygen species) and induces lipid peroxidation, may play a major part in the pathogenic actions of iron in atherogenesis (the formation of plaque in the arteries). Iron overload is seen in vascular smooth muscle cells, monocytes, macrophages, endothelial cells, and platelets within atherosclerotic lesions, all of which are involved in the development of atherosclerosis (an accumulation of plaque that narrows the arteries). According to a recent study, iron overload also increases inflammation and glycolysis in macrophages, aggravating the extent of atherosclerosis.
2. Heart Failure:
In patients with heart failure, the significance of iron deficiency has been extensively studied. Approximately half of patients with chronic heart failure have iron deficiency, which is independently linked to higher rates of morbidity and death. HF-associated iron shortage can be explained by a number of factors, including dietary deficits, poor absorption due to gut edema or the use of proton pump inhibitors, and gastrointestinal bleeding from antiplatelet and anticoagulant medication use.
3. Valvular Disease:
ROS mediated by iron can cause oxidative stress, which in turn can trigger valve calcification. The most frequently impacted heart valve is the aortic valve, which can become calcified in humans and exhibit iron buildup. Heme and iron were found to associate with valve microhemorrhages in histologic samples, indicating that the mineralization of valvular interstitial cells was caused by macrophages.
4. Pulmonary Hypertension
The precise mechanism underlying pulmonary artery hypertension and iron deficiency (ID) is yet unknown; however, over 40 % of patients with the condition also have ID. Through the synthesis of hepcidin, BMPR2 (bone morphogenetic protein receptor type 2) mutations impact pathways involved in iron homeostasis.
5. Stroke:
ID puts the brain at a heightened risk of ischemia injury because of its high metabolic activity. In the brain, ID causes abnormalities in myelination, decreased neurotransmitter synthesis, and dysfunctional neurons.
How to Manage and Treat Cardiovascular Diseases Due to Iron Dysregulation?
Diagnostic Methods - Serious consequences can be avoided by identifying iron dysregulation early and treating it appropriately. Laboratory investigations, medical imaging methods, and clinical symptom analysis are all necessary for an accurate and quick diagnosis. For this, magnetic resonance works well. The primary diagnostic procedures involve determining transferrin saturation and serum ferritin levels. The most accurate preliminary test for determining the presence of an iron shortage is serum ferritin.
Treating Iron Deficiency - In the care of underlying diseases that contribute to the deficiency, iron supplements, and dietary modifications are available as alternatives for iron deficiency. Eating iron-rich foods can help avoid iron insufficiency. The primary treatment is iron supplementation, which can be given intravenously or orally based on severity. For patients who cannot tolerate oral iron or who have situations where oral iron is unlikely to be beneficial, intravenous iron should be examined.
Treating Iron Overload - Endogenous mechanisms to eliminate excess systemic or myocardial iron are absent in humans. One of the most significant ways to manage iron overload is to lower systemic iron levels or stop iron from entering tissues. The main treatment for iron excess is iron chelation therapy. Limiting the consumption of foods high in iron can also aid in the management of iron overload. Patients with cardiac arrhythmia and iron overload toxicity have improved with chelation therapy.
Treating Cardiovascular Diseases - Treating cardiovascular problems may benefit from the therapeutic approach of inhibiting cardiac ferroptosis. Ferroptosis in CVD can be inhibited by a number of targets, including chelators, antioxidants, and activators of Glutathione Peroxidase 4 (GPX4). These targets provide methods for mitigating or avoiding cardiovascular damage caused by ferroptosis. Myocardial damage has been demonstrated to be lessened by treatment with ferroptosis inhibitor and recombinant human GPX4.
In order to prevent and treat CVD, controlling and managing iron metabolism is essential. Depending on the kind and degree of iron metabolism issues, dietary changes, iron supplements, and iron chelation therapy are all viable choices. Treatment for CVD must also address the underlying causes of iron imbalance.
Conclusion:
Iron is a necessary micronutrient for fundamental biological operations. A significant role for iron metabolism in the occurrence of CVD is played by excess and deficiency, both of which carry risks. Therefore, in order to create efficient preventative and therapy plans, it is imperative to comprehend how iron damages cardiovascular systems. It appears that treating iron metabolism holds the potential to lessen the burden of CVD and enhance patient outcomes.
