New Study Examines the Role of Ferroptosis in Heart Disease

Heart disease is a leading cause of death in the United States. The Centers for Disease Control and Prevention cite one American dies every 33 seconds because of cardiovascular disease.¹ Due to the staggering numbers, heart dysfunction is a well-researched subject. Every finding brings new knowledge to the surface — and one recently led to the discovery of ferroptosis.

Ferroptosis is a form of cell death associated with many serious health conditions, like cancer and cardiovascular diseases.² This article explores how ferroptosis is related to developing cardiac dysfunction. Analyzing various studies sheds light on the role of oxidative stress, iron overload, and lipid peroxidation in vascular cell death through a process called ferroptosis.

The Cell Death Processes

Cell death is a vital process in the human body to grow and survive. For instance, babies first develop fetal fingers that are all joined or webbed, looking like flippers. Unnecessary cells then die to allow fingers to separate and lose their webbing.³

The exact cell death mechanism is linked with the onset of many diseases. Before learning about ferroptosis, researchers knew a few ways cells could die, with common ones through necrosis, apoptosis, and pyroptosis.

Necrosis

Necrosis is a cell death pattern in which cells are subjected to extreme conditions, triggering their disintegration.⁴ An example is exposure to freezing weather for a long time, leading to frostbite. Your hands would feel numb and reduce or lose their sensations, marking the deterioration and death of cells.⁵ When cells can't maintain balance under rough conditions, they eventually die.

Pyroptosis

Pyroptosis is a form of cell death related to inflammation. When cells get infected by bacteria, endotoxins, and microorganisms that cause diseases, a signal is sent to your immune system to activate disintegration before they start to divide. The dynamic of how cells die is similar to necrosis, and its purpose is to help control inflammation in the body.⁶

Apoptosis

Meanwhile, apoptosis is a programmed pattern of cell death occurring naturally. When cells sustain damage to the point they can't self-repair, they ‘commit suicide.’⁷ This controlled normal cellular multiplication and turnover can help you prevent diseases like cancer. For example, before worn-out cells reproduce and form a tumor, they actively take part in their own deaths to suppress and inactivate an impending disease.

Ferroptosis

Ferroptosis was discovered in 2012, but its role in heart dysfunction has only recently been identified and established. It has two causes — lipid peroxidation and intracellular iron accumulation.⁸ To maintain the cells' structure and function, they need lipids or fatty compounds, a significant part of their membranes.⁹

Lipid peroxidation is when these lipids degrade because of harmful molecules called free radicals attacking them. If it’s combined with iron overload, which happens when cells are exposed to environmental stress to the point it alters iron metabolism — the result is ferroptosis and cell death.⁸

The death of cells is associated with the onset of diseases. Researchers believe ferroptosis prompts several health conditions, like cancers, acute kidney injury, and neurodegenerative and cardiovascular diseases.⁸ With heart ailments ranking high as a mortality cause among Americans, experts continue to study to fill the knowledge gaps on the role of ferroptosis in deteriorating heart function with the hope of developing novel heart treatment strategies to prevent this specific pattern of cell death.

Overloaded Iron as a Catalyst in Ferroptosis

Iron is an essential nutrient in maintaining metabolism and several body functions. However, as with many other compounds in the body, too much of it can lead to physiological imbalances. When iron stored in cells becomes unstable, it catalyzes the increase of reactive oxygen species (ROS), which are toxic molecules causing oxidative stress, a factor in ferroptosis.¹⁰

Cells have a built-in defense system to protect themselves from harmful molecules causing their death. Glutathione — a powerful antioxidant present in cells — can neutralize ROS and lessen their adverse effects on health.¹⁰ If there are antioxidants to sidestep cell death, why does ferroptosis still happen?

Certain health criteria occurring simultaneously, like iron imbalance, increased ROS, and decreased glutathione caused by infection, stress, or disease that impair the immune system response, can invoke lipid peroxidation. All these changes ripple to ferroptosis and cause cell dysfunction and, ultimately, disease.¹⁰

Iron is a double-edged sword for the body. Inadequate and oversupply of it can have negative health consequences. Hence, iron metabolism is tightly regulated by the iron-responsive element (IRE)-iron regulatory protein (IRP) system and the hepcidin-ferroportin axis. They act as gatekeepers to moderate the iron transport and storage to only the right amount the body needs.¹¹

Heart Health and Ferroptosis Dynamic

How does ferroptosis affect the cells in the heart? Researchers found six fundamental forms of cell death in the cardiovascular system:

• Apoptosis
• Necroptosis
• Mitochondrial-mediated necrosis
• Pyroptosis
• Autophagic cell death
• Ferroptosis

Elements of Ferroptosis

Experts recently found out about ferroptosis and heart connection, so studies are ongoing to further understand its influence on cardiovascular diseases. Unlike other types of cell death, ferroptosis is unique because three elements are required to make it happen. With the absence of one of any of these characteristics, ferroptosis can't take place:

• When there's excess iron in cells
• When lipid peroxidation transpires due to accumulated iron
• When the redox balance or the levels of oxidants and antioxidants are disrupted due to reduced glutathione and glutathione peroxidase

Iron and Heart Health Link

Iron is an important element in creating hemoglobin, a protein in red blood cells responsible for carrying oxygen throughout the body, including the heart. Due to the high demand for energy when pumping blood, a constant yet right supply of this mineral is crucial in homeostasis. Deficiency and overload of iron can result in conditions related to the heart.¹²

Diseases Linked With Iron Deficiency

When the standard balance of iron content is interrupted — whether it goes down or up — it can prompt adverse health outcomes. Up to 60% of patients with coronary artery diseases have iron deficiency. The number is even higher in those with heart failure or pulmonary hypertension.¹³

Often, this mineral inadequacy co-occurs with heart illnesses. It isn't the sole cause leading to the presence of cardiovascular disease, but it contributes to worsening cardiac conditions.

Diseases Linked With Iron Overload

Hemochromatosis is the medical term for iron overload, a condition where the body absorbs excessive iron from the food you eat. This primary phenomenon is often genetic, but anemia, blood transfusions, and iron pills are also contributing bases.

Similar to iron deficiency, exaggerated amounts of this mineral have detrimental side effects on the heart, liver, and pancreas. In regards to cardiovascular health, abnormal deposits can cause arrhythmia and heart failure.¹⁴

Secondary Hemochromatosis

Besides genetic hemochromatosis, there's also secondary iron overload. People living with disorders that impair the normal production of red blood cells are at an elevated risk of mineral oversupply.¹⁵ Here are some examples.

• Inherited disorders like sickle cell disease, sideroblastic anemias, and thalassemia
• Disorders from birth that prevent the normal breakdown of red blood cells, like hereditary spherocytosis and pyruvate kinase deficiency
• Disorders that lead to underdeveloped red blood cells, like myelodysplasia¹⁵

Those living with these disorders may have body systems that absorb iron more than what’s necessary, dysregulating the standard process of red blood cell production and leading to excess storage of this mineral.

Other causes of iron overload are:

• Iron therapy
• Regular blood transfusion¹⁵

This excess supply of iron in the body is what researchers believe prompts lipid peroxidation that then activates ferroptosis and the untimely death of cardiac and vascular cells — and, ultimately, cardiovascular disease.¹⁶ Experts continue conducting studies to better understand the connection between ferroptosis and heart health. Currently, what's clear is that abnormally abundant iron in the body can give rise to toxicity and heart dysfunction.

Symptoms of Iron Toxicity

In most cases, signs of too much iron manifest in middle age.¹⁴ These symptoms may share features with other health conditions, making them challenging to diagnose.

• Fatigue
• Unreasonable weight loss
• Irregular heartbeat
• Joint pain
• Stomach pain
• Iron fist or feeling pain in the knuckles and middle fingers
• Weakness

Your healthcare provider may run blood tests, genetic testing, liver biopsy, and magnetic resonance imaging to measure the amount of iron in your organs and blood.¹⁴

Future Findings May Help Curb Heart Disease Risk

Approximately 620 million people are living with cardiovascular disease around the world. This number continues to balloon with changing lifestyles and the graying of the population.¹⁷ Studies on ferroptosis in heart disease are at an early stage, so there's limited information available to fully understand the interplay between the two.

Still, if future findings could unravel how excess deposits of iron and lipid peroxidation can subsequently lead to ferroptosis and death of cardiac cells, a medical breakthrough that could save millions of people living with high cardiovascular risk may be on the horizon.

The growth rate of cardiovascular disease globally is alarming. Since experts project a rising trend, studies with conclusive findings that can potentially help drive down the number are necessary and can be life-changing. The development of a new and effective therapy can undeniably minimize the number of deaths associated with lethal heart disease.

Sources:

• Heart Disease Facts (2023) Centers for Disease Control and Prevention. Available at: https://www.cdc.gov/heartdisease/facts.htm (Accessed: 17 November 2023).
  
• Tang, D. and Kroemer, G. (2020) Ferroptosis, Current Biology. Available at: https://www.sciencedirect.com/science/article/pii/S096098222031438X (Accessed: 17 November 2023).
  
• Cleveland Clinic Medical (no date a) Cell Death: Types, Causes & Necrosis, Cleveland Clinic. Available at: https://my.clevelandclinic.org/health/articles/cell-death (Accessed: 17 November 2023).
  
• Necrosis (no date) Pathologia. Available at: https://pathologia.ed.ac.uk/topic/necrosis/ (Accessed: 17 November 2023).
  
• Frostbite: Symptoms, Causes, Diagnosis, Treatment, & Recovery (no date) WebMD. Available at: https://www.webmd.com/first-aid/frostbite (Accessed: 17 November 2023).
• Pyroptosis (no date) Science Direct. Available at: https://www.sciencedirect.com/topics/immunology-and-microbiology/pyroptosis (Accessed: 17 November 2023).
  
• Apoptosis (no date) Genome.gov. Available at: https://www.genome.gov/genetics-glossary/apoptosis (Accessed: 17 November 2023).
  
• Han, C. et al. (2020) Ferroptosis and its potential role in human diseases, Frontiers in Pharmacology. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090218/ (Accessed: 17 November 2023).
  
• Cleveland Clinic Medical (no date b) What Are Lipids?, Cleveland Clinic. Available at: https://my.clevelandclinic.org/health/body/24425-lipids (Accessed: 17 November 2023).
  
• Fırat, A.A. (2021) Ferroptosis: Can Iron Be the Downfall of a Cell?, IntechOpen. Available at: https://www.intechopen.com/chapters/79693 (Accessed: 17 November 2023).
  
• Katsarou, A. and Pantopoulos, K. (2020) Basics and principles of cellular and systemic iron homeostasis, Molecular Aspects of Medicine. Available at: https://www.sciencedirect.com/science/article/abs/pii/S009829972030042X (Accessed: 17 November 2023).
  
• Teodor Sawicki, K., De Jesus, A. and Ardehali, H. (2023) Iron Metabolism in Cardiovascular Disease: Physiology, Mechanisms, and Therapeutic Targets, Circulation Research. Available at: https://pubmed.ncbi.nlm.nih.gov/36730380/ (Accessed: 17 November 2023).
  
• Savarese, G. et al. (2023) Iron Deficiency and Cardiovascular Disease, European Heart Journal. Available at: https://academic.oup.com/eurheartj/article/44/1/14/6772672 (Accessed: 17 November 2023).
  
• C.C. Medical (2021) Hemochromatosis (iron overload): Causes, symptoms, treatment, Diet & More, Cleveland Clinic. Available at: https://my.clevelandclinic.org/health/diseases/14971-hemochromatosis-iron-overload (Accessed: 17 November 2023).
  
• Hamilton, J.P.A. (2023) Secondary Iron Overload - Blood Disorders, MSD Manual Consumer Version. Available at: https://www.msdmanuals.com/home/blood-disorders/iron-overload/secondary-iron-overload (Accessed: 17 November 2023).
  
• Fratta Pasini AM, Stranieri C, Busti F, Di Leo EG, Girelli D, Cominacini L. (2023) New Insights into the Role of Ferroptosis in Cardiovascular Diseases. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10047059/ (Accessed: 17 November 2023).
  
• British Heart Foundation. Global Heart & Circulatory Diseases Factsheet. (2023) Global Heart & Circulatory Diseases Factsheet. Available at: https://www.bhf.org.uk/-/media/files/for-professionals/research/heart-statistics/bhf-cvd-statistics-global-factsheet.pdf?rev=e61c05db17e9439a8c2e4720f6ca0a19&hash=6350DE1B2A19D939431D876311077C7B (Accessed: 17 November 2023).