Overview of Cardiovascular Disease
Heart disease and cardiovascular disease are terms used to describe various heart-related conditions and blood arteries. These conditions can include coronary artery disease, heart valve problems, and heart rhythm disorders. Cardiovascular disease is well known to be the leading cause of death and disability globally (Amin et al., 2019).
Coronary artery disease is the most prevalent type of cardiovascular disease, which occurs when the arteries supplying the heart with blood become narrowed or blocked. This condition can lead to chest pain, heart attack, and even death. There are various risk factors for coronary artery disease, including high blood pressure, high cholesterol, smoking, diabetes, and a sedentary lifestyle.
Causes of Cardiovascular Disease
Heart Valve Problems
It is known that heart valve problems can also lead to cardiovascular disease. The heart has four valves that open and close, allowing the blood to flow into the heart and out. If these valves do not work properly, the heart must exert more effort to pump blood, which can lead to heart disease. Risk factors for heart valve problems include a family history of the condition, certain infections, and aging.
Heart Rhythm Disorders (Arrhythmias)
Heart rhythm disorders, also known as arrhythmias, can cause cardiovascular disease. These disorders occur when the heartbeat is not normal. It can lead to dizziness, fainting, and chest pain. Diabetes, high blood pressure, and a family history of the condition are responsible for cardiac rhythm disorders.
Prevention and Treatment of Cardiovascular Disease
Suggestions for early screening of people without symptoms include genes implicated in sustaining cardiovascular physiology, such as CTLA-4 (Zhao et al., 2019). Preventing cardiovascular disease involves adopting healthy habits, such as eating a balanced diet, exercising regularly, not smoking, and managing stress. In addition, regular check-ups with a healthcare practitioner can help identify and manage risk factors for the condition.
Treatment for cardiovascular disease can include medications, surgery, and lifestyle changes. In some cases, a procedure called angioplasty can open narrowed or blocked arteries. In other cases, replacing or repairing heart valves to treat arrhythmias might require surgery. Generally, cardiovascular disease is a serious condition that affects the heart and blood vessels. Making healthy lifestyle choices, getting regular check-ups, and seeking appropriate treatment can help prevent and manage this condition.
The Role of CTLA-4 in Cardiovascular Disease
Heart disease is among the leading causes of death globally; millions die from heart disease yearly (Amin et al., 2019). The CTLA-4 protein is one of the important elements in the emergence of heart disease. Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is a protein surface-expressed in immune cells called T cells (Bansal et al., 2021). It is essential for controlling the immune response, specifically by inhibiting the activation of T cells (Düzgün et al., 2009). However, recent research has shown that CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) may also contribute to the development of heart disease.
Genetic Variations of CTLA-4
Research specifically suggests that genetic variations in the CTLA-4 gene might play a role in the onset of heart disease (Ruppert et al., 2010). Variations in the CTLA-4 gene were connected to a higher risk of coronary artery disease. Variations in the CTLA-4 gene were also associated with an increased risk of heart failure.
The G/G genotype represents a distinct alteration in the DNA sequence of the CTLA-4 gene, influencing the functionality of the protein it encodes. The G/G genotype polymorphism of the CTLA-4 gene has been related to a higher risk of acute myocardial infarction (AMI), also known as a heart attack (Yip et al., 2007). This polymorphism is a change in the CTLA-4 gene’s DNA sequence that impacts how the gene’s protein functions.
People with the G/G genotype may have an impaired ability to regulate immune responses, which can increase their risk of developing AMI. It was discovered that the G/G genotype, a particular variant in the CTLA-4 gene’s DNA sequence, raised the risk of DCM (Ruppert et al., 2010). It suggests that CTLA-4 may be a susceptibility gene for DCM, meaning that it may lead to the development of the disease.
CTLA-4 and Inflammation
The function of the CTLA-4 protein is to regulate the immune system and prevent excessive inflammation (Ruppert et al., 2010). In DCM, upregulated immune reactions in the heart may contribute to inflammatory responses and promote fibrosis, which is the formation of scar tissue in the heart. Protein is involved in the inflammation linked to heart disease. Inflammation is the body’s natural response to infection or injury, which allows the body to heal and repair. However, chronic inflammation, which is long-term and persistent, is believed to initiate the development of heart disease.
CTLA-4 may promote chronic inflammation by inhibiting the activity of immune cells, such as T-cells, which are responsible for fighting off infections and other threats to the body. It can accumulate harmful substances, such as cholesterol, in the arteries, ultimately leading to heart disease.
CTLA-4 as a Target for Immunotherapy
The protein CTLA-4 has been the subject of many clinical trials, as it is a potential target for treating autoimmune diseases. One of the key mechanisms by which CTLA-4 regulates the immune response is competing with another protein called CD28 for binding to a pair of proteins called CD80 and CD86 (Bansal et al., 2021). CTLA-4 proteins are expressed on antigen-presenting cells’ exteriors, which are important for activating T cells.
When CTLA-4 binds to CD80 and CD86, it blocks the activation of T cells, preventing them from mounting an immune response (Sobhani et al., 2021). On the other hand, when CD28 binds to CD80 and CD86, it stimulates T cells to become activated and begin the immune response (Sobhani et al., 2021).
Immunotherapy Drugs Targeting CTLA-4
Because of its role in regulating the immune response, CTLA-4 has been a target for developing immunotherapy drugs. These drugs work by blocking the function of CTLA-4, thereby allowing the immune system to mount a stronger response to cancer cells or other foreign invaders. One of the most promising immunotherapy drugs that target CTLA-4 is ipilimumab, which was first approved by the United States Food and Drug Administration.
Ipilimumab is effective in treating advanced melanoma and is currently being studied as a cure process for other types of cancer. Ipilimumab works by binding to CTLA-4 and preventing it from sending its inhibitory signal, thereby enhancing T-cell activation and the immune response against cancer cells. Ipilimumab has shown some success in treating melanoma, but it can also cause autoimmune side effects such as colitis, hepatitis, and thyroiditis.
It is often reserved for melanoma patients who have advanced disease and have not responded to conventional therapies. Another drug targeting CTLA-4 is called tremelimumab, which is currently in clinical trials for cancer treatment, including melanoma, lung cancer, and bladder cancer. Tremelimumab works similarly to ipilimumab but is thought to have a longer duration of action. In addition to ipilimumab and tremelimumab, several other drugs target CTLA-4 in development. These include durvalumab, avelumab, and MEDI0562, all in clinical trials for the mitigation of various types of cancer.
CTLA-4 and Autoimmune Disorders
CTLA-4 is an important target for cancer immunotherapy because it controls the immunological response. Inhibition of CTLA-4 can enhance the immune system’s ability to attack cancer cells, but it can also cause autoimmune side effects (Sobhani et al., 2021). As a result, the use of drugs that target CTLA-4 is typically reserved for patients with advanced cancer who have not responded to other treatments.
Researchers are also looking at the possibility of using CTLA-4 inhibitors to treat autoimmune disorders, such as rheumatoid arthritis, which has the potential to develop heart disease (Sobhani et al., 2021).
CTLA-4 and Rheumatic and Kawasaki Disease
The post-infectious, non-suppurative, multisystemic inflammatory condition known as acute rheumatic fever leads to common clinical features such as arthritis and valvulitis. It results from an elevated immunological reaction to group A, beta-hemolytic streptococcal pharyngitis (Düzgün et al., 2009). Kuo et al. (2010) researched Kawasaki disease (KD), a structural blood vessel inflammation that usually affects children at the age of five. One possible gene for causing autoimmunity has been identified as CTLA-4, or cytotoxic T lymphocyte-associated antigen-4 (Kuo et al., 2010). That investigation examined the relationship between the CTLA-4 gene polymorphisms in KD and coronary artery lesions (CAL).
According to Kuo et al. (2010), 73 girls and 160 boys, with a mean age of 1.6 years, in the population, patients with KD enrolled from 2001 to 2007 at Chang Gung Memorial Hospital-Kaohsiung Medical Center in Taiwan. Kuo et al. (2010) analyzed the results of 644 healthy children. They concluded that the initial proof was that the CTLA-4 (+49) A/G polymorphism, especially in female patients, is associated with the CAL development of KD.
According to Bansal et al. (2021), the risk is connected to the female gender and the CVL (combined valve lesion) group’s lower prevalence of the CTLA-4 1661G allele. Generally, CTLA-4 is a protein that plays a crucial role in regulating the immune response. Blocking T cells’ activation helps prevent excessive immune responses, which can lead to autoimmune diseases and other problems (Düzgün et al., 2009). The protein has been the subject of many clinical trials and is a target for developing immunotherapy drugs for treating cancer and other conditions.
CTLA-4 and Cardiomyopathy
The study of Liu et al. (2005) investigated the potential association between the CTLA-4 gene and idiopathic dilated cardiomyopathy (IDC) in the Chinese Han population. The results showed that the CTLA-4 exon 1 A49–>G polymorphism might play a role in the genetic susceptibility to IDC in this population. For that reason, Liu et al. (2006) examined the expression of CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) in individuals with idiopathic dilated cardiomyopathy (IDC). They concluded that the CTLA-4 gene is expressed aberrantly in IDC patients.
CTLA-4 as a Regulatory Agent in Immunity and Disease
The above researchers have shown that adaptive immunity provides crucial information and assistance for establishing and sustaining an anticancer response when T-cell lymphocytes are involved. Patient survival and response to therapy were strongly linked with cytotoxic CD8+ T cell infiltration of the whole tumor. Therefore, other investigations have found that cytotoxic T lymphocyte-associated antigen four inhibition in patients with metastatic melanoma causes cancer reversal and autoimmunity.
The crucial immune-regulatory protein known as CTLA-4, which is present in certain regulatory T cells and triggered T cells, can suppress T cell activation (Düzgün et al., 2009). This work established CTLA-4 as a key player in regulating human immunity to self-antigens and suggests that blocking CTLA-4 may help break the immune system’s tolerance to human cancer antigens during cancer immunotherapy. Another important fact is knowing that CTLA-4 is not present on dormant T cells but is upregulated for about two to three days following T cell activation.
References
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Bansal, A., Tasnim, S., Gupta, M. D., MP, G., Batra, V., Kohli, S., Tyagi, S., & Pasha, M. Q. (2021). Susceptibility of CTLA-4 −1661A/G polymorphism towards severity of rheumatic heart disease. Indian Heart Journal, 73(4), 511–515. Web.
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