Cardiovascular Diseases and Clonal Haematopoiesis: Experimental and Epidemiological Research

Michael Rieger^*
*Correspondence: Michael Rieger, Department of Medicine, University of Goethe, Frankfurt, Germany, Email:

Introduction

Worldwide, cardiovascular diseases (CVDs) continue to be the leading cause of death. Numerous studies have demonstrated that both genetic and environmental factors cause atherosclerosis, which in turn causes cardiovascular problems. Age is strongly linked to the development of atherosclerosis, which is an inflammatory disease. Clonal hematopoiesis (CH), according to recent experimental evidence, is an emerging cardiovascular risk factor that contributes to the onset of atherosclerosis, exacerbates cardiovascular disease, and causes cardiac dysfunction. Somatic mutations in hematopoietic stem cell recurrent genes lead to the clonal expansion of mutated blood cell clones, which in turn causes CH. Myeloid neoplasms have revealed many of the mutated genes. However, hematologic abnormalities only occur in a small percentage of CH mutation carriers. CH is obviously age subordinate and isn't interesting: CH affects at least 10%–20% of people over 70. Medical attention has been drawn to the newly discovered link between CVD progression and myeloid leukemia-driver mutations. The current consensus regarding CH's role in various cardiovascular diseases, CVD risk assessment, patient stratification, and the development of novel therapeutic strategies is summarized in this review [1].

Cardiovascular diseases (CVDs) continue to be the leading cause of death worldwide, despite advancements in patient medical and interventional clinical management. It is very much valued that atherosclerosis addresses the hidden reason for most CVDs. Atheromatous lesions in the vessel are caused by atherosclerosis, a chronic inflammatory condition characterized by an increase in the recruitment, adhesion, and proliferation of various subsets of leukocytes to the endothelium. Hypercholesterolemia (HC), diabetes mellitus (DM), hypertension, metabolic syndrome, obesity, and smoking all increase the risk of cardiovascular disease (CVD). Numerous studies have reported that CRFs enhance the production of myeloid cells and multipotent hematopoietic progenitors in the bone marrow, which may in turn promote the development of atherosclerosis and cardiovascular disease. Inflammation plays a crucial role in the progression of CVDs. Conventional CRFs may not be able to fully predict the onset of cardiovascular disease (CVD) and, more importantly, the prevalence of CVDs rises with age. Age-related cardiovascular disease (CVD) predisposition is thought to be caused by cumulative exposure to classic CRFs, but the precise molecular mechanisms are still poorly understood. Genomic instability, telomere attrition, and an accumulation of irreversible epigenetic alterations, such as DNA methylation, histone posttranslational modifications, and dynamic nucleosome occupancy, have all been linked to cardiovascular aging in a number of studies [2].

Description

CH was first identified in elderly patients with hematologic malignancies. Somatic mutations in genes associated with myeloid neoplasms in hematopoietic stem cells (HSCs) cause CH, which results in the expansion of mutated blood cell clones. Technically, clonal hematopoiesis of indeterminate potential (CHIP) is characterized by the absence of hematologic malignancies or other hematologic abnormalities but the presence of somatic variants with a variant allele frequency (VAF) (i.e., variant prevalence among all blood cells) of at least 2%. Human genetic and epidemiological studies demonstrated a correlation between CHIP and elevated CVD mortality. Mechanistic evidence for the role of CHIP in the progression and development of CVD was provided by preclinical animal models. We summarize the role that inflammatory blood cell types and inflammation play in the development of cardiovascular disease (CVD) and atherosclerosis in this review. A feedback loop between CH and CVDs is also discussed, as are the potential mechanisms by which CH contributes to increased cardiovascular risk in older people and how cardiovascular risk factor-induced inflammation further promotes clonal dominance of mutated HSC clones. Finally, we discuss the potential applications of these findings to risk assessment for cardiovascular disease (CVD), patient stratification, and the creation of novel therapeutic approaches [3].

Vasculature-related chronic inflammation is known as atherosclerosis. It is well known that monocyte-derived macrophages play a significant role in the development of plaque, the progression of atherosclerosis, and the prevalence of cardiovascular disease. During atherogenesis, monocyte adhesion to the endothelium and their infiltration into the vessel wall are enhanced by pathological stimuli like hypertension and hyperlipidemia . Monocytes begin to proliferate and transform into macrophages upon entering the vessel wall. These macrophages endocytose lipids and transform into foam cells, which aid in plaque formation. Monocytosis, or an increase in the number of monocytes in the blood, has been linked to the formation of plaque and the onset of carotid artery disease (CAD). In preclinical models, experimental evidence has demonstrated a direct link between monocytosis and the onset of atherosclerosis. In experimental models of atherosclerosis, atherogenesis and plaque formation are reduced when monocyte recruitment is inhibited or depleted [4].

The clonal expansion of transformed blood cells is the cause of hematological malignancies, which typically affect the elderly and have a median age of 60 to 70 years. Hematologic malignancies typically result from recurrent somatic mutations in driver genes, despite the fact that they can be linked to inherited genetic mutations in some instances. Interestingly, despite the fact that the majority of somatic mutations have no effect, certain mutations give HSCs carrying these mutations a distinct advantage in clonal expansion, either through increased proliferation or reduced cell death and enhanced selfrenewal. This could result in hematologic cancers. The aging hematopoietic system was also found to have clonality as one of its main characteristics. A skewed pattern of X-chromosome inactivation in peripheral blood cells, particularly within the myeloid compartment, that is age-related was found in studies conducted on women over 65 who had no hematologic malignancies [3].

In spite of the fact that CH was at first connected with hematologic malignancies, it became obvious that CH prompted diminished patient endurance, which couldn't be made sense of by the expansion in hematological disease. Various examinations utilizing cutting edge sequencing investigation in enormous partners uncovered that CHIP-driver transformations in leukemiarelated qualities DNMT3A, TET2, ASXL1, and JAK2 were related with an expanded gamble of rate of coronary illness (CHD) or stroke and expanded mortality. Importantly, it was reported that people with early-onset myocardial infarction had a higher prevalence of CHIP. In a recent study, CHIP was also linked to ischemic heart disease-related chronic heart failure (CHF). When compared to publish control cohorts, it was discovered that the prevalence of CHIP was higher in CHF patients than in older patients [4].

Different pro-inflammatory profiles are produced by mutations in various CH-driver genes, indicating that distinct underlying mechanisms may exist. As a result, it is crucial to identify the molecular mechanisms by which the various CH-driver gene mutations contribute to cancer and cardiovascular disease. In mice with TET2-deficient BM cells, preclinical studies have shown that NLRP3 inhibitors that stop the production of IL-1 can stop atherosclerosis. As of late, the CANTOS clinical preliminary found that mitigating therapies utilizing a killing neutralizer against IL-1β further develop CVD patient result and, moreover, lower all out malignant growth mortality. In keeping with this, Bick and colleagues found that people with CHIP who also have a genetic defect in IL-6 signaling (by carrying the IL6R p. Asp358Ala allele variant) had a lower risk of cardiovascular disease (CVD) than CHIP patients with normal IL-6 signaling. It may be more efficient to design therapies that target their causal effects because it is technically more difficult to implement targeted therapies against CHIP-driver gene products. Anti-inflammatory treatments and clonal selective immunotherapies are likely to be combined in future strategies [5].

Both the number of coding and non-coding CH driver events and the prevalence of CH in an aging population are rising. Not all mutations that result in CH will also affect the onset and progression of CVDs. As recently demonstrated for the prediction of AML progression ture studies must identify specific mutated genes and even distinct mutations in these genes that are truly associated with and clinically relevant for various cardiovascular diseases with a high predictive value. Cautious assessment of driver changes, likewise inside one specific quality, will assist us with recognizing coordinating occasions from traveler occasions. In addition, in order to illuminate the causative effects that can be targeted in the future, mechanistic studies must be used to generate functional mutation-specific models of these driver mutations in the context of CVD. In the treatment of various CVDs, shared mechanisms of various mutated genes may be identified as common targets [5].

Conclusion

Patients and clinicians alike have been left with a number of unanswered concerns by these most recent findings. CVD patients are currently not routinely screened for the presence of predictive CHIP-driver mutations, despite the fact that screening for patients with a high prevalence of CHIP or hematological malignancies is well established. In the absence of traditional CRFs, it may be reasonable to screen individuals with CVDs for CHIP, particularly those with CAD, given the association between CH and the development of CVDs and the poor prognosis of patients with CVDs. Genotyping for CH may soon become routine based on developments in the field of next-generation sequencing. In addition, recommending lifestyle modifications to reduce confounding factors and initiating a more thorough screening for CVD blood parameters, echocardiography, angiography, or [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) imaging for CH mutation carriers are logical outcomes.

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