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Clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a previously unrecognized, potent, age- related, and common risk factor for atherosclerosis. Somatic mutations in certain known leukemia driver genes give rise to clones of mutant cells in peripheral blood. The increased risk of developing hematologic malignancy does not, on its own, explain excess mortality in individuals with CHIP. Cardiovascular disease accounts for much of this gap. Experimental evidence supports the causality of certain CHIP mutations in accelerated atherosclerosis. CHIP due to mutations in different driver genes varies in their promotion of atherosclerotic events and in the region of augmented atherosclerotic involvement. For example, CHIP due to mutations in DNMT3a appears less atherogenic than CHIP that arises from TET2 or JAK2, forms of CHIP that incite inflammation. The recognition of certain CHIP mutations as promoters of atherosclerotic risk has opened new insights into understanding of the pathophysiology of this disease. The accentuated cardiovascular risk and involvement of distinct pathways of various forms of CHIP also inform novel approaches to allocation of targeted therapies, affording a step toward personalized medicine., Clonal hematopoiesis ofindeterminate potential (CHIP) is defined as the presence of a somatic mutation in a leukemia driver gene involving blood cells of an individual lacking any known hematologic malignancy, [...]

The purpose of this review article is to summarize the preclinical and clinical evidence supporting the notion of clonal hematopoiesis of indeterminate potential (CHIP), highlight current knowledge gap, and provide future directions.Epidemiological studies show that advanced age is a major risk factor for the development of cardiovascular disease (CVD) and cancer, the two leading causes of morbidity and mortality worldwide. While the negative effect of aging on CVD is a reflection of cumulative exposure to various established traditional CVD risk factors, genetic sequencing of whole blood-derived DNA recently revealed that clonal mutations in myeloid stem cells are associated with higher risks of cardiovascular events and hematopoietic malignancies. The clinical repercussions of this biological state, termed CHIP, are increasingly appreciated. Historically, CHIP has been associated with an increased risk of hematological malignancies. However, new research is showing that CHIP is also associated with an increased risk of several cardiac-related conditions, including atherosclerosis, myocardial infarction, aortic valve stenosis, and congestive heart failure. CHIP is increasingly being appreciated worldwide as a CVD risk factor, and further studies are needed to better understand the complex relationship between these two disorders.

Whether cardiovascular (CV) disease is associated with clinical outcomes in cancer patients receiving immunotherapy is unknown. We reviewed the Mayo Clinic database for all cancer patients who received an immune checkpoint inhibitor (ICI). Multivariate logistic regression analysis, survival analyses, and Cox proportional-hazards models were formulated. Between March, 2010 and July, 2019, 3,326 patients received ICI. Mean patient age was 63.5 years (range: 16 to 96 years). In a Cox proportional-hazards model, obesity (hazard ratio [HR] 0.65, 95% confidence level [CI] 0.55 to 0.77, p < 0.001) and hypercholesterolemia (HR 0.80, 95% CI 0.72 to 0.89, p < 0.001) were associated with lower all-cause mortality while hypertension (HR 1.32, 95% CI 1.17 to 1.49, p < 0.001) and smoking (HR 1.17, 95% CI 1.06 to 1.29, p = 0.002) were associated with higher overall mortality. Among patients with lung cancer, multivariable-adjusted hazard ratios for death from any cause for beta blocker users, as compared with patients who had never used a beta blocker, were 1.39 (95% CI 1.10 to 1.76, p = 0.006). A total of 80 patients (2.4%) experienced CV immune-related adverse events. Event-related morality for ICI-induced myocarditis was 41.7% (5/12). Multivariable-adjusted hazard ratios for ICI-induced myocarditis were 5.2 (95% CI 1.4 to 18.7, p = 0.01) for history of heart failure, 4.06 (95% CI 1.15 to 14.3, p = 0.03) for history of acute coronary syndrome, and 1.07 (per each 1-year increase, 95% CI 1.01 to 1.14, p = 0.02) for age. In conclusion, our study shows that CV factors are associated with clinical outcomes in cancer patients receiving ICI and could be used to predict mortality. In patients with lung cancer, pretreatment beta blocker use is associated with higher all-cause mortality. Three clinical factors-history of heart failure, history of acute coronary syndrome, and age greater than 80 years-help identify patients at higher risk of ICI-induced myocarditis who might benefit from more intensive cardiac surveillance.

Multiple myeloma is the second most common hematologic malignancy in the USA, with over 32,000 new cases and nearly 13,000 deaths expected in 2019. The past few decades in myeloma research have yielded significant advances, leading to the expansion of novel anti-myeloma agents. This review describes the incidence and mechanisms of cardiotoxicity for the FDA-approved proteasome inhibitors in myeloma and proposes strategies to assess and manage resultant cardiovascular adverse events.Proteasome inhibition precipitates protein aggregation and alters transcriptional activation of NF-κB targets which contributes to a pro-apoptotic signaling cascade in myeloma cells. Similar effects in cardiomyocytes and vascular smooth muscle endothelium, along with off-target downregulation of autophagy and signaling alterations of nitric oxide homeostasis, may be linked to observed cardiotoxic effects. There is preliminary evidence for cardioprotective potential for rutin, dexrazoxane, and apremilast that could have clinical applicability in the future. Of the proteasome inhibitors used in clinical practice, carfilzomib is the most strongly associated with cardiotoxicity. Patients with anticipated carfilzomib treatment should undergo assessment and optimization of baseline cardiovascular risk, with close monitoring during treatment. Previous clinical trials were not specifically designed to assess proteasome inhibitor-related cardiotoxicity, creating a need for future studies to identify and risk stratify vulnerable individuals and to develop potential cardioprotective strategies in attenuating cardiac injury.