Pharmacogenomics in drug-induced cardiotoxicity: Current status and the future

Abstract

Drug-induced cardiotoxicity (DICT) is an important concern of drug safety in both drug development and clinical application. The clinical manifestations of DICT include cardiomyopathy, arrhythmia, myocardial ischemia, heart failure, and a series of cardiac structural and functional changes. The occurrence of DICT has negative impacts on the life quality of the patients, brings additional social and economic burden. It is important to identify the potential factors and explore the mechanisms of DICT. Traditional cardiovascular risk factors can only partially explain the risk of DICT. Pharmacogenomic studies show accumulated evidence of genetics in DICT and suggest the potential to guide precision therapy to reduce risk of cardiotoxicity. The comprehensive application of technologies such as third-generation sequencing, human induced pluripotent stem (iPS) cells and genome editing has promoted the in-depth understanding of the functional role of susceptible genes in DICT. This paper reviewed drugs that cause DICT, the clinical manifestations and laboratory tests, as well as the related content of genetic variations associated with the risk of DICT, and further discussed the implication of new technologies in pharmacogenomics of DICT.

Insights into Drug Cardiotoxicity from Biological and Chemical Data: The First Public Classifiers for FDA Drug-Induced Cardiotoxicity Rank

“…12 Notably, a single drug might induce cardiotoxicity via multiple mechanisms, and individual patients' responses (which can often manifest as side effects) can be modulated by genetics, concurrent health conditions, and other medications. 13 To move beyond a limited focus on specific adverse reactions or related proxy assays for cardiotoxicity, the FDA recently released the drug-induced cardiotoxicity rank (DICTrank) that categorizes drugs based on their risk of causing cardiotoxicity. 14 Similar to the DILIrank data for liver injury, 15,16 Predictive models for DICT could save considerable time, resources, and human suffering, with the ultimate goal of preventing adverse events in clinical trials and the postmarket stage.…”

“…Furthermore, alterations in growth factors and cytokine balances can induce cardiac conditions like fibrosis, and immunologic drug reactions can also cause cardiotoxicity. , Several neurohormonal pathways also offer indirect routes for drug-induced cardiac stress . Notably, a single drug might induce cardiotoxicity via multiple mechanisms, and individual patients’ responses (which can often manifest as side effects) can be modulated by genetics, concurrent health conditions, and other medications …”

“… 12 Notably, a single drug might induce cardiotoxicity via multiple mechanisms, and individual patients’ responses (which can often manifest as side effects) can be modulated by genetics, concurrent health conditions, and other medications. 13 …”

Association between B-type natriuretic peptide levels after the first dose of cyclophosphamide and early cardiac events and transplantation outcomes

“…Thus, monitoring BNP levels may help identify patients at risk of cardiovascular events, guide treatment decisions, and improve patient outcomes. [16][17][18] However, the use of these biomarkers for predicting PTCy-induced cardiotoxicity is limited because of the scarcity of available data on this speci c aspect.…”

Insights into Drug Cardiotoxicity from Biological and Chemical Data: The First Public Classifiers for FDA DICTrank

“…12 Notably, a single drug might induce cardiotoxicity via multiple mechanisms, and individual patients' responses (which can often manifest as side effects) can be modulated by genetics, concurrent health conditions, and other medications. 13 To move beyond a limited focus on specific adverse reactions or related proxy assays for cardiotoxicity, the FDA recently released the Drug-Induced Cardiotoxicity Rank (DICTrank) that categorizes drugs based on their risk of causing cardiotoxicity. 14 Similar to the DILIrank data for liver injury 15 , the DICTrank system uses FDA drug labeling to comprehensively categorize 1,318 human drugs into four DICT Concern categories based on their potential risk for cardiotoxicity: (1) Most-DICT-Concern, (2) Less-DICT-Concern, (3) No-DICT-Concern and (4) Ambiguous-DICT-Concern.…”