Predicting Risk of Emerging Cardiotoxicity

*Megan Goins, Katie Lovell, Greyson Keel, Julia Cook and Robert Lust*

## **Abstract**

Smoking, hypercholesterolemia, hyperlipidemia, obesity, diabetes, insulin resistance and family history all are well established general risk factors broadly associated with injury in the cardiovascular system. Similarly, echocardiography, electrocardiography, MRI, PET scans and circulating biomarkers like cardiac Troponin (cTn) provide indications that injury has occurred. Traditionally, cardiovascular injury has been attributed to conditions that exacerbate the potential for ischemia, either by producing excessive metabolic/work demands or by impairing the perfusion necessary to support the metabolic/work demands. This review summarizes additional factors that are underappreciated in contributing to the risk of injury, such as iatrogenic injury secondary to treatment for other conditions, infection, environmental exposures, and autoimmune processes.

**Keywords:** cardiovascular, cardiac, heart, myocardial, vascular, endothelium, COVID-19, auto-immunity, autoantibody, anthracycline, diabetes, mitochondria, air pollution, nanomaterials, nanoparticles

## **1. Introduction**

The risk factors generally associated with risk for atherosclerotic cardiovascular disease include age, sex, race, systolic and diastolic blood pressure, total, Total cholesterol, high/low density lipoprotein (HDL and LDL) fractions, overweight and obesity, and history of diabetes or smoking [1, 2]. Evidence-based treatment guidelines based on these factors have been established [1]. Apps/tools for use by the general population to predict risk of a cardiovascular event have been published both by the American Heart Association [3], and by the American College of Cardiology [4]. The gold standard for establishing injury is typically direct histologic evidence of injury, which increasingly have become well correlated with surrogate markers such as circulating cardiac troponin (CTnT or cTnI) levels or natriuretic peptide levels (ANP or BNP).

The purpose of this chapter is to highlight potential areas of emerging concern that are not yet established as directly causing increased risk of cardiovascular disease. They may be iatrogenic toxicity effects associated with treatment for noncardiovascular diseases and therefore no considered a general risk overall [5–7]. They may be effects that alter the progression of an established risk factor, they may be factors that have only recently been considered, or that may not alter the risk of acquiring cardiovascular disease at all but may alter the severity and subsequent mortality of a cardiovascular event, were it to occur secondary to any of the established risk factors. Contributing elements might be disruption of mitochondrial function [8–11], or infectious disease [12–21]. Chronic diseases that have strong systemic inflammatory components such as Systemic Lupus Erythmatosis (SLE) [22–25] or asthma [26–28] may or may not alter the incidence of chronic CVD but may be associated with increased risk of acute events, or may modify the outcome from reperfusion therapies, especially those already known to be complicated by a major inflammatory component [29–32].

In addition, as large-scale health system databases become increasing robust and geo-mapping of environmental influences is increasingly refined, associations between air quality CVD outcomes can now be interrogated with much higher fidelity than before, and what had been experimental and/or local phenomenological observations are becoming increasingly more widely appreciated [33, 34]. Findings previously associated only with air pollution are becoming more generalized to other environmental influences as well [35].

Finally, emerging from across the spectrum of systemic challenges and with wideranging targets, the potential role of auto-immune responses as an aggravating risk factor that is becoming increasingly appreciated will be discussed [36–39].
