From the Outside In: Exploring the Role of the Exposome in Cardiovascular Disease – From Mechanisms to Therapeutics

Cardiovascular diseases (CVDs) is one of the leading causes of death worldwide. While the role of genetic factors in CVDs is well-established, environmental risk factors can significant contribute to its progression and severity. For cancer patients and survivors, these risks are increased by tumour-produced biological intermediates and xenobiotics from chemotherapy regimens. Such observations have led to the establishment of cardio-oncology, a research field dedicated to minimising the risk of cancer patients developing adverse cardiovascular complications associated with the tumour or anticancer treatments. Understanding the environmentally-induced molecular mechanisms underlying CVD development and progression is essential for developing effective treatments for CVDs. The exposome, defined as the totality of environmental exposures and their impact on biological and metabolic processes, has profound effects on cardiovascular health. Exposure to environmental factors, such as pollution, lifestyle factors and mental stress, and internal factors, like metabolic by-products, chemotherapy xenobiotics and tumour-secreted molecules can disrupt key central biochemical pathways, including the circadian clock. These environmentally-induced alterations are often quantified by changes to the transcriptome, epigenome, proteome or lipidome. Together, the exposome and the circadian clock, either independently or in combination with genetic factors or pre-existing CVDs, may promote cardiac dysfunction and exacerbate cardiovascular outcomes. This thesis explores how the internal and external exposome impact cardiovascular disease, with a focus on how circadian rhythms mediate these effects. Chapter 2 reviews the significant impact that the exposome has on mental stress and its contribution to CVD development and severity. We found that environmental exposures, such as light, noise and air pollution in addition to mental stress can trigger a stress response that disrupts the circadian clock. Chapter 3 explored how environmental cues, such as the time of day and its interaction with the circadian clock, regulates the hyperacute immune response that occurs during critical early hours following a myocardial infarction (MI). Chapter 4 builds on these findings by studying the impact of the time of day and circadian clock on the transcriptome in mouse hearts and human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs). In chapter 5, we assessed clinical data from randomised control trials (RCTs) on chronomodulated chemotherapy, that is, administration of chemotherapy in accordance with the patients’ circadian rhythms at specific times to reduce chemotherapy toxic side effects and promote its efficacy. In chapter 6, we focus on carcinoid heart disease (CHD), a rare, multifactorial cardiovascular complication arising from internal environmental exposures, specifically biological intermediates produced by small intestine neuroendocrine tumours (SI-NETs). This chapter investigated the potential of cardiac-derived blood biomarkers to predict and detect CHD. Finally, chapter 7 explores Doxorubicin (DOX) and Trastuzumab (TRZ)- induced cardiotoxicity and the potential of using cardioprotective interventions for reducing DOX-induced cardiotoxicity in hiPSC-CMs. This thesis highlights how the interaction between the exposome with the circadian clock affects many biological processes and can contribute to the development of adverse cardiovascular complications. Integrating the exposome and chronobiology in CVD research may facilitate the development of more precise time-specific therapeutic strategies for preventing and effectively treating various CVDs.