Despite recent advances in the research related to air pollution and associated adverse cardiovascular events, the combined effects of air pollution, climate change, and SARS-CoV-2 infection on cardiovascular health need to be researched further. This Commentary addresses their impacts on cardiovascular health in the approximately 25 million people with a severe form of inherited hypercholesterolemia, called familial hypercholesterolemia (FH). The arterial endothelium in these individuals is potentially under multiple attacks caused by particles of both endogenous and exogenous origin. Thus, they have a lifelong highly elevated level of circulating low density lipoprotein (LDL) cholesterol which drives premature atherosclerosis. The high levels of LDL particles, often associated with an elevated level of circulating lipoprotein(a) particles, are both capable of inducing and maintaining endothelial dysfunction. Such pre-existing endothelial dysfunction can be exacerbated by exposure to SARS-CoV-2 viral particles, by exposure to fine particulate matter generated by climate change-associated wildfires, and by dehydration during deadly heatwaves linked to the globally rising temperatures. The external factors can severely worsen the pre-existing endothelial dysfunction, and thereby significantly increase the risk of a cardiovascular event in the exposed FH patients.