**4. Infectious inflammatory diseases**

A more central role for inflammation processes in the progression of chronic cardiovascular disease is becoming increasingly appreciated both as a direct source of the injury, and also as an aggravating condition that accelerates dysfunction in chronic disease [14–16]. There also are concerns that emergence of immunotherapies for a variety of conditions has the potential for adverse cardiovascular impact [80]. Some infections can produce an inflammatory response in the heart that ranges from subclinical to lethal [16]. Persons who become infected with the parasite *Trigonoscuta cruzi* may develop Chagas disease. The acute phase in many is characterized by asymptomatic, mild myocarditis, but a subset can also develop myocarditis that is severe enough to produce irreversible damage and heart failure. If the infection is not identified and treated, it persists in the system and may remain symptomatic for decades. However, 20–30% of chronically infected individuals will develop dilated cardiomyopathy, heart failure with or without arrhythmia, and are at increased risk for sudden cardiac death [12]. The prevalence of Chagas disease is considered endemic in Central America, South America and portions of the United States. A common cardiac feature of the disease is progressive loss of parasympathetic autonomic drive, creating a proarrhythmic substrate, more labile blood pressure control, and increased spasticity in the coronary microvasculature. Persistent sympathetic over-stimulation is known to cause multi-focal micro-infarctions, excess bioenergetic burden and mitochondrial dysfunction, leading to ROS induced DNA damage, apoptosis and progressive loss of function, similar to what has been described with catecholamine cardiotoxicity [12]. Particularly worrisome, however, is that sudden cardiac death is fairly common, and often occurs without previous signs or symptoms of advanced cardiomyopathy.

Similarly, infections caused by the Coxsackie B virus have had a known association with significant cardiovascular complications for over 60 years [81] and account for 25% of all myocarditis in young adults [82]. The early stages of infection can produce directly cytopathic effects, which can progress to a chronic, pathologic immune response if the virus persists, and in a majority of the patients who progress with chronic manifestations, development of a cardiac specific autoimmune response [83]. In fact, Coxsackie N infection has been a well-established mouse model for studying mechanisms associated with the development autoimmune-mediated myocarditis and heart failure (EAM: Experimental Autoimmune Myocarditis) [84].

More recently, the emergence of HIV and then the development of effective anti-retroviral therapies has led to an appreciation that there is an early onset of cardiovascular diseases, complicated by an inability to determine the extent to which the cardiovascular impact is the direct result of the virus, or if the primary factors are more related to the therapies used to treat the infection [13, 85]. HIV has been associated with early onset ischemic heart disease [86], but also with early onset heart failure in patients without evidence of significant coronary artery disease [87].

Most recently, the worldwide experience with SARS2-COVID19 has once again highlighted the capacity for acute infectious effects on exacerbating cardiovascular diseases, highlighted by the increased early mortality rates among those with pre-existing disease [17, 19]. Initially attributed to hypoxia-induced ischemia or hemodynamic failure secondary to the pulmonary impact of the virus, it was established quickly that there was direct cardiac infection [18], and that extrapulmonary effects of the virus were numerous [20, 21]. Given the cellular route of entry vias the Angiotensin 2 Receptor, and the widespread expression of the receptor throughout

the body, it should be no surprise really that many tissues would have been impacted by the infection [88]. Driven in part by what was seen largely as microvascular injury, increased thromboembolism, and the prevalence of the receptor in the vasculature, several strong reviews strongly suggested that COVID-19 should be considered as an endothelial disease [89, 90]. The presence of cardiac specific autoantibodies in COVID19 patients [38, 39] together with MRI studies suggesting persistent cardiac dysfunction in recovered COVID patients [91] tend to suggest that there is a larger, more multi-mechanistic cardiovascular profile for the disease [92, 93]. One study is particularly concerning. Ratchford and colleagues studied vascular function in previously healthy, active young adults who had tested positive for the infection but had exhibited only mild symptoms that were resolved quickly. One month after resolution of symptoms, the group (male and female) showed persistent and consistent reductions in vasodilator capacity compared to a matched cohort of control subjects that had never been infected with COVID [94].

By the end of 2022, there will be more than 50 million individuals in the US alone who will have recovered from a COVID19 infection. It was widely observed that when COVID infection occurred in individuals who already had significant cardiovascular disease, they were at higher risk [17, 19]. It is highly likely that COVID infection prior to the subsequent development of cardiovascular disease, even if not directly responsible for the cardiovascular injury, will be associated with increased mortality from whatever disease process does evolve. Determining the best methods for identifying who has the highest future risk, and then considering the possibility of prophylactic risk mitigation could be a significant challenge for the next generation [92, 93], but it strongly highlights the need for an increased appreciation for the potential role of prior infection as an aggravating risk.
