Arterial stiffness and COVID‐19: A bidirectional cause‐effect relationship

Coronavirus disease 2019 (COVID19) primarily affects the lungs but the clinical manifestations vary markedly among the patients involved. In more severe cases, COVID19 can lead to acute respiratory distress syndrome (ARDS), multiorgan failure including cardiac injury and toxic shock syndrome with need for intensive care and a ventilator support,1 while at the opposite extreme the signs and symptoms can be those of a mild flu and in many patients the infection is asymptomatic. Since the outbreak of the infection in China, a large number of studies have consistently reported on the cardiovascular (CV) complications of COVID19 which include acute cardiac injury, cardiac arrhythmias, and diffuse endothelial damage leading to microvascular thrombosis and thromboembolic events. Evidence has also consistently suggested that cardiac, vascular, renal, and cerebral damages associated with CV risk factors such as hypertension, diabetes, dyslipidemias, and obesity markedly increase the risk of COVID19 progression to its most severe and lethal forms, presumably because the preexisting structural and functional alterations of the organs affected by longlasting blood pressure elevation and metabolic alterations weaken their resistance to the virus. Resistance to the virus may be further reduced by the pathogenetic nature of some of these organ alterations, that is, by the fact the most common cause of risk factordependent complications, atherosclerosis, is likely to be codetermined by an inflammatory process that may adversely interact with that of the coronavirus.1 As far as obesity, a major component of the metabolic syndrome, is concerned, its relationship with the COVID19 severity may be due to its association with chronic low grade inflammation, higher leptin and lower adiponectin levels, immune response dysregulation, and abnormal proinflammatory cytokine production.2 The association between increased arterial stiffness and the severity and duration of chronic inflammation in a number of systemic inflammatory diseases are well established.3 The vascular structure and function are altered by edema and inflammatory cells. Prior studies have supported the cross talk between inflammation and arterial stiffness by showing that patients with chronic inflammatory diseases such as rheumatoid arthritis and chronic inflammatory bowel disease have higher arterial stiffness than control subjects matched for age, sex and blood pressure.4 Hence, the severity of underlying chronic inflammation in these disease states goes handinhand with the severity of arterial stiffness. For all these interactive factors, there is the basis for a vicious circle because, by increasing the traumatic effect of intravascular pulsatile pressure on the vascular wall, arterial stiffening favors atherosclerosis with an increase in its inflammatory component and a further stiffening effect. The same may be true for COVID19. COVID19 is a multisystem disease with hyperinflammation and altered immune response and may therefore have detrimental effects on the systemic vasculature both on short and long run. A practical example may be the ethnic minorities who experience the more aggressive forms of COVID19 with an enhanced systemic inflammatory response and higher rates of CV complications.5 Of note, these patients have a substantial higher prevalence of preexisting hypertension, obesity, and diabetes, a cluster which is associated with systemic inflammation and may weaken the resistance of target organs against the coronavirus. During the COVID19 pandemic, CV research has reserved little attention to vascular damage such as increased large artery stiffness. This has little justification because large artery stiffening has been repeatedly shown to have a paramount clinical importance because it: 1) predicts future progression to hypertension in people who exhibit a normal BP6,7; 2) increases the longterm risk of future events and death, independently on the contribution of other risk factors8; and 3) favors damage of organ structure and function by increasing pulsatile flow transmission to the microvasculature. The possibility that large artery stiffening is part of the CV phenotype of COVID19 is also supported by the evidence that some factors which are known to operate during the COVID19 disease are known to adversely affect large artery distensibility, which will be discussed below.


| INTRODUC TI ON
Coronavirus disease 2019 (COVID-19) primarily affects the lungs but the clinical manifestations vary markedly among the patients involved. In more severe cases, COVID-19 can lead to acute respiratory distress syndrome (ARDS), multi-organ failure including cardiac injury and toxic shock syndrome with need for intensive care and a ventilator support, 1 while at the opposite extreme the signs and symptoms can be those of a mild flu and in many patients the infection is asymptomatic.
Since the outbreak of the infection in China, a large number of studies have consistently reported on the cardiovascular (CV) complications of COVID-19 which include acute cardiac injury, cardiac arrhythmias, and diffuse endothelial damage leading to microvascular thrombosis and thromboembolic events. Evidence has also consistently suggested that cardiac, vascular, renal, and cerebral damages associated with CV risk factors such as hypertension, diabetes, dyslipidemias, and obesity markedly increase the risk of COVID-19 progression to its most severe and lethal forms, presumably because the pre-existing structural and functional alterations of the organs affected by long-lasting blood pressure elevation and metabolic alterations weaken their resistance to the virus. Resistance to the virus may be further reduced by the pathogenetic nature of some of these organ alterations, that is, by the fact the most common cause of risk factor-dependent complications, atherosclerosis, is likely to be codetermined by an inflammatory process that may adversely interact with that of the coronavirus. 1 As far as obesity, a major component of the metabolic syndrome, is concerned, its relationship with the COVID-19 severity may be due to its association with chronic low grade inflammation, higher leptin and lower adiponectin levels, immune response dysregulation, and abnormal pro-inflammatory cytokine production. 2 The association between increased arterial stiffness and the se- Finally, Rodilla et al showed that a pulse pressure of ≥60 mmHg at admission, as a surrogate marker of arterial stiffness, was associated with higher risk of all-cause mortality (adjusted odds ratio 1.27, P =.0001) in hospitalized COVID-19 patients. 11 In addition, in an individual case study involving a 55-year-old man with obesity and no previously known hypertension, we recently showed that several months after recovery from COVID-19, the patient had sustained tachycardia and elevated blood pressure at rest. We speculated that the activation of renin-angiotensin and sympathetic systems, inflammation-induced systemic cytokine, volume overload and associated hyperreninemia, inflammation, and vasculitis may have contributed to an exaggerated cardiovascular response and sustained tachycardia at rest. 12 However, whether this persistently elevated heart rate and blood pressure was a consequence of COVID-19induced increased arterial stiffness, or an untreated persistent abnormal CV response is the primary responsible factor for an incident increased arterial stiffness, is a matter for well-designed prospective studies on COVID-19 survivors to clarify.

| P OSS IB LE MECHANIS MS OF ENDOTHELIAL DAMAG E IN COVID -19
Endothelial dysfunction is believed to be a key element in the pathogenesis of COVID-19-related organ damage. 13

| P OS T-COVID -19 E ARLY ATHEROSCLEROS IS/IN CRE A S ED ARTERIAL S TIFFNE SS
Whether COVID-19 patients are predisposed to early atherosclerosis is not yet fully understood. However, it is reasonable to be- Statin lower CV risk factors through their lipid-lowering and pleiotropic or anti-inflammatory effects. 25 It has been also postulated that statin may act as a SARS-CoV-2 main protease inhibitor. 26

| PER S PEC TIVE S
We should acknowledge that this opinion piece is prepared from a clinical point of view and hence hypothesis generating. The molecular mechanism is not discussed, although these are still poorly un-

ACK N OWLED G EM ENT
None.

CO N FLI C T O F I NTE R E S T
No conflict of interest.