Covid and Our Arteries

A new study on acceleration of vascular aging adds to the body of evidence

A new finding of accelerated vascular aging after Covid adds to the knowledge base of the toll of this virus on our blood vessels, especially our arteries. Much of the focus of Covid has been on the heart per se, with less attention to the impact on arteries and blood vessels (veins, microvasculature) In this Ground Truths, I’ll review the 3 dimensions for how our understanding Covid’s effect on arteries has evolved: (1) Endothelial Inflammation; (2) Promoting Atherosclerosis; and (3) Accelerating Aging

1. Endothelial Inflammation

Since the early days of the pandemic, inflammation of the endothelium, the lining of the blood vessel wall, was recognized. Endotheliopathy (or endotheliolitis) was demonstrated in post-mortem specimens, schematically shown below, with activated platelets and proteins that operate in the coagulation cascade to increase the risk of clotting (coagulopathy). The inflammation could be engendered by either direct infection the virus into the blood vessel wall or the inflammation mediators (cytokines, chemokines) released throughout the body from Covid. The process leading to an inflammatory endothelium underlies clinical events such as heart attacks and strokes.

Indeed, Libby and Luscher authored a perspective entitled “COVID-19 is, in the end, an endothelial disease” making a strong case in the early months of the pandemic, when the primary focus was just on the respiratory system— that the blood vessel lining effect of Covid was central to its morbidity and mortality.

Since the many studies have added to the mix, showing the Covid-induced endothelial inflammation leads to leaky blood vessels (increased vascular permeability), abnormal vasomotor tone or dysregulation. that it can increase the risk of hypertension, has further exacerbation by abnormal lipids, and results in reduction of myocardial blood flow. Of course, the effects were not confined to arterial endothelium, but also seen in veins with risk of deep vein thrombosis, and the microvasculature. Our review of Long Covid cited the role of blood vessel inflammation and its sequelae as one of the principal mechanisms for this condition.

2. Coronary Atherosclerosis

It took longer for us to understand had Covid promoted atherosclerosis, even though an increase risk of heart attacks was noted in the first year of the pandemic. Now several studies in experimental models and patients have demonstrated this effect, not only in the progression of atherosclerosis but also in its initiation (schematic below, Figure).

Specifically, in post-mortem coronary artery specimens in confirmed severe Covid patients there was detection of the virus in macrophages and foam cells along with the finding of the SARS-CoV-2 antisense strand replicating In these cells, composing an infection fo the blood vessel wall, marked inflammation, and potentiation of plaque instability (schematic below).

Recently, from patients with repeat CT coronary angiograms (690 with Covid, without hospitalization nad 113 controls, without Covid), there was evidence of more arterial plaque progression (left panel, for one metric below) to high-risk non-calcified plaques, increased inflammation, and more major adverse cardiovascular events (MACE) (right panel) among those with Covid.

The accompanying editorial to this paper was subtitled “An Early Warning of a Potential Public Health Crisis.”

3. Acceleration of Vascular Age

The new study reported 17 August in the European Heart Journal was a big project involving 18 countries, 38 centers, and enrollment of over 2,000 participants to measure (on a repeat basis at baseline, 6 months and 1 year) carotid artery pulse wave velocity (PWV), a metric that is an indicator of arterial stiffness..

There were many important findings from this work. The acceleration of early (accelerated) vascular aging (EVA) was not proportionate to severity of COVID. Although participants who required ICU hospitalization had an estimate of 10 years of EVA, those who were not hospitalized had the same—5 years of accelerated arterial aging— as participants who did require hospitalization. The EVA effect was only significant in women and there was a statistically significant interaction term for Sex X EVA. Symptoms of Long Covid were linked to EVA and vaccination was associated with protection from EVA (graphs below, respectively). All of the analyses were adjusted for potential confounders. Some people with early EVA had resolution at 1-year follow-up. There was no assessment for reinfection and this prospective study was largely conducted early in the pandemic. The accompanying editorialist wrote: "The..study makes the case that Covid has aged our arteries, especially for females."

Concluding Remarks

The new report is the first to demonstrate Covid’s impact on accelerated arterial aging. PWV has been used in previous small studies of Covid, but they were not adequately sized (largest had only 140 participants) or with the extent of follow-up as the present report. Particularly intriguing is the predominant effect in women, that is unexplained. We know the risk of Long Covid is greatly increased in women (~2/3rd of cases, if not higher) and that the immune system and propensity to inflammation has been tied to both two copies of the X chromosome (and the XIST gene that inactivates one of the X chromosomes) and hormonal factors, such as estrogen and progesterone. About 80% of autoimmune diseases occur in women. It is possible that there’s more propensity for endothelial inflammation after Covid in women compared with men, which sets up more chance of stiffness, fibrosis, and features of EVA. Another factor acknowledged by the authors is that there is less survivorship among men, a bias that could have contributed to the marked difference by sex.

The new findings of accelerated vascular aging need to be independently replicated. PVW is only one way to estimate the aging of blood vessels. Another is a proteomic artery (organ) clock, as initially advanced by Wyss-Coray and colleagues and now by multiple other groups. The observed Covid effect on artery aging by one metric in one study is important, but it is necessary for more work to be done with different means of assessment to know for certain its impact and magnitude. And to understand the apparent sex-specific effect.

To summarize, we’ve now seen a third dimension of Covid’s potential effect on our arteries, from the early recognized endothelial inflammation, with its attendant propensity for clots (micro or macro), to promoting atherosclerotic plaque, particularly those with high-risk for rupture (precursor for heart attack and stroke), to now accelerated aging. These 3 dimensions are not discrete, but interdependent. Undoubtedly, we will learn more on the future impact of Covid on our vascular health, but for now we can say it is likely well beyond what is generally recognized or anticipated.

Covid is still with us, with a summer wave in the United States that fortunately is not nearly as severe as previous ones, likely accounted , at least in part, by the XFG variant, now dominant, not being more evasive of our immune system than prior SARS-CoV-2 variants. It is unsettling, however, to see the marked reduction of tracking Covid here (be it by genomics or wastewater) and the gutting of funding of mRNA vaccines and platform which have an enormous future role, not just vs infectious diseases, but also combatting cancer, autoimmune diseases and support for genome editing for rare diseases. This is beyond Covid denialism, also representing anti-science, negating the extraordinary progress we’ve made over the past 5 years. Even in the new report we see evidence that vaccination is associated with protection for accelerated vascular aging, which goes along with many other levels of protection, including Long Covid. ←More on that soon!

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