Why Pulmonary Vasodilation May Be Part of a Key Strategy to Improve Survival in COVID-19

Abstract

Oxygenation is a function of both ventilation and perfusion. While approaches to the treatment of COVID-19 have focused largely on ventilation strategies and antiviral therapies, attention towards the improvement of vascular perfusion defects has been neglected. This article examines clinical findings that indicate perfusion defects are a critical component of COVID-19 pathophysiology. They also support the notion that medications that promote perfusion with pulmonary vasodilatation can yield significantly improved outcomes that include overall survival. Calcium channel blocker usage has been associated with improved survival and outcomes in several retrospective reviews of patient populations with COVID-19 from across the world. This includes studies conducted in Paris, France; Wuhan, China; Daegu, South Korea; Brooklyn, New York; Brussels, Belgium; and a national sample from across the United States . These medications are generally prescribed to treat hypertension. Yet, they are also utilized in various pulmonary conditions to effectuate pulmonary vasodilatation. Thus, a concomitant benefit appears to have been revealed as patients that were taking these medications had significantly improved overall survival. Sildenafil is another medication that induces pulmonary vasodilatation. It was found to decrease the need for mechanical ventilation and reduce hospital length of stay in COVID-19 in a triple-blinded randomized control trial. The importance of pulmonary vasodilation in COVID-19 has been evaluated further. In a study of over 100 high-resolution CT scans, patients with COVID-19 showed a significant reduction in pulmonary blood volume contained in small blood vessels of <5 mm 2 compared to healthy volunteers. Moreover, this was found to clinically correlate with a need for more oxygen supplementation. In radiologic perfusion studies, hypoperfusion was observed to occur in the healthy lung while hyperperfusion was present in non-healthy COVID-inflicted lung. It appears that perfusion of oxygen-carrying capacity, in the form of hemoglobin-carrying red blood cells, is being misappropriated towards unhealthy lung tissue. This was observed concurrently while the healthy lung had a paucity of perfusion. This can be a key aspect of hypoxic development in COVID-19. Mathematical modeling of perfusion abnormalities in COVID-19 has also implicated extensive perfusion defects, with ventilation-perfusion mismatching in the non-injured lung and hyperperfusion of up to threefold increases to afflicted regions. Vasodilation in the form of systemic intravascular medications may help improve outcomes by resetting this imbalance and by promoting perfusion of the alveolar-capillary unit where gas exchange and oxygenation occurs particularly in the non-injured lung. Furthermore, endothelialitis and microthrombosis have been observed on pathology specimens as many patients develop micro-thrombi following prolonged perfusion deficits. Vasodilator...

Association of Amlodipine with the Risk of In-Hospital Death in Patients with COVID-19 and Hypertension: A Reanalysis on 184 COVID-19 Patients with Hypertension

“…Several authors, considering: (1) the importance of intracellular calcium for the life cycle of viruses, (2) the positive association between hypocalcemia with COVID-19 severity; (3) the importance of promoting perfusion with pulmonary vasodilatation, have suggested an interest in calcium channel blockers (CCBs) for the treatment of people infected with COVID-19 [ 2 , 3 , 4 ]. To satisfy their need for calcium, several viruses induce an increased flux of calcium across cell membranes: CCBs reduce the levels of intracellular calcium [ 2 ].…”

Acid sphingomyelinase (ASM) and COVID‐19: A review of the potential use of ASM inhibitors against SARS‐CoV‐2

“…Le Corre and Loas have summarized most of the information about in silico, in vitro, and in vivo studies specifically for different FIASMAs in their reviews 23,30 . Of potential therapeutic significance, calcium channel blockers (CCB) have been reported to decrease the risk of death by COVID‐19 18,31–36 . Although CCB are usually prescribed for hypertension treatment (e.g., amlodipine), they can also cause pulmonary vasodilatation.…”

“…Although CCB are usually prescribed for hypertension treatment (e.g., amlodipine), they can also cause pulmonary vasodilatation. Of therapeutic significance, pulmonary vasodilators can have beneficial effects in moderate or severe COVID‐19 infection by increasing the oxygenation of the lung cells 35,37,38 . As we will discuss in the following sections, amlodipine is a characteristic FIASMA, 29 and can also inhibit SARS‐CoV‐2 replication by different mechanisms.…”

“…23,30 Of potential therapeutic significance, calcium channel blockers (CCB) have been reported to decrease the risk of death by COVID-19. 18,[31][32][33][34][35][36] Although CCB are usually prescribed for hypertension treatment (e.g., amlodipine), they can also cause pulmonary vasodilatation. Of therapeutic significance, pulmonary vasodilators can have beneficial effects in moderate or severe COVID-19 infection by increasing the oxygenation of the lung cells.…”

Difficulty in Repurposing Selective Serotonin Reuptake Inhibitors and Other Antidepressants with Functional Inhibition of Acid Sphingomyelinase in COVID-19 Infection

“…Furthermore, taking into account that hypoxia could be a strong factor in COVID-19 progression, the use of fluvoxamine in the early phase of COVID-19 has been suggested in order to counteract some early posthypoxic events ( Grieb et al, 2021 ; Grieb and Rejdak, 2021 ; Rejdak and Grieb, 2021 ). Additionally, retrospective observational studies have shown that calcium channel blockers (particularly amlodipine that is a FIASMA) promoting pulmonary vasodilatation, have improved clinical outcomes ( Solaimanzadeh 2021 ).…”