SARS-CoV-2 SPIKE PROTEIN AS VIROPORIN, INDUCING BRAINSTEM SPREADING DEPOLARIZATION (SD) RESULTING IN SUDDEN CARDIAC DEATH

THE SUDEP-SIDS CONNECTION

The current epidemic of sudden cardiac deaths, ranging from occurrence during physical exertion to occurrence during sleep may be explained by a sudden spreading depolarization initiated in the brain stem by the viroporin actions of the Spike Protein.

One prominent gene family present in an analysis of spike binding affinity is the voltage-gated potassium channel (Kv channel) family. This enrichment of potassium channels and other genes of interest within a functional group pointed to specific host pathways that may mediate or facilitate SARS-CoV-2 entry.

This is the EXACT channel that initiates a fatal spreading depolarization originating in the brainstem. Kv1.1 channels conduct a critical potassium current in neurons that prevents hyperexcitability, and mice lacking the gene recapitulate critical SUDEP phenotypes, including frequent generalized seizures, autonomic instability, and premature death at a young age. We investigated the excitability in the dorsal medulla during seizures triggered in the cortex of these anesthetized juvenile mice [postnatal day 18 (P18) to P25], an age when roughly 50% of Kv1.1 mice die suddenly.

The young are particularly vulnerable. Sudden unexpected death in epilepsy (SUDEP) is the leading cause of mortality in individuals with seizure disorders. Among neurological disorders, SUDEP is second only to stroke in the number of potential life years lost. One major class of causative genes expressed in the heart and brain and two epidemiological SUDEP risk factors (younger age and high incidence of pharmacoresistant seizures) have been identified,

Spreading depolarization (SD) is a pathological, self-regenerating wave of depolarization in neurons and glia that is associated with excess glutamate release and extracellular potassium elevation. A variety of factors regulate the onset and propagation of the slow (2 to 6 mm/min) wave, which contributes to transient human neurological deficits during cerebral ischemia, trauma, and migraine. SD has been studied in the neocortex, hippocampus, and brainstem, where it produces profound reversible or irreversible loss of neural activity. Although SD can be evoked experimentally by high potassium or tetanic neuronal stimulation, it can also arise spontaneously during limited energy substrate availability (hypoxia and ischemia) or hyperthermia.

There was a variable latency (1 to 3 min) between the onset of arrhythmias and apneas, which occurred during the seizure, and detection of SD after the end of the seizure, which may have been in part due to microscopic differences in the placement of the brainstem recording electrode and in the patterns of SD propagation. The time to complete cardiac arrest after the onset of irrecoverable sinus bradycardia was ∼3 min and was usually preceded by loss of cortical EEG activity and apneas, although variations in this sequence were observed, as in monitored human cases.

A variable amount of time was noted (up to ∼13 min) between the end of a cortical seizure and the onset of the lethal cardiorespiratory depression, whereas the brainstem SD was followed closely by cardiorespiratory arrest and death in KO mice. Brainstem SD occurred 17 s after the termination of a brief seizure and coincided with postictal cortical EEG suppression and cardiorespiratory depression. Full cardiac arrest occurred 230 s later.

The Spike Protein has been found in the Medulla. The respiratory center is located in the medulla oblongata and is involved in the minute-to-minute control of breathing. An autopsy study has isolated 32 brain sections from 16 victims of COVID-19 and found concentrated SARS-CoV-2 RNA (>5 copies/mm3) in three sections from the olfactory nerves and the brainstem’s medulla.35 More convincingly, in another autopsy study of deceased COVID-19 patients, SARS-CoV-2 RNA and proteins (nucleocapsid or spike) were detected in 50% and 40% of brainstem samples, respectively.

Please note that in a 2018 paper, the STABILIZED SPIKE structures of the SARS-CoV S 2P ectodomain bound to a soluble form of human ACE2 receptor show that any conformational changes induced in S by receptor binding are more likely to be due to the disruption of protein-protein interactions rather than the formation of additional contacts between the S1 RBD and other regions of S. The only conformational change that we observe in the ACE2-SARS-CoV S 2P structures is the transition to a short 310-helix at the top of the S2 central α-helix when uncapped by receptor-bound S1 RBD suggesting that more extensive conformational changes may be initiated here. 310-helices have been hypothesized to act as intermediates in coil-to-α-helix transitions32. Transitions between 310-helices and α-helices has also been hypothesized for the voltage sensing domains of potassium channels where it has been proposed that the transition plays a role in changing from a resting or activated state to a relaxed state

I believe this demonstrates a certain mechanism to explain the astounding numbers of sudden cardiac deaths.

Referenced/Related Papers

https://www.nature.com/articles/s41598-018-34171-7

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874499/

https://www.biorxiv.org/content/10.1101/2021.07.01.450475v1.full

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4852131/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374125/