Use the labels in the right column to find what you want. Or you can go thru them one by one, there are only 34,483 posts. Searching is done in the search box in upper left corner. I blog on anything to do with stroke. DO NOT DO ANYTHING SUGGESTED HERE AS I AM NOT MEDICALLY TRAINED, YOUR DOCTOR IS, LISTEN TO THEM. BUT I BET THEY DON'T KNOW HOW TO GET YOU 100% RECOVERED. I DON'T EITHER BUT HAVE PLENTY OF QUESTIONS FOR YOUR DOCTOR TO ANSWER.
Changing stroke rehab and research worldwide now.Time is Brain!trillions and trillions of neuronsthatDIEeach day because there areNOeffective hyperacute therapies besides tPA(only 12% effective). I have 523 posts on hyperacute therapy, enough for researchers to spend decades proving them out. These are my personal ideas and blog on stroke rehabilitation and stroke research. Do not attempt any of these without checking with your medical provider. Unless you join me in agitating, when you need these therapies they won't be there. Did your doctor somehow miss the recovery protocol that Pedro Bach-y-Rita used to recover fully back in 1958 with only a partial brain?
What this blog is for:
My blog is not to help survivors recover, it is to have the 10 million yearly stroke survivors light fires underneath their doctors, stroke hospitals and stroke researchers to get stroke solved. 100% recovery. The stroke medical world is completely failing at that goal, they don't even have it as a goal. Shortly after getting out of the hospital and getting NO information on the process or protocols of stroke rehabilitation and recovery I started searching on the internet and found that no other survivor received useful information. This is an attempt to cover all stroke rehabilitation information that should be readily available to survivors so they can talk with informed knowledge to their medical staff. It lays out what needs to be done to get stroke survivors closer to 100% recovery. It's quite disgusting that this information is not available from every stroke association and doctors group.
Simple, because NO ONE looked at the recovery protocol that Pedro Bach-y-Ritaused to recover fully back in 1958 with only a partial brain!But you don't have anyone COMPETENT AT ALL, DO YOU?
A clot forms. Blood flow to the brain is blocked. Starved of oxygen, neurons begin to die.
This scenario, known as an ischemic stroke, plays out in roughly 21,000 people worldwide each day, threatening them with long-term disability or even death. In recent decades, the advent of drugs and mechanical tools for removing clots has revolutionized stroke care.
Yet, even with the clot gone and the vessel clear, up to 50% of patients never recover neurologically. New research from the University of Colorado Boulder and the University of Antwerp helps explain why.
The study, published in the journal PNAS, reveals in unprecedented detail how the brain's own defense mechanisms against stroke can backfire, triggering yet more clots-micro-clots-in minor vessels, damaging tissue long after the primary culprit is gone.
We now have a way to explain why so many of these patients are not seeing neurological improvements. Our findings also point to a new potential target for therapeutics that could be extremely impactful for stroke patients."
Debanjan Mukherjee, co-author, assistant professor of mechanical engineering, CU Boulder
The mystery behind "no reflow"
Doctors have long known that removing a stroke-causing clot cannot always restore full blood flow to the brain. But why this phenomenon, known as "no reflow," occurs has remained a mystery.(Just maybe because Capillaries that don't open due to pericytes and then there is the neuronal cascade of death in the first week)
To unravel it, Mukherjee, who studies the physics of blood flow, teamed up with senior author Frederik Denorme, an assistant professor of biology at the University of Antwerp who studies, as he puts it, "life after the clot."
"The dogma used to be that you just need to get rid of that blood clot and then all problems should be solved," said Denorme. "We now know that is not the case."
In fact, only about 1 in 10 surviving stroke patients recover completely after a stroke; 25% have minor impairments; and half have moderate to severe impairments.
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To examine what, precisely, goes on in the brain after a clot is removed, the research team first turned to mice.
Using a technique called intravital microscopy, they observed in real time how blood flowed in the brain and cells behaved in the hour after the mice suffering from stroke underwent endovascular thrombectomy-a procedure in which a tool is threaded through a blood vessel to pluck out an obstructive clot.
While blood quickly started flowing again post-procedure, the researchers were stunned to see that in many mice, it flowed haphazardly, in fits and starts, even reversing course at certain points.
"We saw it happening with our own eyes. Blood that was flowing left all of a sudden flowed right and vice versa," said Denorme. "It was remarkable."
A Jekyll and Hyde protein
An even closer look revealed that, as the brain tried to divert blood around the original obstruction, tiny clots formed where the haphazard channels converged.
To drill down on why those clots formed, Mukherjee's FLOWLab recreated this scenario using computer simulations. In other research, his lab has recreated similar scenarios using a 3D artificial brain filled with fake blood.
These experiments implicated Von Willebrand Factor - a protein best known for stopping us from bleeding when we get a cut.
In its resting state, Mukherjee explained, Von Willebrand Factor is coiled up like a ball of string inside blood vessels, waiting for distress signals from the body that make it stretch out and start forming clots to stop bleeding.
In a brain experiencing a stroke, something else unfolds the ball.
"If there is some kind of fluid motion induced after the clot is removed, it can stretch out that ball into an extended thread that attracts platelets, forms new clots and blocks flow even after the original culprit clot is gone," Mukherjee said.
Meanwhile, the study showed, the brain's inflammatory response to stress interferes with safeguards that normally keep the protein's clotting efforts in check, creating what the authors call "a perfect storm" of collateral damage.
Other experiments, looking at blood from stroke patients at the University of Washington in St. Louis, suggest a similar phenomenon happens in humans too.
"We are the first to really show in this hyperacute phase of stroke what is happening with these cells inside blood vessels," said Denorme. "Seeing is believing."
More research is necessary to determine why no reflow happens in some stroke patients but not others. But the study did find that stroke patients with higher blood levels of a pro-inflammatory compound called Interleukin 6 had more overactive Von Willebrand Factor and worse long-term outcomes.
The researchers envision a day when therapeutics targeting Von Willebrand Factor, or the inflammatory compounds that exacerbate its clotting capabilities, could be given to stroke patients alongside clot-busting drugs and surgery.
Notably, several drugs targeting Von Willebrand Factor already exist and are approved for use for other disorders.
"It's early days. But now that we have a lead on what drives these micro-clots, we have a promising new avenue to explore for improving recovery," said Denorme.
Laroche, A., et al. (2026). Mechanisms of von Willebrand factor activation driving no reflow in ischemic stroke. Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.2610397123. https://www.pnas.org/doi/10.1073/pnas.2610397123
Previous studies have found that the use of intravenous thrombolysis (IVT) before endovascular treatment (EVT) could mitigate the “no‐reflow” phenomenon in large‐vessel occlusion of the anterior circulation. However, the effect of preoperative IVT on reducing the “no‐reflow” phenomenon in vertebrobasilar artery occlusion (VBAO) is still uncertain. This study aimed to compare the outcomes of IVT before EVT versus EVT alone in patients with VBAO with complete reperfusion (mTICI [Modified Thrombolysis in Cerebral Infarction] 3).
Methods
We performed a retrospective analysis of patients with acute VBAO at 65 stroke centers in China. Patients with complete reperfusion after EVT were included. These patients were divided into 2 groups on the basis of whether IVT was used before EVT, and propensity score matching was applied to balance the groups. The primary outcome was favorable functional outcome, defined as a modified Rankin Scale score of 0 to 3 at 90 days. Secondary outcomes were functional independence (modified Rankin Scale score of 0–2 at 90 days) and modified Rankin Scale shift at 90 days. Safety end points included symptomatic intracranial hemorrhage and death at 90 days.
Results
Of the 2422 patients with VBAO who received EVT, 1452 patients achieved complete reperfusion. Among these, 273 patients received IVT before EVT. After propensity score matching, 268 patients treated with IVT before EVT were compared with 519 patients without IVT. In the matched cohort, the group that received IVT before EVT showed a higher rate of favorable functional outcome (modified Rankin Scale score, 0–3) (adjusted odds ratio, 1.40 [95% CI, 1.03–1.91]; P=0.033) and a lower mortality rate at 90 days (adjusted odds ratio, 0.72 [95% CI, 0.52–0.99]; P=0.044) compared with the EVT alone group.
Conclusions
Our study indicates that IVT before EVT could improve favorable functional outcomes and reduce death in patients with VBAO who achieve complete reperfusion.
In real-world clinical practice, a substantial number of ischemic
stroke patients fail to achieve functional independence, even after
technically successful thrombectomy with excellent angiographic
reperfusion scores (TICI 2C-3). This discordance has been described as
futile recanalization and may be attributable to a phenomenon referred
to as “no-reflow.” This has been conceptualized as the failure of
downstream microvascular reperfusion at the tissue level despite
successful macrovascular recanalization. Several mechanisms including
microvascular obstruction by microthrombi, edema-related microvascular
compression, and pericyte-induced capillary contraction may be at play.1
Its clinical relevance is magnified in the context of recent trials
expanding thrombectomy to patients with large core infarcts and
perfusion mismatch — groups where optimizing tissue-level perfusion may
be especially crucial. Prior research supports use of CTP imaging as a
better predictor of outcomes following successful recanalization than CT
angiogram alone and was even utilized as an indicator of therapeutic
success in recent thrombolytic trials.
The authors Rivet et al. aimed to investigate the clinical impact of
this no-reflow mechanism on functional outcomes by comparing patient
characteristics between patients with “no-reflow” mechanism on perfusion
imaging and varying degrees of angiographic recanalization (TICI
scores). They conducted a post hoc analysis on the data from three
clinical trials: EXTEND-IA (Endovascular Therapy for Ischemic Stroke
with Perfusion-Imaging Selection) and EXTEND-IA TNK (Tenecteplase Versus
Alteplase Before Thrombectomy for Ischemic Stroke) part 1 and 2 trials.
Both qualitative and quantitative evidence of tissue perfusion
evaluation for “no-reflow” were evaluated in a two-step process through
application of commercially available fully automated software (RAPID;
iSchemaView, Menlo Park, CA) on post-thrombectomy follow-up 24-hour
perfusion imaging (CTP or MR Perfusion). The authors identified 2
distinct regions of interest (ROI) which were superimposed into
perfusion maps and excluded signals associated with hemorrhagic
transformation of infarct. No-reflow was defined when both qualitative
and quantitative criteria were met — that is, visually demonstrable
reduced intralesional rCBV or rCBF and >15% interside reduction in
median rCBV or rCBF value2 (Figure 1). It is
worth noting that since the primary studies were not primarily designed
to evaluate for this phenomenon, not all patients had both MRP and CTP.
Figure 1. Imaging analysis method.
They compared both clinical and radiological characteristics of
patients with combinations of no-reflow or completeFlow with different
levels of angiographic success (full-TICI 2c3, partial-2b,
unsuccessful-0-2a). No significant difference in the rate of no-reflow
detection according to imaging modality (CT perfusion 13.6% [n=9/66]
versus MRP 25.0% [n=21/84]; P=0.10) was observed. No-reflow
mechanism occurred more frequently in successful angiographic
recanalization (TICI 3) (n=17/30, 56.7%). Among patient characteristics
across varying degrees of technical success, it is worth noting a
statistically significant difference among time of onset and proportion
of patients receiving thrombolytic (alteplase or tenecteplase).
The primary outcome of functional independence (mRS score of 0–2) was
achieved in 43.33% (n=13/30) of patients with eTICI 2c3–NoReflow,
versus 67.50% (n=81/120) of patients with eTICI 2c3–CompleteFlow, 63.03%
(n=150/238) of patients with eTICI 2b and 50.00% (n=34/68) of patients
with unsuccessful thrombectomy. In unadjusted analysis, patients with
no-reflow were less likely to experience functional independence
despite technical success, TICI 2c-3 compared to completeFlow (odds
ratio [OR], 0.37 [95% CI, 0.16–0.83]; P=0.02) or those with eTICI 2b (OR, 0.45 [95% CI, 0.21–0.97]; P=0.04) but had similar rate to patients with unsuccessful thrombectomy (OR, 0.76 [95% CI, 0.32–1.82]; P=0.54).
When adjusted for age, premorbid mRS, baseline NIHSS, and baseline core
volume, multivariable analysis confirmed lower odds of functional
independence with no-reflow and full/partial recanalization, and similar
odds of functional independence with unsuccessful thrombectomy.
Furthermore, exploratory analysis of functional infarct volumes (FIV)
showed that despite similar volumes, patients with no-reflow had worse
outcomes despite full recanalization compared to partial recanalization.
These findings suggest that “no-reflow” phenomenon negates benefit of
macrovascular recanalization in achieving favorable clinical outcome.
The authors further caution that no-reflow mechanism tends to occur more
frequently with prolonged periods of ischemic injury, suggesting that
this prevalence could be underestimated by this study given the
inclusion of patients within the 4.5-hour time window. Their major
strength includes use of prospectively collected data from clinical
trials. As we push the boundaries of thrombectomy eligibility, tackling
the no-reflow phenomenon may be the next frontier in improving
patient-centered outcomes — representing a crucial step not only in
restoring macrovascular blood flow but also in minimizing downstream
ischemic injury, thereby broadening the therapeutic benefit for patients
with acute ischemic stroke.
Endovascular
reperfusion therapy is the primary strategy for acute ischemic stroke.
No-reflow is a common phenomenon, which is defined as the failure of
microcirculatory reperfusion despite clot removal by thrombolysis or
mechanical embolization. It has been reported that up to 25% of ischemic
strokes suffer from no-reflow, which strongly contributes to an
increased risk of poor clinical outcomes. No-reflow is associated with
functional and structural alterations of cerebrovascular
microcirculation, and the injury to the microcirculation seriously
hinders the neural functional recovery following macrovascular
reperfusion. Accumulated evidence indicates that pathology of no-reflow
is linked to adhesion, aggregation, and rolling of blood components
along the endothelium, capillary stagnation with neutrophils, astrocytes
end-feet, and endothelial cell edema, pericyte contraction, and
vasoconstriction. Prevention or treatment strategies aim to alleviate or
reverse these pathological changes, including targeted therapies such
as cilostazol, adhesion molecule blocking antibodies, peroxisome
proliferator-activated receptors (PPARs) activator, adenosine, pericyte
regulators, as well as adjunctive therapies, such as extracorporeal
counterpulsation, ischemic preconditioning, and alternative or
complementary therapies. Herein, we provide an overview of
pathomechanisms, predictive factors, diagnosis, and intervention
strategies for no-reflow, and attempt to convey a new perspective on the
clinical management of no-reflow post-ischemic stroke.
Metformin inhibited pericytes apoptosis contributing to promoting SVZneurogenesis and neurologic outcome in tMCAO mice.
•
Metformin supressed JNK p38 MAPK signalling activation in tMCAO mice which inhibited pericytes apoptosis.
•
Anisomycin abolished neuroprotective effects of Metformin through activating JNK p38 MAPK signalling.
Abstract
Metformin
(MET) has been the subject of many classic studies in possessing
antiapoptotic, anti-inflammatory, antioxidation activities and
antiviral. Recently investigators have examined the anti-apoptosis
effects of MET in acute myocardial infarction and Intracerebral
hemorrhage, but very little is currently known about how it regulates
ischemic stroke-induced pericytes apoptosis and neural stem cells (NSCs)
proliferation. The present research explored the potential
neuroprotective mechanisms of MET using transient middle cerebral artery
occlusion(tMCAO) mice. The experimental work presented that tMCAO mice
treated by metformin had better neurologic outcomes on days 1, 3, and 7
after operation, and alleviated blood–brain barrier (BBB) destruction,
brain water content and infarct volume on 72 h after surgery. The data
showed that MET alleviated BBB disruption by reducing PDGFRβ/ matrix
metalloproteinase-9 (MMP9) positive cells, relieving zonula occludens-1
(ZO-1) drop away and increasing pericyte coverage through remarkably
reducing the percentage of PDGFRβ/caspase-3 positive cells. In addition,
MET induced antiapoptotic activity followed by downregulating cleaved
caspase-3 and Bax expression. Moreover, JNK signaling pathway has been
proved to be pivotal in mediating apoptosis in cerebral
ischemia/reperfusion (I/R) injury. The results of this research
illustrated that MET treatment downregulated the levels of
phosphorylated JNK and P38 in vivo, however the use of JNK activator
anisomycin (ANI) could reverse the neuroprotection effect of MET,
demonstrating that the JNK pathway is associated with the anti-apoptosis
mechanisms of MET. Finally, metformin remarkably increased the
percentage of BrdU/DCX-positive cells in subventricular zone (SVZ) and
up-regulated BDNF、VEGF and NGF expression after
ischemia/reperfusion(I/R) injury on day 7. Our data illustrated that
metformin provides an effective therapy for I/R injury.
Why I'm getting heparin. Heparin
binds to cells at a site adjacent to ACE2, the portal for SARS-CoV-2
infection, and "potently" blocks the virus, which could open up therapy
options.
Researchers found that hospitalized COVID patients
who took a daily low dose of aspirin had a significantly lower risk of
complications and death from the virus. Aspirin users were 43 percent
less likely to be put in the intensive care unit (ICU) and 44 percent
less likely to be placed on a ventilator. They also had a 47 percent
decrease in the risk of dying from their coronavirus infection compared to hospitalized patients who were not taking daily aspirin doses.
But
I'm sure your doctor will be more worried about bleeding risks from
aspirin. I'm doing 325(low dose is 81) and have been for 15 years.
This review was supported by the VELUX Foundation
(ARCADIA II, grant no. 0026167) and a Lundbeck Foundation Professorship
to the author (grant no. R310‐2018‐3455).
Abstract
Corona virus disease 2019 (COVID‐19) causes symptoms from
multiple organs after infection by severe acute respiratory syndrome
corona virus 2 (SARS CoV‐2). They range from early, low blood oxygen
levels (hypoxemia) without breathlessness (“silent hypoxia”), delirium,
rashes, and loss of smell (anosmia), to persisting chest pain, muscle
weakness and ‐pain, fatigue, confusion, memory problems and difficulty
to concentrate (“brain fog”), mood changes, and unexpected onset of
hypertension or diabetes. SARS CoV‐2 affects the microcirculation,
causing endothelial cell swelling and damage (endotheliitis),
microscopic blood clots (microthrombosis), capillary congestion, and
damage to pericytes that are integral to capillary integrity and barrier
function, tissue repair (angiogenesis), and scar formation. Similar to
other instances of critical illness, COVID‐19 is also associated with
elevated cytokine levels in the systemic circulation. This review
examines how capillary damage and inflammation may contribute to these
acute and persisting COVID‐19 symptoms by interfering with blood and
tissue oxygenation and with brain function. Undetectable by current
diagnostic methods, capillary flow disturbances limit oxygen diffusion
exchange in lungs and tissue and may therefore cause hypoxemia and
tissue hypoxia. The review analyzes the combined effects of
COVID‐19‐related capillary damage, pre‐existing microvascular changes,
and upstream vascular tone on tissue oxygenation in key organs. It
identifies a vicious cycle, as infection‐ and hypoxia‐related
inflammation cause capillary function to deteriorate, which in turn
accelerates hypoxia‐related inflammation and tissue damage. Finally, the
review addresses the effects of low oxygen and high cytokine levels in
brain tissue on neurotransmitter synthesis and mood. Methods to assess
capillary functions in human organs and therapeutic means to protect
capillary functions and stimulate capillary bed repair may prove
important for the individualized management of COVID‐19 patients and
targeted rehabilitation strategies.
1 INTRODUCTION
In the past year, severe acute respiratory syndrome
coronavirus 2 (SARS‐CoV‐2) infections have swept across continents,
claiming over 1.5 million lives (The Johns Hopkins Coronavirus Resource
Center (CRC), 2020).
First considered a respiratory disease, coronavirus disease 2019
(COVID‐19) also affects other organ systems, including the brain, heart,
kidneys, liver, skeletal muscle, and skin of infected patients.
SARS‐CoV‐2 is asymptomatic in some, whereas others develop
severe symptoms, some requiring ventilator treatment. Elderly patients,
and patients with preexisting respiratory disease or cardiovascular risk
factors, are at greater risk of a severe disease course (Liu et al., 2020). In many patients, symptoms persist after the infection, affecting patients’ return to work and quality‐of‐life—see Table 1 (Yelin et al., 2020).
While most symptoms disappear over the weeks and months following the
infection, the extent of long‐term COVID‐19 sequela remains unclear.
TABLE 1.
Long‐term complaints of people recovering from acute COVID‐19. Adapted from Yelin et al. (2020)
Extreme fatigue
Muscle weakness
Low‐grade fever
Inability to concentrate
Memory lapses
Changes in mood
Sleep difficulties
Headaches
Needle pains in arms and legs
Diarrhea and bouts of vomiting
Loss of taste and smell
Sore throat and difficulties to swallow
New onset of diabetes and hypertension
Skin rash
Shortness of breath
Angina (Chest pains)
Palpitations (irregular heartbeat)
SARS‐CoV‐2 infection affects the vascular system and blood's
coagulation properties, injuring vascular walls and causing blood clots
to form in both large and microscopic blood vessels (Ackermann et al., 2020; Liu et al., 2020; Teuwen et al., 2020).
While we are familiar with the pathophysiology, symptoms, diagnostic
findings, and management of large vessel occlusions (e.g., acute stroke,
coronary occlusion, pulmonary embolism, deep venous thrombosis), the
consequences of microcirculatory disturbances, for example, the
narrowing or occlusion of individual capillaries, remain unclear
(Ackermann et al., 2020; Fox et al., 2020; Varga et al., 2020). This review addresses this knowledge gap (Østergaard, 2020).
Our current vascular disease paradigm focuses on blood flow‐limiting
conditions on the one hand, and symptoms of hypoxia and hypoxic tissue
injury, on the other. Blood's capillary transit time, however,
determines the time availability for blood‐tissue oxygen exchange, and
any deviations from a homogenous distribution of blood across the
capillary bed therefore reduce the capillary bed's functional capillary
permeability surface area product (PS) for oxygen transport (Jespersen
& Østergaard, 2012; Østergaard, 2020). Therefore, blood's uptake of oxygen in the lungs, and the uptake of oxygen by tissue, not only depend on blood flow, but also on bloods microscopic distribution across the capillary bed (Angleys & Østergaard, 2020; Hsia et al., 1999; Jespersen & Østergaard, 2012; Østergaard, 2020).
Biophysically, the redistribution of blood among open capillaries can
account for the puzzling increase in oxygen PS observed as blood flow
increases through most organs, without the need to invoke classical
“capillary recruitment” (the active opening of previously closed
capillaries), which has now been ruled out in most organs (Østergaard, 2020; Poole et al., 2020). This review focuses on the effects of break‐downs
in the factors that ensure the crucial, parallel increase in PS and
blood flow, after biophysical models have predicted that capillary
occlusions and severe capillary flow disturbances can limit tissue
oxygenation to the same extent as symptomatic reductions in blood flow (ischemia) in brain, heart, and kidneys (Østergaard et al., 2013, 2014, 2015).
Consistent with these predictions, patients with mild
cognitive impairment (MCI) and Alzheimer's Disease (AD), who show
widespread cerebral microvascular flow disturbances compared to controls
(Eskildsen et al., 2017; Nielsen et al., 2020),
also display loss of cognitive functions across patients and over time
in proportion to these disturbances and the resulting decline in
critical brain regions’ ability to extract blood's oxygen (Eskildsen et
al., 2017; Nielsen et al., 2017). Such capillary dysfunction
is believed to develop over decades, as microvascular injuries
accumulate due to aging, risk factor, and diseases—but only to cause
symptoms when the injuries reach a certain threshold. The review
examines how sudden, COVID‐19‐related microvascular changes affect
oxygen availability in subjects with different, pre‐existing levels of
capillary dysfunction, and asks whether, for example, unexpected
hypertension and COVID‐19‐related cognitive symptoms (“brain fog”) are
related to transient reductions in blood and brain oxygenation.
Reductions in tissue oxygen levels activate inflammation and cytokine release (Eltzschig & Carmeliet, 2011),
which may interfere with neurotransmission, just as oxygen is important
for the brain's serotonin synthesis (Østergaard et al., 2018). The review discusses how microvascular damage and inflammation could affect brain functions, including mood.
The availability of oxygen in tissue depends on the function
of its capillaries as well as arterial blood's oxygen concentration,
both of which may be limited by COVID‐19. This integrative review
therefore addresses putative consequences of capillary flow disturbances
in both lungs and other tissues.
2 HOW CAN COVID‐19‐RELATED CAPILLARY CHANGES AFFECT BLOOD OXYGENATION?
The oxygen uptake in lung alveoli is limited by capillary
blood's mean transit time (MTT), the time available for blood‐air oxygen
exchange in lung alveoli before blood returns the heart. Capillary
occlusions in the lung can therefore limit blood's oxygen uptake as the
cardiac output has to pass through fewer capillaries, only faster. In
patients who died from respiratory failure caused by SARS‐CoV‐2,
Ackermann et al. found alveolar capillary microthrombi to be nine times
more prevalent than in patients who died from acute respiratory distress
(ARDS) secondary to influenza A[H1N1] (Ackermann et al., 2020),
suggesting that alveolar capillary occlusions are characteristic of
COVID‐19. Unlike influenza‐related ARDS, COVID‐19 was further
characterized by significant new blood vessel formation by
intussusceptive angiogenesis, giving rise to substantial distortions of
the alveolar capillary plexus’ architecture (Ackermann et al., 2020).
The benefits, in terms of blood oxygenation, of this response to
parenchymal hypoxia is contingent on alveolar ventilation as well as the
function of these new, chaotic microvessels, keeping in mind that
angiogenesis tends to result in capillaries that act as “shunts” for
blood through the microcirculation (Pries et al., 2010).
Reynolds et al. found evidence of blood being shunted through the lung
circulation in more COVID‐19 patients with severe pneumonia (83%) than
in patients with ARDS (26%; Reynolds et al., 2020a).
Unlike ARDS patients, the extent of this shunting was associated with
poor blood oxygenation in COVID‐19 patients (Reynolds et al., 2020a).
The authors attribute these findings to abnormally dilated alveolar
capillaries with diameters in excess of 24 μm (normal alveolar
capillaries <15 μm; Reynolds et al., 2020b),
consistent with significant capillary shunting, possibly related to
changes in alveolar angio‐architecture and congested, parallel capillary
pathways.
The alveolar blood–air barrier is less than a micrometer
thick and provides efficient gas exchange by its high permeability to
oxygen and 5–10 times higher permeability to carbon dioxide (CO2).
In ARDS, fluid, immune cells, and cell debris accumulate in lung
alveoli and within alveolar walls, preventing gas exchange so poorly
oxygenated, CO2‐rich blood returns to the heart – so‐called right‐to‐left shunting. Hypoxic vasoconstriction
counteracts such shunting and matches perfusion and ventilation across
normal lungs by limiting blood flow through poorly ventilated alveoli.
The apparent capillary transit‐time effects in COVID‐19
differ from “traditional” right‐to‐left shunting in two respects: First,
transit time effects limit blood's oxygen uptake even in well‐aerated
alveoli. Second, CO2 exchange is largely insensitive to
transit‐time effects due to its high permeability. In patients with
well‐ventilated alveoli, transit‐time effects are therefore expected to
cause normocapnic hypoxemia, and may therefore contribute to
“silent hypoxia” because hypercapnia, in some, confers the sense of
breathlessness. Reports of severe hypoxemia in COVID‐19 patients whose
lung compliance and chest CT suggest that their alveoli remain both
aerated (Gattinoni et al., 2020) and perfused (Lang et al., 2020), are also consistent with severe alveolar capillary microthrombosis and capillary shunting early in the course of the disease.
In patients with obliterative lung diseases, such as
emphysema and pulmonary fibrosis, lung capillary blood volume is reduced
(Hsia, 2002)
and alveolar MTT (~the ratio between the lungs’ capillary blood volume
and cardiac output) may therefore become critically short if hypoxic
vasoconstriction redistributes blood among fewer alveoli and capillary
occlusions further shorten individual alveolar MTT. Transit‐time effects
may therefore contribute to the vulnerability of these patients to
COVID‐19.
3 PRE‐EXISTING CAPILLARY DYSFUNCTION AND OXYGEN AVAILABILITY IN TISSUE
Transit time effects can limit air‐blood and blood‐tissue oxygen transport even in the absence
of capillary occlusions. Oxygen extraction from the capillary bed is
most efficient if end‐capillary oxygen concentrations are equal
(Jespersen & Østergaard, 2012; Lucker et al., 2018) – see Figure 1a.
Any capillary flow disturbances, for example, due to endothelial
swelling or the slow passage of activated neutrophils through some
capillaries, shorten bloods transit times through the remaining, patent
capillaries, limiting oxygen uptake (Østergaard, 2020) – see Figure 1b.
Capillary
dysfunction and tissue oxygenation (a) Schematic capillary bed. Fully
oxygenated blood is indicated by red and its transition to blue
illustrates gradual deoxygenation as oxygen diffuses into tissue. In
this illustration, the distribution of blood across parallel capillary
paths is homogenous (no capillary transit‐time heterogeneity, i.e.,
CTH=0), providing optimal oxygen extraction. Modified from (Østergaard, 2020).
(b) Capillary flow disturbances can be caused by either a narrowing or a
widening of individual capillary segments, or by altered blood
properties, such as reduced erythrocyte deformability or neutrophil
adhesion after glycocalyx shedding. Note how the inability to homogenize
capillary transit times across the capillary bed (CTH > 0) leads to
poorer oxygen extraction although blood flow is identical to panel a.
Modified from (Østergaard, 2020). (c) This panel illustrates how, for modest increases in CTH, tissue oxygen tension (tO2) can be maintained by a compensatory increase in blood flow, contrary to our current vascular disease paradigm (Østergaard, 2020). The dashed red line indicates CTHc, above which metabolic demands can only be met by limiting blood flow (Angleys et al., 2015; Jespersen & Østergaard, 2012). The lower blood supply causes tO2
to decrease, whereas the longer blood transit times and higher
blood‐tissue oxygen concentration gradients provide more efficient
oxygen extraction from blood, understood as a higher oxygen extraction
fraction (OEF). The futility of increasing blood flow beyond the
capillary bed's capacity to extract blood's oxygen may be reflected in
reperfusion injury after ischemic episodes, during which capillaries
irreversibly constrict (O'Farrell et al., 2017; Yemisci et al., 2009). As CTH increases beyond CTHc, BF, and tO2
gradually decreases. The red arrow indicates a 50% reduction in tissue
oxygen tension to highlight the threat to critical, ATP‐sensitive cell
processes and organ functions. (d) The curves illustrate how
cardiovascular risk factors that accelerate capillary injury (Østergaard
et al., 2016) modify the curves displayed in panel c (indicated in lighter, gray, green and blue, respectively). Note how CTHc
and the onset of critically low tissue oxygen levels are expected to be
reached earlier in the affected tissues. The clinical correlates of
this earlier attenuation of blood flow may be earlier onset of
endothelial dysfunction and hypertension, higher morbidity due to
accelerated microvascular injury in critical organs, and lower life
expectancy
Capillary transit‐time heterogeneity (CTH) quantifies the extent of capillary flow disturbances, typically in terms of the standard deviation
of capillary transit times or blood velocities within a microscopic
tissue volume. Importantly, CTH also quantifies the combined,
accumulated impact of aging, risk factors, and disease‐related
microvascular damage on capillary hemodynamics at a given time point—and
allows its impact on tissue oxygenation to be calculated, alongside
that of tissue blood flow, by biophysical models (Angleys et al., 2015; Jespersen & Østergaard, 2012).
Tissue blood flow (BF) is closely regulated to meet local metabolic demands while maintaining tissue oxygen tension (tO2) within a narrow range. Figure 1c
illustrates how tissue blood flow (BF) can sustain a constant rate of
oxygen metabolism as capillary function deteriorates (CTH increases, PS
decreases) over time. Notice how a gradual BF increase initially
compensates for the reduction in oxygen extraction efficacy. Because of
the opposing effects of higher blood supply and shorter MTT on tissue
oxygenation, however, CTH invariably reaches a critical threshold, CTHc, beyond which further vasodilation can no longer sustain normal tO2. To meet metabolic demands, BF must instead be reduced to limit the “shunting” of oxygenated blood through the microcirculation—at the expense of a gradual reduction of tO2.
Note that such critical levels of capillary shunting can be reached at
any CTH level by a sufficiently large blood flow increase (MTT
reduction; Angleys et al., 2015; Jespersen & Østergaard, 2012). The critical transition at CTHc
is therefore expected to be presaged by a gradual attenuation of
vasodilator responses before this threshold is reached, as the
accompanying blood flow increases critically shorten transit times. This
property has been linked to endothelial dysfunction (attenuated
flow responses to endothelial‐dependent vasodilators) characteristic of
cardiovascular risk factors, and the subsequent increase in vascular
resistance and vascular wall remodeling associated with hypertension
(Østergaard, 2020).
As CTH increases further, tissue oxygen tension is expected
to fall to levels where critical cell functions become compromised (red
arrow), after which failure of critical organ functions may ensue.
Figure 1d
illustrates how accelerated deterioration of capillary function due to
life‐long exposure to vascular risk factors (e.g., hypercholesterolemia,
smoking) is expected to result in earlier onset of capillary
dysfunction‐related disorders (Østergaard et al., 2016) and possibly reduce life expectancy.
Figure 2
illustrates how short‐term COVID‐19‐related capillary flow disturbances
(increased CTH) are predicted to affect tissue oxygenation and organ
functions for subjects with different levels of pre‐existing age and
risk factor‐related capillary dysfunction. In younger subjects,
capillary damage is expected to be asymptomatic, except during exercise
where lung, heart, or muscle capillary function is affected—Figure 2a. Note how patients with asymptomatic pre‐existing capillary dysfunction in brain tissue (Figure 2b)
could experience the sudden deterioration to CTH and tissue oxygen
levels characteristic of mild cognitive impairment or AD (Nielsen et
al., 2020)
as “brain fog” and memory problems. In elderly patients with
symptomatic pre‐existing capillary dysfunction in certain organs,
additional capillary flow disturbances are expected to worsen symptoms
significantly and to potentially be life‐threatening—Figure 2c.
Temporary
capillary flow disturbances and tissue oxygenation. This figure
illustrates how temporary COVID‐19‐related flow disturbances are
expected to affect flood flow (BF) and tissue oxygen tension (tO2).
Panels show expected responses in tissue with mild (panel a), moderate
(panel b), and severe (panel c) pre‐existing capillary dysfunction. (a)
If tissue CTH remains below CTHc during COVID‐19‐related capillary flow disturbances, tO2,
and thereby organ functions during rest, are likely to remain
unaltered. For organs that rely on capillary transit time homogenization
to meet their metabolic demands during work, such as the heart and
skeletal muscle (Angleys & Østergaard, 2020),
the additional capillary dysfunction is expected to reduce maximum
aerobic capacity, affecting the performance of, for example, young
athletes. These signs are expected to reverse upon successful
therapeutic or intrinsic capillary recanalization/repair. Irreversible
changes to the capillary bed's oxygen extraction capacity, however, may
accelerate the emergence of symptoms and disease changes in the affected
tissues, cf. Figure 1d.
(b) For patients with asymptomatic, moderate preexisting capillary flow
disturbances, a COVID‐19‐related CTH increase may cause them to exceed
CTHc and lead to a reduction in blood flow and tissue oxygen
tension. While, for example, MCI‐like symptoms are expected to disappear
with disease‐related capillary flow disturbances, they may herald
developing capillary dysfunction and the benefits of managing
cardiovascular risk factors to prevent or delay their recurrence in
later life (Hachinski et al., 2019). In COVID‐19 patients with pre‐existing myocardial capillary dysfunction, a sudden CTH increases may reduce tO2 to levels so that they experience angina during exercise in the absence of flow‐limiting coronary disease (Østergaard et al., 2014).
(c) In patients with symptomatic, pre‐existing severe capillary
dysfunction, further increases in CTH are expected to cause immediate
drops in oxygen availability and worsen preexisting symptoms (e.g.,
confusion or delirium in patients who already have dementia, myocardial
damage, or kidney failure). If oxygen levels fall below the metabolic
requirement of critical cell functions, tissue and organ damage is
expected to cause lasting symptoms or even organ failure and premature
death
4 SARS‐COV‐2 INFECTION AND ITS EFFECT ON THE MICROCIRCULATION
The SARS‐CoV‐2 virus can bind to angiotensin‐converting
enzyme 2 (ACE2) receptors on cell surfaces and be internalized by the
cell (Liu et al., 2020).
The virus‐receptor interaction is thought to reduce ACE2 action and
increase levels of angiotensin II, a powerful capillary and arteriolar
vasoconstrictor (Capone et al., 2011; Kawamura et al., 2004; Tilton et al., 1979) that propagates thrombogenicity, oxidative stress, and inflammation (Liu et al., 2020).
With respect to COVID‐19 respiratory symptoms, alveolar epithelial, and
capillary endothelial cells express ACE2 receptors and SARS‐CoV‐2
particles are found within both cell types in COVID‐19 patients
(Ackermann et al., 2020; Carsana et al., 2020).
As for the anosmia (loss of smell) experienced by COVID‐19 patients,
ACE2 receptors are observed on sustentacular (support) cells in human
olfactory epithelium in the nasal cavity but not on brain olfactory
nerve cells in mice (Brann et al., 2020).
4.1 Capillary pericytes
In the heart (Chen et al., 2020; He et al., 2020) and brain (including the olfactory bulb; Brann et al., 2020; He et al., 2020) of mice, capillary pericytes
express ACE2. Pericytes are embedded in the capillary basement membrane
and are important for the formation, maintenance, and remodeling of
capillaries (Armulik et al., 2011). In the lungs, severe COVID‐19 is related to an extensive loss of capillary pericytes (Burel‐Vandenbos et al., 2020), an essential substrate for angiogenesis (Kato et al., 2018)
and possibly for lung repair and lung function recovery after COVID‐19.
Notably, lung capillaries in COVID‐19 show extensive signs of
angiogenesis, suggesting reparative processes in response to tissue
hypoxia (Ackermann et al., 2020).
Some pericytes are contractile and respond to a range of vasoactive molecules (Diaz‐Flores et al., 2009). They are involved in blood flow control (Hall et al., 2014)
but brain and myocardial pericytes may also die in a contracted state
(“rigor”), hindering subsequent erythrocyte passage, when exposed to
hypoxia and oxidative stress (Hall et al., 2014; O'Farrell et al., 2017; Yemisci et al., 2009). Pericyte damage is implicated in the development of diabetes (Richards et al., 2010), and pericyte infection could contribute to COVID‐19‐related diabetes (Coate et al., 2020). Pericytes undertake microvascular barrier functions (Armulik et al., 2010) and facilitate tissue's recruitment of immune cells in response to viral and bacterial proteins (Proebstl et al., 2012; Wang et al., 2012). During such immune responses, pericytes change phenotype to become migratory (Wang et al., 2012), possibly abandoning other functions of importance to capillary bed integrity, function, and repair.
4.2 Endothelial cells
In most human organs, microvascular endothelium express ACE2 surface receptors (Donoghue et al., 2000; Hamming et al., 2004), but see (He et al., 2020). SARS‐CoV‐2 particles have been observed in the endothelium of the lung (Ackermann et al., 2020), heart (Fox et al., 2020), brain (Paniz‐Mondolfi et al., 2020), skin (Colmenero et al., 2020), and kidney (Varga et al., 2020).
Notably, SARS‐CoV‐2 infection of endothelial cells (ECs) is associated
with changes in cell morphology and with EC apoptosis—and coincide with
findings indicative of severe hypoxia in surrounding tissue.
Accordingly, lung capillaries from deceased COVID‐19 patients show
caliber changes as some ECs protrude into the capillary lumen (Ackermann
et al., 2020), some undergo apoptosis (Varga et al., 2020), and some show signs of angiogenesis in response to severe, local tissue hypoxia (Ackermann et al., 2020).
In the heart, endothelial infection is associated with EC swelling
(plumpness) in small arterioles, capillaries and venules, and scattered
necrosis of individual myocytes (Fox et al., 2020).
In the brain, infection of subcortical white matter microvessel
endothelium is associated with hyper‐acute, microscopic ischemic
lesions, and older ischemic and hemorrhagic microscopic lesions
(Paniz‐Mondolfi et al., 2020).
Finally, EC infection in the skin is associated with endothelial
swelling and in some patients with thrombosis and fibrinoid necrosis in
surrounding tissue (“COVID toes”) (Colmenero et al., 2020).
Endothelial damage is likely to disturb capillary flow
patterns, keeping in mind that erythrocyte diameters exceed that of the
capillary lumen. Importantly, disruptions of intercellular gap junctions
between endothelial cells (Ackermann et al., 2020) and endothelial cell apoptosis (above) disrupt intercellular connexin channels that allow signaling between endothelial cells and to upstream vascular smooth muscle cells (Isakson et al., 2006).
This fast, bidirectional communication allows feed‐back control of
blood flow across the microcirculation to maintain cellular oxygenation
(Segal., 2005; Segal & Duling, 1986),
and disruption of this communication is associated with extreme
shunting of oxygenated blood through the shortest capillary pathways
(Pries et al., 2010).
4.3 Glycocalyx
The capillary endothelium's luminal surface is covered by a 0.3–0.6 µm thick glycocalyx (Vink & Duling, 1996), a matrix that acts as a fluid barrier (Haaren et al., 2003) and impacts erythrocytes’ passage (Secomb et al., 1998). In critical illness, partly due to elevated TNF‐α levels, the glycocalyx is shed (Henry & Duling, 2000; Nieuwdorp et al., 2009), exposing cellular adhesions molecules that interact with immune cells to facilitate their extravasation. Cortisol protects the endothelial glycocalyx against TNF‐α induced shedding (Chappell et al., 2009). Glycocalyx shedding profoundly affects microvascular resistance and capillary hemodynamics (Cabrales et al., 2007; Lipowsky et al., 2011). In newly intubated COVID‐19 patients, Stahl et al.
found evidence of glycocalyx shedding before signs of any EC injury and
verified glycocalyx thinning by sublingual optical imaging (Stahl et
al., 2020).
4.4 Capillary obstruction by neutrophils (“stalled flow”)
Neutrophils are involved in the immune response to
SARS‐CoV‐2 infection. Much larger than erythrocytes and the average
capillary diameter, they may occlude capillaries for several seconds,
and especially when activated, cause significant capillary flow
disturbances (Harris & Skalak, 1993).
Neutrophil adhesion in brain capillaries impairs memory function and
causes sizeable reductions in cerebral blood flow in animal models (Cruz
Hernandez et al., 2019).
The adhesion of hyper‐activated neutrophils to capillaries within the
lungs, brain, heart, and other organs may therefore contribute to the
poor prognosis of some COVID‐19 patients (Wang et al., 2020).
4.5 Microthrombosis
Capillary congestion and microthrombosis in the absence
of upstream thrombi are common findings in the lungs of patients who
died from COVID‐19‐related respiratory failure (Ackermann et al., 2020; Carsana et al., 2020). Microthrombosis has also been observed in the skin (Colmenero et al., 2020) and the kidney's glomerular capillaries (Hanley et al., 2020).
Capillary COVID‐19 effects may trigger symptoms and tissue
injury by critically reducing local tissue oxygenation, but symptoms may
also be the result of direct parenchymal cell infection.
In the lungs, infection of lung epithelium and capillary
damage both seem to contribute to severe respiratory symptoms. In brain
tissue, endothelial or pericyte infections, alongside systemic
inflammation, may cause local hypoxia, but SARS‐CoV‐2 is also thought to
be neurotrophic (capable of infecting nervous tissue). Nerve
terminals have been speculated to take up virus particles and transmit
them across synapses to other brain regions (Gu & Korteweg, 2007; Iadecola et al., 2020; Song et al., 2021). Neuropathological examination suggests that cortical neurons are infected in some patients (Song et al., 2021), possibly following entry through the olfactory mucosa (Meinhardt et al., 2020).
New‐onset diabetes in COVID‐19 patients was ascribed to
direct infection of insulin‐producing pancreatic islet β cells, but
recently deemed unlikely due to their lack of ACE2‐binding protein
(Coate et al., 2020).
ACE2 was observed on islet capillary pericytes and exocrine
capillaries, however, suggesting that, in this case, a microvascular
origin is more likely for the metabolic sequelae of COVID‐19 (Coate et
al., 2020).
Many COVID 19 patients show elevated troponin levels early
in the course of their disease, indicative of myocyte injury (Liu et
al., 2020).
It remains uncertain whether SARS‐CoV‐2 infects heart myocytes and
cause persistent immune cell infiltration (myositis), or whether myocyte
injury is the result of hypoxia, caused by pericyte infection and/or
microvascular injury. Recent findings seemingly contradict the former
(Fox et al., 2020). Finding the sources of heart injury in COVID‐19 remains urgent (Maleszewski et al., 2020):
In one study, 78% of mostly un‐hospitalized COVID‐19 patients showed
abnormal cardiac MRI 2–3 months after diagnosis (Puntmann et al., 2020).
6 HYPOXIA, INFLAMMATION, AND CAPILLARY FUNCTION
COVID‐19, like other instances of critical illness that involve systemic hypoxia (Kox et al., 2020; Sinha et al., 2020),
is associated with cytokine release. TNF‐α and other inflammatory
factors are known to damage the glycocalyx and impair endothelial
functions (Liu et al., 2020; Zhang et al., 2020). This immune response is likely to contribute to capillary dysfunction and reduced tO2
in affected tissue, where cellular oxygen sensors, in turn, activate
hypoxia‐inducible transcription factor (HIF) and the transcription of
genes that help tissue adapt to hypoxia (Eltzschig & Carmeliet, 2011).
Notably, hypoxia also activates the production of nuclear factor kappa
beta (NF‐κB), the master‐switch for the transcription of genes that
elicit inflammatory responses (Eltzschig & Carmeliet, 2011). Figure 3
illustrates how hypoxia‐induced inflammation, by adding further to
capillary dysfunction and hypoxia, may constitute a vicious cycle in
severe COVID‐19.
Interactions
between capillary function, inflammation, hypoxia, and
neurotransmission. The expression of ACE2 and other SARS‐CoV‐2 entry
factors on parenchymal cells and observations of infected cells in
biopsy material hold important clues to understand COVID‐19‐related
organ damage
7 HYPOXIA, INFLAMMATION, AND NEUROTRANSMISSION
Low brain levels of serotonin are associated within lowered mood, anxiety, and susceptibility to depression (Praag, 2004).
Oxygen is a substrate for serotonin synthesis, and even at
physiological oxygen levels, oxygen availability seemingly limits 5‐HT
production (Katz, 1980; Nishikawa et al., 2005). Also, when present in brain tissue, inflammatory cytokines such as TNF‐α, IL‐1, and IL‐6 give rise to sickness behavior—changes in subjective experience and behavior that resemble those experienced in depression (Dantzer & Kelley, 2007; Iadecola et al., 2020).
Cytokines are thought to reduce serotonin levels by turning its
precursor, tryptophan, into kynurenine instead. Kynurenine metabolism,
in turn, reduces glutamate and dopamine release (Capuron & Miller, 2011), see also (Miller et al., 2009).
These mechanisms could affect cognitive functions and quality‐of‐life
for COVID‐19 patients patient with hypoxemia, high cytokine levels,
and/or reduced brain tO2—see Figure 3.
8 THERAPEUTIC IMPLICATIONS?
Anticoagulant, antithrombotic, and antiplatelet drugs are already implemented in the management of COVID‐19 (Godino et al., 2020),
and this review merely reiterates the need to consider microvascular
function, perhaps even early in the disease. The review suggests that
cellular energy crises may contribute to tissue vulnerability during
severe COVID‐19. Therapies that limit metabolic demands could therefore
prove protective, keeping in mind that our knowledge of COVID‐19 remains
limited and that any interventions should be carefully designed,
monitored, and reported. For example, maintenance of SGLT2 inhibitor
treatment might be tested in diabetic COVID‐19 patients with the aim of
maintaining lowered kidney oxygen demands if precautions are taken to
avoid ketoacidosis (Das & Dutta, 2020).
Similarly, glucocorticoids, besides protecting the microcirculation,
have dose‐dependent effects on mitochondrial ATP yields that may inform
optimal dosing (Du et al., 2009).
The choice of sedatives during ventilator treatment may be guided by
their effects on the brain's metabolic demands and blood flow,
respectively (Koch et al., 2020) and monitored via plasma markers of neuronal injury and glial activation (Kanberg et al., 2020).
9 CONCLUSION—AND UNANSWERED QUESTIONS
SARS‐CoV‐2‐related inflammation and capillary damage may
contribute synergistically to acute and long‐term COVID‐19 symptoms by
interfering with blood and tissue oxygenation. Further studies of
microvascular changes during COVID‐19—and especially subsequent
capillary repair—are needed to understand capillary dysfunction's impact
on the acute and chronic health effects of the disease. If
COVID‐19‐related capillary dysfunction persists in some organs, future
attention to the vascular health in younger subjects with a history of
COVID‐19 may be warranted. The COVID‐19 pandemic highlights a need to
develop biomarkers of capillary function across organs in humans—and may
increase our understanding of the microcirculation's role in human
health and disease.
ACKNOWLEDGMENT
The author is indebted to Prof. P. Gutiérrez‐Lizardi for his inspiration and to Ms Henriette Blæsild Vuust for artwork.
DISCLOSURES
LØ is a minority shareholder and Scientific Advisory Board
member in Cercare Medical Aps, Denmark and received honoraria for
lecturing from Takeda Pharmaceutical Company Limited.
