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Table of Contents
NOVEL THERAPEUTIC APPROACH
Year : 2020  |  Volume : 17  |  Issue : 5  |  Page : 50-54

COVID19 infection and vascular rearrangement/ controlled angiogenesis – A new supportive therapeutic approach in patients with pre-existing ischemic and high-shear vascular conditions


1 Department of Laboratory Services, Apollo Gleneagles Hospitals, Kolkata, West Bengal; Department of Research, Apollo Hospitals Educational and Research Foundation, Delhi, India
2 Department of Research, Apollo Hospitals Educational and Research Foundation, Delhi, India

Date of Submission14-Jul-2020
Date of Acceptance15-Jul-2020
Date of Web Publication21-Aug-2020

Correspondence Address:
Debatosh Datta
Department of Laboratory Services, Apollo Gleneagles Hospitals, Kolkata, India; 58, Canal Circular Road, Kadapara, Phool Bagan, Kankurgachi, Kolkata, West Bengal - 700 054
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/am.am_93_20

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  Abstract 

This is an indicative mini-review on possible new therapeutics for COVID-19 with preexisting ischemic morbidities. The review highlights a new supportive therapeutic approach where lysine-induced controlled vascular organization (angiogenesis) has been demonstrated in reversal of cerebrovascular ischemic stroke which appears to be one of the few final fatal clinical outcomes of current COVID-19 infections. Further, a parallel supportive time-bound induction of fresh exchange beds, by way of rapid collateral formation, is proposed in all comorbid ischemic patients with the low-molecular-weight angiogen(s), with an objective of mitigation of tissue/organ ischemia.

Keywords: Controlled angiogenesis, low molecular weight angiogen, new therapeutics COVID-19, reversal of cerebrovascular ischaemic stroke, vascular rearrangement


How to cite this article:
Datta D, Saha GK, Ganguly NK. COVID19 infection and vascular rearrangement/ controlled angiogenesis – A new supportive therapeutic approach in patients with pre-existing ischemic and high-shear vascular conditions. Apollo Med 2020;17, Suppl S1:50-4

How to cite this URL:
Datta D, Saha GK, Ganguly NK. COVID19 infection and vascular rearrangement/ controlled angiogenesis – A new supportive therapeutic approach in patients with pre-existing ischemic and high-shear vascular conditions. Apollo Med [serial online] 2020 [cited 2021 Sep 24];17, Suppl S1:50-4. Available from: https://www.apollomedicine.org/text.asp?2020/17/5/50/292964


  Brief Background Top


Current global emergency by way of COVID-19 infections is beyond parallels, except possibly the famous Spanish flu exactly a 100-years' old. Unfortunately, our recalls from that episode are of hardly any value.

Still, with remarkable advances in science and even after over 0.7 million deaths and 18 million infected patients around the world and rising, our handling of this infective viral condition does not give us nearly any conclusive direction about definite diagnostics or uniform lines of therapy, particularly in patients with comorbidities.

Covid-19 episode began as lung disease where respiratory failures were held to be the end pathology. Subsequent analyses opened up other directions – cardiac, kidney, and neural affections led to it being a multi-organ disease with variable endings. All these organ involvements were observed to have a common denominator – extensive vasculopathy resulting in the development of disseminated clots distributed all over.

Still, after these costly learnings, there is a slim consensus about any primary line of affection and its subsequent spread, particularly in premorbid population, which might help develop a uniform line of therapy in this population.[1],[2],[3],[4]

As mentioned, postmortem findings of COVID-19 patients who are confirmed to have died of this virus infection have been pointing toward a common denominator which is extensive vascular obstructions from intravascular coagulation and a uniform sequence of molecular events leading to such intravascular coagulations. Such intravascular clots that are extensive and of varying sizes have been observed nearly in all subjects with viral infection and nearly in all organs.


  COVID-19 Infection Severity Probably Centers Around Two Sets of Events Top


First, COVID19 infection severity centers around virus induced overflowing inflammatory response, with production of excess inflammatory mediators including interleukins (ILs). These inflammatory responses probably originate in organs wherever Angiotensin-converting enzyme 2 (ACE2) is distributed (primarily in the lung because of entry route of the virus) and disseminates into the systemic circulation, leading to the formation of intravascular macro and micro coagulum. This leads to compromised supply and reduced drainage from the organs without any selectivity. Therefore, any central therapeutic approach must address:

  1. Control of inflammation
  2. Suppression of inflammatory mediators in circulation
  3. Intense anti-coagulation.


Without any preexisting morbidities, these collectively constitute nearly a comprehensive therapeutic approach.

Second, in patients with existing morbidities, i.e., mostly with ischemic organs resulting from flow hindrance and diffusion hindrance, an additional proposed therapeutic approach includes simultaneous mitigation of compromised circulation status through controlled collateral development, resulting in a reduction in the level of ischemia – in general. This can be brought about through induced controlled vascular re-arrangement (that is induced controlled angiogenesis) mediated by low-molecular-weight angiogen(s) in ischemic organs (cerebral/neural tissue, kidney, heart, and lung).


  Molecular Pathology Top


Renin–angiotensin axis under normal physiological conditions elaborates angiotensin 1–9 and angiotensin 1–7 mediated by ACE2, leading to local vasodilatation in tissues [Figure 1]. This is countered by AT1R expression in situ ations of Covid-19 infection which deactivates ACE2, resulting in less or no formation of the above vasodilatory, anti-inflammatory peptides (angiotensin 1–7 and angiotensin 1–9) [Figure 1]. This results in relative quantitative augmentation of vasoconstriction and pro-inflammation events (including the release of inflammatory mediators through the counter pathway by AT1R). Resident peri-alveolar fibroblasts are a potential source of IL-8 and collagen under intense inflammatory conditions [Figure 2].
Figure 1: Renin–angiotensin axis. Angiotensin-converting enzyme 2 is the receptor that allows severe acute respiratory syndrome coronavirus 2 entry into cells and is distributed across the tissues including the nasal epithelium, nasopharynx, tongue, and oropharynx

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Figure 2: Alveoli capillary arrangement in diabetic patients (schematic presentation)

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In uncomplicated cases without any flow stasis, the balance between vasodilatation and vasoconstriction is determined by the level of loss of ACE2 (effectively, viral load).

Representative lung alveoli are lined with close-set capillary on the wall under normal conditions. Under uncomplicated situations, flow pattern differs from comorbid ischemic conditions (like diabetes with or without hypertension, stroke, chronic kidney disease [CKD], and coronary artery disease [CAD]) because of varying degrees of adherent glucose load on the walls and in all components of the flowing phase of blood (all blood proteins and blood cells get glycosylated to different extents) [Figure 2].

In diabetes/ischemic conditions, flow hindrance and diffusion hindrance are the central pathologies resulting from variable degrees of nonenzymatic nonspecific glucose adherence among individuals (although degree of ischemia is never considered – till now –to be the guiding factor in clinical and prognostic assessments). In such ischemic conditions, with or without high wall shear (elevated blood pressure [BP] particularly with coexisting diabetes), endothelial damages take place much more extensively compared to normotensive individuals because of wall shear force getting magnified by the adherent/hanging glucose slime.

These endothelial damage sites act as the foci for coagulation events.

Therefore, high blood glucose – irrespective of the intensity of therapy – complicates the circulatory status negatively (because of extreme lability of the analyte with nearly unending possibility of intraday fluctuations based on uncountable influencing parameters and each upward surge of blood glucose level causes the said glycosylation by default, irrespective how intense the ongoing therapy is) and along with high BP, as mentioned above, generates quantitatively much more endothelial foci for intravascular coagulation to proceed (in COVID-19 infections).

Five dissected events are described here which result in overflowing inflammatory reactions resulting in the described Cytokine Storm (in lung tissue as the primary site). These mediators subsequently go into circulatory spread promoting systemic coagulation events – both macro and micro [Figure 3].
Figure 3: Mechanism COVID-19 infection induced inflammation in the alveolar sac

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Event I: Viral entry into Type-II alveolar cells mediated by ACE2 (well documented) and intracellular viral replication resulting in the release of loads of viral particles in alveolar cavities.

Event II: Relative early vasoconstriction mediated by AT1R predominance.

Event III: Acute inflammatory response from resident alveolar macrophage, releasing – IL1, IL6, IL8, IL29 and few other macrophage cytokines. Of these mixed ILs, IL6 predominates quantitatively and spreads into systemic circulation, giving rise to abnormal coagulation events.

Of the ILs, IL6 is the clinical marker in assessing overall cytokine release status and hence the onset of any clinically dreaded uncontrolled inflammatory reactions.

Event IV: Extensive polymorphonuclear (PMN) leukocyte intravasation into alveolar space from the wall adherent capillaries with resulting release of a host of other nonspecific inflammatory mediators such as leukotrienes, oxygen-derived radicals, proteases, and acetyl–glyceryl–ether–phosphorylcholine (a potent phospholipid activator and mediator of many leukocyte functions, platelet aggregation, de-granulation, and inflammation). These mediators cause extensive vasodilatation and fluid accumulation in alveolar space [Figure 3].

Both these cellular responses – resident macrophage cell releasing a family of ILs and PMN leukocytes releasing other mediators – are logically proportionate to viral load and possibly explains why (at least partly) there are variable pulmonary clinical expressions by way of symptoms and signs.

Event V: Under augmented inflammatory response in the alveoli and peri-alveolar space, resident fibroblasts, by all means, release IL8 and collagen, contributing to lung consolidation and rigidity (fluid and collagen).


  Final Common Vascular Events in Both Uncomplicated and Comorbid Patients Top


Systemic vascular events are the final common molecular pathology involving all organs (where lung acts as the initiator of events) resulting in clinical presentations and outcomes depending on which organ gets affected maximally and which one marginally.

Final common vascular events are examined from two different angles, as discussed above:

  • With preexisting obstructive vascular pathology (diabetes, stroke, hypertension, CKD, and CAD).
  • Without preexisting vascular pathology.


In both, the prognosis depends on the extent of wall damage, viral load, and subject immunity.

It is important to re-emphasize here, that this virus-induced coagulation process although extensive, is different from disseminated intravascular coagulation (DIC).

Sites of coagulation in this viral infection are mostly determined by anatomical flow bifurcations or presence of preexisting wall damage, unlike in DIC which does not need any foci.

Preexisting cardiac affections (CAD or cardiac failures) contribute toward these intravascular extensive coagulation processes, most possibly through sluggish flow phenomenon or through relative peripheral bed stasis. Premature ischemic cerebral stroke events are one of the negative clinical outcomes along with chronic ischemic kidney diseases. All these can effectively be explained with systemic coagulation and development of organ ischemia.


  What's New Top


  1. While the cytokine storm is common in both uncomplicated and preexisting comorbid conditions, clinical management results depend on preexisting vascular pathologies as well as preexisting wall damage locations and extents
  2. Basic therapeutic approach has to be focused toward:


    • Suppression and neutralization of uncontrolled inflammatory reactions mediated by inflammatory mediators, IL releases, their interplays, and random results thereof
    • Supportive vascular therapy (proposed) may be instituted parallelly through a time-bound controlled induction of vascular reorganization/controlled angiogenesis, in all ischemic tissues and organs, in patients with comorbid conditions, mediated by low-molecular-weight angiogens.[5],[6],[7]


  3. This fresh new set of induced exchange bed, in all ischemic organs, in a time-bound induction (within 72–96 h), will possibly mitigate the organ failures because extensive coagulation-induced compromises in vascular supply may well be the deciding factor in overall clinical outcome
  4. While cytokine neutralization remains the central therapeutic approach, proposed induced vascular reorganization (induced controlled angiogenesis) may well take care of the restoration of flow status in microvascular beds through time-bound induction of optimum collaterals. This is hypothesized to prevent Ischemic cerebral stroke as well as rectify compromised filtration in Ischemic filters beds in kidneys and even prevent Ischemic cardiac events.



  Molecular Intervention Using Low-Molecular-Weight Angiogen(S) as a Therapeutic Approach Top


Essential amino acid lysine has been observed to have profound controlled angiogenic property.[5],[6] The molecule belongs to the basic amino acid family, with arginine and histidine being the other two members. All three members have been observed to be vasoactive now-either directly or indirectly, apart from having known metabolic roles. Arginine is the onlyin vivo starting material for the most potentin vivo vasodilator nitric oxide (biological activity).[7] Parallelly, lysine has been observed to induce controlled angiogenic response in all ischemic tissues through binding stabilization of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFr) (capillary bed action) – its biological property.

Controlled vascular reorganization (angiogenic) phenomenon is based on the enhanced coupled elaboration of VEGF and VEGFr by ischemic endothelium in general.[8] Natural VEGF-VEGFr binding on the endothelial membrane is a loose-fit phenomenon and hence biologically inefficient.[9] Lysine has been hypothesized to act as a molecular bridge between the growth factor and its receptor, thereby stabilizing the ligand-receptor complex resulting in enhanced biological response – vascular reorganization/angiogenesis.[9]

Synthetic low-molecular-weight lysine analog – 1,6 diaminohexanoic acid– has also been observed to have controlled angiogenic property in an experimental model (unpublished Data, Prof. D. Mukhopadhyay, Mayo Clinic Jacksonville, Florida, USA).

While the natural amino acid has been taken to human studies in the reversal of ischemic cerebral injury and needs to be taken to other Ischemic conditions, the synthetic molecule needs characterization – both in multi-model angiogenic abilities and in toxicity clearance (initial studies show the synthetic analog to be profoundly angiogenic and nontoxic in cell culture and small animals). The natural amino acid is long known not to have nearly any adverse effects even in loading doses.


  Conclusion Top


As a proposed new supportive therapeutic approach, Low Molecular Weight Angiogen-induced controlled vascular organization (angiogenesis) has been demonstrated in reversal of cerebrovascular ischemic stroke[6] (which appears to be one of the few final fatal clinical outcomes of current COVID-19 infections).

Parallel supportive time-bound induction of fresh exchange beds, by way of rapid collateral formation, is proposed in all comorbid ischemic patients with the low-molecular-weight angiogen(s), with an objective of mitigation of tissue/organ ischemia and subsequent failure.

Acknowledgment

The authors would like to thank Apollo Hospitals Educational and Research Foundation, Delhi office, for support and cordination. Angiogenic potential study of the synthetic lysine analogue of – 1,6 diaminohexanoic acid- was carried out by Prof. D. Mukhopadhyay from Mayo Clinic Jacksonville, Florida, USA, is gratefully acknowledged.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020;395:1417-8.  Back to cited text no. 1
    
2.
Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med 2020;383:120-8. [doi: 10.1056/NEJMoa2015432].  Back to cited text no. 2
    
3.
Becker, R.C. COVID-19 update: Covid-19-associated coagulopathy. J Thromb Thrombolysis 50, 54-67. https://doi.org/10.1007/s11239-020-02134-3 Available from: https://link.springer.com/article/10.1007/s11239-020-02134-3. [Last accessd on 2020 Jul 29].  Back to cited text no. 3
    
4.
Teuwen L, Geldhof V, Pasut A, Carmeliet P. COVID-19: The vasculature unleashed. Nat Rev Immunol 2020;20:389-91. [doi: 10.1038/s41577-020-0343-0].  Back to cited text no. 4
    
5.
Datta D, Bhinge A, Chandran V. Lysine: Is it worth more? Cytotechnology 2001;36:3-2.  Back to cited text no. 5
    
6.
Gupta R, Agarwal A, Agarwal S, Mohan P, Husain M, Alger J, et al. Reversal of acute human brain ischemic injury by lysine induced therapeutic angiogenesis: Preliminary results of a pilot study. Int J Neurol 2004;4. Available from: https://ispub.com/IJN/4/1/12495. [Last accessd on 2020 Jul 29].  Back to cited text no. 6
    
7.
Bian K, Doursout MF, Murad F. Vascular system: Role of nitric oxide in cardiovascular diseases. J Clin Hypertens (Greenwich) 2008;10:304-10. [doi: 10.1111/j. 1751-7176.2008.06632.x].  Back to cited text no. 7
    
8.
Boodhwani M, Ramlawi B, Laham RJ, Sellke FW. Targeting vascular endothelial growth factor in angina therapy. Expert Opin Ther Targets 2006;10:5-14.  Back to cited text no. 8
    
9.
Datta D, Verma P, Banerjee A, Kar S, Sengupta T, Sengupta N, et al. Lysine as a potential low molecular weight angiogen: Its clinical, experimental and in-silico validation- A brief study. bioRxiv 080176; doi: https://doi.org/10.1101/080176 (published in preprint server for biology BioRxiv server of Cold Spring Harbor Laboratories). Available from: https://www.biorxiv.org/content/10.1101/080176v1. [Last accessd on 2020 Jul 29].  Back to cited text no. 9
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

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Abstract
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Molecular Pathology
Final Common Vas...
What's New
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