Ischemic preconditioning for the treatment of COVID-19: Not only protection from cardiac ischemia

Elpidio Santillo

doi:10.4103/ACCJ.ACCJ_34_20

OPINION

Year : 2021 | Volume : 3 | Issue : 2 | Page : 51-53

Ischemic preconditioning for the treatment of COVID-19: Not only protection from cardiac ischemia

Elpidio Santillo
Geriatric Rehabilitative Department, Rehabilitative Cardiology Unit, Italian National Research Center on Aging (IRCCS-INRCA), Contrada Mossa 2, 63900 Fermo, Italy

Date of Submission	13-Sep-2020
Date of Decision	05-Oct-2020
Date of Acceptance	29-Nov-2020
Date of Web Publication	06-Jul-2021

Correspondence Address:
Dr. Elpidio Santillo
Geriatric Rehabilitative Department, Rehabilitative Cardiology Unit, Italian National Research Center on Aging (IRCCS-INRCA), Contrada Mossa 2, 63900 Fermo
Italy

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ACCJ.ACCJ_34_20

Abstract

Ischemic preconditioning (IPC) is an innate mechanism of tissue protection from ischemia, which is easily replicable in clinical settings in the form of remote IPC. The final protective effect of IPC comprises the induction of favorable anti-inflammatory and anti-thrombotic molecular pathways. Recent studies on humans have confirmed that IPC protocols may exert cardioprotective actions. Moreover, IPC was also found to be capable of reducing surgical lung injury through the contrast of inflammatory response. Hence, IPC seems an ideal candidate to be tested as an innovative therapeutic weapon against a disease as coronavirus disease 19 (COVID-19), in which inflammation plays a key role. Interestingly, the use of IPC protocols for COVID-19 patients, beyond the potentiality of reducing the cardiologic complications, could also prove useful for the attenuation of inflammatory phenomena that characterize the course of coronavirus disease.

Keywords: Cardiovascular disease, coronavirus disease 19, inflammation, ischemic preconditioning, lung injury

How to cite this article:
Santillo E. Ischemic preconditioning for the treatment of COVID-19: Not only protection from cardiac ischemia. Ann Clin Cardiol 2021;3:51-3

How to cite this URL:
Santillo E. Ischemic preconditioning for the treatment of COVID-19: Not only protection from cardiac ischemia. Ann Clin Cardiol [serial online] 2021 [cited 2023 Jun 4];3:51-3. Available from: http://www.onlineacc.org/text.asp?2021/3/2/51/336220

Introduction

Recent coronavirus disease 19 (COVID-19) pandemic has forced health systems worldwide to face the challenging task of preventing the contagion among the populations, even by adopting severe measures of public policy as quarantine and whole countries' lockdowns.^[1]

Because of the rapid spread of the disease, pharmacological research has been hardly engaged in finding effective drugs for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), pending the development of a specific vaccine. Meanwhile, a lot of molecules previously used for other viral diseases have been tested against SARS-CoV-2 infection in early randomized clinical trials, which have shown conflicting results.^[2],[3]

Unfortunately, in addition to affecting the respiratory system, SARS-CoV-2 has also proved capable of triggering serious cardiovascular complications, such as myocarditis, pericarditis, heart failure, and arrhythmias.^[4] Moreover, some drugs which have been used for the treatment of COVID-19 patients, as chloroquine and azithromycin, share the potentiality of prolonging the QT interval on electrocardiography, thereby predisposing to fatal heart arrhythmias.

Surely, some pathogenic links between COVID-19 and cardiovascular diseases (i.e., the interactions of coronavirus with components of renin–angiotensin–aldosterone system) remain to be fully clarified.

Therefore, given the very high epidemiological impact of the disease and the problematic clinical management, especially for cardiological patients, the need to test and introduce additional treatment options for COVID-19 is now well recognized.

Ischemic Preconditioning: A Cardioprotective Promising Approach for COVID-19

Ischemic preconditioning (IPC) represents a well-known nonpharmacological therapeutic approach for tissue and organ protection. Interestingly, it could prove to be an innovative weapon to utilize against SARS-CoV-2 infection.

IPC can be defined as an adaptive physiological mechanism, whereby short periods of ischemia/reperfusion exerted on a vascular bed confer protection against a subsequent more prolonged ischemia.

It has been described for the first time by Murry et al. in 1986 in a murine model of myocardial ischemia, in which the application of IPC was able to significantly reduce infarct area after a protracted ischemic period.^[5] IPC is defined as “remote” (RIPC) when initial short ischemic events, occurring in a vascular bed, provide protection from ischemia in a distant organ.^[6]

RIPC protocols can be easily and safely performed in clinical contexts and so far have been investigated in numerous studies that examined the benefits of RIPC in various organs, especially heart, kidney, brain, and liver.

In the last years, the clinical translation of RIPC has been questioned. Indeed, some large multicenter trials of patients undergoing heart surgery, have shown no advantages in RIPC arms as compared to controls.^[7],[8]

However, more recent studies have caused a revival of interest in the possible utility of RIPC when applied in the same clinical setting.

In fact, a recent meta-analysis of 27 randomized clinical trials, including a total of 5652 patients undergoing cardiac or vascular surgery, observed that patients randomized to RIPC had significantly less myocardial infarctions.^[9] What is more, patients in the RIPC's arms had significantly less acute renal failure and a shorter hospital stay, even if the RIPC itself was not able to decrease the overall mortality.

The protection of RIPC against myocardial infarctions as observed in subjects undergoing cardiac or vascular surgery could also be evaluated in people affected by COVID-19. If confirmed, this beneficial action would be of particular clinical importance for cardiological patients with SARS-CoV-2 infection. In fact, patients with COVID-19 and pre-existing cardiovascular disease are particularly frail. Their death rate is 10.5%, which is higher than in patients with COVID-19 and chronic respiratory disease or cancer in which it has been estimated to be 6.3% and 5.6%, respectively.^[10]

Moreover, it has been estimated that between 8% and 28% of COVID-19 patients undergo an increase in troponin levels in the early stages of the disease, which would most likely result from myocardial injury.^[4]

Taking into account the reported evidence, pioneering studies are desirable for investigating the capability of IPC in reducing both myocardial injury and mortality in individuals with COVID-19.

Ischemic Preconditioning and Contrast of Inflammation

COVID-19 is a viral disease in which the initial inflammation in the lungs can rapidly intensify and become systemic through a cytokine storm, provoking even fatal complications, such as shock and multiorgan failure.

The rationale for the use of IPC-based protocols to counteract the inflammation due to SARS-CoV-2 infection lies in the pleiotropic molecular and cellular mechanisms thought to be on the basis of the IPC itself. In particular, the protection conferred from IPC after short ischemic periods seems triggered by chemical (nitric oxide, autacoids, etc.) and physical (myocardial stretch, mild hypothermia) stimuli, which promote intracellular signaling. Subsequently, components of the mitochondria and cytoskeleton appear involved as key effectors of the protection.^[11]

Regarding RIPC, it has been shown that, in humans, its defensive effect includes the prevention of inflammation through the positive modification of the expression of the inflammatory gene.^[12]

Congruently, in a systematic review of clinical randomized and controlled trials, Zheng et al. found that RIPC protocols were helpful even for the prevention of lung injury in patients who underwent cardiovascular surgery via the reduction of the pulmonary inflammatory responses.^[13]

In addition, initial evidence from animal models suggests that IPC could prove beneficial also when it is used for counteracting septic cardiomyopathy.^[14]

These findings are not surprising as, in previous studies, IPC also reduced circulating levels of tumor necrosis factor-alpha and interleukin-6.^[15],[16] Interestingly, these two cytokines are known to enhance systemic inflammation and contribute to lung inflammation in COVID-19.

Ischemic Preconditioning: Beyond Anti-inflammatory Effects for COVID-19

Beyond favoring tissue resistance to ischemia and counteracting inflammation, IPC could antagonize other pathogenic key players of COVID-19 as the altered immune response and the pro-thrombotic state.^{[17],[18],[19],[20]}

In addition, radical damage, endothelial dysfunction, and apoptosis, which occur during SARS-CoV-2 infection, could be potentially mitigated by IPC.^{[21],[22],[23],[24]}

However, it is reasonable thinking that IPC would reveal most effective in the early phases of the coronavirus disease, preventing hypothetically the progression from mild to severe forms [Figure 1].

Figure 1: At the initial stages of coronavirus disease 19, IPC-based protocols might produce maximal clinical benefits. When used in this phase, in most responsive patients, IPC could arrest or slow the progression from mild to severe form of the disease. After cytokines' storm has started, the helpful effects of IPC might become less and less clinically relevant. ARDS: Acute respiratory distress syndrome; MOF: Multiple organ failure; PIC: Pulmonary intravascular coagulopathy; IPC: Ischemic preconditioning.

Click here to view

Conclusions

Conceptually, the use of IPC-based protocols for the treatment of COVID-19 offers the intriguing potential of exerting benefits on various organs, such as the heart and lungs, especially during the early stages of the SARS-CoV-2 infection.

However, although theoretically promising, the evaluation of clinical efficacy of IPC for the treatment of COVID-19 may not be very simple. In fact, the best preconditioning protocol in terms of duration and timing remains to be defined. Moreover, some patients like the elderly seem to be less responsive to IPC. Finally, in clinical studies, the benefits of IPC are often confounded by other variables, as the use of certain drugs such as anesthetics. On the other hand, should future trials confirm the usefulness of RIPC protocols for the treatment of COVID-19, clinicians could quickly include it among their treatment options. In fact, RIPC is widely and inexpensively reproducible in clinical settings by only inflating/deflating a blood pressure cuff.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Xiao Y, Torok ME. Taking the right measures to control COVID-19. Lancet Infect Dis 2020;20:523-4.
2.	Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, et al. Remdesivir in adults with severe COVID-19: A randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020;395:1569-78.
3.	Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. Remdesivir for the treatment of Covid-19 Preliminary report. N Engl J Med 2020;383:1813-26.
4.	Liu PP, Blet A, Smyth D, Li H. The science underlying COVID-19: Implications for the cardiovascular system. Circulation 2020;142:68-78.
5.	Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation 1986;74:1124-36.
6.	Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P. Regional ischemic 'preconditioning' protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation 1993;87:893-9.
7.	Hausenloy DJ, Candilio L, Evans R, Ariti C, Jenkins DP, Kolvekar S, et al. Remote ischemic preconditioning and outcomes of cardiac surgery. N Engl J Med 2015;373:1408-17.
8.	Meybohm P, Bein B, Brosteanu O, Cremer J, Gruenewald M, Stoppe C, et al. A multicenter trial of remote ischemic preconditioning for heart surgery. N Engl J Med 2015;373:1397-407.
9.	Sardar P, Chatterjee S, Kundu A, Samady H, Owan T, Giri J, et al. Remote ischemic preconditioning in patients undergoing cardiovascular surgery: Evidence from a meta-analysis of randomized controlled trials. Int J Cardiol 2016;221:34-41.
10.	Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020; 5(7): 811-18.
11.	Heusch G. Molecular basis of cardioprotection: Signal transduction in ischemic pre-, post-, and remote conditioning. Circ Res 2015;116:674-99.
12.	Konstantinov IE, Arab S, Kharbanda RK, Li J, Cheung MM, Cherepanov V, et al. The remote ischemic preconditioning stimulus modifies inflammatory gene expression in humans. Physiol Genomics 2004;19:143-50.
13.	Zheng L, Han R, Tao L, Yu Q, Li J, Gao C, et al. Effects of remote ischemic preconditioning on prognosis in patients with lung injury: A meta-analysis. J Clin Anesth 2020; 63:109795. doi: 10.1016/j.jclinane.2020.109795.
14.	Honda T, He Q, Wang F, Redington AN. Acute and chronic remote ischemic conditioning attenuate septic cardiomyopathy, improve cardiac output, protect systemic organs, and improve mortality in a lipopolysaccharide-induced sepsis model. Basic Res Cardiol 2019;114:15.
15.	Meldrum DR, Dinarello CA, Shames BD, Cleveland JC Jr. Cain BS, Banerjee A, et al. Ischemic preconditioning decreases postischemic myocardial tumor necrosis factor-alpha production. Potential ultimate effector mechanism of preconditioning. Circulation 1998;98:II214-8.
16.	Harkin DW, Barros D'Sa AA, McCallion K, Hoper M, Campbell FC. Ischemic preconditioning before lower limb ischemia-reperfusion protects against acute lung injury. J Vasc Surg 2002;35:1264-73.
17.	Shi Y, Wang Y, Shao C, Huang J, Gan J, Huang X, et al. COVID-19 infection: The perspectives on immune responses. Cell Death Differ 2020;27:1451-4.
18.	Dolhnikoff M, Duarte-Neto AN, de Almeida Monteiro RA, Ferraz da Silva LF, de Oliveira EP, Nascimento Saldiva PH, et al. Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19. J. Thromb. Haemost 2020;18:1517-19.
19.	Shimizu M, Saxena P, Konstantinov IE, Cherepanov V, Cheung MM, Wearden P, et al. Remote ischemic preconditioning decreases adhesion and selectively modifies functional responses of human neutrophils. J Surg Res 2010;158:155-61.
20.	Przyklenk K, Whittaker P. Ischemic conditioning attenuates platelet-mediated thrombosis: A Tale of reverse translation. J Cardiovasc Pharmacol Ther 2017;22:391-6.
21.	Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endothelitis in COVID-19. Lancet 2020;395:1417-8.
22.	Schönrich G, Raftery M.J, Samstag Y. Devilishly radical NETwork in COVID-19: Oxidative stress, neutrophil extracellular traps (NETs), and T cell suppression. Adv Biolog Regulat 2020;77:100741. doi: 10.1016/j.jbior.2020.100741.
23.	García-de-la-Asunción J, Bruno L, Perez-Griera J, Galan G, Morcillo A, Wins R, et al. Remote ischemic preconditioning decreases oxidative lung damage after pulmonary lobectomy: A single-center randomized, double-blind, controlled trial. Anesth Analg 2017;125:499-506.
24.	Albrecht M, Zitta K, Bein B, Wennemuth G, Broch O, Renner J, et al. Remote ischemic preconditioning regulates HIF-1α levels, apoptosis and inflammation in heart tissue of cardiosurgical patients: A pilot experimental study. Basic Res Cardiol 2013;108:314.