Plasmapheresis as a Potential Generalizable Therapy for Myocardial Infarction

Abstract

Myocardial infarction (MI) remains the leading cause of mortality and morbidity worldwide. It is caused by a thrombotic occlusion of coronary vessel/s that leads to cardiomyocyte death. As a response, inflammatory and fibrotic responses are initiated to replace the necrotic tissue and remodel the heart. However, in most cases, these responses are excessively activated, which accentuates the injury and causes adverse cardiac remodeling, often leading to heart failure. This is highly attributed to the dysregulated repair mechanism brought by reduced regenerative capacity of the adult heart, chronic inflammation, and other patient factors, such as comorbidities, diet, and lifestyle. Because of the negative consequences of excessive inflammation and fibrosis in post-MI responses, inhibiting factors associated with these processes are one of the major approaches in MI management. Several therapies have been developed to broadly and/or selectively inhibit inflammation- and fibrosis-associated proteins over the past decades and have shown promise in addressing post-MI complications. However, challenges (e.g., off-targets, problems with drug delivery, dosage, route, and cost) and efficacy of these interventions in the clinical setting remain. Hence, alternative approaches to optimally alleviate these post-MI processes are still much needed. In this review, we discuss the possible use of plasmapheresis, a technique that involves extracorporeal replacement of blood plasma, as a treatment for MI. We provide an overview of the inflammatory and fibrotic responses after MI and focus on how plasmapheresis can be an approach to target these pathways.

Introduction

Myocardial infarction (MI) contributes to the global health burden and results in high morbidity and mortality worldwide. MI occurs when there is an abrupt reduction of blood flow in the myocardium, causing necrosis, ultimately leading to heart failure. Immediate restoration of blood flow to rescue the ischemic tissue and reduce the infarct size, usually through thrombolysis, percutaneous coronary intervention, and coronary artery bypass grafting, has been the main clinical intervention for MI. Aside from these, patients receive pharmacological interventions such as aspirin, statins, beta-blockers, angiotensin-converting enzyme inhibitors (ACEis), and angiotensin receptor blockers (ARBs) with the goal to reduce infarct size and improve ventricular remodeling. However, studies have shown that these therapies have limited efficacy in reducing MI recurrence and 10-year mortality risk, and rehospitalization remains high.^1

–4 Thus, new strategies for treating MI are in high demand.

The severity of inflammatory and fibrotic response post-MI are major therapeutic targets, as these processes play critical roles in determining the extent of infarct and subsequent left ventricle remodeling. Moreover, improving cardiac regeneration post-MI has been of great interest because the restricted regeneration capacity of adult cardiomyocytes has been shown to contribute to the elaborated fibrosis post-MI.⁵ However, amid the many attempts to target inflammation, fibrosis, and regeneration after MI, no therapy was shown to address all these factors. Moreover, off-target events, high cost, and complexity of the treatments summarize the key challenges of these therapies.^1,6

Recent studies reported the involvement of systemic responses in the clinical outcomes of MI.^7,8 For example, MI is associated with elevated levels of circulating inflammatory factors, increased activation of peripheral immune cells and age-associated pathways, dysregulated immune system, and generalized increase in atherosclerotic inflammation.^7,9 Moreover, systemic effects of MI were also found to be linked with the release of paracrine factors that cause inflammation and senescence in distal organs, such as the spleen, kidney, and liver.¹⁰

Here, we evaluate the potential use of therapeutic plasma exchange (TPE), also referred to as plasmapheresis, as a treatment for MI. It involves systemic removal or exchange of blood elements and was recently found to reduce systemic inflammation and fibrosis, while promoting multitissue rejuvenation using age-neutral saline as replacement fluid in murine models.^11,12 This review describes the molecular responses, which are elicited by MI, and the potential of plasmapheresis to attenuate these pathogenic systemic changes via dilution of the factors in blood.

Inflammatory Response After MI

Following an acute myocardial infarction episode, ischemic cellular damage triggers a series of inflammatory reactions to clear debris and facilitate healing.^13,14 The inflammatory response consists of proinflammatory and anti-inflammatory phases, which should be in balance for productive wound healing (Fig. 1).

FIG. 1.

Overview of the inflammatory response following an acute myocardial infarction (AMI). AMI triggers intense initial proinflammatory responses, such as elevation of inflammatory mediators and complement cascades, and recruitment of inflammatory cells via DAMPs/TLR4/IL-1 signaling. Inflammasomes activate caspase-1, which initiate the release of IL-1β, a known proinflammatory factor that amplifies the secretion of other proinflammatory cytokines. These responses lead to leukocyte infiltration in the injured area to clear necrotic cells. To modulate these responses, CD4⁺ T cells and dendritic cells are recruited in the injured area and initiate the anti-inflammatory responses. Overlap between inflammation and regeneration leads to minimal fibrosis and effective wound healing. IL-1, interleukin-1; DAMPs, damage-associated molecular patterns; TLR, toll-like receptor.

The proinflammatory responses (e.g., recruitment of immune cells, activation of complement cascades, and release of endogenous alarm signals called damage-associated molecular patterns) take place after MI.^9,15 The release of cytokines (IL-1β, IL-6) and chemokines (CCL2 and CCL5), which are the main drivers of post-MI inflammation, mediate the recruitment of leukocytes; their roles after MI have been extensively reviewed.^16
–18 Briefly, IL‐1β signaling stimulates chemokine synthesis and promotes leukocyte infiltration in the infarct area to clear dead cells and debris, as well as to delay myofibroblast conversion,¹⁹ and suppress the synthesis of α‐smooth muscle actin.^20,21 Meanwhile, IL-6, aside from its role in leukocyte infiltration, contributes to the development of atherosclerotic plaque, cardiac hypertrophy, and cardiomyocyte loss.²² Chemokines (CC and CXC) have been implicated in neutrophil, monocyte, fibroblast, and vascular cell recruitment, and work together with cytokines to modulate inflammatory responses post-MI.^23,24

To limit the extent of inflammatory response, anti-inflammatory signals are activated in the infarct area by recruiting macrophage subsets and Tregs, CD4⁺ T cells, and dendritic cells. They release anti-inflammatory factors, such as IL-10, which trigger the differentiation of cardiac fibroblasts to myofibroblasts and secretion of extracellular matrix (ECM) proteins, eventually leading to cardiac fibrosis.¹⁵

The balance between the inflammatory and anti-inflammatory mediators is required for productive cardiac repair and for preventing adverse cardiac remodeling.²⁵ In animal models, defects in these regulatory mechanisms result in prolonged and expanded inflammatory responses, which in turn prolong the fibrotic response and aggravate collagen deposition.^26,27

Fibrotic Response after MI

Cardiac fibrosis is an important part of the reparative process following MI. It occurs acutely following inflammation and is initiated by immune cell migration and ECM deposition around the infarcted area.^28,29 This mainly results in replacement fibrosis, wherein an expanding interstitium replaces the necrosed cellular tissue.

The process involves complex interactions of immune cells, endothelial cells, cardiomyocytes, ECM components, and a wide array of molecular mediators. Some of the key factors associated in this post-MI fibrosis are interleukins IL-1β, IL-6, tumor necrosis factor (TNF)-α, and matrix metalloproteinases, which recruit macrophages to clear the cellular debris and degrade the extracellular matrix, while transforming growth factor (TGF)-β activates fibroblasts (Fig. 2).

FIG. 2.

Overview of the fibrotic response following an acute myocardial infarction (AMI). AMI triggers fibrotic response, which is initiated by inflammation and TGF-β activation. This leads to myofibroblast proliferation to produce and organize collagen and other extracellular matrices (ECM), forming scar tissue. In young individuals, this response often leads to normal scarring. But with age, excessive myofibroblast activation occurs, which causes excessive fibrosis.

Post-MI fibrosis is needed for the survival of an organism. The deposited ECM provides tensile strength to the injured myocardium, maintains structural integrity, and provides a scaffold for future remodeling. Without fibrosis, the injured myocardium is more prone to cardiac aneurysm and rupture.^26,30
–32 Moreover, the repaired scaffold maintains the function of the heart conduit by retaining the blood passageway, serving as a temporary bridge for the cellular gaps in the myocardium.³³ Fibrosis is also a migratory medium for the inflammatory and reparative cells to migrate toward the affected areas.

Despite these clear benefits and roles in the reparative process, myocardial fibrosis, if excessive, causes pathological cardiac remodeling with subsequent adverse outcomes. Because of the lack of inherent contractility and inherent stiffness, scar tissue can interfere with the effective blood pumping.^30,31 This results in a loss in pumping efficiency and filling capacity, leading to systolic and diastolic dysfunction. The highly dense and fibrous tissue also hampers the migration and formation of cellular structures that are acutely needed during the remodeling process. A lack of tissue remodeling can seriously affect the reparative process by interfering with gas and nutrient exchange and the establishment of cell niches that are important for the immediate regeneration of the surrounding areas.

Ultimately, excessive fibrosis is deemed a major cause of heart failure, arrhythmias, and other adverse sequelae that increase patients’ risk for hospitalization and mortality after MI. This has led to interest in targeting fibrosis as a potential therapy over the past decades.^34,35 Yet, currently, most therapies targeting the activity of fibroblasts are still in early preclinical stages.³⁵

The importance of post-MI processes for cardiac health highlights the need to further investigate the modulation of cardiac fibrosis after MI with the goal of modifying disease via appropriate repair response while clinically minimizing the extent of defective scar formation and adverse remodeling.

Therapeutic Targeting of Inflammation and Fibrosis After MI

Given the negative consequences of excessive and prolonged inflammation and fibrosis after MI, several strategies have aimed to attenuate the initial proinflammatory response, enhance the anti-inflammatory response, and reduce the fibrotic response (Table 1).²⁰

Table 1.

Examples of Broad-Range and Targeted Therapies for MI Patients

	Mechanism of action	Major findings
Broad range
Glucocorticoids	Reduce leukocyte infiltration by decreasing chemokine expression and suppressing adhesive interactions between leukocytes and endothelial cells	Available studies showed varying results on its effectiveness. Some showed that it did not affect infarct size and hemodynamic response.^36,37 But some has reported reduced infarct size, reduced collagen deposition, and apoptotic cardiomyocytes.^38,39
NSAIDs	Inhibit COX‐1 and COX‐2	Some clinical trials have shown high incidence of cardiac rupture after NSAID use.^40 –42
Selective
Targeting cytokines	Anti-IL1B Anti-IL6	No significant effects on coronary blood flow, infarct size, or the rate of ECG ST‐segment elevation among STEMI patients.^43,44
Targeting cytokines	Anti-IL-1	Anti-IL1 treatment, anakinra, reduced the acute inflammatory response among STEMI patients, but did not show improvement on LV remodeling or function.^45,46
Targeting chemokines	Anti‐CCL2	Therapy against monocyte chemoattractant protein-1 (MCP-1/CCL2), reduced infarct size in experimental models of MI.^47,48 However, clinical evidence for CCL2 therapy use remains limited.
Targeting the complement cascade	Complement inhibition	Pexelizumab, an anti-C5 complement antibody, neither reduced infarct size nor improved clinical outcomes.⁴⁹ It also did not have a significant effect on mortality, cardiogenic shock, and heart failure after MI.⁵⁰
Targeting signaling pathways	TGF-β pathway	Several molecular targets against TGF-β have been investigated, including drugs (i.e., simvastatin, valsartan), noncoding RNAs, gene therapies, and cell therapies.^51 –55 Of note, these treatments were able to reduce fibrosis and ameliorate ventricular remodeling. Statins, ACEi, and ARBs which target TGF-β are also widely used in the clinical setting. However, challenges on the pleiotropic effects of TGF-β inhibitions remain.^56,57 And large-scale clinical trials involving targeted TGF-β inhibition after MI are still limited.
	Notch1/Mfn2 pathway	Melatonin treatment has significantly reduced infarct size in patients with STEMI after PCI.⁵⁸
	MAPK pathway	Losmapimod, a p38 MAPK inhibitor, showed varying clinical outcomes. While it was found to improve outcomes of MI patients,⁵⁹ these findings were not observed in a larger clinical trial which noted no significant reduction in mortality, morbidity, and recurrent-MI risks post-MI.⁶⁰
	PDGF pathway	Imatinib, a small molecule inhibitor of tyrosine kinase, reduced cardiac fibrosis and improved diastolic dysfunction in rats, but its clinical effects are yet to be studied.^61,62

ACEi, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers; CCL, chemokine C-C motif ligand; COX, cyclooxygenase; ECG, electrocardiogram; MI, myocardial infarction; IL, interleukin; LV, left ventricle; MAPK, mitogen-activated protein kinase; NSAID, nonsteroidal anti‐inflammatory drugs; PCI, percutaneous coronary intervention; PDGF, platelet-derived growth factors; STEMI, ST-elevation myocardial infarction; TGF, transforming growth factor.

Of key interest, most targets for MI are circulating factors, including but not limited to cytokines, chemokines, and miRNA.⁶³ To reiterate, these factors are vital in facilitating the healing process post-infarction. However, their excessive levels post-injury contribute to pathological remodeling. The dysregulated expression of these factors has been associated with aging,⁶⁴ lifestyle and diet,⁶⁵ comorbidities, and environmental factors.⁶⁶

Some of the most studied targets are the complement system, cytokines such as IL-1 β, IL-6, and TGF-β, and chemokines such as CCL2. These anti-inflammatory strategies have shown promise in animal models, being able to reduce infarct size and improve cardiac contractility and overall cardiac function. However, translation of these results to MI patients has been challenging (Table 1). Targeting the complement system through an antibody, pexelizumab, did not improve patients’ prognosis.⁵⁰ And while targeting IL-1 through anakinra, a recombinant interleukin‐1 receptor antagonist, has shown promise in reducing inflammation post-MI,⁶⁷ its effectiveness to reduce infarct size has shown variable results in clinical trials.⁴⁶ Similar limitations were noted for targeting inflammatory chemokines, such as CCL2, which showed fibrosis reduction and improved diastolic function post-MI in murine models, but limited reported clinical studies.^47,48

Targeting cell signaling pathways, which are responsive to MI, has also emerged as a clinical strategy in past decades. A network of pathways is activated post-MI to initiate the wound healing, and these are extensively reviewed.⁶⁸ This includes TGF-β/SMADs pathway, proangiogenic phosphoinositide-3 kinase/protein kinase B (PI3K/Akt) pathway, Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, and mitogen-activated protein kinases (MAPK) pathway, among others. Several molecular targets for these pathways have been applied post-MI (Table 1) and have shown benefits in addressing adverse cardiac remodeling. However, targeting these pathways has its limitations and challenges, following their complex role in other physiological functions and deleterious consequences of their skewing.

The limitations of these currently available strategies highlight the need to optimize and identify new therapeutic targets for MI management.

Plasmapheresis

The use of plasmapheresis in humans dates back to the 1950s when it was applied for the treatment of thrombotic thrombocytopenic purpura.⁶⁹ It involves the removal of plasma components (i.e., autoantibodies, immune complexes, cytokines, and toxins) in exchange for a replacement fluid such as saline with albumin or fresh frozen plasma (FFP).⁷⁰ To date, applications of TPE in the medical field have grown extensively and this procedure is currently use to treat several disease, for example, a first line treatment for myasthenia gravis, Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy, and chronic acquired demyelinating polyneuropathies, among others.⁷⁰ Table 2 enumerates the pathologies for which the therapeutic use of plasmapheresis is strongly indicated.

Table 2.

List of Diseases with Strong Recommendation (Grade 1A and 1B) for Therapeutic Plasmapheresis or Similar Techniques

Diseases	Indication	Procedure	Grade
Acute inflammatory demyelinating polyradiculoneuropathy	Primary treatment	TPE	1A
Acute inflammatory demyelinating polyradiculoneuropathy	Primary treatment	IA	1B
Acute liver failure	Acute liver failure	TPE-HV	1A
Acute liver failure	Dialysis-independence	TPE	1B
Chronic acquired demyelinating polyneuropathies	IgG/IgA/IgM related	TPE	1B
Chronic inflammatory demyelinating polyradiculoneuropathy		TPE/IA	1B
Cutaneous T-cell lymphoma	Erythrodermic mycosis fungoides/Sézary syndrome	ECP	1B
Erythrocytosis	Polycythemia vera	Erythrocytapheresis	1B
Familial hypercholesterolemia	Homozygotes	LA	1A
Focal segmental glomerulosclerosis	Recurrent in kidney transplant	TPE/IA	1B
Hereditary hemochromatosis		Erythrocytapheresis	1B
Hyperviscosity in hypergammaglobulinemia	Symptomatic	TPE	1B
Myasthenia gravis	Acute, short-term treatment	TPE/DFPP/IA	1B
Sickle cell disease, nonacute	Stroke prophylaxis	RBC exchange	1A
Thrombotic microangiopathy, thrombotic thrombocytopenic purpura		TPE	1A
Transplantation, kidney, ABO compatible	Antibody-mediated rejection	TPE/IA	1B
Transplantation, kidney, ABO compatible	Desensitization/prophylaxis, living donor	TPE/IA	1B
Transplantation, kidney, ABO incompatible	Desensitization, living donor	TPE/IA	1B

DFPP, Double filtration plasmapheresis; IA, immunoadsorption; RBC exchange, red blood cell exchange; GRADE, Grading of Recommendations Assessment, Development, and Evaluation, 1 to 5, 1A being the highest; TPE, therapeutic plasma exchange. Adopted from Connelly-Smith et al.⁷⁰

Moreover, potential benefits of plasmapheresis in other pathologies are currently being investigated clinically. As of 2024, there are 263 ongoing clinical trials involving plasmapheresis.⁷¹ Table 3 lists some clinical trials with published results that were performed the trials with healthy controls.

Table 3.

Comprehensive Table of Clinical Trials of Plasmapheresis from ClinicalTrials.gov with Results

*NCT#	Study title	Condition	Outcome
NCT01214317	Study of Induction Therapy with Mitoxantrone and Plasmapheresis to Treat Aggressive Multiple Sclerosis	Multiple Sclerosis	No change in disability status, reduced number of brain plaques
NCT01210716	Evaluation of Therapeutic Plasma Exchange Procedure Using the AMICUS Device	Autoimmune DiseasesRenal DisordersHematological DisordersOncologic Disorders	AMICUS device more effective than either separate SPECTRA
NCT01895127	Efficacy and Safety of Eculizumab for Treatment of Antibody-mediated Rejection Following Renal Transplantation	Antibody-mediated Rejection\|Humoral Rejection	Drug plus plasmapheresis is better than treatment
NCT04374149	Therapeutic Plasma Exchange Alone or in Combination with Ruxolitinib in COVID-19 Associated CRS	Cytokine Release Syndrome\|COVID19	Pure plasmapheresis shows more improvement than combined with drug
NCT04441996	Therapeutic Plasma Exchange for COVID-19-associated Hyperviscosity	COVID-19	Plasmapheresis reduced plasma viscosity, with increased survivability
NCT04456413	Convalescent Plasma as Treatment for Subjects with Early COVID-19 Infection	COVID-19	Lesser hospitalization rate, otherwise, no differences
NCT01561053	A Study to Evaluate Albumin and Immunoglobulin in Alzheimer’s Disease	Alzheimer’s Disease	Plasmpaheresis shows improvement over no plasmapheresis
NCT03897205	An Efficacy and Safety Study of Imlifidase in Treatment of Antibody-Mediated Rejection in Kidney Transplant Patients	Kidney Transplant Rejection	Drug reduces donor antibodies to greater extent until day 6, no differences after. Plasmapheresis resulted in less kidney failure overall
NCT04320823	Improving Plasma Collection Clinical Trial	Apheresis Related Hypotension	New feature proves reduced adverse effects
NCT01777412	Efficacy of Bevacizumab (Avastin) in Treatment of Acute NMO Exacerbations	Neuromyelitis Optica\|Neuromyelitis Optica Spectrum Disorder	Limited serious side effects
NCT02878603	Follow-up Study for Patients Who Completed Study ALX0681-C301 (Post-HERCULES)	Acquired Thrombotic Thrombocytopenic Purpura	Drug treated group show less thrombocytopenic purpura-related events
NCT02553317	Phase III Trial with Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura	Acquired Thrombotic Thrombocytopenic Purpura	Improvement in platelet response with the drug
NCT02033213	Volume Restriction in Esophageal Carcinoma Surgery: Randomized Clinical Trial	Esophageal Neoplasm	Similar overall outcome

*NCT# = National Clinical Trial number. Terms “Plasmapheresis”, “plasmapheresis device”, “plasma exchange”, and “plasma exchange with albumin” were used. Only studies with results available are shown. Only studies that include a control group are shown (phase I trials are excluded).

As discussed, curtailing excessive inflammation is a key element in treating MI, for which plasmapheresis can potentially provide an effective means to do so. To date, based on Table 3, none of the reported clinical trials investigated the use of plasmapheresis for MI cases. It has been used for heart transplants with the goal of limiting the circulating antibodies that interfere with organ transplants and lupus myocarditis with a similar goal of diluting the auto-reactive antibodies.^72
–74 Other examples, such as Wilson disease, which involves copper accumulation, leading to cardiac fibrosis,^75,76 are also treated with plasmapheresis to physically reduce the systemic toxins.^75,77,78

Interestingly, there are also several examples of inflammation-associated pathologies for which plasmapheresis has provided clear evidence of effectiveness. Here we provide some examples.

COVID has been observed to cause a cytokine storm in the most severe cases. To treat this, plasmapheresis was approved as a potential therapy,⁷⁹ quickly showing its advantages while having minimal side effects. This has been discussed at length elsewhere⁸⁰ but it is interesting to note that plasmapheresis provided significant benefits on proinflammatory clearance by lowering cytokine levels, as well as, reducing mortality risk.^80,81

In acute disseminated encephalomyelitis (ADEM) and GBS, excessive inflammation was linked to brain and spinal cord damages, and TPE showed some success as second line therapy to eliminate autoantibodies, immune complexes, cytokines, and cellular debris.^82,83 Of note, the inflammatory response for ADEM and GBS involves T cell activation and overexpression of inflammatory cytokines (IFN-γ, TNF-α, IL-1β and IL-6).^84,85

Further, in atopic dermatitis, TPE and similar had some potential.^33,86
–88 In atopic dermatitis, there is a dysregulated immune response featuring enhanced type 2 inflammation, involving several cytokines such as IL-4, IL-5, IL-13, and IL-31 and chemokines.⁸⁹ These cytokines mediate several downstream processes that result in mast cell activation, IgE production, and skin barrier dysfunction. In a 2015 case report, the use of TPE was able to reduce plasma IgE and improve patient symptoms and quality of life.⁸⁷

Moreover, for the purposes of this review, plasmapheresis has been deemed useful in certain diseases revolving fibrosis. These include neonatal lupus,⁹⁰ graft-versus-host disease,^91,92 organ transplant, nephrogenic systemic fibrosis,⁹³ and systemic sclerosis.⁹⁴ These pathologies have an autoimmune basis, but these demonstrate how plasmapheresis can be applied to fibrosis-based complications.

Lastly, in preclinical studies, TPE improved the balance of circulating leukocytes and of systemic proteome in older individuals, and this procedure reduced fibrosis of skeletal muscle and liver in old mice.^12,95

Overall, plasmapheresis has been shown effective in modulating immune and inflammatory responses in a wide array of diseases. It is mainly used to eliminate immune complexes, cytokines, and toxins that contribute to the pathogenesis of various diseases. A single or a few procedures of plasmapheresis are relatively safe. The patient may suffer from dizziness, chills, faintness, nausea, blurry vision, feeling of coldness or breathlessness, or temporary low blood pressure. There have also been reports of other, more serious side effects, albeit with a lower incidence. These may include reduced immunity to disease, allergic reactions, blood clotting, infections, and shock. Still, compared to the anticytokine antibodies, exogenous receptors, and other comparable factors, TPE is expected to be less harmful for the overall organismal homeostasis.

Plasmapheresis as a Therapy for MI

After MI, immune cells (e.g., leukocytes, neutrophils, monocytes/macrophages), cytokines (e.g., IL-1β, IL6, TNF-α, TGF-β), and chemokines (e.g., CCL2) orchestrate heart inflammation and fibrosis, while key regulators of signal transduction pathways become highly elevated in plasma.^44,96

–99 At their healthy normal levels, these circulating factors and pathways are needed to initiate the repair mechanisms; however, their excessive levels amplify the inflammatory and fibrotic responses. Such dysregulation promotes pathological cardiac remodeling, which causes severe clinical complications. Hence, proper modulation of these factors and pathways is needed to achieve balance in proinflammatory, anti-inflammatory, and fibrotic responses, and plasmapheresis is known to restore the systemic balance to the determinants of signal transduction.⁹⁵

Through plasmapheresis, blood elements become systemically lowered. This includes reduction of immunological factors, such as cytokines (IL-1, IL-6),¹⁰⁰ pathogenic antibodies,¹⁰¹ and complement components.^102,103 Our studies have explored the role of plasmapheresis in specific dampening of disease-associated signaling pathways,⁹⁵ and it is interesting to note that some of the mentioned factors, such as IL-1, IL-6, complement proteins, are associated with activation of inflammasome (NLRP3/Caspase-1) pathways,^104,105 MAPK, JAK/STAT3, and PI3K/AKT pathways,¹⁰⁶ and TGF-β pathways,¹⁰⁷ which are all associated with the pathogenesis of MI.

With these evidences, it is surmised that in the context of MI, plasmapheresis play a major positive role in attenuating ongoing inflammation and fibrosis. Of note, through plasmapheresis, the goal is not to systemically inhibit or remove blood factors, a challenge that has been raised in most targeted therapy. Instead, the aim is to reduce concentrations of these factors to reach their optimal levels, which productively activate the physiological repair mechanisms (Fig. 3). To date, no studies have investigated calibration of circulating factors after MI via TPE.

FIG. 3.

Therapeutic potential of plasmapheresis for acute myocardial infarction (AMI). Heart failure (HF) and associated cardiac complications following AMI are brought by excessive inflammatory and fibrotic factors which play a role in activating networks of signaling pathways, such as NLRP3/Caspase-1, PI3K/Akt, JAK/STAT, MAPK, and TGF-β. In this review, we highlight the potential of plasmapheresis, known to reduce cytokines, chemokines, immune complexes through blood dilution, to address these post-MI complications.

Furthermore, plasmapheresis has been shown to improve rejuvenation of three germ layers (liver, brain, and muscles) in murine models by resetting the old systemic milieu to a youthful state.¹² Hence, it would be interesting to investigate the effects of this procedure on the health of cardiac tissue.

Amid this promising potential of plasmapheresis as a treatment for MI, several factors are yet to be investigated. Compared to the diseases that use plasmapheresis, inflammation, and fibrosis after MI occur acutely, mainly during the initial steps of cardiac repair, ranging from onset of injury until 7 to 14 days.⁴⁶ Some reviews in this topic suggest that the initial reparative period after infarction could be as early as 24 hours.¹⁸ Hence, the timing of plasmapheresis should be considered and coordinated with the event of MI. Moreover, the number and length of exchanges to reach the optimal levels of blood factors should also be determined.

In addition, vascular access is also an important factor to consider for doing plasmapheresis. It is necessary to have a steady flow of blood while doing the procedure, as interrupted flow can disrupt the procedure and alter its effectiveness. Most apheresis devices require blood flow rates of 50–120 mL/min.¹⁰⁸ Although vascular patency and angiogenesis are highly affected in MI cases, a therapeutic opportunity was demonstrated in a study on rats, which showed that the vasculature in infarcted areas, remains patent until the gradual progression of fibrosis contributes to flow impedance.¹⁰⁹ Moreover, reperfusion therapies have significantly improved over the decades and were proven to restore blood flow in the ischemic area.¹¹⁰ Thus, we posit that the benefits of plasmapheresis can be maximized if it is performed during the early stages of MI after a reperfusion therapy was applied, to ensure stable blood flow during the TPE.

Conclusion

MI management has been improving over the past decade, yet many challenges still exist. Although several therapies have shown promising outcomes in animals, their translation to MI patients remains without success. Here, we propose the use of plasmapheresis to address the excessive inflammation and fibrosis following MI, through diluting plasma, thereby systematically reducing the MI-elicited excessive inflammatory, profibrotic factors, and immune cells. Although more research is needed to explore its application for MI and other cardiovascular diseases, plasmapheresis has long been used to treat diseases with the same pathogenic features (excessive inflammation, immune cells, toxins, etc.). Moreover, as more studies highlight the involvement of systemic responses after MI, TPE seems to be perfectly suited to ameliorate the MI pathology. Lastly, more work is needed to understand MI-related changes in plasma proteomes, which would aid in the design of future therapies.

Footnotes

Acknowledgments

All images were created in BioRender [].

Authors’ Contributions

J.M.C.C. and I.M.C. cowrote the article. J.M.C.C., J.L.G., A.R.M., A.J.A.M., J.V.S.P., and J.B.N. did the literature search. J.M.C.C., A.J.A.M., and J.V.S.P. contributed the figures. All the authors listed have made a substantial contribution to the work. All the authors have read and approved the article.

Author Disclosure Statement

The authors declare no conflict of interest.

Funding Information

This work was supported by Department of Science and Technology-Philippine Council for Health Research and Development (DOST-PCHRD) Research Enrichment Program (REP) grant (J.M.C.C.), Commission on Higher Education (CHED) Philippine-California Advanced Research Institutes-Institute for Health Innovation and Translational Medicine (PCARI IHITM) 2018-033 grant (J.M.C.C. and I.M.C.), National Institutes of Health-National Heart, Lung and Blood Institute (NIH-NHLB) R01 139605 (I.M.C.), National Institutes of Aging (NIA) R01AG071787 (I.M.C.), Open Philanthropy award (I.M.C.).

References

Saito

, Oyama

, Tsujita

, et al. Treatment strategies of acute myocardial infarction: Updates on revascularization, pharmacological therapy, and beyond. J Cardiol, 2023; 81(2):168–178; doi: 10.1016/j.jjcc.2022.07.003

Wang

, Zhao

, Wei

, et al. The prevalence of 30‐day readmission after acute myocardial infarction: A systematic review and meta‐analysis. Clin Cardiol, 2019; 42(10):889–898; doi: 10.1002/clc.23238

Yndigegn

, Lindahl

, Mars

, et al.; REDUCE-AMI Investigators. Beta-blockers after myocardial infarction and preserved ejection fraction. N Engl J Med, 2024; 390(15):1372–1381; doi: 10.1056/NEJMoa2401479

Nedkoff

, Briffa

, Murray

, et al. Risk of early recurrence and mortality in high-risk myocardial infarction patients: A population-based linked data study. Int J Cardiol Cardiovasc Risk Prev, 2023; 17:200185; doi: 10.1016/j.ijcrp.2023.200185

Alonaizan

, Carr

. Cardiac regeneration following myocardial infarction: The need for regeneration and a review of cardiac stromal cell populations used for transplantation. Biochem Soc Trans, 2022; 50(1):269–281; doi: 10.1042/BST20210231

Tajabadi

, Goran Orimi

, Ramzgouyan

, et al. Regenerative strategies for the consequences of myocardial infarction: Chronological indication and upcoming visions. Biomed Pharmacother, 2022; 146:112584; doi: 10.1016/j.biopha.2021.112584

Dutta

, Courties

, Wei

, et al. Myocardial infarction accelerates atherosclerosis. Nature, 2012; 487(7407):325–329; doi: 10.1038/nature11260

Joshi

, Toor

, Shah

ASV

, et al. Systemic atherosclerotic inflammation following acute myocardial infarction: Myocardial infarction begets myocardial infarction. J Am Heart Assoc, 2015; 4(9):e001956; doi: 10.1161/JAHA.115.001956

Fang

, Moore

X-L

, Dart

, et al. Systemic inflammatory response following acute myocardial infarction. J Geriatr Cardiol, 2015; 12(3):305–312; doi: 10.1190/9/j.issn.1671-5411.2015.03.020

10.

Zimmermann

, Beer

, Ullrich

, et al. Analysis of region specific gene expression patterns in the heart and systemic responses after experimental myocardial ischemia. Oncotarget, 2017; 8(37):60809–60825; doi: 10.1863/2/oncotarget.17955

11.

Mehdipour

, Etienne

, Liu

, et al. Attenuation of age-elevated blood factors by repositioning plasmapheresis: A novel perspective and approach. Transfus Apher Sci, 2021; 60(3):103162; doi: 10.1016/j.transci.2021.103162

12.

Mehdipour

, Skinner

, Wong

, et al. Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin. Aging (Albany NY), 2020; 12(10):8790–8819; doi: 10.1863/2/aging.103418

13.

Swirski

, Nahrendorf

. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science, 2013; 339(6116):161–166; doi: 10.1126/science.1230719

14.

Libby

, Nahrendorf

, Swirski

. Leukocytes link local and systemic inflammation in ischemic cardiovascular disease: An expanded “Cardiovascular Continuum. J Am Coll Cardiol, 2016; 67(9):1091–1103; doi: 10.1016/j.jacc.2015.12.048

15.

Ong

S-B

, Hernández-Reséndiz

, Crespo-Avilan

, et al. Inflammation following acute myocardial infarction: Multiple players, dynamic roles, and novel therapeutic opportunities. Pharmacol Ther, 2018; 186:73–87; doi: 10.1016/j.pharmthera.2018.01.001

16.

, Chen

, et al. Cytokine storm: Behind the scenes of the collateral circulation after acute myocardial infarction. Inflamm Res, 2022; 71(10–11):1143–1158; doi: 10.1007/s00011-022-01611-0

17.

Pluijmert

, Atsma

, Quax

PHA

. Post-ischemic Myocardial Inflammatory Response: A Complex and Dynamic Process Susceptible to Immunomodulatory Therapies. Front Cardiovasc Med, 2021; 8:647785; doi: 10.3389/fcvm.2021.647785

18.

Yap

, Irei

, Lozano-Gerona

, et al. Macrophages in cardiac remodelling after myocardial infarction. Nat Rev Cardiol, 2023; 20(6):373–385; doi: 10.1038/s41569-022-00823-5

19.

Frangogiannis

. Regulation of the inflammatory response in cardiac repair. Circ Res, 2012; 110(1):159–173; doi: 10.1161/CIRCRESAHA.111.243162

20.

Huang

, Frangogiannis

. Anti‐inflammatory therapies in myocardial infarction: Failures, hopes and challenges. Br J Pharmacol, 2018; 175(9):1377–1400; doi: 10.1111/bph.14155

21.

Shinde

, Frangogiannis

. Fibroblasts in myocardial infarction: A role in inflammation and repair. J Mol Cell Cardiol, 2014; 70:74–82; doi: 10.1016/j.yjmcc.2013.11.015

22.

Groot

, Al Ali

, van der Horst

ICC

, et al. Plasma interleukin 6 levels are associated with cardiac function after ST-elevation myocardial infarction. Clin Res Cardiol, 2019; 108(6):612–621; doi: 10.1007/s00392-018-1387-z

23.

Zhang

, Yang

, Chen

, et al. Role of the CCL2-CCR2 axis in cardiovascular disease: Pathogenesis and clinical implications. Front Immunol, 2022; 13:975367; doi: 10.3389/fimmu.2022.975367

24.

Mentkowski

, Euscher

, Patel

, et al. Monocyte recruitment and fate specification after myocardial infarction. Am J Physiol Cell Physiol, 2020; 319(5):C797–C806; doi: 10.1152/ajpcell.00330.2020

25.

Chalise

, Becirovic-Agic

, Lindsey

. The cardiac wound healing response to myocardial infarction. WIREs Mech Dis, 2023; 15(1):e1584; doi: 10.1002/wsbm.1584

26.

Frangogiannis

. The inflammatory response in myocardial injury, repair and remodeling. Nat Rev Cardiol, 2014; 11(5):255–265; doi: 10.1038/nrcardio.2014.28

27.

Prabhu

, Frangogiannis

. The biological basis for cardiac repair after myocardial infarction. Circ Res, 2016; 119(1):91–112; doi: 10.1161/CIRCRESAHA.116.303577

28.

Frangogiannis

. Cardiac fibrosis. Cardiovasc Res, 2021; 117(6):1450–1488; doi: 10.1093/cvr/cvaa324

29.

Scalise

RFM

, De Sarro

, Caracciolo

, et al. Fibrosis after myocardial infarction: An overview on cellular processes, molecular pathways, clinical evaluation and prognostic value. Med Sci (Basel), 2021; 9(1):16; doi: 10.3390/medsci9010016

30.

Rusu

, Hilse

, Schuh

, et al. Biomechanical assessment of remote and postinfarction scar remodeling following myocardial infarction. Sci Rep, 2019; 9(1):16744; doi: 10.1038/s41598-019-53351-7

31.

Weber

, Sun

, Bhattacharya

, et al. Myofibroblast-mediated mechanisms of pathological remodelling of the heart. Nat Rev Cardiol, 2013; 10(1):15–26; doi: 10.1038/nrcardio.2012.158

32.

Yin

, Yin

, Pan

, et al. Post-myocardial infarction fibrosis: Pathophysiology, examination, and intervention. Front Pharmacol, 2023; 14:1070973; doi: 10.3389/fphar.2023.1070973

33.

Scridon

, Balan

. Targeting myocardial fibrosis-a magic pill in cardiovascular medicine? Pharmaceutics, 2022; 14(8):1599; doi: 10.3390/pharmaceutics14081599

34.

Webber

, Jackson

, Moon

, et al. Myocardial fibrosis in heart failure: Anti-fibrotic therapies and the role of cardiovascular magnetic resonance in drug trials. Cardiol Ther, 2020; 9(2):363–376; doi: 10.1007/s40119-020-00199-y

35.

Travers

, Tharp

, Rubino

, et al. Therapeutic targets for cardiac fibrosis: From old school to next-gen. J Clin Invest, 2022; 132(5):e148554; doi: 10.1172/JCI148554

36.

Spath

, Lefer

. Effects of dexamethasone on myocardial cells in the early phase of acute myocardial infarction. Am Heart J, 1975; 90(1):50–55; doi: 10.1016/0002-8703(75)90256-2

37.

Genth

, Hofmann

, Schaper

. Ineffectiveness of methylprednisolone to reduce infarct size in experimental coronary occlusion. Basic Res Cardiol, 1982; 77(2):182–187; doi: 10.1007/BF01908171

38.

Vivaldi

, Eyre

, Kloner

, et al. Effects of methylprednisolone on collagen biosynthesis in healing acute myocardial infarction. Am J Cardiol, 1987; 60(4):424–425; doi: 10.1016/0002-9149(87)90277-3

39.

, Strom

, Chen

. Dexamethasone induces transcriptional activation of Bcl-xL gene and inhibits cardiac injury by myocardial ischemia. Eur J Pharmacol, 2011; 668(1–2):194–200; doi: 10.1016/j.ejphar.2011.06.019

40.

Silverman

, Pfeifer

. Relation between use of antiinflammatory agents and left ventricular free wall rupture during acute myocardial infarction. Am J Cardiol, 1987; 59(4):363–364; doi: 10.1016/0002-9149(87)90817-4

41.

Metz

, Stubbs

, Hearron

. Significance of infarct site and methylprednisolone on survival following acute myocardial infarction. J Int Med Res, 1986; 14 Suppl 1:11–14; doi: 10.1177/03000605860140S102

42.

Varga

, Sabzwari

SRA

, Vargova

. Cardiovascular risk of nonsteroidal anti-inflammatory drugs: An under-recognized public health issue. Cureus, n.d; 9(4):e1144; doi: 10.7759/cureus.1144

43.

Baran

, Nguyen

, McKendall

, et al.; Limitation of Myocardial Infarction Following Thrombolysis in Acute Myocardial Infarction (LIMIT AMI) Study Group. Double-blind, randomized trial of an anti-CD18 antibody in conjunction with recombinant tissue plasminogen activator for acute myocardial infarction: Limitation of myocardial infarction following thrombolysis in acute myocardial infarction (LIMIT AMI) study. Circulation, 2001; 104(23):2778–2783; doi: 10.1161/hc4801.100236

44.

Hartman

MHT

, Groot

, Leach

, et al. Translational overview of cytokine inhibition in acute myocardial infarction and chronic heart failure. Trends Cardiovasc Med, 2018; 28(6):369–379; doi: 10.1016/j.tcm.2018.02.003

45.

Abbate

, Kontos

, Grizzard

, et al.; VCU-ART Investigators. Interleukin-1 Blockade With Anakinra to Prevent Adverse Cardiac Remodeling After Acute Myocardial Infarction (Virginia commonwealth university anakinra remodeling trial [VCU-ART] Pilot Study). Am J Cardiol, 2010; 105(10):1371–1377; doi: 10.1016/j.amjcard.2009.12.059

46.

Morton

, Rothman

AMK

, Greenwood

, et al. The effect of interleukin-1 receptor antagonist therapy on markers of inflammation in non-ST elevation acute coronary syndromes: The MRC-ILA Heart Study. Eur Heart J, 2015; 36(6):377–384; doi: 10.1093/eurheartj/ehu272

47.

Hayashidani

, Tsutsui

, Shiomi

, et al. Anti-monocyte chemoattractant protein-1 gene therapy attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation, 2003; 108(17):2134–2140; doi: 10.1161/01.CIR.0000092890.29552.22

48.

Dewald

, Zymek

, Winkelmann

, et al. CCL2/Monocyte Chemoattractant Protein-1 regulates inflammatory responses critical to healing myocardial infarcts. Circ Res, 2005; 96(8):881–889; doi: 10.1161/01.RES.0000163017.13772.3a

49.

Mahaffey

, Granger

, Nicolau

, et al.; COMPLY Investigators. Effect of pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to fibrinolysis in acute myocardial infarction: The COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) trial. Circulation, 2003; 108(10):1176–1183; doi: 10.1161/01.CIR.0000087404.53661.F8

50.

Armstrong

, Granger

, Adams

, et al.; APEX AMI Investigators. Pexelizumab for acute ST-elevation myocardial infarction in patients undergoing primary percutaneous coronary intervention: A randomized controlled trial. JAMA, 2007; 297(1):43–51; doi: 10.1001/jama.297.1.43

51.

Sui

, Wei

, Wang

. Novel mechanism of cardiac protection by valsartan: Synergetic roles of TGF-β1 and HIF-1α in Ang II-mediated fibrosis after myocardial infarction. J Cellular Molecular Medi, 2015; 19(8):1773–1782; doi: 10.1111/jcmm.12551

52.

Xiao

, Chang

, Liu

, et al. Simvastatin ameliorates ventricular remodeling via the TGF-β1 signaling pathway in rats following myocardial infarction. Mol Med Rep, 2016; 13(6):5093–5101; doi: 10.3892/mmr.2016.5178

53.

, Am

, Wj

. Cardiovascular gene therapy for myocardial infarction. Expert Opinion on Biological Therapy, 2014; 14(2); doi: 10.1517/14712598.2014.866085

54.

Rainer

, Hao

, Vanhoutte

, et al. Cardiomyocyte-specific transforming growth Factor β suppression blocks neutrophil infiltration, augments multiple cytoprotective cascades, and reduces early mortality after myocardial infarction. Circ Res, 2014; 114(8):1246–1257; doi: 10.1161/CIRCRESAHA.114.302653

55.

Chen

L-L

, Yin

, Huang

. Inhibition of TGF-β1 signaling by eNOS gene transfer improves ventricular remodeling after myocardial infarction through angiogenesis and reduction of apoptosis. Cardiovasc Pathol, 2007; 16(4):221–230; doi: 10.1016/j.carpath.2007.02.007

56.

Vistnes

. Hitting the target! challenges and opportunities for TGF-β inhibition for the treatment of cardiac fibrosis. Pharmaceuticals (Basel), 2024; 17(3):267; doi: 10.3390/ph17030267

57.

Massagué

, Sheppard

. TGF-β signaling in health and disease. Cell, 2023; 186(19):4007–4037; doi: 10.1016/j.cell.2023.07.036

58.

Dominguez-Rodriguez

, Abreu-Gonzalez

, de la Torre-Hernandez

, et al.; MARIA Investigators. Usefulness of early treatment with melatonin to reduce infarct size in patients with st-segment elevation myocardial infarction receiving percutaneous coronary intervention (From the Melatonin Adjunct in the Acute Myocardial Infarction Treated With Angioplasty Trial). Am J Cardiol, 2017; 120(4):522–526; doi: 10.1016/j.amjcard.2017.05.018

59.

Newby

, Marber

, Melloni

, et al.; SOLSTICE Investigators. Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: A randomised phase 2 trial. Lancet, 2014; 384(9949):1187–1195; doi: 10.1016/S0140-6736(14)60417-7

60.

O’Donoghue

, Glaser

, Cavender

, et al.; LATITUDE-TIMI 60 Investigators. Effect of losmapimod on cardiovascular outcomes in patients hospitalized with acute myocardial infarction: A randomized clinical trial. JAMA, 2016; 315(15):1591–1599; doi: 10.1001/jama.2016.3609

61.

Konijnenberg

LSF

, Luiken

TTJ

, Veltien

, et al. Imatinib attenuates reperfusion injury in a rat model of acute myocardial infarction. Basic Res Cardiol, 2023; 118(1):2; doi: 10.1007/s00395-022-00974-z

62.

Wang

L-X

, Yang

, Yue

, et al. Imatinib attenuates cardiac fibrosis by inhibiting platelet-derived growth factor receptors activation in isoproterenol induced model. PLoS One, 2017; 12(6):e0178619; doi: 10.1371/journal.pone.0178619

63.

Cheng

, Yang

, Zhao

, et al. Circulating myocardial microRNAs from infarcted hearts are carried in exosomes and mobilise bone marrow progenitor cells. Nat Commun, 2019; 10(1):959; doi: 10.1038/s41467-019-08895-7

64.

Rea

, Gibson

, McGilligan

, et al. Age and age-related diseases: Role of inflammation triggers and cytokines. Front Immunol, 2018; 9:586; doi: 10.3389/fimmu.2018.00586

65.

D’Esposito

, Di Tolla

, Lecce

, et al. Lifestyle and dietary habits affect plasma levels of specific cytokines in healthy subjects. Front Nutr, 2022; 9:913176; doi: 10.3389/fnut.2022.913176

66.

Furman

, Campisi

, Verdin

, et al. Chronic inflammation in the etiology of disease across the life span. Nat Med, 2019; 25(12):1822–1832; doi: 10.1038/s41591-019-0675-0

67.

Bujak

, Dobaczewski

, Chatila

, et al. Interleukin-1 receptor type I signaling critically regulates infarct healing and cardiac remodeling. Am J Pathol, 2008; 173(1):57–67; doi: 10.2353/ajpath.2008.070974

68.

Zhang

, Wang

, et al. Signaling pathways and targeted therapy for myocardial infarction. Signal Transduct Target Ther, 2022; 7(1):78–38; doi: 10.1038/s41392-022-00925-z

69.

Wijdicks

EFM

. The self-confirmatory history of plasmapheresis and IVIG. Neurocrit Care, 2024; doi: 10.1007/s12028-024-01968-6

70.

Connelly-Smith

, Alquist

, Aqui

, et al. Guidelines on the use of therapeutic apheresis in clinical practice—evidence-based approach from the writing committee of the American Society for apheresis: The ninth special issue. J Clin Apher, 2023; 38(2):77–278; doi: 10.1002/jca.22043

71.

Anonymous. Search for: Plasmapheresis | List Results. ClinicalTrials.Gov. n.d. Available from: https://clinicaltrials.gov/search?intr=Plasmapheresis&viewType=Table [Last accessed: August 18, 2024 ].

72.

Smith

, Guglin

, Dougherty

, et al. A unique case of systemic lupus erythematosus myocarditis complicated by plasmapheresis-responsive cardiogenic shock. JACC Case Rep, 2020; 2(15):2376–2380; doi: 10.1016/j.jaccas.2020.09.043

73.

Manla

, Chang

, Patel

, et al. Therapeutic plasma exchange is associated with increased survival in heart transplant recipients experiencing severe primary graft dysfunction. The. J Heart Lung Transplant, 2025; 44(4):627–633; doi: 10.1016/j.healun.2024.11.014

74.

Xing

Z-X

, Yu

, Yang

, et al. Successful use of plasma exchange in fulminant lupus myocarditis coexisting with pneumonia: A case report. World J Clin Cases, 2020; 8(10):2056–2065; doi: 10.1299/8/wjcc.v8.i10.2056

75.

Camarata

, Gottfried

, Rule

, et al. Outcomes of acute liver injury in adults due to Wilson’s Disease: Is survival without transplant possible? Liver Transpl, 2020; 26(3):330–336; doi: 10.1002/lt.25703

76.

Salatzki

, Mohr

, Heins

, et al. The impact of Wilson disease on myocardial tissue and function: A cardiovascular magnetic resonance study. J Cardiovasc Magn Reson, 2021; 23(1):84; doi: 10.1186/s12968-021-00760-1

77.

Pawaria

, Sood

, Lal

, et al. Ninety days transplant free survival with high volume plasma exchange in Wilson disease presenting as acute liver failure. J Clin Apher, 2021; 36(1):109–117; doi: 10.1002/jca.21848

78.

Fang

W-Y

, Abuduxikuer

, Shi

, et al. Pediatric Wilson disease presenting as acute liver failure: Prognostic indices. World J Clin Cases, 2021; 9(14):3273–3286; doi: 10.1299/8/wjcc.v9.i14.3273

79.

Commissioner O of the. Coronavirus (COVID-19) Update: FDA Authorizes Blood Purification Device to Treat COVID-19. FDA; 2020. Available from: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-blood-purification-device-treat-covid-19 [Last accessed: August 12, 2024 ].

80.

Fonseca-González

, Alamilla-Sánchez

, García-Macas

, et al. Impact of plasmapheresis on severe COVID-19. Sci Rep, 2023; 13(1):163; doi: 10.1038/s41598-022-25930-8

81.

Lee

OPE

, Kanesan

, Leow

, et al. Survival benefits of therapeutic plasma exchange in severe sepsis and septic shock: A systematic review and meta-analysis. J Intensive Care Med, 2023; 38(7):598–611; doi: 10.1177/08850666231170775

82.

Bhardwaj

, Kumar

, Parashar

, et al. Evaluating therapeutic plasma exchange in pediatric acute disseminated encephalomyelitis: A comprehensive review. Cureus, 2024; 16(7):e64190; doi: 10.7759/cureus.64190

83.

Nieto-Aristizábal

, Vivas

ÁJ

, Ruiz-Montaño

, et al. Therapeutic plasma exchange as a treatment for autoimmune neurological disease. Autoimmune Dis, 2020; 2020(1):3484659; doi: 10.1155/2020/3484659

84.

Esposito

, Di Pietro

, Madini

, et al. A spectrum of inflammation and demyelination in acute disseminated encephalomyelitis (ADEM) of children. Autoimmun Rev, 2015; 14(10):923–929; doi: 10.1016/j.autrev.2015.06.002

85.

Rezania

. Chapter 24—Role of Inflammatory Mechanisms in Guillain-Barre’ Syndrome. In: Neuroinflammation. 2nd Edition. ( Minagar

. ed) Academic Press; 2018; pp. 505–516; doi: 10.1016/B978-0-12-811709-5.00026-0

86.

Ahn

, Kim

, et al. Recent advances in atopic dermatitis. Curr Opin Immunol, 2020; 66:14–21; doi: 10.1016/j.coi.2020.02.007

87.

Fuller

, Maru

, Isserlis

, et al. Case Report: Successful treatment of a patient with severe atopic dermatitis and severe asthma by centrifugal therapeutic plasma exchange. BMJ Case Rep, 2015; 2015; doi: 10.1136/bcr-2014-209008

88.

Wollenberg

, Thomsen

, Lacour

J-P

, et al. Targeting immunoglobulin E in atopic dermatitis: A review of the existing evidence. World Allergy Organ J, 2021; 14(3):100519; doi: 10.1016/j.waojou.2021.100519

89.

Beck

, Cork

, Amagai

, et al. Type 2 Inflammation contributes to skin barrier dysfunction in atopic dermatitis. JID Innov, 2022; 2(5):100131; doi: 10.1016/j.xjidi.2022.100131

90.

Sharobim

, Scribner

ASJ

, Rose

. Plasmapheresis in Neonatal Lupus. Rheumato, 2022; 3(1):8–22; doi: 10.3390/rheumato3010002

91.

Cai

, Zhen

, He

, et al. Effect of plasma exchange on acute graft versus host disease after allogeneic hematopoietic stem cell transplantation. Blood, 2005; 106(11):5246–5246; doi: 10.1182/blood.V106.11.5246.5246

92.

Abu-Dalle

, Reljic

, Nishihori

, et al. Extracorporeal photopheresis in steroid-refractory acute or chronic graft-versus-host disease: Results of a systematic review of prospective studies. Biol Blood Marrow Transplant, 2014; 20(11):1677–1686; doi: 10.1016/j.bbmt.2014.05.017

93.

Baron

, Cantos

, Hillebrand

, et al. Nephrogenic fibrosing dermopathy after liver transplantation successfully treated with plasmapheresis. Am J Dermatopathol, 2003; 25(3):204–209; doi: 10.1097/00000372-200306000-00004

94.

Harris

, Meiselman

, Moriarty

, et al. Therapeutic plasma exchange for the treatment of systemic sclerosis: A comprehensive review and analysis. J Scleroderma Relat Disord, 2018; 3(2):132–152; doi: 10.1177/2397198318758606

95.

Kim

, Kiprov

, Luellen

, et al. Old plasma dilution reduces human biological age: A clinical study. Geroscience, 2022; 44(6):2701–2720; doi: 10.1007/s11357-022-00645-w

96.

Shahrivari

, Wise

, Resende

, et al.; Cardiovascular Cell Therapy Research Network (CCTRN). Peripheral blood cytokine levels after acute myocardial Infarction: IL-1β and IL-6 related impairment of bone marrow function. Circ Res, 2017; 120(12):1947–1957; doi: 10.1161/CIRCRESAHA.116.309947

97.

Alturfan

, Basar

, Emekli-Alturfan

, et al. Galectin-3 and plasma cytokines in patients with acute myocardial infarction. Lab Med, 2014; 45(4):336–341; doi: 10.1309/LM3JZKBDA7D4QFOC

98.

Devaux

, Bousquenaud

, Rodius

, et al. Transforming growth factor β receptor 1 is a new candidate prognostic biomarker after acute myocardial infarction. BMC Med Genomics, 2011; 4(1):83; doi: 10.1186/1755-8794-4-83

99.

Hanna

, Frangogiannis

. Inflammatory cytokines and chemokines as therapeutic targets in heart failure. Cardiovasc Drugs Ther, 2020; 34(6):849–863; doi: 10.1007/s10557-020-07071-0

100.

Hassaniazad

, Vahedi

, Samimagham

, et al. Improvement of clinical outcome, laboratory findings and inflammatory cytokines levels using plasmapheresis therapy in severe COVID-19 cases. Respir Med, 2021; 189:106669; doi: 10.1016/j.rmed.2021.106669

101.

Katsumoto

, Wilson

, Giri

, et al. Plasma exchange for severe immune-related adverse events from checkpoint inhibitors: An early window of opportunity? Immunother Adv, 2022; 2(1):ltac012; doi: 10.1093/immadv/ltac012

102.

Volkin

, Starz

, Winkelstein

, et al. Changes in coagulation factors, complement, immunoglobulins, and immune complex concentrations with plasma exchange. Transfusion, 1982; 22(1):54–58; doi: 10.1046/j.1537-2995.1982.22182154218.x

103.

Reeves

. Continuous plasmafiltration in sepsis syndrome. Plasmafiltration in Sepsis Study Group. Critical Care Medicine, 1999; 27(10); doi: 10.1097/00003246-199910000-00003

104.

Van Tassell

, Toldo

, Mezzaroma

, et al. Targeting Interleukin-1 in Heart Disease. Circulation, 2013; 128(17):1910–1923; doi: 10.1161/CIRCULATIONAHA.113.003199

105.

Abbate

, Toldo

, Marchetti

, et al. Interleukin-1 and the inflammasome as therapeutic targets in cardiovascular disease. Circ Res, 2020; 126(9):1260–1280; doi: 10.1161/CIRCRESAHA.120.315937

106.

Feng

, Ye

, Wang

, et al. The role of Interleukin-6 family members in cardiovascular diseases. Front Cardiovasc Med, 2022; 9:818890; doi: 10.3389/fcvm.2022.818890

107.

J-H

, Luo

M-Y

, Liang

, et al. Interleukin-6: A novel target for cardio-cerebrovascular diseases. Front Pharmacol, 2021; 12:745061; doi: 10.3389/fphar.2021.745061

108.

Cervantes

, Bloch

, Sperati

. Therapeutic plasma exchange: Core curriculum 2023. Am J Kidney Dis, 2023; 81(4):475–492; doi: 10.1053/j.ajkd.2022.10.017

109.

Dedkov

. Large- and medium-sized arteries remaining in transmural scar distal to permanent coronary ligation undergo neointimal hyperplasia and inward remodeling. J Histochem Cytochem, 2021; 69(5):321–338; doi: 10.1369/00221554211004297

110.

Verheugt

FWA

. Reperfusion therapy starts in the ambulance. Circulation, 2006; 113(20):2377–2379; doi: 10.1161/CIRCULATIONAHA.106.626713