Cardiovascular disease continues to lead as the predominant cause of death worldwide. In particular, cerebrovascular accidents (stroke) account for the second leading cause of death globally (Katan & Luft, 2018). The overall increasing rate of stroke is attributed to an ageing population and lifestyle factors despite the onset of preventative strategies and treatments in place to decrease the global burden (Johnson et al., 2016). Ischemic stroke accounts for the majority of stroke cases and as such resides as a disease requiring further development for more optimal treatments. With the dependence of current treatments on time barriers, the need for new enhanced treatments is urgent. It is critical that current established treatments are delivered as quickly as possible to ensure a decreased possibility of permanent and irreversible damage (Macrae & Allan, 2018). Neurocardiology appears as an emerging research speciality- addressing the impacts of heart injury and disease on the brain- with potential for developing improved treatment methods for ischemic stroke patients (Chen et al., 2018). This phenomenon is platformed with evidence suggesting a clear causal correlation between brain damage and cardiovascular (cardiac) dysfunction (Chen et al., 2018). With the fundamental and ultimate aim of therapy residing in improving patient outcomes, the future directions and viability of stroke treatment research are reviewed in evaluating the potential for pursuing currently emerging therapy strategies.
Pathophysiology of ischemic stroke
The underlying cause of stroke is attributed to a blockage of blood flow to the brain, whereby brain cells are starved of essential nutrients necessary for homeostatic brain function (Woodruff et al., 2011). Ischemic stroke is one type of stroke in which an artery in the brain narrows or is completely occluded in preventing normal blood flow (Figure 1). The extent of damage is dependent on the location of vessel obstruction and the duration of blood flow obstruction. Generally, cholesterol or atherosclerotic plaques that accumulate within the wall of the artery result in the narrowing or occlusion of the artery, thereby halting the passage of blood (Macrae & Allan, 2018). In embolic events, clots formed extracranially within the circulatory system-usually in the heart- travel in the bloodstream before lodging into cerebral arteries. Atrial fibrillation is indicated as a primary cause of initial embolism formation, ultimately resulting in blood flow obstruction in the brain (Woodruff et al., 2011). This establishes the primary pathophysiology of ischemic stroke as attributed to an underlying cardiovascular disease and provides a potential area for developing more optimal and feasible treatment targets.
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In the brain, the ischemic cascade proceeds via various pathways, eventually resulting in excessive glutamate release in the extracellular space. Glutamate then acts on neuronal NMDA, AMPA and kainite receptors to increase Ca2+ influx (Ballarin & Tympianski, 2018). Ultimately, the Ca2+ mediated intracellular enzymatic activity reaches pathological levels inducing cell damage and cell death via necrotic and apoptotic processes (glutamate cytotoxicity) (Catanese et al., 2017). Overactivation of lipolytic, proteolytic and membrane breakdown processes as well as the production of reactive oxygen species further drive cytoskeletal, mitochondrial and inflammatory changes in cells resulting in apoptotic events (Woodruff et al., 2011) (Figure 2).
Figure 1. Diagrammatic representation of ischemic stroke pathophysiology. An atherosclerotic plaque in the internal carotid artery is represented to decrease blood flow to regions of the brain supplied by the internal carotid artery (Adapted from American Stroke Association).
Figure 2. The neurological effects of the ischemic cascade. Ischemic stroke is represented to induce various effects triggering cerebral damage and neural cell death (Adapted from Catanese et al., 2017).
Ischemic stroke has recently been suggested to cause cardiac dysfunction via stroke eliciting mechanisms that 1) activate the hypothalamus-pituitary axis, 2) regulate parasympathetic and sympathetic nervous systems, 3) cause surges in catecholamines, 4) cause dysbiosis of the gut microbiome, 5) elevate immune responses and 6) produce inflammatory responses (Chen et al., 2018). This suggests a multifaceted complexity embedded in desirable treatment therapies with a need for more cardiovascular orientated research in establishing viable therapy options, particularly during post-stroke periods (Figure 3).
Figure 3. Neuro-cardiac interactions exhibiting the onset of cardiac dysfunction following ischemic stroke. The activation of various physiological mechanisms are evidenced to mediate the onset of cardiac dysfunction (Adapted from Chen et al., 2017).
Current treatment methods: how suboptimal are they
There is a broad range of therapy strategies for treating ischemic stroke. Primary intervention strategies rely on managing reducible risk factors which encompass lowering high blood pressure, lowering cholesterol levels, stopping smoking and compliant management of heart disease and diabetes (Macrae & Allan, 2018). Current treatment methods target the need for clot removal whilst attempting to decrease microvascular obstruction, reduce inflammation and elicit neuroprotection. However, while there exists a diaspora of treatment options, no novel therapies for ischemic stroke have been developed recently (Ballarin & Tymianski, 2018). With inherent flaws observed in the various frontline treatment options, an urgent need for enhanced treatment methods is established.
Ischemic strokes are predominantly treated with thrombolytics which induce thrombolysis and target the need for clot removal. Administration of tissue plasminogen activator (tPA) (within a 3 to 4.5 hour window) allows for thrombolysis, lysing the fibrin mesh and promoting recanalization (Yip & Benavente, 2011). However, it is important to note the increased risk of bleeding and haemorrhagic stroke with the administration of thrombolytic drugs. Resultantly, not all patients are eligible to receive thrombolytic treatment. The rapidly progressive nature of stroke is easily able to elicit long-term disability due to the failure of administering early preventative treatments other than tissue plasminogen activator (Ballarin & Tymianski, 2018). Resultantly, this platforms concerns in terms of the viability of current treatment options and establishes the urgency for more optimal treatment methods.
Currently, two classes of antithrombotic drugs exist including anti-platelet drugs (or therapy) and anticoagulants to assist in decreasing the risk of recurrent strokes and recurrent vascular accidents. Most commonly aspirin is utilised as the primary anti-platelet drug for decreasing the risk of clot initiation (Yip & Benavente, 2011). As an irreversible cyclooxygenase (COX) inhibitor, aspirins acts to acetylate the hydroxyl group of the COX enzyme, whereby inhibiting the formation of prostaglandin G2/H2 and thromboxane A2. Essentially, aspirin cleaves plasminogen to plasmin, thereby inhibiting the clotting cascade (Figure 4). This results in the irrevocable inhibition of platelet activation and aggregation (Yip & Benavente, 2011). Alternatively, the administration of clopidogrel proceeds via a comparable mechanism, ultimately leading to the prevention of fibrinogen binding to its receptor (Bhaskar et al., 2018). However, despite this feasibility, stroke reoccurrences suggest the likelihood of antiplatelet resistance. In antiplatelet therapy resistance there is a failure in the mode of inhibition of platelet activation. This failure is attributed to various physiological mechanisms including drug-drug interactions and genetic polymorphisms resulting in increased metabolism of antiplatelet drugs or decreased receptor site availability (Yip & Benavente, 2011; Woodruff et al., 2011). Moreover, patients receiving long-term anti-platelet therapy (DAPT) are associated with higher rates of all-case mortality (Yip & Benavente, 2011). This raises concerns into treatment efficacy and highlights the sub-optimal nature of anti-platelet drugs and therapy.
Figure 4. Mechanism of action of tissue plasminogen activator resulting in thrombolysis. This resides as the current primary pharmacological therapeutic intervention method. Anti-platelet drugs (and therapy) work by converting plasminogen to plasmin in initiating clot removal and preventing vascular obstruction (Adapted from Bhaskar et al., 2018).
Anticoagulants are another current frontline choice of treatment, particularly in managing patients with atrial fibrillation (high-risk group for ischemic stroke). Most commonly, heparin and warfarin are utilised to reduce blood clotting. The predominant difference resides in heparin’s fasting acting ability for longer-term treatment and warfarin’s short acting nature (Bhaskar et al., 2018). Adverse effects including gastrointestinal bleeding and possible intracranial haemorrhage highlight inherent flaws with the administration of anticoagulants. Generally, there is a clinical move away from anticoagulant administration for ischemic stroke patients due to the increased risk of excessive bleeding (Yip & Benavente, 2011; Bhaskar et al., 2018). This underpins the suboptimal mode of action of anticoagulant drug therapies and urges for the need for improved and more viable therapy options.
Surgical intervention resides as an alternate option for clot removal and acts to directly decrease vascular obstruction and clot presence. Carotid artery revascularisation proceeds with an incision made to the blocked artery in which the removal of the plaque causing blockage occurs. Carotid stenting may be utilised to ensure that the vessel remains open with a continuous passage of blood flow to the brain (Bhaskar et al., 2018). However, intrinsic flaws reside with evidenced cases of severe internal carotid restenosis. Essentially, while a stent provides temporary cessation of the blockage, issues of restenosis still persist and thrombosis formation still remains possible (Chen et al., 2018). This suggests a suboptimal intervention process and urges for more viable and non-invasive treatment options.
Current Research and Future Directions
Novel therapies currently investigated explore alternative fibrinolytic agents, mixed approaches that involve combinations of rtPA and other therapies such as GP IIb/IIIa antagonists, low-molecular-weight heparin, and drugs achieving greater clot manipulation (Macrae & Allan, 2018).
More recently, tenecteplase has emerged as a promising treatment option for acute, moderate and severe ischemic stroke in groups eligible for alteplase administration and in groups not treated with thrombolytics. The Australian TNK trial evidenced tenecteplase (0.1mg/kg) as superior to alteplase in achieving enhanced reperfusion and patient outcomes (Figure 5). In large vessel occlusion, tenecteplase administration resulted in substantial reperfusion with an immediate thrombolytic effect. Tenecteplase is therefore identified as an enhanced thrombolytic, easily administered as a single IV bolus (Coutts et al., 2018).
Figure 5. Recanalization in patient groups administered with tenecteplase and alteplase recorded at 1hr post-treatment and 14 hrs post-treatment (Adapted from Coutts et al., 2018)
Lately, statins have garnered considerable interest due to their pleiotropic effects for both the prevention and treatment of ischemic stroke. Statins are generally utilised to assist with lowering cholesterol levels which normally induce plaque formation in vessels. Statins work to block the HMG-CoA reductase enzyme which is responsible for cholesterol formation. Statins are further understood to improve endothelial function by upregulating endothelial nitric oxide synthase (eNOS). Statins essentially inhibit Rho which in turn activates the PI3K/Akt/eNOS pathway, increasing eNOS mRNA stability due to cytoskeletal actin changes and enhanced mRNA half-life (Sladojevic et al., 2018; Zhao et al., 2014). Moreover, statins are also deduced to exhibit a protective nature over vascular endothelium via the upregulation of the decay-accelerating factor. Statins further decrease the presence of angiotensin II type 1 receptor genes whereby promoting vasorelaxation. This is further mediated through statins ability to block the expression of endothelin-1 in achieving vasorelaxation and vascular smooth muscle cell proliferation (Zhao et al., 2014). Statins have also been deduced to possess a diaspora of clinical benefits in modulating thrombogenesis, attenuating inflammatory damage, reducing oxidative stress and facilitating angiogenesis. However, it is still important to consider that stroke patients receiving statins survive stroke but have increased mortality due to myocardial infarction (Zhao et al., 2014).
Nanomedicine shows potential in enhancing thrombolysis in ischemic stroke. Nanoparticles coated with tPA and fucoidan were evidenced to lyse plate-rich thrombi which were resistant to tPA treatment alone. Smart delivery nanodevices which utilise thrombus formation and elevated levels of oxidative stress manipulate the characteristics of thrombi to trigger tPA release (Bonnard et al., 2019). In essence, the fibrinolytic drugs are self-adjusting, opening a new avenue for therapy regimens. Nonetheless, it is still critical to note that currently no nanomedical research has been translated into patients as beneficial. Risks associated with toxicity are ameliorated through blood cell membrane camouflage which reduces thrombogenicity in vivo. Renal compatibility and clearance of nanomedicines also serves to reduce toxic build up. It is important for further explorations to gauge the significance and success of nanomedical efforts for treating thrombus formation and subsequent ischemic stroke (Bonnard et al., 2019).
Neuroprotectants emerge as the most commonly researched ischemic stroke treatment option. Essentially neuroprotectants serve the purpose of salvaging the ischemic penumbra as a monotherapy whilst also regulating secondary damage due to inflammatory processes (Ballarin & Tympianski, 2018). Particularly, serotonin agonists have been established to inhibit excitatory neurotransmission whereby inducing protection from glutamate-mediated neuronal apoptosis and necrosis. Generally neuroprotective agents which produce neuroprotection in animals have predominantly failed to induce similar results in clinical trials. However, these agents still provide a therapeutic target window with potential future use (Moustafa & Baron, 2008). The discovery of Tat-NR2B9c is shown to interfere with the signalling complex NMDAR-PSD-956-nNOS whereby a disruption to the interaction between NMDAR and PSD-95 occurs. This in turn halts the downstream neurotoxic effects which result in neuronal cell death. Essentially, the critical feature of Tat-NR2B9c resides in the fact that it does not directly block the synaptic activity of NMDAR even though it works intracellularly (Figure 6) (Ballarin & Tympianski, 2018). This exhibits a neuroprotective effect on cells. Thus, compounds mediating the effects of excitotoxicity are of significant use in hindering the ischemia-induced death of neuronal cells. Other research groups also corroborate the use of Tat-NR2B9c and other compounds with similar modes of action which exhibit neuroprotective effects (Moustafa & Baron, 2008). Reduction in infarct volume and a fewer number of lesions are particularly indicative of this characteristic (Ballarin & Tympianski, 2018). Hence, this showcases potential significance for neuroprotectants as an optimal treatment option for ischemic stroke patients whereby the initial time barriers are overcome in achieving more ideal and salvageable results.
Figure 6. By disrupting NMDAR-PSD-95 complexes there is an immediate reduction in the proficiency of Ca2+ which is normally involved in activating excitotoxic NO production. Essentially, Tat-NR2B9c (interfering peptide) disrupts the NMDAR-PSD95-nNOS complex thereby dissociating NMDARs from subsequent neurotoxic signals without blocking normal synaptic function. Tat-NR2B9c has completed phase 2 trials successfully and opens a potential therapeutic window (Adapted from Ballarin & Tymianski, 2018).
Conclusion
Conclusively, the suboptimal treatments that are currently available for stroke prevention, management and treatment illicit the urgency for new treatment options in ischemic stroke patients. Cardiovascular research currently aims at underpinning the mitigation of thrombotic formations by utilising more potent and precise drug regimens which target clot removal, neuroprotection, inflammation and microvascular obstruction. By avoiding initial stroke occurrence, reoccurrences of stroke risk are mitigated and pose a viable target for optimal treatment methods. This is critical in overcoming the time restrictions current suboptimal treatments enforce on stroke patients. As such, patient outcomes reside as a fundamental basis of current research in ensuring that the long-term impacts of disability and discomfort are prevented. Nonetheless, further clinical research is required to holistically underpin the specific physiological mechanisms and clinical impacts of potential treatment methods.
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