Exploring Mechanisms to Understand and Overcome Microvascular Dysfunction

Background and Context

Coronary perfusion is one of the important objectives in ST-segment elevation myocardial infarction (STEMI) studies. When interventions to reduce coronary perfusion fail, there are instances of myocardial infarcts, cardiogenic shock, ventricular arrhythmias, and cardiac failure leading to death (Ma et al. 2015). The goal of reperfusion therapy is to very quickly restore myocardium, coronary and normal epicardial blood flow (Gershlick et al. 2013). Current pharmacological therapy and adjunctive interventional techniques have helped in bringing thrombolysis to grade 3 epicardial flows for 95% of patients (Kristensen et al. 2014). However, timely interventions to control and restore the epicardial coronary vessel, infarct-related artery, optimal microvascular perfusion, and salvage, have not reached the required accuracy (Fordyce et al. 2015).

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Over the years, several methods to manage and salvage microvascular dysfunction and lethal reperfusion injury (RI) have emerged in clinical studies. However, the methods have not been translated into clinical practices successfully. Some of these methods are the RISK pathway, where the family of protein kinase Cε, activated during reperfusion that reduces mitochondrial permeability transition pore (MPTP) opening, prevents myocyte calcium overload, inhibiting, and developing antiapoptotic pathways, have been targeted (Lapchak 2015). Other methods are the inhibition of MBTP, ischemic preconditioning and modified reperfusion (IP), opening sarcolemmal and mitochondrial K-ATP channel, metabolic modulation with insulin, mechanical adjunctive strategies, and others (Kummer et al. 2015). These interventions were developed in limited clinical studies. Successful transfer to widespread clinical practices has not happened and patients continue to face the danger of myocardial infarction with reperfusion injury (Steg et al. 2012). This research aims to develop methods and practices in clinical studies and transfer them to widespread clinical practices.

Problem Statement

The problem statement is “to develop procedures and processes for accurate diagnosis and prevention of microvascular dysfunction, caused by reperfusion injury.”

Research Questions

The research questions are:

  1. What does published research say about reperfusion and its occurrence?
  2. What are the reasons for mortality for some patients who suffer from lethal reperfusion?
  3. What clinical and therapeutic interventions are available to prevent reperfusion?
  4. What passive and invasive tests can be used for cardiac assessment and microvascular function and structure?
  5. What recommendations can be made to clinics for the treatment of reperfusion?

Literature Review

Gerczuk and Kloner (2012) speak about the latest methods to reduce ST-segment elevation myocardial infarction size and left ventricular dysfunction in patients suffering from heart failures. While instances of mortality and morbidity have increased, several new methods are under research. Some of these interventions are ischemic post-conditioning and remote ischemic per-conditioning, reducing core body temperate using cold saline infusion and cooling catheters. Researchers have also used cyclosporine, adenosine, and atrial natriuretic peptide as pharmaceutical cardioprotective methods. Research in these methods is ongoing. Heusch et al. (2014) speak of remodelling of the myocardium due to reperfusion for acute myocardial infarction. The author argues that while clinical experiments use certain invasive and non-invasive methods to overcome reperfusion, in the operating room, reperfusion occurs very rapidly and before the doctors can react. One method to overcome this problem is to stimulate molecular defences with RISK and SAFE pathways by providing protective pathways using metoprolol or cyclosporine A at the areas of reperfusion. Limb reconditioning can be used before surgical revascularisation in the ambulance and administering GIK to protect patients. Larger clinical trials are needed to test this method.

Inafuku et al. (2013) examined the assumption that oxidative stress from reactive oxygen has a significant effect on reperfusion injury of cardiovascular muscles. The researchers experimented with rat hearts using a Langendorff apparatus. St. Thomas’s cardioplegic solution was used to arrest the hearts and then reperfused. Measures were taken for pressures of the left ventricle, end-diastolic, positive maximum pressure, coronary flow, creatine kinase, 8-hydroxy-2’deoxyguanosine (8OHdG) that measures oxidative DNA damage, and Adenosine triphosphate. Samples were then immunohistochemically measured and levels of 8-OHdG were ascertained after reperfusion. The conclusion is that reperfusion injury has more impact on 8-OHdG than ischemic duration. The findings are significant even though the experiments were conducted on rat hearts. Ibáñez et al. (2015) examine recent trends in reducing mortality due to ischemia and reperfusion injuries. The authors point out that mortality due to these injuries has reduced from 20% in the 1980s to less than 5%. The main challenge is to measure infarct size and this is done with CMR, single-photon emission computed tomography, electrocardiogram parameters, and biomarker release. Pharmacological interventions are glucose modulators, Glycoprotein IIb/IIIa inhibitors to reduce thrombotic events, cyclosporine-A, β-blockers such as metoprolol, and others.

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Eltzschig and Eckle (2011) discuss various therapeutic processes to prevent reperfusion and to increase tolerance. Some of these methods are ischemic conditioning with pre, post, and remote conditioning, where short exposures to reperfusion help to develop attenuated tissue injury. Pharmacological agents that use the underlying mechanisms are under testing. Energy metabolism switches from oxidation of fatty acids to oxidation efficient glycolysis are also used. In some cases, therapeutic gases such as hydrogen, nitric oxide, hydrogen sulphide, and carbon monoxide are used for the treatment of reperfusion. Nucleotide and nucleoside signalling is used to develop pharmacological strategies that block the release of ATP, and MicroRNAs such as miR-17~92 is used as therapeutic targets. Pizarro et al. (2014) studied the effects of intravenous metoprolol before reperfusion on the left ventricular function. Early IV metoprolol was known to reduce infarct size. The researchers tested 270 patients with Killip class II anterior STEMI and administered random pre-reperfusion of IV metoprolol. Tests were run for six months and the results showed that patients suffering from anterior Killip class II STEMI and undergoing IV metoprolol before reperfusion, showed fewer instances of severe systolic dysfunction and lesser admission for heart failures.

Kloner et al. (2012) examined the cardioprotective effects of mitochondria-targeted peptides and Bendavia Stealth Peptides for reperfusion. The administration of Bendavia helped in reducing the infarct size, in ex-vivo and in vivo models. Coronary no-reflow was examined with Thioflavin S staining. Cardiac hemodynamics postischemic recovery was not impacted by Bendavia, and myocytes that were exposed to reoxygenation had better survival rates. The conclusion is that reperfusion injury is reduced by Bendavia, a mitochondria-targeted therapy. Prasad et al. (2009) argue that the main and urgent objective of reperfusion therapy is to bring the epicardial blood flow to normal using the primary percutaneous coronary intervention. While medical technology has advanced and normal flow is achieved in 95% of cases, around 5% of patients are in acute danger of reperfusion injury. The exact pathophysiology of reperfusion injuries is not yet established. Some interventions developed to reduce the infarct size include adenosine administration, ischemic postconditioning, inhibition of the mitochondrial permeability transition pore (MTTP), supersaturated oxygen delivery through intracoronary means, Therapeutic hypothermia, antithrombotic drugs, Insulin use for metabolic modulation, and others.

Aim

The aim of the research is to review the current knowledge on the clinical relationships between cardiovascular microvascular diseases in different clinical events and reperfusion parameters and to define diagnostic approaches available and use these inputs to develop standardised, diagnostic, and therapeutic potentials to assess CMD non-invasively.

Research Objectives

The objectives are:

  1. To examine the current literature to gain critical knowledge of reperfusion, cause, pathways, pathology, and reperfusion parameters.
  2. To understand the reason as to why some patients suffer from this ailment and perish while others survive.
  3. To identify clinical and therapeutic interventions.
  4. To use passive, invasive tests in clinics for techniques for cardiac assessment of microvascular function, for peripheral assessment of microvascular function, and structure.
  5. To make recommendations for the implementation of interventions in clinical practices.

Research Methodology

The research will use mixed methods with a combination of primary and secondary research methods. An extensive literature review, which will focus on microvascular dysfunction and reperfusion injury, will help in establishing a knowledge base. An initial literature review for the proposal has provided a number of keywords and these will be refined and used to run a search in databases with peer-reviewed articles in MedLine, Pro-Quest, Questia, and Google Scholar. Articles will be selected based on the relevance, methods, settings, metrics, research processes, and other important factors. For the research, 40-50 articles will be selected and findings will provide a deep understanding of research in the subject, challenges, and gaps.

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Secondary research will be carried out by applying experimental models in the laboratory to study microvascular diameters and perfusion. In-situ measurements and ex-vivo isolated heart measurements will be taken of patients. The laboratory facilities will be used to run tests on cultured endothelial and smooth muscles cells. Access will be requested to cardiovascular disease patients with prior history of angina, ischemic heart diseases, and patient records in clinics and hospitals. A detailed analysis will be carried out with the aim of isolating and identifying links and common characteristics. The objective will be to devise protocols for service improvement by improving current SOP and protocols for treatments using national healthcare guidelines.

The primary research will be in the form of lab and clinical research, where the researcher will use a number of experiments and tests. The researcher has access to the lab and patients admitted for cardiac problems at a major hospital. The following set of actions is proposed to measure myocardial microcirculatory perfusion in humans. Separate techniques will be applied for cardiac assessment of microvascular function and for peripheral assessment of microvascular function and structure. Both these sets of techniques will have invasive and non-invasive methods. The following tables list these techniques.

Table 1.1. Techniques for cardiac assessment of microvascular function

Type Method Quantification Tracer Spatial resolution Recording time
Non-invasive SPECT None Radio isotopes Very low Long
PET Perfusion (mL/min/g) Gold standard ) Radio isotopes (cyclotron-generated) Low Long
CT Perfusion (mL/min/g) Contrast agent Very high Low
Moderate MRI Perfusion (mL/min/g) Contrast agent Moderate
Ultrasound Perfusion (mL/min/g) Microbubbles High Real time
Invasive Doppler wire Flow velocity (mm/s) None Selective assessment in target vessel territory
Thermo-dilution Blood flow (mL/min) Saline (body temperature)
CTFC None Contrast agent

Table 1.2. Techniques for peripheral assessment of microvascular function and structure

Type Method Target vessels Stimulus Comments
Non-invasive Brachial artery post-ischaemic reflow Conduit artery Shear stress Validated to predict clinical outcome
Laser Doppler flux (imaging)/iontophoresis Cutaneous microvessels Vasoactive drugs Iontophoresis: local application of a broad selection of drugs; current may have direct effect on local microvascular tone
Clinical intravital microscopy Cutaneous, mucosal, or retinal microvessels None Information on microvascular structure and function; limited range of tissues and parameters to be analysed
Invasive Venous occlusion plethysmography (forearm blood flow) All forearm microvessels Vasoactive drugs Validated to predict clinical outcome; problem: systemic recirculation of drugs
Biopsy Subcutaneous/ muscular microvessels None Analysis of microvascular structure; no functional information

Original Contribution

Current research and practices to prevent reperfusion has gaps and lacks higher accuracy. The study will use knowledge from published literature to develop a set of invasive and non-invasive methods to assess microvascular function and structure. These tests will help in developing a deep understanding of reperfusion so that methods can be developed for prevention and clinical measures to treat the ailment.

References & Bibliography

Eltzschig, H & Eckle, T 2011 ‘Ischemia and reperfusion—from mechanism to translation’, Nature Medicine, vol. 17, no. 11, pp. 1391-1402.

Fordyce, CB, Gersh, BJ, Stone, GW. & Granger, CB 2015, ‘Novel therapeutics in myocardial infarction: targeting microvascular dysfunction and reperfusion injury’, Trends in Pharmacological Sciences, vol. 36, no. 9, pp. 605-616.

Gerczuk, PZ & Kloner, RA 2012, ‘A review of the latest adjunctive therapies to limit myocardial infarction size in clinical trials,’ Journal of the American College of Cardiology, vol. 59, no. 11, pp. 969-978.

Gershlick, A.H., Banning, A.P., Myat, A., Verheugt, F.W. & Gersh, B.J 2013, ‘Reperfusion therapy for STEMI: is there still a role for thrombolysis in the era of primary percutaneous coronary intervention?,’ The Lancet, vol. 382, no. 9892, pp.624-632.

Heusch, G, Libby, P, Gersh, B, Yellon, D, Böhm, M, Lopaschuk, G & Opie, L 2014, ‘Cardiovascular remodelling in coronary artery disease and heart failure,’ The Lancet, vol. 383, no. 9932, pp.1933-1943.

Ibáñez, B, Heusch, G, Ovize, M & Werf, F, V 2015, ‘Evolving therapies for myocardial ischemia/ reperfusion injury,’ Journal of the American College of Cardiology, vol. 65, no. 14, pp. 1454-1471.

Inafuku, H, Kuniyoshi, Y, Yamashiro, S, Arakaki, K, Nagano, T, Morishima, Y. & Kise, Y 2013, ‘Determination of oxidative stress and cardiac dysfunction after ischemia/reperfusion injury in isolated rat hearts,’ Annals of Thoracic and Cardiovascular Surgery, vol. 19, no. 3, pp.186-194.

Kloner, RA, Hale, SL, Dai, W, Gorman, RC, Shuto, T, Koomalsingh, KJ & Gorman, JH 2012, ‘Reduction of ischemia/reperfusion injury with bendavia, a mitochondria-targeting cytoprotective peptide,’ Journal of the American Heart Association, vol. 1, no. 3, pp. 1644-1657.

Kristensen, SD, Laut, KG, Fajadet, J, Kaifoszova, Z, Kala, P, Di Mario, C, Wijns, W, Clemmensen, P, Agladze, V, Antoniades, L & Alhabib, KF 2014, ‘Reperfusion therapy for ST elevation acute myocardial infarction 2010/2011: current status in 37 ESC countries,’ European Heart Journal, vol. 35, no. 29, pp.1957-1970.

Kummer, R, Broderick, JP, Campbell, BC, Demchuk, A, Goyal, M, Hill, MD, Treurniet, KM, Majoie, CB, Marquering, HA, Mazya, MV & San Román, L 2015, ‘The Heidelberg Bleeding Classification: classification of bleeding events after ischemic stroke and reperfusion therapy,’ Stroke, vol. 46, no. 10, pp.2981-2986.

Lapchak, PA 2015, ‘Critical early thrombolytic and endovascular reperfusion therapy for acute ischemic stroke victims: a call for adjunct neuroprotection,’ Translational Stroke Research, vol. 6, no. 5, pp.345-354.

Ma, S, Wang, Y, Chen, Y & Cao, F 2015, ‘The role of the autophagy in myocardial ischemia/ reperfusion injury,’ Biochimica et Biophysica Acta, vol. 1852, pp, 271-276.

Prasad, A, Stone, GW, Holmes, DR & Gersh, B ‘Reperfusion Injury, microvascular dysfunction, and cardioprotection: the dark-side of reperfusion,’ Circulation, vol. 120, no. 21, pp.2105-2112.

Pizarro, G, Fernández-Friera, L, Fuster, V, Fernández-Jiménez, R, García-Ruiz, J, M, García-Álvarez, A & Mateos, A 2014, ‘Long-term benefit of early pre-reperfusion metoprolol administration in patients with acute myocardial infarction,’ Journal of the American College of Cardiology, vol. 63, no. 22, pp. 2356-2362.

Steg, PG, James, SK, Atar, D, Badano, LP, Lundqvist, CB, Borger, MA, Di Mario, C, Dickstein, K, Ducrocq, G & Fernandez-Aviles, F 2012, ‘ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the task force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC), European heart Journal, vol. 33, no. 20, pp.2569-2619.

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