Prof. Moshe Flugelman, Haifa Israel

The heart is a unique organ in many respects since its activity is mandatory to sustain life. The heart’s circulatory system and coronary flow regulation are highly adapted to the vital role of the heart in sustaining life and to everyday physiological challenges.


Understanding coronary physiology is key for treating patients with ischemic heart disease in general, and patients with acute ST elevation myocardial infarction (STEMI) specifically. Coronary flow is regulated by myocardial oxygen consumption and can be increased by four-fold in healthy individuals. The ability to increase coronary flow is referred to as coronary flow reserve. Increased coronary flow is required for increased oxygen supply to the myocardium, as each molecule of hemoglobin that enters the coronary circulation delivers all the carried oxygen during its pass through the myocardium. Thus, only increased flow can provide more oxygen to the heart muscle. Blood flow in the coronary circulation is determined by intramyocardial resistance arteries. Vasodilation of these arteries increases coronary flow, which leads to some degree of vasodilation of the epicardial coronary arteries. In STEMI, all these physiological mechanisms are disrupted. For more details regarding physiology of the coronary system see references1-5.


The last five decades have witnessed the advent of coronary angiography and physiological measurements of coronary flow in catheterization and experimental laboratories. These have contributed substantial knowledge regarding how myocytes are nourished by the coronary system without disrupting myocardial contraction. While the epicardial coronary arteries, which are demonstrated during coronary angiography, can be regarded as conductance vessels, the resistance vessels that determine blood distribution and flow rate cannot be demonstrated using contrast media. The diameter of these arteries is in the range of 30-500 microns. The endothelial cells that cover the luminal surface of all blood vessels, and the smooth muscle cells that constitute the media layer of blood vessels must operate in synchrony to provide the physiological challenges of normal heart function. Resistance arteries that penetrate the left and right ventricular wall are squeezed during systole; hence, most myocardial blood flow occurs during diastole. The driving force for coronary flow is the gradient of pressures during diastole, between the aorta and the right atrium, which drains most of the coronary flow. Nutrients and gas are exchanged between coronary blood and heart tissue, in the capillaries that connect the arterial and venous system1,2. Each myocyte is in direct contact with several capillaries, thus securing continuous and sufficient supply of oxygen and nutrients1,2.


While atherosclerotic plaques are the hallmark of atherosclerosis in the epicardial coronary arteries, dysfunction of microcirculation in the heart, namely malfunctioning resistance arteries and capillaries, plays a major role in chronic syndromes of atherosclerotic heart disease, and even more so in acute coronary syndrome.  Measurement of microvascular resistance is based on thermodilution6-8. Temperature measurements are taken from the ostium of the coronary artery and the distal coronary artery. These are performed after pharmacological vasodilation is induced by intra-coronary injection of adenosine or papaverine. Pressure and temperature are measured simultaneously in the proximal and distal coronary artery using a pressure wire; the procedure requires only a few minutes. Microcirculatory resistance is calculated using Ohm’s law V=IR, in which V equals the pressure gradient between the distal coronary artery and the pressure in the venous system that drains the coronary flow. Coronary flow is measured using thermodilution and is denoted as I in the equation, and R is the resistance. The index of microcirculatory resistance (IMR) can be calculated after measuring the index distal coronary pressure and index coronary artery flow (the venous pressure is relatively low and considered to be zero), using the equation IMR=index distal coronary artery pressure/index coronary artery flow. Several technical issues must be considered in measuring IMR, but these issues are beyond the scope of this document. More details on measuring IMR can be found in references (6-12). Normal IMR is defined as IMR<20 units. IMR>25 units is considered abnormally high and an indication of disturbances to coronary flow. Continuous coronary resistance is also possible and normal values are defined as <450 woods units12-14.


A second major method to measure coronary microcirculation function is by cardiac magnetic resonance. Contrast echocardiography, Doppler echo, CT, and PET are also currently used to assess microcirculation in the heart15.


For many years, the driver-regulator of arterial vasodilation in the myocardium was unknown. An oxygen sensor element was recently identified in smooth muscle cells of coronary resistance arteries16. When oxygen consumption exceeds oxygen supply, reduced myocardial oxygen tension leads to vascular dilation and increased coronary flow. Endothelial cells in the microcirculation and epicardial coronary have flow sensing elements17. With increased flow following dilation of resistance arteries, these cells secrete nitric oxide, which enhances vasodilation and increases coronary flow.


The importance of coronary microcirculation in STEMI cannot be understated. Ample evidence indicates that the return to normal of microvascular flow after myocardial infarction is an excellent predictor of short- and long-term prognosis and of left ventricular recovery. Patients with STEMI who have disturbed microcirculation (increased resistance) after angioplasty develop late complications, mostly heart failure, at higher rates than do patients with STEMI with functioning microcirculation (normal resistance) after angioplasty18-22.


There is a clear relationship between the time between onset pf symptoms and revascularization to the short- and long-term outcome of STEMI and many patients who arrive late to the catheterization laboratory after the onset of STEMI symptoms develop massive myocardial loss. A minority of patients who arrive early may also suffer from massive myocardial loss. These two groups of patients usually present with TIMI flow grade 0 or 1 and in many instances, flow after stent implantation is TIMI 2 or lower23,24. Several explanations are possible for this phenomenon, which is related to the pathophysiology of STEMI25-27. First, embolization of downstream microcirculation with micro thrombi and microscopic debris from the ruptured plaque is integral to the STEMI syndrome. Notably, embolization can occur several hours or days before onset of STEMI symptoms. Second, the microcirculation responds to vasospastic materials that are released by the thrombus; the prolonged spasm results in very high resistance to flow and possibly damages both endothelial and smooth muscle cells. Third, myocardial edema compresses microcirculation and prevents flow through microcirculation. In addition to the three mechanisms delineated above, the role of reperfusion injury in irreversible myocardial damage has been investigated over many years, and optimal clinical practice is yet to be determined.


Multiple pharmacological interventions are advocated to alleviate microcirculatory dysfunction in patients with STEMI28, among them, intracoronary adenosine and nitroglycerine injection; however, their effects are usually short term. Heparin, anti-platelet aggregation drugs, and thrombolytic therapy also contribute to normalization of microcirculation in patients with STEMI, but these cannot be effective in blood vessels with no sustained flow, as in the event of STEMI28-29.


Devices to treat patients with STEMI are directed to unload the left ventricle and reduce afterload, and hence reduce myocardial oxygen consumption, to aspirate epicardial coronary thrombus30,31. However, in large scale studies, these devices were not shown so far to have a beneficial effect on prognosis.


Currently, the only device directed at microcirculatory perfusion is the Pressure-controlled intermittent Coronary Sinus Occlusion (PiCSO) system, developed by Miracor, a company based in Belgium32-36. This device explores the novel concept espoused by Prof. Mohl from the University of Vienna, Austria. Accordingly, a balloon catheter is placed in the coronary sinus of patients with anterior STEMI; the balloon is periodically inflated and the coronary sinus thereby intermittently occluded. Prof. Mohl showed that this system can improve coronary microcirculatory perfusion and achieve myocardial salvage.


The PiCSO therapy has been explored in multiple animal models and in several human trials and received CE mark for its use in patients with anterior STEMI. PiCSO therapy is started after restoration of flow in the epicardial artery and during stenting. The PiCSO procedure therefore does not interfere with the intervention in the epicardial coronary artery31-33. The mechanism of action involves three basic consequences of intermittently occluding the coronary sinus:


  1. The pressure in the coronary microcirculation is increased and the size of the small arteries and capillaries is enlarged. Larger size enables clearance of occluding thrombi and debris, and results in better flow during PiCSO balloon deflation.
  2. The increased coronary sinus pressure leads to redistribution of coronary flow, with recruitment of collaterals and improved myocardial perfusion. In anterior STEMI, the protocol requires a 20-60-minutes of PiCSO.
  3. In addition to the mechanistic effects, recent studies showed that the PiCSO treatment leads to the release of several cytokines and small RNAs that are associated with myocardial regeneration.

Currently, a large-scale, multicenter, multination, randomized study of the use of PiCSO in patients with anterior STEMI presenting with TIMI 0-1 flow is ongoing. The primary endpoint is infarct size measured by cardiac MRI at 5 days after reperfusion.


  1. Klabunde RE. Cardiovascular Physiology Concepts. 3rd Wolters Kluwer. 2021.
  2. Guyton AC, Hall JE. Textbook of medical physiology. 11th Elsevier Sanders 2006.
  3. Chilian W M. Coronary Microcirculation in Health and Disease: Summary of an NHLBI Workshop. Circulation 1997;95:552-8.
  4. Feigl EO. Coronary physiology. Physiological reviews 1983;63:1-205.
  5. Gimbrone MA Jr, García-Cardeña G. Endothelial Cell Dysfunction and the Pathobiology of Atherosclerosis. Circ Res. 2016;118:620-36. doi: 10.1161/CIRCRESAHA.115.306301. PMID: 26892962; PMCID: PMC4762052.
  6. Fearon WF, Balsam LB, Farouque HM, Caffarelli AD, Robbins RC, Fitzgerald PJ, Yock PG, Yeung AC. Novel index for invasively assessing the coronary microcirculation. Circulation. 2003;107:3129–3132. doi: 10.1161/01.CIR.0000080700.98607.D1.
  7. Fearon WF, Kobayashi Y. Invasive Assessment of the Coronary Microvasculature: The Index of Microcirculatory Resistance. Circ Cardiovasc Interv. 2017 Dec;10(12):e005361. doi: 10.1161/CIRCINTERVENTIONS.117.005361. PMID: 29222132.
  8. De Maria GL, Garcia-Garcia HM, Scarsini R, Hideo-Kajita A, Gonzalo López N, Leone AM, Sarno G, Daemen J, Shlofmitz E, Jeremias A, Tebaldi M, Bezerra HG, Tu S, Lemos PA, Ozaki Y, Dan K, Collet C, Banning AP, Barbato E, Johnson NP, Waksman R. Novel Indices of Coronary Physiology: Do We Need Alternatives to Fractional Flow Reserve? Circ Cardiovasc Interv. 2020;13:e008487. doi: 10.1161/CIRCINTERVENTIONS.119.008487. Epub 2020. Erratum in: Circ Cardiovasc Interv. 2020;13:e000071. PMID: 32295416.
  9. Xaplanteris P, Fournier S, Keulards DCJ, Adjedj J, Ciccarelli G, Milkas A, Pellicano M, Van’t Veer M, Barbato E, Pijls NHJ, De Bruyne B. Catheter-Based Measurements of Absolute Coronary Blood Flow and Microvascular Resistance: Feasibility, Safety, and Reproducibility in Humans. Circ Cardiovasc Interv. 2018;11:e006194. doi: 10.1161/CIRCINTERVENTIONS.117.006194. PMID: 29870386
  10. Viewed 1 July 2021.
  11. Kodeboina M, Nagumo S, Munhoz D, Sonck J, Mileva N, Gallinoro E, Candreva A, Mizukami T, Van Durme F, Heyse A, Wyffels E, Vanderheyden M, Barbato E, Bartunek J, De Bruyne B, Collet C. Simplified Assessment of the Index of Microvascular Resistance. J Interv Cardiol. 2021;2021:9971874. doi: 10.1155/2021/9971874. PMID: 34149324; PMCID: PMC8189791.
  12. Rivero F, Gutiérrez-Barrios A, Gomez-Lara J, Fuentes-Ferrer M, Cuesta J, Keulards DCJ, Pardo-Sanz A, Bastante T, Izaga-Torralba E, Gomez-Hospital JA, García-Guimaraes M, Pijls NHJ, Alfonso F. Coronary microvascular dysfunction assessed by continuous intracoronary thermodilution: A comparative study with index of microvascular resistance. Int J Cardiol. 2021;333:1-7. doi: 10.1016/j.ijcard.2021.03.005. Epub 2021. PMID: 33684380.
  13. Konst RE, Elias-Smale SE, Pellegrini D, Hartzema-Meijer M, van Uden BJC, Jansen TPJ, Vart P, Gehlmann H, Maas AHEM, van Royen N, Damman P. Absolute Coronary Blood Flow Measured by Continuous Thermodilution in Patients With Ischemia and Nonobstructive Disease. J Am Coll Cardiol. 2021 ;77:728-741. doi: 10.1016/j.jacc.2020.12.019. PMID: 33573743.
  14. Everaars H, de Waard GA, Schumacher SP, Zimmermann FM, Bom MJ, van de Ven PM, Raijmakers PG, Lammertsma AA, Götte MJ, van Rossum AC, Kurata A, Marques KMJ, Pijls NHJ, van Royen N, Knaapen P. Continuous thermodilution to assess absolute flow and microvascular resistance: validation in humans using [15O]H2O positron emission tomography. Eur Heart J. 2019;40:2350-2359. doi: 10.1093/eurheartj/ehz245. PMID: 31327012.
  15. Mathew RC, Bourque JM, Salerno M, Kramer CM. Cardiovascular Imaging Techniques to Assess Microvascular Dysfunction. JACC Cardiovasc Imaging. 2020 Jul;13(7):1577-1590. doi: 10.1016/j.jcmg.2019.09.006. Epub 2019 Oct 11. PMID: 31607665; PMCID: PMC7148179.
  16. Ohanyan V, Raph SM, Dwenger MM, Hu X, Pucci T, Mack G, Moore JB 4th, Chilian WM, Bhatnagar A, Nystoriak MA. Myocardial Blood Flow Control by Oxygen Sensing Vascular Kvβ Proteins. Circ Res. 2021;128:738-751. doi: 10.1161/CIRCRESAHA.120.317715. Epub 2021 Jan 27. PMID: 33499656.
  17. Resnick N, Gimbrone MA Jr. Hemodynamic forces are complex regulators of endothelial gene expression. FASEB J. 1995;9:874-82. doi: 10.1096/fasebj.9.10.7615157. PMID: 7615157.
  18. Fearon WF, Low AF, Yong AS, McGeoch R, Berry C, Shah MG, Ho MY, Kim HS, Loh JP, Oldroyd KG. Prognostic value of the Index of Microcirculatory Resistance measured after primary percutaneous coronary intervention. Circulation. 2013;127:2436-41. doi: 10.1161/CIRCULATIONAHA.112.000298. Epub 2013 May 16. PMID: 23681066; PMCID: PMC5429864.
  19. de Waha S, Patel MR, Granger CB, Ohman EM, Maehara A, Eitel I, Ben-Yehuda O, Jenkins P, Thiele H, Stone GW. Relationship between microvascular obstruction and adverse events following primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: an individual patient data pooled analysis from seven randomized trials. Eur Heart J. 2017 ;38:3502-3510. doi: 10.1093/eurheartj/ehx414. PMID: 29020248.
  20. Maznyczka AM, Oldroyd KG, McCartney P, McEntegart M, Berry C. The Potential Use of the Index of Microcirculatory Resistance to Guide Stratification of Patients for Adjunctive Therapy in Acute Myocardial Infarction. JACC Cardiovasc Interv. 2019;12:951-966. doi: 10.1016/j.jcin.2019.01.246. PMID: 31122353.
  21. Scarsini R, Shanmuganathan M, De Maria GL, Borlotti A, Kotronias RA, Burrage MK, Terentes-Printzios D, Langrish J, Lucking A, Fahrni G, Cuculi F, Ribichini F, Choudhury R, Kharbanda R, Ferreira VM, Channon KM, Banning AP; OxAMI Study Investigators. Coronary Microvascular Dysfunction Assessed by Pressure Wire and CMR After STEMI Predicts Long-Term Outcomes. JACC Cardiovasc Imaging. 2021:S1936-878X(21)00205-9. doi: 10.1016/j.jcmg.2021.02.023. Epub ahead of print. PMID: 33865789.
  22. Maznyczka AM, McCartney PJ, Oldroyd KG, Lindsay M, McEntegart M, Eteiba H, Rocchiccioli JP, Good R, Shaukat A, Robertson K, Malkin CJ, Greenwood JP, Cotton JM, Hood S, Watkins S, Collison D, Gillespie L, Ford TJ, Weir RAP, McConnachie A, Berry C. Risk Stratification Guided by the Index of Microcirculatory Resistance and Left Ventricular End-Diastolic Pressure in Acute Myocardial Infarction. Circ Cardiovasc Interv. 2021;14:e009529. doi: 10.1161/CIRCINTERVENTIONS.120.009529. Epub 2021 Feb 16. PMID: 33591821.
  23. Karkabi B, Meir G, Zafrir B, Jaffe R, Adawi S, Lavi I, Flugelman MY, Shiran A. Door-to-balloon time and mortality in patients with ST-elevation myocardial infarction undergoing primary angioplasty. Eur Heart J Qual Care Clin Outcomes. 20206:qcaa037. doi: 10.1093/ehjqcco/qcaa037. Epub ahead of print. PMID: 32374838.
  24. Schaaf MJ, Mewton N, Rioufol G, Angoulvant D, Cayla G, Delarche N, Jouve B, Guerin P, Vanzetto G, Coste P, Morel O, Roubille F, Elbaz M, Roth O, Prunier F, Cung TT, Piot C, Sanchez I, Bonnefoy-Cudraz E, Revel D, Giraud C, Croisille P, Ovize M. Pre-PCI angiographic TIMI flow in the culprit coronary artery influences infarct size and microvascular obstruction in STEMI patients. J Cardiol. 2016;;67:248-53. doi: 10.1016/j.jjcc.2015.05.008. PMID: 26116981.
  25. Jaffe R, Dick A, Strauss BH. Prevention and treatment of microvascular obstruction-related myocardial injury and coronary no-reflow following percutaneous coronary intervention: a systematic approach. JACC Cardiovasc Interv. 2010 ;3:695-704. doi: 10.1016/j.jcin.2010.05.004. PMID: 20650430.
  26. Kloner RA, King KS, Harrington MG. No-reflow phenomenon in the heart and brain. Am J Physiol Heart Circ Physiol. 2018 ;315:H550-H562. doi: 10.1152/ajpheart.00183.2018. Epub 2018 Jun 8. PMID: 29882685.
  27. Heusch G, Gersh BJ. The pathophysiology of acute myocardial infarction and strategies of protection beyond reperfusion: a continual challenge. Eur Heart J. 2017 ;38:774-784. doi: 10.1093/eurheartj/ehw224. PMID: 27354052.
  28. Niccoli G, Montone RA, Ibanez B, Thiele H, Crea F, Heusch G, Bulluck H, Hausenloy DJ, Berry C, Stiermaier T, Camici PG, Eitel I. Optimized Treatment of ST-Elevation Myocardial Infarction. Circ Res. 2019;125:245-258. doi: 10.1161/CIRCRESAHA.119.315344. Epub 2019 Jul 3. PMID: 31268854.
  29. Maznyczka AM, McCartney PJ, Oldroyd KG, Lindsay M, McEntegart M, Eteiba H, Rocchiccioli P, Good R, Shaukat A, Robertson K, Kodoth V, Greenwood JP, Cotton JM, Hood S, Watkins S, Macfarlane PW, Kennedy J, Tait RC, Welsh P, Sattar N, Collison D, Gillespie L, McConnachie A, Berry C. Effects of Intracoronary Alteplase on Microvascular Function in Acute Myocardial Infarction. J Am Heart Assoc. 2020;9:e014066. doi: 10.1161/JAHA.119.014066. Epub 2020 Jan 28. PMID: 31986989; PMCID: PMC7033872.
  30. De Maria GL, Garcia-Garcia HM, Scarsini R, Finn A, Sato Y, Virmani R, Bhindi R, Ciofani JL, Nuche J, Ribeiro HB, Mathias W, Yerasi C, Fischell TA, Otterspoor L, Ribichini F, Ibañez B, Pijls NHJ, Schwartz RS, Kapur NK, Stone GW, Banning AP. Novel device-based therapies to improve outcome in ST-segment elevation myocardial infarction. Eur Heart J Acute Cardiovasc Care. 2021:zuab012. doi: 10.1093/ehjacc/zuab012. Epub ahead of print. PMID: 33760016.
  31. Jang JH, Lee MJ, Ko KY, Park JH, Baek YS, Sung-Woo K, Shin SH, Woo SI, Kim DH, Suh YJ, Kwan J, Park SD. Mechanical and Pharmacological Revascularization Strategies for Prevention of Microvascular Dysfunction in ST-Segment Elevation Myocardial Infarction: Analysis from Index of Microcirculatory Resistance Registry Data. J Interv Cardiol. 2020 Jul 9;2020:5036396. doi: 10.1155/2020/5036396. PMID: 32728350; PMCID: PMC7368229.
  32. Mohl W. The development and rationale of pressure-controlled intermittent coronary sinus occlusion–a new approach to protect ischemic myocardium. Wien Klin Wochenschr. 1984 6;96:20-5. PMID: 6608832.
  33. Mohl W, Gangl C, Jusić A, Aschacher T, De Jonge M, Rattay F. PICSO: from myocardial salvage to tissue regeneration. Cardiovasc Revasc Med. 2015 ;16:36-46. doi: 10.1016/j.carrev.2014.12.004. Epub 2014 Dec 23. PMID: 25616738.
  34. van de Hoef TP, Nijveldt R, van der Ent M, Neunteufl T, Meuwissen M, Khattab A, Berger R, Kuijt WJ, Wykrzykowska J, Tijssen JG, van Rossum AC, Stone GW, Piek JJ. Pressure-controlled intermittent coronary sinus occlusion (PICSO) in acute ST-segment elevation myocardial infarction: results of the Prepare RAMSES safety and feasibility study. EuroIntervention. 2015 May;11(1):37-44. doi: 10.4244/EIJY15M03_10. PMID: 25868741.
  35. Egred M, Bagnall A, Spyridopoulos I, Purcell IF, Das R, Palmer N, Grech ED, Jain A, Stone GW, Nijveldt R, McAndrew T, Zaman A. Effect of Pressure-controlled intermittent Coronary Sinus Occlusion (PiCSO) on infarct size in anterior STEMI: PiCSO in ACS study. Int J Cardiol Heart Vasc. 2020 ;28:100526. doi: 10.1016/j.ijcha.2020.100526. PMID: 32435689; PMCID: PMC7229496.
  36. Scarsini R, Terentes-Printzios D, Shanmuganathan M, Kotronias RA, Borlotti A, Marin F, Langrish J, Lucking A, Ribichini F; Oxford Acute Myocardial Infarction (OxAMI) Study, Kharbanda R, Ferreira VM, Channon KM, De Maria GL, Banning AP. Pressure-controlled intermittent coronary sinus occlusion improves the vasodilatory microvascular capacity and reduces myocardial injury in patients with STEMI. Catheter Cardiovasc Interv. 2021 May 29. doi: 10.1002/ccd.29793. Epub ahead of print. PMID: 34051133.