Primary percutaneous coronary intervention in acute
myocardial infarction : a double edged sword
Citation for published version (APA):
Wijnbergen, I. F. (2015). Primary percutaneous coronary intervention in acute myocardial infarction : a double
edged sword. Technische Universiteit Eindhoven.
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A Double Edged Sword
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A catalogue record is available from the Eindhoven University of Technology Library ISBN 978-90-386-3842-3
Cover design: Esther Ris, www.proefschriftomslag.nl Lay-out: Esther Ris, www.proefschriftomslag.nl
Printed by: Gildeprint Drukkerijen, Enschede, The Netherlands Financial support for the printing of this thesis was provided by:
Pfizer bv, Abbott Vascular, St. Jude Medical Nederland, TOP Medical, Boehringer-Ingelheim, Biosensors
PROEFSCHRIFT
ter verkrijging van de graad van doctor aan de Technische Universiteit Eindhoven, op gezag van de rector magnificus prof.dr.ir. F.P.T. Baaijens, voor een commissie aangewezen door het College voor Promoties, in het
openbaar te verdedigen op donderdag 4 juni 2015 om 16:00 uur
door
Inge Franciska Wijnbergen
voorzitter: prof.dr. P.A.J. Hilbers 1e promotor: prof.dr. N.H.J. Pijls
2e promotor: prof.dr. J.G.P. Tijssen (UVA-AMC)
copromotor(en): dr.ir. M. van ’t Veer (Catharina Ziekenhuis Eindhoven) leden: prof.dr. F. Zijlstra (EUR)
dr. H.R. Michels (Catharina Ziekenhuis Eindhoven) prof.dr. ir. F.N. van de Vosse
Chapter 1 Introduction and outline of this thesis
Chapter 2 Measurement of myocardial blood flow in acute myocardial infarction
Chapter 3 A Novel Monorail Catheter for Volumetric Coronary Blood Flow Measurement in Humans
Chapter 4 Absolute Coronary Blood Flow Measurement and Microvascular Resistance in ST-elevation Myocardial Infarction in the acute and subacute phase
Chapter 5 A Comparison of Drug Eluting and Bare Metal Stents for Primary Percutaneous Coronary Intervention with or without Abciximab in ST- segment elevation Myocardial Infarction: The Eindhoven Reperfusion Study (DEBATER)
Chapter 6 Circadian and Weekly Variation and the Influence of Environmental Variables in Acute Myocardial Infarction Chapter 7 Gender Differences in Long-term Outcome after Primary
Percutaneous Intervention for ST-segment elevation Myocardial Infarction
Chapter 8 Longterm Comparison of Sirolimus-eluting and Bare-metal stents in ST-Segment Elevation Myocardial Infarction
Chapter 9 General discussion and future perspectives
Summary Samenvatting Curriculum vitae Dankwoord List of publications 7 17 31 41 59 79 95 109 123 130 132 135 136 137
unfavorable consequences, the term double edged
sword is often used.”
Chapter 1
Introduction and
outline of this thesis
Epidemiology and history of ST-segment elevation myocardial
infarction (STEMI)
Despite major advances in therapy, cardiovascular diseases are still the leading cause of death worldwide 1. Ischemic heart disease is responsible for over 7 million deaths annually. In The Netherlands, more than 10.000 people die annually from ischemic heart disease, of which at least 6.800 as a direct result of acute myocardial infarction 2. Clinical features of acute myocardial infarction were described in 1912 by James Herrick 3. He found that AMI was caused by a sudden obstruction of the coronary arteries and advised bed rest as treatment. For years, treatment consisted of six weeks of absolute bed rest and in-hospital mortality averaged about 50%. Over the past decades, fatality rate could be reduced to 5% by the introduction of defibrillation, coronary care units, aspirin, thrombolysis and percutaneous coronary intervention (PCI). The first percutaneous transluminal balloon angioplasty (PTCA) in humans was performed by Gruntzig in 1977. Five years later, the first primary angioplasty was used in the treatment of acute myocardial infarction. This procedure was based on observational studies on total occlusion of the coronary arteries by a thrombus in the first hours of acute myocardial infarction 4. It became clear that early opening of the infarct-related coronary artery improved survival 5. Since a number of years, primary PCI has become the treatment of choice in acute myocardial infarction 6. Outcomes after primary PCI have improved by using stents, thrombosuction and adjunctive pharmacotherapy. Furthermore, improved logistics with prehospital triage in the ambulance and skilled personnel have made primary PCI accessible for almost all patients with STEMI in The Netherlands and set up of such advanced logistic system has been described by Brueren in his thesis in 2005 7. Further improvement of this system has reduced door-to-balloon times leading to better outcomes 8.
Management of STEMI
According to the European guidelines primary PCI is recommended in STEMI as soon as possible in patients who present within 12 hours after pain onset 9, 10. By using a well-functioning network based on pre-hospital diagnosis, the patient must be transported to the closest available primary-PCI capable centre as soon as possible and PCI must be performed within 90 minutes from the first medical contact. In early presenters and high risk cases, PCI must be performed within 60 minutes from the first medical contact 11. Besides pharmacotherapy consisting of heparin, aspirin and an ADP-receptor blocker, standard therapy includes stenting of the related artery. Stenting of the infarct-related lesion has proved to reduce the need for repeat revascularization and decreases
1
the infarction rate resulting in a reduction of long term mortality, when compared to balloon angioplasty alone 12-16. Prior to the introduction of a balloon or stent into the coronary artery, routine use of manual thrombus aspiration may be associated with an improvement in indices of myocardial reperfusion, such as ST-segment resolution and myocardial blush grade, and a reduction in mortality after one year 17-19. Post procedural treatment with adjunctive glycoprotein 2B3A inhibitors is left to the decision of the operator, but continuation of dual anti-platelet therapy after primary PCI is paramount.
No reflow phenomenon
While impressive progress has been made in the treatment of acute myocardial infarction, knowledge on pathophysiological processes in the myocardium during and after the acute phase is far behind. Whereas epicardial coronary blood flow and hemodynamics can be easily assessed directly after primary PCI by standard cathlab techniques, complex and poorly understood phenomena might occur in the myocardial microvasculature immediately after primary PCI and persist for several days. Prognosis of a patient on the longterm and preservation of left ventricular ejection fraction is most likely determined to a considerable degree by these processes in the unvisible part of the coronary circulation. Unravelling the unsolved issues with respect to regulation, distribution and restoration of coronary and myocardial perfusion is not only interesting from a scientific point of view, but also paramount from the clinical point of view and for developing additional targets of treatment.
Reperfusion therapy was earlier referred to as a “double edged sword”, because with the obtained ability to open a coronary artery and thereby reducing ischemic cell death, a new problem was observed: the “no reflow phenomenon”, also referred to as reperfusion injury 20. No reflow is the inability to adequately perfuse myocardium after temporary occlusion of an epicardial coronary artery without evidence of persistent epicardial obstruction, thus implying ongoing myocardial ischemia.
In 1974, Kloner et al described this phenomenon in dogs and showed that, after temporary occlusion of a coronary artery, subendocardial perfusion defects were detectable and persistent after 90 minutes of occlusion 21. Failure of reflow was associated with extensive capillary damage and myocardial cell swelling and led to damage of the myocardial microvasculature.
The pathogenesis of no-reflow has not been elucidated completely and seems to be complex and multifactorial. During the past decade, several potential mediators of the no reflow phenomenon have been suggested and are referred to as the oxygen, calcium and pH paradox 22. The oxygen paradox means that reoxygenation of the ischemic myocardium with an increase in myocardial pO2 leads to the production of toxic reactive
oxidants damaging myocytes. The calcium paradox involves the abrupt increase in intracellular calcium causing an intracellular and mitochondrial Ca2+ overload leading to hypercontracture of myocytes inducing cell death. The pH paradox means that the rapidly restored physiologic pH during myocardial reperfusion can cause lethal cell injury. It has been postulated that forementioned mechanisms are associated with mitochondrial permeability transition pore (PTP) opening, resulting in rapid intracellular changes in oxygen, calcium and pH. This in turn leads to mitochondrial damage preventing production of high energy phosphate and leading to myocyte death. Severe myocardial edema may result in further compression and obstruction of the microvasculature. Other possible causes of no reflow involve an inflammation reaction with infiltration of the coronary circulation by neutrophils that can directly cause endothelial damage. Also, coronary capillaries can be plugged by aggregates from neutrophils with platelets, or by small thrombi originating from an epicardial thrombus (distal embolization). Finally, transient spasm of small vessels shortly after occlusion or reperfusion might play a role in the no-reflow phenomenon.
After opening of the epicardial coronary artery in acute myocardial infarction up to one third of patients do not, or only very shortly, achieve myocardial microvascular reperfusion 23, 24. Clinical predictors associated with the occurrence of no reflow in acute myocardial infarction are thrombus burden, duration of ischemia, diabetes, acute hyperglycemia and hypercholesterolemia 25.
Several methods to evaluate microvascular reperfusion have been proposed. Myocardial perfusion imaging using cardiovascular magnetic resonance imaging (CMR), invasive measurement of coronary flow velocity using a Doppler wire and determination of ST-resolution on the electrocardiogram (ECG) are examples of indirect measures of microvascular reperfusion. Another specific method to assess microvascular flow and function is measuring the index of microcirculatory resistance (IMR), which was introduced by Fearon et al 26 and has been validated in animal models and tested in stable patients 27-29. Nowadays, it is known that the presence of no reflow contributes to final infarct size 22 and, more recently, IMR in STEMI patients was found to be a determinant of preservation of left ventricular function 30-32. Therefore, prevention or treatment of reperfusion injury could improve outcome after primary PCI (Figure 1). A disadvantage of all known methods to assess microvascular flow and function is that these only give indirect and relative measures, are operator-dependent or rather inaccurate, or only available in a minority of patients. Especially when comparing flow or resistance within one subject at different points in time (eg hyperacute phase and follow up after STEMI), a more precise and direct method of measuring blood flow and resistance in the myocardial microvasculature, is needed.
In this thesis, therefore, a rather new methodology is used to assess myocardial blood flow and resistance quantitatively, as recently developed in the department of
1
biomedical engineering of the Technical University and the Department of Cardiology of the Catharina Hospital Eindhoven, and described by Aarnoudse and van ‘t Veer 26,33.
Figure 1
Contribution of reperfusion injury to final myocardial infarct size. This hypothetical scheme shows the large reduction in myocardial infarct size obtained by early and successful myocardial reperfusion after a sustained episode of acute myocardial ischemia. The full benefits of myocardial reperfusion are not realized because of the presence of reperfusion injury, which diminishes the magnitude of the reduction in infarct size elicited by myocardial reperfusion. Infarcted myocardium is depicted in pink, and the viable, at-risk myocardium is stained red. Infarct size is expressed as a percentage of the volume of myocardium at risk for infarction.
Reproduced with permission from “Myocardial Reperfusion Injury”, Derek M. Yellon, Derek J. Hausenloy, N Engl J Med 2007;357:1121, Copyright Massachusetts Medical Society.
Outline of this thesis
To optimize treatment or create new targets for treatment, a good understanding of underlying pathophysiological processes is needed. This thesis addresses two main topics with respect to STEMI. The first part is dedicated to pathophysiologic aspects of STEMI and in particular the microcirculation of the heart. The etiology, pathophysiology of myocardial damage and reduction of damage after STEMI will be investigated, in particular with respect to the microcirculation. It is known that a high microcirculatory resistance can be reversible or sustained, but the exact time-course and its relation to outcome is unknown. Furthermore, the relation between absolute coronary flow and outcome has never been established. The second part of this thesis investigates clinical
aspects of acute myocardial infarction. Different contemporary treatment strategies are compared and specific characteristics of STEMI are investigated.
For understanding the background of hemodynamic measurements used to determine epicardial flow and microcirculatory perfusion, pressure and flow measurement techniques are discussed in chapter 2. More specifically, the methodology for assessment of absolute flow and resistance in STEMI will be presented, based upon the earlier work of Aarnoudse and van ‘t Veer 33.
In chapter 3, the results of an innovative clinical study performed at the Catharina Hospital in patients in the hyperacute phase of STEMI is described. In this study, absolute coronary flow and resistance are measured in 20 patients with STEMI directly after primary PCI en 3-5 days post primary PCI and results are related to the index of microvascular resistance and the area at risk determined by cardiac magnetic resonance imaging. This study is the missing link between microcirculatory function or damage in the acute phase of STEMI and long term outcome.
The cornerstones of the present management of STEMI besides opening of the infarct-related artery are stent placement and adjunctive pharmacotherapy. Development of drug-eluting stents led to a reduction of instent stenosis in elective PCI 34-36. In patients with STEMI, this matter has been unclear for a long time. That was the background for designing and performing the DEBATER study 37. This randomized, largest single center STEMI trial ever performed, evaluates treatment of STEMI with bare-metal stents versus drug-eluting stents, with or without adjunctive therapy with abciximab. The clinical results after 1 year are described in chapter 4. Questions about timing and the possible influence of climatic variables on the occurrence of acute myocardial infarction are answered in chapter 5. In this chapter, a substudy of the DEBATER trial, the impact of seasons, temperature and circadian variation is investigated among almost 3000 STEMI patients in The Netherlands. Another issue raising many questions over the past years is the impact of gender on mortality rates after primary PCI for STEMI. Earlier studies report that the higher mortality rate in women can be explained by higher baseline risk profiles in women compared to men 38-40. In contrast, later studies show that the mortality rate in women remains higher compared to men after adjustment for differences in baseline characteristics 41-43. Most studies on this subject have been performed before current PCI techniques and concomitant pharmacotherapy became the standard treatment of STEMI and had short duration of follow up. Therefore, in chapter 6, the influence of gender on long term outcome in patients with STEMI in the DEBATER study is assessed. To investigate if the advantage of using drug-eluting stents in STEMI persists over time, in chapter 7, the 5 year results of the DEBATER study are reported.
Finally, in chapter 8, a general discussion is presented and future perspectives are discussed.
1
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17. Svilaas T, Vlaar PJ, van der Horst, I, et al. Thrombus aspiration during primary percutaneous coronary intervention. N Engl J Med 2008; 358:557-67.
18. Vlaar PJ, Svilaas T, van der Horst, I, et al. Cardiac death and reinfarction after 1 year in the Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study (TAPAS): a 1-year follow-up study. Lancet 2008; 371:1915-20.
19. Burzotta F, De Vita M, Gu YL, et al. Clinical impact of thrombectomy in acute ST-elevation myocardial infarction: an individual patient-data pooled analysis of 11 trials. Eur Heart J 2009; 30:2193-203.
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salvage assessed by cardiovascular magnetic resonance in acute reperfused myocardial infarction. J Am Coll Cardiol 2010; 55:2470-9.
24. Wu KC, Zerhouni EA, Judd RM, et al. Prognostic significance of microvascular obstruction by magnetic resonance imaging in patients with acute myocardial infarction. Circulation 1998; 97:765-72.
25. Niccoli G, Burzotta F, Galiuto L, et al. Myocardial no-reflow in humans. J Am Coll Cardiol 2009; 54:281-92.
26. Fearon WF, Balsam LB, Farouque HM, et al. Novel index for invasively assessing the coronary microcirculation. Circulation 2003; 107:3129-32.
27. Fearon WF, Aarnoudse W, Pijls NH, et al. Microvascular resistance is not influenced by epicardial coronary artery stenosis severity: experimental validation. Circulation 2004; 109:2269-72.
28. Aarnoudse W, Fearon WF, Manoharan G, et al. Epicardial stenosis severity does not affect minimal microcirculatory resistance. Circulation 2004; 110:2137-42.
29. Ng MK, Yeung AC, Fearon WF. Invasive assessment of the coronary microcirculation: superior reproducibility and less hemodynamic dependence of index of microcirculatory resistance
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compared with coronary flow reserve. Circulation 2006; 113:2054-61.
30. Fearon WF, Shah M, Ng M, et al. Predictive value of the index of microcirculatory resistance in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol 2008; 51:560-5. 31. McGeoch R, Watkins S, Berry C, et al. The index of microcirculatory resistance measured
acutely predicts the extent and severity of myocardial infarction in patients with ST-segment elevation myocardial infarction. JACC Cardiovasc Interv 2010; 3:715-22.
32. Lim HS, Yoon MH, Tahk SJ, et al. Usefulness of the index of microcirculatory resistance for invasively assessing myocardial viability immediately after primary angioplasty for anterior myocardial infarction. Eur Heart J 2009; 30:2854-60.
33. Aarnoudse W, Van’t Veer M, Pijls NH, et al. Direct volumetric blood flow measurement in coronary arteries by thermodilution. J Am Coll Cardiol 2007; 50:2294-304.
34. Kastrati A, Mehilli J, Pache J, et al. Analysis of 14 trials comparing sirolimus-eluting stents with bare-metal stents. N Engl J Med 2007; 356:1030-9.
35. James SK, Stenestrand U, Lindback J, et al. Long-term safety and efficacy of drug-eluting versus bare-metal stents in Sweden. N Engl J Med 2009; 360:1933-45.
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37. Wijnbergen I, Helmes H, Tijssen J, et al. Comparison of Drug-Eluting and Bare-Metal Stents for Primary Percutaneous Coronary Intervention With or Without Abciximab in ST-Segment Elevation Myocardial Infarction: DEBATER: The Eindhoven Reperfusion Study. JACC Cardiovasc Interv 2012; 5:313-22.
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40. Park JS, Kim YJ, Shin DG, et al. Gender differences in clinical features and in-hospital outcomes in ST-segment elevation acute myocardial infarction: from the Korean Acute Myocardial Infarction Registry (KAMIR) study. Clin Cardiol 2010; 33:E1-E6.
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Chapter 2
Measurement of
myocardial blood flow
in acute myocardial
infarction
Introduction
Until recently, techniques for direct measurement of absolute coronary or myocardial blood flow were not available for common clinical practice. However, several indirect invasive measures have been developed over the past years for the determination of coronary and myocardial blood flow. For a good understanding of this thesis, the general principles of commonly used methods to assess flow in the coronary circulation are explained.
Coronary flow reserve
Coronary flow reserve was introduced by Gould in 1974 1, 2 and is defined as the extent to which the coronary circulation can augment myocardial blood flow in response to exercise or a hyperaemic stimulus. It can be calculated by dividing hyperaemic flow by resting flow.
Normal coronary flow reserve is 4 to 6, which means that, at maximum exercise levels, the healthy coronary circulation can increase blood flow 4 to 6-fold. In the presence of a stenosis, the resting flow does not change until a tight narrowing of 80 to 85% in diameter is reached. However, hyperaemic coronary flow begins to decline when a 50% diameter stenosis is present.
CFR can be measured by positioning a pressure wire in the distal part of the coronary artery. The sensor at the tip of the wire can measure both pressure and temperature and CFR can be calculated by using the principles of thermodilution. The technique of thermodilution-derived measurements is further explained in the paragraph on absolute flow.
Alternatively, a Doppler guide wire can be used in the coronary artery to assess resting and hyperaemic flow velocity. The ratio of flow velocities (also called CFVR) is then used as a surrogate for CFR.
CFR is influenced by several factors such as heart rate, blood pressure and left ventricular hypertrophy. These factors affect the level of resting flow and therefore also absolute flow reserve. Another disadvantage of absolute CFR for clinical decision-making is the wide variability of normal values, depending on age, extent of myocardial perfusion territory, and interindividual genetic variation. Furthermore, CFR does not distinguish between the effects of epicardial coronary disease and microvascular disease on coronary flow 3.
2
Finally, to measure CFR or any other index relying upon resting flow, true resting conditions are mandatory and these can hardly ever be achieved reliably in the human catheterization laboratory.
Myocardial fractional flow reserve
The exercise tolerance of patients with stable coronary artery disease is determined by maximum achievable myocardial blood flow. Therefore, from a practical point of view of the patient, maximum achievable myocardial blood flow is the most important parameter to quantify the degree of coronary disease and functional impairment. In the presence of a stenosis, the exercise level at which ischemia will occur is directly related to the maximum coronary blood flow that is still achievable by the stenotic vessel. Therefore, not resting flow but maximum achievable blood flow to the myocardium at risk is the best parameter to determine the functional capacity of the patient. Expressing myocardial blood flow in absolute dimensions, however, has considerable disadvantages because this is dependent on the size of the distribution area which is unknown, and will differ between patients, vessels and distribution areas. To overcome this, it is better to express maximum achievable blood flow to a distribution area as a ratio to normal maximum blood flow. For that purpose, the concept of Fractional Flow Reserve (FFR) has been developed 4, 5.
Fractional flow reserve of the myocardium (FFRmyo) is an index defined as the maximum achievable blood flow to a distribution area in the presence of a stenosis as a ratio to the normal maximum achievable blood flow to that distribution area in the hypothetical situation the supplying vessel would be completely normal. FFR can be measured by the ratio of distal coronary pressure to aortic pressure at maximum hyperemia (Figure 1).
Where Qmax,s is the myocardial blood flow in the presence of a stenosis and Qmax,n represents the normal maximum myocardial blood flow. Because at maximum hyperaemia (corresponding with maximum arteriolar vasodilatation), blood flow is directly proportional to perfusion pressure, FFRmyo can also be expressed as:
where Pa, Pd and Pv represent mean aortic, distal coronary and central venous pressure, obtained at maximum coronary hyperemia. Because generally, central venous pressure
is close to zero, the equation can be further simplified to:
From the equations above, it is obvious that FFRmyo for a normal coronary artery equals 1.0 for every person and every normal coronary artery. The threshold value of inducible ischemia is 0.80, with a small gray zone (0.75-0.80) 6-9. For the scientific background and mathematical derivation of the pressure flow equations, the reader is referred to the literature 3.
FFR is not dependent on resting flow or changing hemodynamic conditions and takes into account the extent of the perfusion area and presence of collaterals, and is therefore not subject to many of the limitations related to the concept of coronary flow reserve.
Figure 1
Simplified representation of a coronary artery and the supplied myocardium to clarify the rationale of FFRmyo. In this example at maximum vasodilation, myocardial perfusion pressure would be 100
mmHg if no stenosis were present. Because of the stenosis, this perfusion pressure has decreased to 70 mmHg. Therefore, at maximum vasodilation, the ratio between maximum achievable flow in the presence of that stenosis and normal maximum flow is represented by (70-0)/(100-0). That ratio represents the fraction of normal maximum flow that is preserved despite the presence of the stenosis and is called FFRo. It may also be clear that it is not the hyperaemic pressure gradient
(∆P) that determines the effect of the stenosis on myocardial blood flow, but rather the remaining fraction of myocardial perfusion pressure. Pa, mean aortic pressure; Pd, mean hyperaemic distal
coronary pressure; Pv, mean hyperaemic central venous pressure.
FFR can be simply obtained by measuring Pa and Pd simultaneously during maximum coronary hyperemia. Pa can be measured in a regular way by the guiding catheter and Pd is obtainable by positioning a sensor-tipped guidewire in the distal part of the coronary artery.
2
FFR has become the gold standard in catheterization laboratories to determine the functional significance of a coronary artery stenosis 9.
Figure 2
Two frequently used indexes to assess different compartments of the coronary circulation. Fractional flow reserve of the myocardium (FFR) is measured during hyperemia, which means that the microvascular compartment is fully vasodilated and thus microvascular resistance is minimal and fixed. Therefore, FFR is a specific measure for the functional significance of epicardial artery stenosis, regardless of microcirculatory disease.
Coronary flow reserve (CFR) measures the extent to which coronary flow can increase, and is thus dependent on the microcirculatory vasodilatory reserve as well as the state of the epicardial artery. By combining the two indexes, theoretically, assumptions can be made regarding microvascular dysfunction.
Index of microcirculatory resistance (IMR)
In Figure 2, a schematic representation of the coronary circulation is depicted. As mentioned above, FFR specifically describes the influence of a coronary artery stenosis or epicardial coronary disease on myocardial perfusion. CFR (and absolute flow) is a measure for epicardial and microcirculatory abnormalities together, but cannot differentiate between both. Theoretically, measuring FFR and CFR simultaneously would provide indirect assessment of the microcirculation, but is difficult to perform and not practical. Therefore, more specific indices to assess the microcirculation have been developed.
To more specifically interrogate the myocardial microcirculation, the index of microcirculatory resistance was introduced by Fearon et al 10. IMR is calculated from the simultaneous measurement of distal coronary pressure and thermodilution-derived mean transit time (Tmn) of a bolus of saline injected at room temperature into the coronary artery during maximal hyperaemia. As demonstrated previously, the inverse of Tmn strongly correlates to absolute coronary blood flow 11-13. Therefore, in the absence of an epicardial stenosis and collateral flow, IMR is equal to the product of Pd and Tmn at maximum hyperemia and correlates well with the true myocardial resistance (TMR).
IMR can be measured easily. First, by advancing a pressure wire to the distal part of the coronary artery, the distal coronary pressure can be recorded from the pressure wire after achieving maximal hyperemia by intravenous adenosine. The hyperaemic mean transit time can be obtained after rapid injection of 3ml of room-temperature saline through the coronary catheter (Figure 3). The hyperaemic mean transit time is measured three times and is averaged. The IMR can be calculated using the equation.
Myocardial blood flow is the sum of antegrade coronary flow and collateral flow. In the presence of an epicardial stenosis, collateral flow as measured by the coronary wedge pressure must be incorporated into the equation, which becomes more complex then:
Where Pd, Pa and Pw represent distal coronary, mean aortic and coronary wedge pressure. Therefore, calculation of IMR in a case of a severely stenotic coronary artery is less trivial. When using the last equation above, IMR is independent of the presence of an epicardial stenosis, irrespective of the severity 14. A disadvantage of IMR is the rather high inter- and intra operator variability.
Measurement of absolute coronary blood flow
Coronary blood flow can be measured by using the continuous infusion thermodilution technique. This technique uses steady state infusion of saline into the blood, and monitoring temperature changes in the distal blood vessel. This method was already described by Ganz et al in 1971, but could only be applied in the coronary sinus and was not useful for clinical application Mathey, Weisse, Rossen 15-17. Recently, a methodology for measurement of maximum coronary blood flow in individual coronary arteries based
2
upon the theory described by Ganz et al, was developed 18. When coronary blood flow is measured together with distal coronary pressure by the same sensor-tipped guidewire, also absolute myocardial blood flow, collateral flow and myocardial resistance can be calculated.
Figure 3
Calculation of mean transit time (Tmn) from thermodilution curve (sensor); blue line, and injection signal (shaft); black line. “Inj” indicates injection of saline; t=0 is defined as halfway injection.
Using this technology of continuous infusion of a low rate saline at a low infusion rate, absolute hyperaemic coronary blood flow (Qb) can be calculated by the infusion rate
(Qi), temperature of the infused saline (Ti) and distal blood temperature after complete
mixing (T). Taking the differences in specific heat and density of the blood and the saline into account and expressing T and Ti as the deviation with respect to the blood temperature (Tb), the actual blood flow can be calculated using the following equation:
and saline. In contrast to the use of this technique in the coronary sinus, complete mixing is easily achieved by the design of the infusion catheter, the anterograde infusion, and the rheologic characteristics of fast-flowing arterial blood 19, 20. For the theoretical background and mathematical derivation of this equation, the reader is referred to the literature 19, 20.
Figure 4
Set-up for measuring absolute coronary blood flow during catheterization using the technology of continuous infusion of saline at low infusion rate.A sensor-tipped pressure/temperature guidewire is positioned in the distal part of the coronary artery. Next, a special infusion catheter with four small sideholes in the last 5mm proximal to its tip is advanced over the guidewire. This catheter is designed to ensure adequate mixing of blood and saline, and has to be placed in the coronary artery. The infusion catheter is connected to an infusion pump. The distance between the distal tip of the infusion catheter and the position of the pressure/temperature sensor must is 3-6cm. The sensor-tipped guidewire can then be connected to the interface for recording pressure and temperature (Analyzer; St Jude Medical Systems).
Absolute hyperaemic coronary blood flow (Qb) can be calculated by the infusion rate (Qi), temperature of the infused saline (Ti) and distal blood temperature after complete mixing (T).
2
In the catheterization laboratory, the measurement of volumetric blood flow in a selective coronary artery is safe, reproducible, relatively simple and takes 15-20 minutes to perform in experienced hands. The instrumentation and set-up needed to measure absolute coronary blood flow is shown in Figure 4. First, a sensor-tipped pressure/ temperature guidewire has to be positioned in the distal part of the coronary artery. Next, a special infusion catheter with four small sideholes in the last 5mm proximal to its tip has to be advanced over the guidewire. This catheter is designed to ensure adequate mixing of blood and saline, and has to be placed in the coronary artery. The distance between the distal tip of the infusion catheter and the position of the pressure/ temperature sensor must be 3-6cm. The sensor-tipped guidewire can then be connected to the interface (RADI analyzer; Analyzer Express, St Jude Medical Systems, Uppsala, Sweden) (Figure 5).
Figure 5
Example of absolute flow measurement by thermodilution in a patient. On the left, blood temperature at steady state hyperaemia (Tb) set to zero. Next, infusion of saline is started and temperature T is recorded during steady state infusion. Then, the sensor is pulled back to the tip of the infusion catheter to measure Ti. Using the equation from page 23, coronary blood flow can be calculated.
After achieving steady state hyperaemia by administering adenosine intravenously, the temperature sensor can measure the distal blood temperature (Tb) and continuous infusion of saline at a chosen rate of 15-25 ml/min can be started by using a dedicated infusion pump. During steady state continuous infusion of saline, the temperature of
the blood after adequate mixing with the infused saline (T) will decrease and can be measured. Thereafter, the pressure/temperature sensor has to be pulled back into the infusion catheter, so that the temperature of the saline (Ti) at the location of the most proximal side hole can be measured. Absolute blood flow in the coronary artery can then be calculated using the equation.
Measuring absolute blood flow and resistance has no meaning in itself as long as the distribution territory is unknown and it is difficult to compare blood and resistance between different territories, not to speak of different patients. However, if the area of interest is the occluded coronary artery or its dependent myocardial territory and one is interested in studying this (identical) territory over time, the technique is extremely accurate and useful. Simply spoken, the tip of the infusion catheter can be placed at the level of the stent placed and measurements can be done and repeated later in time with the infusion catheter and the sensor tipped guidewire at exactly identical positions. In such way, a true gold standard is obtained to monitor absolute flow and resistance in an infarcted area and to monitor recovery (or absence of recovery) over time. This technique of absolute flow and resistance measurement is applied in the studies in humans, presented in the next chapter.
2
References
1. Gould KL, Lipscomb K. Effects of coronary stenoses on coronary flow reserve and resistance. Am J Cardiol 1974; 34:48-55.
2. Gould KL, Lipscomb K, Hamilton GW. Physiologic basis for assessing critical coronary stenosis. Instantaneous flow response and regional distribution during coronary hyperemia as measures of coronary flow reserve. Am J Cardiol 1974; 33:87-94.
3. Pijls NH, De Bruyne B. Coronary Pressure. Second ed. Kluwer Academic Publishers, 2000. 4. Pijls NH, De Bruyne B, Peels K, et al. Measurement of fractional flow reserve to assess the
functional severity of coronary-artery stenoses. N Engl J Med 1996; 334:1703-8. 5. Pijls NH, van Son JA, Kirkeeide RL, et al. Experimental basis of determining maximum
coronary, myocardial, and collateral blood flow by pressure measurements for assessing functional stenosis severity before and after percutaneous transluminal coronary angioplasty. Circulation 1993; 87:1354-67.
6. Bech GJ, De Bruyne B, Pijls NH, et al. Fractional flow reserve to determine the appropriateness of angioplasty in moderate coronary stenosis: a randomized trial. Circulation 2001; 103:2928-34.
7. Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009; 360:213-24.
8. De Bruyne B, Pijls NH, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012; 367:991-1001.
9. Pijls NH, Sels JW. Functional measurement of coronary stenosis. J Am Coll Cardiol 2012; 59:1045-57.
10. Fearon WF, Balsam LB, Farouque HM, et al. Novel index for invasively assessing the coronary microcirculation. Circulation 2003; 107:3129-32.
11. Aarnoudse W, van den Berg P, van de Vosse F, et al. Myocardial resistance assessed by guidewire-based pressure-temperature measurement: in vitro validation. Catheter Cardiovasc Interv 2004; 62:56-63.
12. De Bruyne B, Pijls NH, Smith L, et al. Coronary thermodilution to assess flow reserve: experimental validation. Circulation 2001; 104:2003-6.
13. Pijls NH, De Bruyne B, Smith L, et al. Coronary thermodilution to assess flow reserve: validation in humans. Circulation 2002; 105:2482-6.
14. Aarnoudse W, Fearon WF, Manoharan G, et al. Epicardial stenosis severity does not affect minimal microcirculatory resistance. Circulation 2004; 110:2137-42.
15. Mathey DG, Chatterjee K, Tyberg JV, et al. Coronary sinus reflux. A source of error in the measurement of thermodilution coronary sinus flow. Circulation 1978; 57:778-86.
16. Weisse AB, Regan TJ. A comparison of thermodilution coronary sinus blood flows and krypton myocardial blood flows in the intact dog. Cardiovasc Res 1974; 8:526-33.
17. Rossen JD, Oskarsson H, Stenberg RG, et al. Simultaneous measurement of coronary flow reserve by left anterior descending coronary artery Doppler and great cardiac vein thermodilution methods. J Am Coll Cardiol 1992; 20:402-7.
18. Aarnoudse W, Van ‘t Veer M, Pijls NH, et al. Direct volumetric blood flow measurement in coronary arteries by thermodilution. J Am Coll Cardiol 2007; 50:2294-304.
19. Van’t Veer M, Geven MC, Rutten MC, et al. Continuous infusion thermodilution for assessment of coronary flow: theoretical background and in vitro validation. Med Eng Phys 2009; 31:688-94.
20. Van’t Veer M. Hemodynamic measurements in coronary, valvular and peripheral vascular disease. 2008.
Chapter 3
A novel monorail catheter for
volumetric coronary blood flow
measurement in humans
Gabor G Toth
1, Inge Wijnbergen
2, Marcel C. M. Rutten
3,
Emanuele Barbato
1, Nico H.J. Pijls
2,3, Jan Weber
4,
Bernard De Bruyne
1, Marcel van’t Veer
2,3.
1Cardiovascular Center Aalst, OLV Clinic, Aalst, Belgium, 2Department of Cardiology, Catherina Hospital,
Eindhoven, the Netherlands,
3Department of Biomedical Engineering, Eindhoven University
of Technology, Eindhoven, the Netherlands
Abstract
Objective The aim of our work was to design a novel device allowing accurate measure-ment and a handy use.
Background The method to quantify absolute coronary blood flow based on the principle of continuous thermodilution has been described and validated in animals and in humans. However, the used perfusion catheter was prematurely experimental, and is no longer available.
Methods The new design aimed to met the prerequisites of thermodilution-derived flow measurements, namely: a) infused saline should be homogenously mixed with the blood to obtain a correct mixing temperature; b) it must be possible to measure accurately the temperature of the saline when it is entering the coronary artery; c) the presence of the catheter should influence the coronary blood flow as little as possible.
Results Device was tested in a physiologic representative experimental model, simulating the left ventricle, the systemic and the coronary circulation. Calculated flow (Qthermo) showed a strong overall correlation with measured flow (Q)over three groups of different infusion rates, namely the low infusion rates (Qi below 30mL/min; r=0.93, 95% CI 0.83 to 0.97; p<0.0001), the intermediate infusion rates (Qi between 30 and 40 mL/min; r=0.98, 95% CI 0.95 to 0.99; p<0.0001) and the high infusion rates (Qi above 40 mL/min; r=0.99, 95% CI 0.90 to 1.00; p<0.0001).
Conclusion The present data indicate that this novel catheter allows absolute coronary blood flow measurement which opens a window towards a better understanding of microvascular pathophysiology.
3
Introduction
Quantification of volumetric coronary flow (mL/min) and microvascular resistance (mmHg.min/mL) in humans is currently not possible. The index of microvascular resistance1 has been proposed to obtain a semi-quantitative approach and has recently been shown to bear prognostic information in patients with STEMI and Non-STEMI.2-4 Absolute myocardial blood flow assessment can be obtained in humans by 15O-labeled water or 13NH
3 and positron emission tomography but requires a cyclotron on site. In animals, electromagnetic flow meters and microspheres have been considered the standard of reference but they are not applicable to humans. In the absence of a simple and reproducible method for quantifying microvascular resistance, investigations of microvascular dysfunction has been limited.
A method to quantify absolute coronary blood flow based on the principle of continuous infusion of a small volume of saline with thermodilution has been described and validated in animals and in humans.5 However, the infusion catheter, used at that time, was experimental, and is not commercially available. Accordingly, we designed a novel monorail catheter to ensure complete and homogeneous mixing of saline with blood, a prerequisite to the continuous thermodilution technique. The catheter and the measurements of flow were tested in in-vitro model of the coronary circulation.6
Methods
Measurement of volumetric coronary blood flow
As described earlier5,7,8blood flow (Q
b, mL/min) can be calculated, by continuous
intracoronary infusion of saline at room temperature by the following equation:
where Qi is the injection rate of saline by the pump (in mL/min); Tb is the temperature
of blood before infusion of saline; Ti is the temperature of the injected saline when it
exits the infusion catheter; and T is the temperature of the homogenous mixture of blood and saline in the distal part of the coronary artery. The constant Cp relates to the difference between the specific heats of blood and saline.9 In the case where saline is injected in blood this constant equals 1.08. In practice, temperature of blood (Tb) is taken as a reference value to which other temperatures can be compared. Therefore, Ti and T stand for relative temperatures, so that the formula can be simplified as follows:
saline and that of the injected room temperature saline are identical, Cp equals 1.00. Since we do not use blood in our set-up it is more correct to express the calculated flow not as blood flow (Qb) but as thermodilution derived flow; therefore, in the present study
we used the symbol Qthermo instead of Qb.
Infusion catheter design
To allow thermodilution-derived flow measurements an infusion catheter must comply to a number of prerequisites: a) as mentioned above the infused saline should be homogenously mixed with the blood to obtain a correct mixing temperature (T); b) when the sensor is pulled into the infusion catheter it must be possible to measure accurately the temperature of the saline when it is entering the coronary artery (Ti); c) the presence of the catheter should influence the coronary blood flow as little as possible.
Therefore we designed the novel catheter based on the structure of a conventional monorail balloon catheter with an outer diameter of 0.95 mm (Figure 1).
Figure 1
Schematic design of a novel catheter based on the structure of a monorail balloon catheter. There are four 150 µm outer holes (perfusion holes) between the outer lumen and the surface, allowing adequate mixing of blood with saline.
In this design, the conventional balloon part was replaced by the non-blow, molded pre-shape of the balloon. It consists of a 22 cm long monorail inner lumen for the 0.014” guidewire with temperature sensor, and an outer lumen running over the whole length of the catheter for saline infusion. This is the inflation lumen of the conventional balloon catheter. There are four 150 µm outer holes (perfusion holes) between the outer lumen and the surface made by ultrashort-pulse laser ablation. Two pairs of infusion holes are located at 7 and 8 millimeters from the tip and positioned at 0°, 180° and 90°,
3
270°, respectively. These holes aim at providing instantaneous and homogenous mixing of saline with blood. There are two 50 µm inner holes (sensor holes) between the outer and the inner lumen. Sensor holes are located 9 and 10 millimeters from the tip and positioned 90° and 270°, respectively. These holes provide a direct contact between the injected saline and the guidewire temperature sensor, when the latter is pulled-back in the catheter, and so they enable the precise assessment of the temperature of saline, at the very moment it enters the coronary artery (Ti). The hub is standard sized, and compatible with any automated pump injector, used for the continuous injection of saline at room temperature.
Validation tests
The physiologic representative experimental model we used, simulating the left ventricle, the systemic and the coronary circulation is described elsewhere.6,10 In short, the model combines a piston pump, a left ventricular chamber and two valves. Originating from the left ventricular chamber, a polyurethane tube with the dimensions and mechanical properties of the native aorta leads to a system of compliances and resistances, creating physiological aortic pressure- and flow patterns. Coronary circulation is modelled with polyurethane tubes of physiologic dimensions, branching off the aorta directly distal to the aortic valve. The coronary circulation is bifurcated into an epicardial compartment and a sub-endocardial compartment. The latter is led through the left ventricular chamber, inducing periodic collapse during systole, similarly to the typical physiologic phenomenon. A perivascular ultrasound flow probe (4PSB, Transonic Systems Inc, Ithaca, NY, US) was placed around the main branch of the coronary artery to measure coronary flow as reference. Using an adjustable clamp distal to the flow probe the reference flow was set between 50 and 400 mL/min (Q).
Continuous injection of room temperature saline (Qi) was provided by automated pump injector (Medrad Inc., Warrendale, PA, US) with a flow rate of the injected saline at varied between 20 to 50 mL/min by steps of 5 mL/min. In total n=69 measurements were performed with varied pairs of Q and Qi. The model was submerged in water which
was kept at a constant temperature of 37.00±0.05 °C by an external thermal bath and circulator (F34-HL, Julabo GmbH., Seelbach, Germany).
Temperatures (Tb, Ti, T) were measured using the PressureWireTM (St. Jude Medical Inc., St. Paul, MI, US). T is expressed as the mean temperature of five heart cycles.
Statistical analysis
Correlation was calculated using the Pearson test. Agreement between calculated (Qthermo) and measured (Q) flow was assessed by Bland-Altman plots of the relative
differences. Pressure values were compared with Kruskal-Wallis test, and expressed as median [interquartile range], as appropriate.
Figure 2
Correlation between calculated flow (Qthermo) and measured flow (Q) at low, intermediate and high
infusion rates.
Results
Calculated flow (Qthermo) showed a strong overall correlation with measured flow (Q)over three groups of different infusion rates, namely the low infusion rates (Qi below 30mL/ min; r=0.93, 95% CI 0.83 to 0.97; p<0.0001), the intermediate infusion rates (Qi between 30 and 40 mL/min; r=0.98, 95% CI 0.95 to 0.99; p<0.0001) and the high infusion rates (Qi above 40 mL/min; r=0.99, 95% CI 0.90 to 1.00; p<0.0001, Figure 2). Nevertheless, figure 2 indicates a slight underestimation of Q by Qthermo in the higher flow ranges, as
well as a larger scatter of data in the values obtained with low infusion rates.
The pressure, needed to achieve the desired infusion rates increased from 10.17 bars [9.99; 12.6] vs 18.68 bars [15.79; 22.96] vs 27.85 bars [27.79; 27.89]; (p<0.0001) in the low-, in the intermediate and in the high infusion rates, respectively.
3
Discussion
The present data indicate that using this novel infusion catheter absolute coronary blood flow can be measured by the principle of thermodilution. In addition, the data confirm that an infusion rate of 30 to 40 mL is sufficient to reach a good accuracy of the measurements, while infusion pressures are kept lower than 20 bars thus remaining within safety margins of the catheter.
A number of practical and conceptual points, related to the novel infusion catheter and to the principle of thermodilution need to be highlighted.
This novel catheter is a monorail system. Therefore it can be easily advanced over a 0.014” guidewire with temperature sensor, while already connected to the infusion pump and purged outside the body. Measurements therefore take only a few minutes. The perfusion holes should be placed in the first few millimeters of the epicardial vessel under study. The sensor of the pressure wire should be positioned in the distal part of the artery. From a conceptual point of view, it should be emphasized that the coronary flow is measured, where the saline enters the coronary artery, and not where the temperature of
T is measured. This is important given the unavoidable presence of side branches between
the infusion point and the place where blood temperature is measured.
Second, the outer diameter of the catheter is 0.95 millimeter, corresponding to an area stenosis of less than 10% in a coronary segment of 3 mm of diameter, and less than 15% in a coronary segment of 2.5mm of diameter. Therefore, it is very unlikely that its presence might significantly impede absolute coronary flow. In addition, would it happen, it can be easily corrected by multiplying flow by the ratio of fractional flow reserve measured with and without the infusion catheter in situ.5
Only maximal hyperemic flow can be accurately obtained by this continuous infusion technique. If measured under “resting” condition, the volume of saline should be subtracted from the measured blood flow. In addition, the infusion of saline at room temperature might itself be responsible of some hyperemic response.
The underestimation of Q by Qthermo at high flow rates and low infusion rates is of little
clinical relevance. Flow rates higher than 300 mL/min are rarely observed even in large coronary arteries. In addition, in these large arteries, the infusion rate can be set rather high. With this in mind, the difference between Q and Qthermo is always smaller than 10%.
Conclusion
This novel perfusion catheter used in combination with a Pressure/temperature sensor-tipped guide wire allows absolute flow and resistance measurement which opens a window towards a better understanding of microvascular pathophysiology.
References
1. Fearon WF, Balsam LB, Farouque HM et al. Novel index for invasively assessing the coronary microcirculation. Circulation 2003;107:3129-32.
2. Fearon WF, Shah M, Ng M et al. Predictive value of the index of microcirculatory resistance in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol 2008;51:560-5. 3. Layland J, Carrick D, McEntegart M et al. Vasodilatory capacity of the coronary
microcirculation is preserved in selected patients with non-ST-segment-elevation myocardial infarction. Circ Cardiovasc Interv 2013;6:231-6.
4. Fearon WF, Low AF, Yong AS et al. Prognostic value of the Index of Microcirculatory Resistance measured after primary percutaneous coronary intervention. Circulation 2013;127:2436-41.
5. Aarnoudse W, Van’t Veer M, Pijls NH et al. Direct volumetric blood flow measurement in coronary arteries by thermodilution. J Am Coll Cardiol 2007;50:2294-304.
6. Geven MC, Bohté VN, Aarnoudse WH et al. A physiologically representative in vitro model of the coronary circulation. Physiol Meas 2004;25:891-904.
7. Ganz W, Tamura K, Marcus HS, Donoso R, Yoshida S, Swan HJ. Measurement of coronary sinus blood flow by continuous thermodilution in man. Circulation 1971;44:181-95.
8. Zieler KL. Circulation times and the theory of indicator delution methods for determining blood flow and volume. Handbook of Physiology. Washington, DC: American Physiological Society, 1962: 585-615
9. Weisse AB, Regan TJ. A comparison of thermodilution coronary sinus blood flows and krypton myocardial blood flows in the intact dog. Cardiovasc Res 1974;8:526-33.
10. Aarnoudse W, van den Berg P, van de Vosse F et al. Myocardial resistance assessed by guidewire-based pressure-temperature measurement: in vitro validation. Catheter Cardiovasc Interv 2004;62:56-63.
Chapter 4
Absolute coronary blood flow
measurement and microvascular
resistance in ST-elevation
myocardial infarction in the
acute and subacute phase
Inge Wijnbergen, MD
*†, Marcel van ’t Veer, MSc, PhD*†,
Jeroen Lammers, MD
*, Joey Ubachs, MD, PhD*,
Nico H.J. Pijls, MD, PhD
*†.
Eindhoven, The Netherlands
From the Department of Cardiology, Catharina Hospital Eindhoven* and the Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven†.
Abstract
Background In a number of patients with acute myocardial infarction, myocardial hypoperfusion known as the no-reflow phenomenon, persists after primary percutaneous intervention (PPCI). The aim of this study was to evaluate feasibility and safety of a new quantitative method of measuring absolute blood flow and resistance within the perfusion bed of the infarct-related artery. Furthermore, we sought to study no reflow by correlating these measurements to the index of microvascular resistance (IMR) and the area at risk (AR) determined by cardiac magnetic resonance imaging (CMR). Methods and Results Measurements of absolute flow and myocardial resistance were performed in 20 selected patients with acute myocardial infarction in the acute phase immediately following PPCI and after 3-5 days, using the technique of thermodilution with continuous infusion of saline. Average time needed for measurement of absolute flow, resistance and IMR was 20 minutes and all measurements could be performed without any complication. Flow was expressed in ml/min/g of tissue for the area at risk. A higher flow to the AR correlated with a low IMR in the acute phase. Absolute flow in the AR increased from 3.14 to 3.68 ml/min/g (p=0.25) and absolute resistance in the AR decreased from 1317 to 1099 dyne.sec.cm-5/g (p=0.40) between the first day and fifth day after AMI.
Conclusions Measurement of absolute flow and microvascular resistance is safe and feasible in STEMI patients and may allow better understanding of microvascular (dys) function in the early phase of AMI. In part of the patients undergoing timely PPCI, microvascular function recovers over time.
4
Introduction
In acute myocardial infarction, early restoration of blood flow to the jeopardized myocardium is of paramount importance to limit infarct size and obtain favourable long-term outcome. Primary percutaneous coronary intervention (PPCI) is the treatment of choice for reestablishing epicardial blood flow in patients with ST-segment elevation myocardial infarction (STEMI) 1, 2. Despite achievement of reperfusion of the epicardial coronary artery in approximately 90% of all patients, in a number of these patients myocardial hypoperfusion persists due to moderate or severe microvascular dysfunction, also referred to as the “no-reflow” phenomenon 3-6. In 1974, Kloner et al described this phenomenon in dogs and showed that, after temporary occlusion of a coronary artery, subendocardial perfusion defects were detectable and persistent after 90 minutes of occlusion 7. Failure of reflow was associated with extensive capillary damage and myocardial cell swelling and led to damage of the myocardial microvasculature. The pathogenesis of no-reflow has not been elucidated completely and seems is complex and multifactorial. Microvascular thromboembolism, spasm, intramyocardial edema and inflammatory response of the myocardium with neutrophil plugging of the capillaries are suggested to be responsible for this condition. It is well known that in patients in whom no or poor reflow occurs, prognosis is poor and more severe left ventricular dysfunction can be expected in comparison to those patients in whom microvascular reperfusion after PPCI is restored 6, 8. Therefore, knowledge about the actual state of the microvasculature and myocardial perfusion shortly after PPCI, is important from a prognostic point of view. Moreover, if microvascular reperfusion is still limited immediately after myocardial infarction, but recovers quickly in the days thereafter, this might be beneficial for long-term prognosis 8. Lastly, knowledge about microvascular reperfusion in the acute phase might be important with respect to choice of adjunct mechanical or medical therapy, such as intra aortic balloon pumping (IABP), GP IIb/IIIa inhibitors or continuation of nitroglycerine.
Assessment of microvascular perfusion and function has been difficult so far and has been hampered by a number of methodological and technical shortcomings. Furthermore, measurement of absolute blood flow in the infarcted area and true quantitative calculation of absolute resistance in acute MI has never been performed.
Recently, a new invasive technique for measuring absolute coronary blood flow and absolute myocardial resistance has been developed for patients with stable coronary disease9. This technique is based upon thermodilution and continuous infusion of a low amount of saline by a microcatheter positioned selectively in a coronary artery. This technique is precise and not operator-dependent 9. Measuring absolute blood flow and resistance has no meaning in itself as long as the distribution territory is unknown and it is difficult to compare flow and resistance between different territories, not to
