Invasive assessment of the coronary microcirculation by pressure and temperature measurements

Coronary angiography and percutaneous coronary interventions have played a pivotal role in the diagnosis and treatment of coronary heart disease. However, it has to be realized that angiography is a purely anatomical way of assessing coronary artery narrowings, and therefore has its limitations. In chapter 1, the introduction of this thesis, it is explained that coronary angiography and several other anatomy-based diagnostic modalities to interrogate the coronary circulatory system are hampered by the lack of functional information to decide whether or not an epicardial lesion will be responsible for myocardial ischemia. For example, whether or not ischemia will result from a specific coronary stenosis will also depend on the size of the perfusion territory of that artery or the presence of collaterals. Fractional flow reserve (FFR) and coronary flow reserve (CFR) are introduced as functional measures of the coronary circulation. Furthermore, in this chapter, the role of the microcirculation in coronary disease is discussed as well as the current lack of diagnostic techniques to specifically assess the microcirculatory compartment in the catheterization laboratory. Especially the quantitative assessment of myocardial flow is often problematic because myocardial flow is the sum of coronary flow and collateral flow, while with most techniques used thus far, only coronary flow is measured and collateral flow is often neglected. For a good understanding of the different techniques that are used to measure coronary and myocardial flow and resistance, knowledge of the normal and pathological coronary circulation is required. In chapter 2, a basic overview of the coronary circulation is provided. For simplicity, the coronary arterial system is schematically divided into 3 functional compartments of conductive vessels, preartioles and arterioles. Importantly, the epicardial coronary arteries are conductive vessels, in which there is no resistance to flow. The pre-arterioles and arterioles are resistive vessels, which can control coronary blood flow according to the metabolic needs of the myocardium, through metabolic, neurogenic and vascular messenger systems. The principle and importance of coronary autoregulation to maintain coronary blood flow within wide limits of blood pressures is discussed in this chapter. The role and importance of coronary collateral flow is explained, and the processes of angiogenesis and arteriogenesis are described. The indices FFR and CFR, which were introduced in chapter 1, are extensively explained and discussed in this chapter. For accurate measurement of the fractional and coronary flow reserve, the presence of hyperemia is of paramount importance. It has been suggested that the effect of the conventionally used hyperemic stimulus, adenosine, could be submaximal in patients with microvascular disease, and that adding alpha-blocking agents could augment the hyperemic response in these patients. In chapter 3, we studied the effect of the nonselective alpha-blocking agent phentolamine, which was administered in addition to adenosine after achieving hyperemia, in patients who had microvascular disease and those who did not. Although statistically significant, the observed additional decrease in microvascular resistance after addition of phentolamine we found in patients with microvascular disease was small and did not affect clinical decision making in any patient. We conclude therefore that routinely adding an alpha-blocking agent to adenosine does not affect clinical decision making. Chapter 4 deals with the concept and practical use of coronary flow reserve. CFR and FFR provide complementary information on the coronary circulation. More specifically, as explained in chapter 2, by combining CFR and FFR, assumptions can be made on the status of the microcirculation. However, in contrast to FFR, CFR is an index which is not so easy to obtain reliably in the catherization laboratory. Using a pressure wire, it is possible to calculate CFR by thermodilution, so that FFR and CFR can be measured with a single guide wire, making a diagnostic procedure quicker and less complicated. In this chapter, this new method for measuring CFR is validated against the gold standard of Doppler-derived CFR. We conclude that thermodilution-derived CFR is feasible and reliable, allowing simultaneous assessment of CFR and FFR using a single guide wire. The safety and swiftness of assessing FFR and CFR with one single guide wire greatly facilitates evaluation of the coronary circulation. In chapter 5, in an attempt to quantify microvascular disease, a novel index of microcirculatory resistance, IMR, is introduced and tested in an in-vitro model in the laboratory. By combining intracoronary pressure and thermodilution-derived flow parameters, IMR can be calculated. In this chapter, it was demonstrated that thermodilution-derived mean transit time (Tmn) was closely correlated to absolute coronary blood flow. Furthermore, the feasibility of calculating IMR (IMR = Pd . Tmn ) was excellent and the new index proved to be independent on epicardial stenosis severity in an in-vitro setup. Therefore, by combining this index with simultaneously determined FFR, the contribution of epicardial and microvascular abnormalities to ischemic heart disease can be quantified in a simple and straightforward way by single guide wire technology. Importantly, in this first in- vitro study on IMR, recruitable collateral flow was not incorporated into the measurements. To further validate IMR in animals and to assess the effect of epicardial stenosis severity and collateral flow on myocardial microvascular resistance, the study in chapter 6 was performed. In an open-chest porcine model, distal coronary pressure was measured with a pressure wire, and microvascular resistance was calculated using thermodilution and the new index IMR as introduced in chapter 5. In this study, IMR was compared with true microcirculatory resistance, measured directly with a flow probe around the coronary artery. The contribution of collaterals was taken into account by coronary wedge pressure. It was proved that IMR was closely correlated to true myocardial resistance. Without consideration of collateral flow, apparent microvascular resistance increased progressively and significantly with increasing epicardial stenosis. If collateral flow was accounted for, true minimum microcirculatory resistance was found to be independent of epicardial stenosis severity. It was therefore concluded that the minimum achievable microvascular resistance is not affected by increasing epicardial artery stenosis. To evaluate the feasibility and reliability of IMR in humans, a human validation study was carried out as descibed in chapter 7. In this study we used a unique protocol to create variable coronary artery stenoses in humans: after stent placement, a smallersized balloon was placed within the stented segment and inflated with increasing pressures to create different degrees of area stenoses. This study again shows that IMR can be easily calculated in conscious humans in the presence of an epicardial stenosis. Furthermove, it proves that minimal microcirculatory resistance, if calculated appropriately and accounting for collateral flow, is independent of epicardial stenosis severity. For calculating absolute microcirculatory resistance, true volumetric blood flow measurement is necessary. So far however, a methodology for volumetric blood flow measurement in selective coronary arteries has not been available in intact humans. In chapter 8, a method for direct measurement of coronary blood flow is introduced, using a technique of continuous low rate infusion of intracoronary saline and thermodilution. Reproducibility of this technique was proven to be excellent, and a good correlation with FFRcor -based predicted flow rates was seen. Together with distal coronary pressure measurement, measured by the same sensor simultaneously, also absolute resistance of the coronary artery and coronary microcirculation can be calculated. Though additional studies are warranted, this new methodology therefore might be a useful diagnostic tool to assess microvascular disease.