Abstract
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.
Original language | English |
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Qualification | Doctor of Philosophy |
Awarding Institution |
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Supervisors/Advisors |
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Award date | 14 Dec 2006 |
Place of Publication | Eindhoven |
Publisher | |
Print ISBNs | 90-386-3058-1 |
DOIs | |
Publication status | Published - 2006 |