Currently, there is little doubt that interpretation of coronary artery disease and decision making with respect to revascularization based on visual assessment of the angiogram is a fundamentally flawed approach. The importance of additional functional testing to assess the hemodynamic severity of a coronary stenosis is undisputable. Over the decades, a number of physiologic indices have emerged to assess the functional significance of coronary artery disease. Of these, fractional flow reserve (FFR) is most commonly used. There is incontrovertible proof now that stenting of ischemic stenoses as indicated by a FFR ≤ 0.80 generally improves outcome, whereas stenting of non-ischemic stenosis as indicated by a FFR > 0.80 offers no benefit compared to medical treatment and can mostly be avoided .
To assess the true strength or quality of anything in the world around us—whether in science, engineering, or biology—testing under conditions of stress is mandatory. In analogy, therefore, the wind tunnel for physiologic testing of coronary arteries is maximum hyperemia. Accurate assessment of FFR can be done only during maximum hyperemic conditions. An interesting analysis of a rather new hyperemic drug, regadenoson, is published in the current issue of Cardiovascular Revascularization Medicine ( CRM ) .
1
Fractional flow reserve
Fractional flow reserve has been introduced in a seminal publication in Circulation in 1993 . In that paper, the complete coronary circulation, including coronary, myocardial, and collateral blood flow and their respective resistances, was completely described in terms of pressure measurement in the different parts of the coronary circulation. Over the years, one particular part of this theory, initially called myocardial fractional flow reserve or FFR myo and presently just called FFR, has evolved as a simple and practical tool to assess the ischemic nature of a coronary artery stenosis. FFR is defined as the ratio of distal coronary pressure (P d ) measured by a pressure wire to aortic pressure (P a ) measured by the guiding catheter under conditions of maximum coronary hyperemia . Although presently a binary cut-off value of 0.80 is used for decision making with respect to revascularization, as a matter of fact, a continuum is present between absolute value of FFR and future risk . In clinical practice, a threshold of FFR of 0.80 has a diagnostic accuracy of 95% for correct classification of myocardial ischemia related to a specific stenosis. Therefore, that value is used most commonly in clinical practice, and its validity (with a small gray zone between 0.75 and 0.80) has been confirmed in more than 40 studies in patients with almost all clinical and angiographic conditions. The only situation where FFR should not be applied is the culprit artery in ST segment elevation myocardial infarction with a severely blotted microcirculation .
FFR is the only physiological index that has been validated against a true gold standard, based on a multitesting Bayesian approach . All other indices, often derived from FFR, have been validated only against single noninvasive indices or against FFR itself. In addition, a number of randomized controlled trials have shown the prognostic benefit of FFR in terms of reduction of mortality and myocardial infarction when decisions with respect to revascularization were based on FFR .
2
Importance of maximum hyperemia
One of the prerequisites to measure FFR is the presence of maximum hyperemia. Only under those conditions are proportionality between perfusion pressure and maximum blood flow and optimal decision making with regard to revascularization possible.
The first important work on hyperemic drugs was performed by Wilson et al. in the late eighties and early nineties . Since then, many studies have been performed to evaluate hyperemic drugs, such as papaverine, intracoronary and intravenous adenosine (both peripherally and centrally administered), adenosine triphosphate (ATP), dobutamine, nitroglycerine, and contrast agent .
Papaverine is a cheap drug that can easily be administered intracoronarily, induces maximum hyperemia, and has a plateau phase that is long enough to make a pullback recording but is sometimes accompanied by polymorphic ventricular tachycardia. Therefore, papaverine as hyperemic stimulus is abandoned in many countries.
Intracoronary adenosine is cheap, easy to administer, reliable, and (if administered in doses of 100 μg and 200 μg for the right and left coronary arteries, respectively) equivalent to central venous adenosine infusion to induce maximum hyperemia. However, because of its short action, it is not suitable to make a pullback recording.
ATP as used in some other countries is completely identical to adenosine. Dobutamine, nitroglycerine, and some other drugs have too many hemodynamic side effects to be used as a routine.
2
Importance of maximum hyperemia
One of the prerequisites to measure FFR is the presence of maximum hyperemia. Only under those conditions are proportionality between perfusion pressure and maximum blood flow and optimal decision making with regard to revascularization possible.
The first important work on hyperemic drugs was performed by Wilson et al. in the late eighties and early nineties . Since then, many studies have been performed to evaluate hyperemic drugs, such as papaverine, intracoronary and intravenous adenosine (both peripherally and centrally administered), adenosine triphosphate (ATP), dobutamine, nitroglycerine, and contrast agent .
Papaverine is a cheap drug that can easily be administered intracoronarily, induces maximum hyperemia, and has a plateau phase that is long enough to make a pullback recording but is sometimes accompanied by polymorphic ventricular tachycardia. Therefore, papaverine as hyperemic stimulus is abandoned in many countries.
Intracoronary adenosine is cheap, easy to administer, reliable, and (if administered in doses of 100 μg and 200 μg for the right and left coronary arteries, respectively) equivalent to central venous adenosine infusion to induce maximum hyperemia. However, because of its short action, it is not suitable to make a pullback recording.
ATP as used in some other countries is completely identical to adenosine. Dobutamine, nitroglycerine, and some other drugs have too many hemodynamic side effects to be used as a routine.
3
Non-hyperemic approaches
To avoid pharmacological hyperemia, several approaches have been proposed to evaluate stenosis significance under resting conditions, such as P d /P a at rest and iFR .
Although commendable, these approaches in general have a poor scientific basis and have not been experimentally validated. From Poiseuille’s law, it is obvious that it is very difficult to predict a hyperemic gradient from baseline measurements, especially in young patients with a high hyperemic response, in large and proximal coronary arteries, in cases of a large perfusion territory, and in cases of ostial stenosis. Consequently, in all studies investigating the diagnostic accuracy of resting indices (whether performed by proponents or opponents of resting indices), the accuracy of P d /P a at rest and iFR never exceeded approximately 80% of the accuracy achieved with hyperemia . Moreover, the coefficient of variation of all such indices is significantly larger than that of hyperemic indices . Also, the signal to noise ratio in resting measurements is inferior to that of FFR since the intrinsic error in pressure measurements and the occurrence of drift are identical for both resting and hyperemic conditions and therefore relatively affect resting indices more. As a matter of fact, especially the resolution of the pullback recording is negatively affected by leaving out hyperemia. For these reasons, we believe that studying new hyperemic stimuli as done by Stolker et al. is relevant . An intermediate approach balancing between avoiding a hyperemic stimulus and accepting suboptimal decision making has been investigated by Johnson et al., who evaluated the hyperemic effect of a single bolus of contrast injection. Such contrast injection has to be performed anyway during coronary pressure measurement to check the position of the pressure wire. Contrast agent induces submaximum hyperemia. The so-called contrast-FFR (cFFR) had a better accuracy than pure resting indices like iFR but was still significantly less reliable than “true” hyperemic FFR. The different accuracies achieved by the different indices are summarized in Fig. 1 . A simple lesson from this figure is the more hyperemia, the more accurate the decision. In our opinion, it would be a shame for the physician and painful for the patient if, in an attempt to shorten the procedure by 10 minutes and to save a few dollars, the most appropriate decision and treatment are performed in 80% of the patients only, whereas 95% is achievable.
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