Stenosis

In his seminal experimental work, Lance Gould established that CFR of 2 discriminates significant (≥70%) from nonsignificant (<70%) coronary stenoses. A series of clinical studies using single photon-emission computed tomography as well as intracoronary and transthoracic coronary Doppler ultrasound have consistently confirmed that a flow-limiting stenosis introduces a strong proximal resistance that is rapidly normalized after the mechanical relief of the stenosis by coronary stenting. According to these findings, a cut-off value of 2 was widely adopted as the “magic number” demonstrating impairment of coronary flow significant enough to treat invasively by mechanical removal of the stenosis. Very elegantly, Fukui et al in this issue of The American Journal of Cardiology have confirmed that preoperative CFR was <2 in left anterior descending coronary arteries (LADs) with significant stenoses and that there was a trend for CFR to be more blunted in long LAD lesions compared to short lesions. Interestingly, coronary artery bypass grafting normalized CFR regardless of the preoperative presentation of the stenosis. The investigators correctly measured CFR in the LAD, not in the graft, to prevent the bias of flow competition blunting CFR of the graft.

Coronary Doppler ultrasound is very effective to follow patients with coronary stents, in whom symptoms and other stress tests may be misleading. In fact, a reduction of CFR <2 after stenting identifies ≥70% LAD restenosis with great sensitivity and specificity, whereas CFR between 2 and 2.5 reflects nonsignificant (intermediate) restenosis that should be conservatively monitored, indicating the safety of deferring treatment when CFR is >2.

Microcirculation

Microcirculation disturbances have been described in a number of conditions, including coronary stenting, remote coronary artery disease, gender hormone changes, cigarette smoking, hypertension, left ventricular hypertrophy, hypertrophic cardiomyopathy, non-insulin-dependent diabetes, and aging. Yet much disagreement still exists regarding how to define and measure this dysfunction and what ultimately is its clinical impact. However, consistent anatomic observations supporting a definite role of microvascular dysfunction are still lacking.

The reduction of CFR in different hormonal states and passive smoking was too mild to explain cyclic chest pain and positive stress test results in fertile women with normal epicardial coronary arteries. Similarly, studies using positron emission tomography showed no difference in CFR between smokers and nonsmokers. In light of these findings, it appears that, for most patients, microcirculatory dysfunction, if present, does not significantly affect the value of CFR needed to detect significant coronary stenosis.

A diffuse and profound reduction in CFR was described using positron emission tomography in remote, angiographically normal coronary arteries in clinically stable patients with myocardial infarction. In some cases, CFR was even close to 1, indicating a complete inability to increase flow at stress, typical of coronary subocclusion. However, it is very hard to imagine a patient with anterior infarction and almost no flow reserve in the remote coronary arteries who is not close to or in overt cardiogenic shock.

The belief that focal coronary artery disease generates a diffuse alteration of coronary flow in a generalized, yet unexplained manner can be easily challenged by everyday clinical practice showing that (1) CFR in an angiographically normal coronary artery is never affected by any remote stenosis, previous acute myocardial infarction, or stenting, and (2) serial measurements along a coronary artery show that CFR is impaired only distal, but not proximal, to the stenosis, confirming that even within the diseased vessel, the disorder is not transmitted to neighboring segments.

Elective coronary artery stenting was thought to produce persistent but still unexplained microvascular dysfunction lasting for days or weeks. Conversely, transthoracic coronary Doppler ultrasound allowed us and others to show that CFR actually normalizes within the first day after the procedure.

Finally, we have found an average CFR of 2.8 even in patients who should have had profound microvascular disturbances, such as those with dilated or hypertrophic cardiomyopathy, including those in functional class IV, and orthopnea. Corroborating this finding is an intracoronary Doppler ultrasound study depicting an average CFR of 2.8 in patients with dilated cardiomyopathy.

We may conclude that the issue of microcirculation and CFR has been overemphasized and that, at least in terms of coronary Doppler ultrasound, its biasing effect on the detection of coronary stenosis is at least minimal, which is a great advantage for a technique to be used as a quantitative diagnostic tool.

Microcirculation

Microcirculation disturbances have been described in a number of conditions, including coronary stenting, remote coronary artery disease, gender hormone changes, cigarette smoking, hypertension, left ventricular hypertrophy, hypertrophic cardiomyopathy, non-insulin-dependent diabetes, and aging. Yet much disagreement still exists regarding how to define and measure this dysfunction and what ultimately is its clinical impact. However, consistent anatomic observations supporting a definite role of microvascular dysfunction are still lacking.

The reduction of CFR in different hormonal states and passive smoking was too mild to explain cyclic chest pain and positive stress test results in fertile women with normal epicardial coronary arteries. Similarly, studies using positron emission tomography showed no difference in CFR between smokers and nonsmokers. In light of these findings, it appears that, for most patients, microcirculatory dysfunction, if present, does not significantly affect the value of CFR needed to detect significant coronary stenosis.

A diffuse and profound reduction in CFR was described using positron emission tomography in remote, angiographically normal coronary arteries in clinically stable patients with myocardial infarction. In some cases, CFR was even close to 1, indicating a complete inability to increase flow at stress, typical of coronary subocclusion. However, it is very hard to imagine a patient with anterior infarction and almost no flow reserve in the remote coronary arteries who is not close to or in overt cardiogenic shock.

The belief that focal coronary artery disease generates a diffuse alteration of coronary flow in a generalized, yet unexplained manner can be easily challenged by everyday clinical practice showing that (1) CFR in an angiographically normal coronary artery is never affected by any remote stenosis, previous acute myocardial infarction, or stenting, and (2) serial measurements along a coronary artery show that CFR is impaired only distal, but not proximal, to the stenosis, confirming that even within the diseased vessel, the disorder is not transmitted to neighboring segments.

Elective coronary artery stenting was thought to produce persistent but still unexplained microvascular dysfunction lasting for days or weeks. Conversely, transthoracic coronary Doppler ultrasound allowed us and others to show that CFR actually normalizes within the first day after the procedure.

Finally, we have found an average CFR of 2.8 even in patients who should have had profound microvascular disturbances, such as those with dilated or hypertrophic cardiomyopathy, including those in functional class IV, and orthopnea. Corroborating this finding is an intracoronary Doppler ultrasound study depicting an average CFR of 2.8 in patients with dilated cardiomyopathy.

We may conclude that the issue of microcirculation and CFR has been overemphasized and that, at least in terms of coronary Doppler ultrasound, its biasing effect on the detection of coronary stenosis is at least minimal, which is a great advantage for a technique to be used as a quantitative diagnostic tool.

Are All Agents the Same?

The agent, the administration modality, and the individual response to the administered drug are crucial to obtain maximal microcirculatory vasodilation and may explain the different results obtained by groups supporting either stenosis or the microcirculation.

Most published research on microvascular dysfunction has been conducted using dipyridamole either at low (0.56 mg/kg) or high (0.84 mg/kg) dose. Dipyridamole is not the ideal drug for CFR, because (1) at low dose, it produces only submaximal vasodilation ; (2) at high dose, it may produce myocardial ischemia, which in turn elicits vasodilation of the epicardial vessel; (3) it may significantly increase heart rate, which increases oxygen consumption and may affect the quality of Doppler ultrasound at hyperemia, because of enhanced wall motion noise; (4) it works indirectly by inhibiting the cellular reuptake of adenosine, a process that may vary from patient to patient, precluding standardization of the final concentration of adenosine (why use a “precursor” if the final active agent is available?); (5) it requires aminophylline as an antidote; and (6) it is not repeatable. For these reasons, it may be possible that many cases studied with dipyridamole (particularly at low dose) have been misinterpreted as cases of microvascular dysfunction.

In contrast, adenosine produces an almost instantaneous, maximal, and brisk vasodilation of the microcirculation, with minimal hemodynamic changes, and is repeatable.