Number 20, 2003
Hibernation preconditioning

Hemodynamics of coronary stenoses

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Koen M.J. Marques
Department of Cardiology, Free University Medical Center, Amsterdam, The Netherlands Correspondence: Drs K.M.J. Marques, Department of Cardiology, VU University Medical Center, De Boelelaan 1117, P.O. Box 7057, 1007 MB Amsterdam, the Netherlands.
Tel: +31 20 4442244, fax: +31 20 4442446, e-mail: km.marques@vumc.nl

Introduction
The coronary circulation is designed to supply the myocardium with blood for its widely and rapidly changing needs. The physiologic ability of coronary blood flow to increase above resting values is defined as the coronary flow reserve (CFR). When myocardial metabolic requirements remain constant, autoregulation maintains coronary blood flow within a relatively narrow range, regardless of changes in coronary pressure, between upper limits of 120 to 140 mm Hg and lower levels of 50 to 60 mm Hg. This is achieved by adaptation of the resistance vessels to changes in coronary pressure. A rise in pressure evokes arteriolar vasoconstriction, while a fall in pressure results in vasodilatation and reduced resistance. The normal coronary vascular bed has the capacity to reduce its resistance to approximately 20% of basal level. Below the critical level of 50 to 60 mm Hg the coronary vessels are maximally dilated and beyond this point myocardial perfusion becomes pressure-dependent. A further reduction in coronary pressure directly results in myocardial ischemia and the patient becomes symptomatic.
Fluid-dynamic equations have been adapted to describe the loss of energy and pressure in coronary arteries in clinical practice. The following expression approximates closely to the hemodynamic behavior of a coronary stenosis: DP = fQ + sQ2 [1]. The pressure gradient (DP, mm Hg) is calculated in terms of stenosis flow (Q, mL/s). The equation characterizes the principal modes of pressure loss. The first term accounts for frictional energy loss, generated by the layers of blood sliding against each other; this occurs in all arteries, but, since it is inversely related to the fourth power of lumen diameter, in a tight stenosis it is huge. The viscous friction is also directly related to the length of the stenosis. The second term in the equation accounts for the inertial loss of energy. Blood flow is accelerated to the point of greatest narrowing; beyond the stenosis, the high-velocity flow mixes with the slow moving blood in the distal, normal-sized coronary artery. At this point the kinetic energy of the accelerated blood is lost and forms eddies and localized turbulence. This inertial pressure loss increases with the square of blood flow and again is inversely related to the fourth power of the stenosis diameter.

Assessment of the hemodynamics of coronary stenoses in the catheterization laboratory
When performing coronary angiograms, intermediate stenoses (40% to 70% diameter reduction) are often found. The physician is faced with the uncertainty of whether such a stenosis is clinically significant and whether it should therefore be treated. Percentage diameter reduction is a notoriously unreliable predictor of the hemodynamic significance of a stenosis [2]. Therefore, tools have been developed to assess the hemodynamic impact of a coronary stenosis in the catheterization laboratory.

Coronary flow velocity and pressure measurements
The flow velocity of blood in coronary arteries can be measured using a Doppler-tipped guide wire. The piezoelectric transducer at the tip of the wire determines the velocity of red blood cells from the frequency shift (difference between transmitted and returning frequency). The coronary flow velocity reserve (CFVR) represents the extent to which coronary flow velocity can increase and is defined as the ratio of average peak hyperemic to average peak resting flow velocity. An example is given in Figure 1.

Absolute Doppler flow velocities are directly related to volumetric coronary flow if the coronary diameter remains constant; maximal epicardial vasodilatation is realized by intracoronary administration of nitroglycerine. Maximal coronary flow is evoked by intracoronary delivery of adenosine or papaverine. In normal coronary arteries, the CFVR is generally between 3 and 5. Several studies have demonstrated that a CFVR below 2.0, measured distal to a coronary stenosis, is often associated with the induction of myocardial ischemia, indicating that the narrowing is clinically significant [3]. The level of resting and/or maximal flow velocity, however, is also determined by hemodynamic factors such as heart rate, blood pressure, contractility, preload, and ventricular hypertrophy. Therefore, assessment of the same coronary stenosis in different hemodynamic settings will result in varying CFVR values.
To eliminate the confounding effect of varying heart rate or blood pressure in the determination of CFR, the relative CFR (rCFR) can be measured. rCFR is defined as the ratio of maximum blood flow in a stenotic artery to maximum flow in an adjacent normal artery. When using a Doppler wire, the relative CFVR (rCFVR) is the ratio of CFVR in a target vessel to CFVR in an angiographically normal reference vessel. The normal value is between 0.8 and 1.0; a value below 0.65 is considered to indicate a clinically significant stenosis [4]. In patients with three-vessel coronary artery disease, however, there is no suitable reference vessel, invalidating the use of rCFVR. Furthermore, presumably normal arteries at coronary angiography often have some degree of plaque formation at intravascular ultrasound imaging, which can result in a lower CFVR compared with truly normal coronary arteries [5, 6].
The ratio of the maximum flow in a stenotic coronary artery to the maximum flow in the same artery if it were completely normal is called the fractional flow reserve (FFR). In other words, FFR indicates the maximum flow in the presence of a stenosis as a fraction of its normal value. It has been shown that FFR can be derived from pressure data obtained at maximal hyperemia: FFR = (Pd - Pv)/(Pa - Pv), where Pa is mean proximal coronary pressure, Pv is mean central venous pressure, and Pd is mean pressure distal to the stenosis [7–9]. Generally, Pv is low and constant, and therefore is usually omitted; thus, FFR » Pd/Pa. The distal coronary pressure can be measured with a pressure guide wire and the proximal pressure is measured at the tip of the guiding catheter (Figure 2).

Figure 2. Phasic and mean proximal and distal pressure recordings in an intermediate coronary stenosis at rest and at maximum hyperemia induced by intracoronary administration of adenosine. FFR is calculated as the ratio of mean distal (Pd) to mean proximal (Pa) pressure at maximum hyperemia.

In contrast to CFVR, this index is independent of hemodynamic conditions and specifically characterizes the obstructing effect of a coronary stenosis. The normal value of FFR is 1.0 and a value below 0.75 has been found to reliably indicate a clinically significant stenosis.

The microcirculation
Maximal coronary blood flow may be hampered not only by an epicardial obstruction but also by alterations at the microvascular level. Generally, it is assumed that the microcirculatory resistance is uniform in different perfusion areas. This is not true in patients with a prior myocardial infarction or a chronic total coronary occlusion [10]. Furthermore, in patients with stable angina pectoris, direct measurement of minimal microvascular resistance has revealed wide variability [11]. In patients with hypertension, diabetes, or hypertrophic cardiomyopathy, structural abnormalities of the small vessels are known to limit the vasodilatory reserve. The microcirculatory resistance is not constant in time. Immediately after CABG or coronary angioplasty and stenting an impaired CFR is often found due to microvascular dysfunction; CFR recovers slowly in the following months [12–14]. Changing levels of minimal microvascular resistance in coronary vessels with the same epicardial stenosis will influence the level of maximal coronary flow velocity or pressure gradient. Therefore, a reduced CFVR can not specifically indicate the amount of epicardial flow obstruction. The hyperemic trans-stenotic pressure gradient and FFR will also vary according to the level of minimal microvascular resistance, invalidating use of the established FFR cutoff values. This could lead to incorrect diagnoses and therapeutic decisions.

Combined pressure and flow velocity measurement
The simultaneous measurement of flow velocity and trans-stenotic pressure gradient can clearly distinguish the two possible mechanisms of a limited hyperemic flow increase. If a large hyperemic pressure gradient is found, the reduced flow increase can be attributed to epicardial stenosis; if the trans-stenotic pressure gradient remains small at maximal hyperemia, the flow obstruction is located at the microcirculatory level. Due to the nonlinear nature of the flow-pressure gradient relation, calculating the ratio of mean pressure gradient to mean flow velocity possibly underestimates the epicardial resistance if measurements are not performed at minimal microvascular resistance. Assessment of the instantaneous mid-diastolic flow velocity-pressure gradient (v-dp) relation avoids this pitfall; evaluation during mid-diastole eliminates the phases of acceleration and deceleration of coronary flow. Data are recorded at baseline and during induction of hyperemia (Figure 3).

Figure 3. From top to bottom: ECG, instantaneous proximal coronary pressure (Prox p), distal coronary pressure (Dist p), and coronary flow velocity recordings at maximal hyperemia, intermediate hyperemia and baseline in an intermediate coronary stenosis. The arrows indicate the mid-diastole; these data are used to calculate the v-dp relation.

The flow velocity and pressure gradient measurements are fitted using the equation: DP = fv + sv2 (v being the instantaneous peak velocity) [15–17]. An example is shown in Figure 4.

Figure 4. Example of the v-dp relation in a patient with an intermediate coronary stenosis. The solid line is the regression line according to the formula: DP = fv + sv2.

The v-dp relation is not dependent on hemodynamic conditions and neither maximal hyperemia nor minimal microvascular resistance is required. Assessment of the v-dp relation necessitates the use of two separate guide wires, which artificially increases the flow obstruction. Online calculation of the v-dp relation is not yet available, thus invalidating its use in the catheterization laboratory. Further studies must establish the advantage of this index in comparison with CFVR or FFR.

Conclusion
Nowadays, several indexes can be used in the catheterization laboratory to assess the hemodynamic impact of a coronary stenosis. Single coronary flow velocity or distal coronary pressure measurements at maximal hyperemia are useful, but CFVR, rCFVR, and FFR values can be influenced by changing levels of minimal microvascular resistance. Combined flow and pressure measurements give the most comprehensive description of the fluid dynamics across the stenotic epicardial lesion but are not yet available in routine practice.

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REFERENCES

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