Coronary flow reserve

Coronary flow reserve (CFR) is defined as the ratio of coronary blood flow under maximal drug-induced coronary vasodilation to coronary blood flow under resting conditions. Coronary flow reserve is used to describe the amount of additional blood flow that can be supplied to the heart above baseline blood flow ¹. The maximal vasodilatation can be brought with pharmacologic stress by using three different drug stressors such as adenosine, dipyridamole,or regadenoson ². The coronary flow reserve mirrors the capacity of the coronary circulation to increase flow and thus, oxygen and substrate delivery in response to increased myocardial demand. The heart can increase blood flow through coronary circulation three to six times in the settings of increased demand compared to the flow under resting conditions. Consequently, the cut-off at coronary flow reserve >3 is regarded as the lower threshold for the normal value in the healthy human heart ³.

Coronary flow reserve accounts for flow through both the epicardial vessels and microvasculature. Coronary flow reserve is a strong and independent predictor of major adverse cardiovascular events both in individuals without epicardial coronary artery disease as well as in those with known coronary artery disease ⁴. Usually, in the absence of epicardial coronary artery disease, coronary flow reserve increases by factor 5 or more while in presenceof 50% epicardial coronary artery lumen reduction coronary flow reserve decreases up to be abnormal at rest in the presence of high degree of stenoses (>85%) ⁵.

Unfortunately, the coronary flow reserve is an expression of a pressure gradient between epicardial coronary artery and microcirculation and therefore it is reduced in case of collaterals or microcirculation disease even in theabsence of epicardial stenosis ⁶. For this reason, these stressperfusion tests are not able to distinguish between the two entities. To this regard, the invasive fractional flow reserve (FFR) has been introduced to overcome these limitations.

Coronary flow regulation is mainly controlled at the microcirculatory level, where endothelium has a central regulatory role. However, other factors influence coronary flow reserve (CFR) including atherosclerotic narrowing of the vessel lumen, rheological properties of blood, inflammation, and coagulation ⁷. The absence of coronary flow reserve implies maximal vasodilatation of the resistance vessels at rest and an inability to further increase myocardial blood flow. Coronary flow reserve can be thought of as the capacity of the coronary circulation to dilate and thus increase flow following an increase in myocardial metabolic demands ⁸. Coronary flow reserve (CFR) is a strong and independent predictor of major adverse cardiovascular events (e.g., death, heart attack and stroke) ³. The coronary flow reserve is a powerful tool to guide therapy and to assess prognosis. Changes in coronary flow reserve can assess both the presence ⁹ and severity ¹⁰ of coronary artery disease and can also be used in various other conditions (e.g. to determine if a patient presenting for the first time with heart failure has an ischemic or non-ischemic atiology or to determine prognosis in heart failure patients) ¹¹, ¹².

Figure 1. Coronary flow reserve

Footnote: The coronary flow reserve (CRF) is defined as the ratio between the coronary blood flow at maximum vasodilatation and the coronary blood flow at rest condition. Relationship between the coronary artery gradient pressure (difference between the epicardial coronary artery and microcirculation pressure) and coronary blood flow at rest condition (blue line) and at maximal vasodilatation (red line).

[Source ¹³ ]

Coronary flow reserve can be measured invasively with a Doppler-tipped coronary guide wire that determines coronary velocity at rest and during hyperemia, typically induced with intracoronary or intravenous adenosine. Because velocity is proportional to flow, the coronary flow velocity reserve is a reflection of the coronary flow reserve. If in addition to the velocity the area of the coronary vessel is known, the absolute coronary flow reserve can be calculated. Coronary flow reserve also can be measured invasively by using a wire-based thermodilution technique. On one of the commercially available coronary pressure wires (St. Jude Medical, MIN), the pressure sensor also can act as a thermistor. With the commercially available software, the shaft of the wire acts as a proximal thermistor. Room temperature saline can be injected into the coronary artery and this system will calculate the transit time, which is inversely proportional to coronary flow. After three injections at rest, the resting mean transit time is calculated. Hyperemia is then induced with intravenous adenosine, and three injections are performed to determine the hyperemic mean transit time. coronary flow reserve is measured in this situation by dividing the resting mean transit time by the hyperemic mean transit time. The thermodilution-derived coronary flow reserve has been validated in animal and human models and has been compared in an animal model to a reference standard of absolute flow. The thermodilution-derived coronary flow reserve appears to correlate more closely to the standard than does Doppler-derived coronary flow reserve.

A normal coronary flow reserve is considered to be greater than 2.0 and in most patients should be somewhere between 3 and 5. Initially, invasive coronary flow reserve was performed to interrogate the functional significance of an intermediate coronary stenosis with studies showing a correlation between coronary flow reserve and noninvasive tests for ischemia.8 However, a number of limitations of invasively measured coronary flow reserve impaired its broad clinical utility. First, it can be difficult to measure with a Doppler wire because of the challenge in obtaining a suitable Doppler signal. Second, because coronary flow reserve relies on resting flow for its calculation, the repeatability of measurements is less than optimal. Any hemodynamic perturbation such as a change in heart rate, blood pressure, or left ventricular contractility will significantly change the coronary flow reserve value as a result of the change in resting flow. The lack of a clear cut-off between a normal and abnormal coronary flow reserve makes it difficult to use for clinical decisions. Because there is a range of normal coronary flow reserve values between approximately 2.5 and 6, in one patient a value of 3.0 might be normal whereas in another patient normal coronary flow reserve may be 5.0 and therefore a recorded value of 3.0 could be quite abnormal. Finally, by definition coronary flow reserve is a measure of the entire coronary circulation. It interrogates the epicardial vessel as well as the coronary microvasculature. Therefore, a low coronary flow reserve value may be a result of significant epicardial coronary artery disease, microvascular dysfunction, or both. For all of these reasons, invasively measured coronary flow reserve has largely been abandoned as a method for interrogating intermediate coronary lesions. However, in patients with normal appearing epicardial coronary vessels, invasively measured coronary flow reserve can be used to assess microvascular function. However, because of the previously mentioned limitations and the availability of other methods for assessing the microvasculature independently of the epicardial system (for example, the index of microcirculatory resistance), invasively measured coronary flow reserve is not performed routinely on a clinical basis.

Fractional flow reserve

Fractional flow reserve (FFR) measurement involves determining the ratio between the maximum achievable blood flow in a diseased coronary artery and the theoretical maximum flow in a normal coronary artery. FFR measures the intracoronary pressure before and after aspecific coronary lesion in the presence of hyperemic stimuli by adenosine reaching a direct relationship between pressure and flow. A FFR of 1.0 is widely accepted as normal. An fractional flow reserve lower than 0.75-0.80 is generally considered to be associated with myocardial ischemia (MI) ¹⁴. Note that fractional flow reserve (FFR) procedure is not intended for use in the setting of a total vessel occlusion. Coronary artery lesions with FFR ≤0.80 have been proved to receive benefits from revascularization while, in a setting of a stenosis with a FFR>0.80, the patient can be safely deferred to optimal medical treatment ¹⁵

More important, unlike the ischemia stressors induced, FFR is not influenced by systemic hemodynamic ¹⁶, it takes into account the contribution of collaterals ¹⁶, it specifically relates to the severity of the stenoses and to the mass of tissue to be perfused ¹⁷ and it reaches a per-lesion accuracy rather than per-myocardial territory with a very high spatial resolution ⁶.

• The 2014 European Society of Cardiology guidelines recommend the use of FFR to detect a hemodynamically relevant coronary lesion in stable patients when other evidence of ischemia is not available ¹⁸.
• The 2012 American College of Cardiology/American Heart Association guidelines recommends revascularization of coronary stenoses with FFR ≤ 0.8 ¹⁹.
• The 2017 Society of Cardiovascular Angiography and Interventions guidelines recommend that if no stress test is available or if the stress results are indeterminate, the FFR ≤ 0.8 can be used to guide revascularization ²⁰.

FFR (fractional flow reserve) is easily measured during routine coronary angiography by using a pressure guidewire to calculate the ratio between coronary pressure distal to a coronary artery stenosis and aortic pressure under conditions of maximum myocardial hyperemia ¹⁴. This ratio represents the potential decrease in coronary flow distal to the coronary stenosis. More recently, computed tomography (CT)-based fractional flow reserve computations have been used to evaluate the functional severity of coronary artery stenoses, with fractional flow reserves derived from outflow boundary conditions based on conventional morphology generally agreeing with those based on positron-emission tomography (PET) conditions ²¹. However, fractional flow reserves measurements based on conventional morphology had a tendency to overestimate functional severity, particularly in the setting of reduced vasodilatory response under hyperemia (and thus abnomal myocardial perfusion) ²¹.

Over the past two decades, fractional flow reserve measurement has been increasingly used in cardiac catheterization laboratories. It provides a quantitative assessment of the functional severity of a coronary artery stenosis identified during coronary angiography and cardiac catheterization.

A severe coronary artery stenosis can limit myocardial blood flow, resulting in myocardial ischemia. In most cases, the severity of a coronary artery stenosis is judged by visual inspection by the cardiologist during cardiac angiography. A lesion is generally considered severe and flow-limiting if the narrowing of the luminal diameter is estimated to be 70% or greater ²².

After a diagnostic cardiac catheterization has been performed and a stenosis has been identified, the cardiologist makes the decision as to whether FFR measurement is likely to be useful.

During angiography, the cardiologist typically assesses the patient’s symptoms and clinical characteristics, evaluates the angiographic appearance of the coronary tree, and then decides whether revascularization with angioplasty, stenting, or coronary bypass surgery is most appropriate ²².

However, the ability of the cardiologist to discriminate between lesions that can cause myocardial ischemia and lesions that are physiologically insignificant on the basis of coronary angiography alone is limited ²³. The use of fractional flow reserve measurement provides the cardiologist with a straightforward, readily available, quantitative technique for evaluating the physiologic significance of a coronary stenosis.

Risks specific to the FFR procedure include the need for additional contrast use and radiation exposure, as well as a slightly increased risk of coronary arterial dissection with FFR wire passage.

Fractional flow reserve indications

Indications for FFR measurement are as follows:

• To determine the physiologic and hemodynamic significance of an angiographically intermediate coronary stenosis
• To identify appropriate culprit lesion(s) in multivessel coronary artery disease (CAD)
• To measure the functional importance of stenosis in the presence of distal collateral flow
• To identify the precise location of a coronary lesion when the angiographic image is unclear.

Fractional flow reserve measurement technique

Typically, conscious sedation is administered as part of the cardiac catheterization. Unless the patient is uncomfortable, no other anesthesia is required. The patient is placed in the supine position.

To measure fractional flow reserve (FFR), the operator crosses the coronary stenosis with an FFR-specific guide wire designed to record the coronary arterial pressure distal to the stenosis. The pressure transducer is located approximately 20 mm proximal to the distal tip of the wire, and it can be seen fluoroscopically.

Once the transducer is distal to the stenosis, a hyperemic stimulus is administered by injection through the guide catheter, and the FFR is monitored for a significant change. To achieve maximum hyperemia, adenosine is typically used: a 15-30 µg bolus in the right coronary artery, a 20-40 µg bolus in the left coronary artery, or intravenous (IV) infusion for 3-4 minutes at 140 µg/kg/min. The mean arterial pressures from the pressure wire transducer and from the guide catheter are then used to calculate FFR.

An FFR value lower than 0.75 indicates a hemodynamically significant stenosis. An FFR value higher than 0.8 indicates a stenosis that is not hemodynamically significant. Values between 0.75 and 0.80 are indeterminate and should be considered in the context of patient’s clinical history to determine if revascularization is necessary.

Fractional flow reserve complications

Complications associated with cardiac catheterization are similar to any percutaneous coronary intervention and include the following:

• Coronary vessel dissection, occlusion, or perforation
• Embolism (coronary, cerebral, or other arterial)
• Coronary artery spasm
• Local or systemic infection
• Acute renal failure or contrast induced nephropathy
• Myocardial infarction
• Stroke
• Serious arrhythmias
• Death

Fractional flow reserve outcomes

In a study ²⁴ designed to test the hypothesis that experienced interventional cardiologists could identify patients with fractional flow reserves below 0.75 by means of coronary angiography, FFR was measured in 83 angiographically moderate coronary lesions, which were also visually assessed by 3 interventional cardiologists; the reviewers’ classification matched the FFR in only about half of the lesions, and concordance between reviewers was poor. In this study, when visual assessment was compared with fractional flow reserve, it resulted in good sensitivity (80%) and negative predictive value (91%) but poor specificity (47%) and positive predictive value (25%) ²⁴. Angiographic assessment of an angiogram by experienced interventional cardiologists did not predict the significance of most moderate coronary lesions.

In the DEFER study, which assessed patients with single-vessel coronary artery disease (CAD) and angiographically intermediate coronary stenosis, patients with an FFR above 0.75 were randomized to either medical management or stent implantation; at 5-year follow-up, those who did not receive a stent had the same risk of death or acute myocardial ischemia as those who did, which suggests that patients with an fractional flow reserve higher than 0.75 do not benefit from revascularization of the stenosis.

The Fractional Flow Reserve versus Angiography for Multivessel Evaluation (FAME) study ²⁵, which studied the role of fractional flow reserve in the evaluation of multivessel coronary artery disease, reported results suggesting that a revascularization strategy using fractional flow reserve yields superior clinical outcomes in patients with multivessel coronary artery disease (CAD). In this study ²⁵, patients with multivessel coronary artery disease identified by angiography were randomized to undergo either angiography alone or fractional flow reserve plus angiography. Patients in the angiography-only arm underwent stenting of all angiographically severe lesions. Patients in the fractional flow reserve-plus-angiography arm underwent stenting only if fractional flow reserve was 0.80 or less. At 2-year follow-up, patients who underwent fractional flow reserve-driven stenting had fewer stents than those in the angiography-only group, along with reductions in mortality, MI, and repeat revascularization.

More recently, investigators retrospectively (2016-2018) evaluated fractional flow reserve in 246 German patients with coronary artery disease (CAD) undergoing transcatheter aortic valve implantation who had coronary lesions with a diameter stenosis of at least 50% ²⁶. They found concomitant coronary artery disease in 53.3% of transcatheter aortic valve implantation patients ²⁶. Postprocedure fractional flow reserve measurements performed in those with a positive fractional flow reserve up to and including 0.80 did not significantly change 6-8 weeks after transcatheter aortic valve implantation, which the investigators indicated confirmed the validity of fractional flow reserve for assessing coronary lesions in this specific clinical setting ²⁶.

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