Prevalence of pathological FFR_CT values without coronary artery stenosis in an asymptomatic marathon runner cohort

One of the most important developments in the diagnosis of significant coronary artery disease (CAD) over the last two decades is the assessment of the hemodynamic significance of coronary artery stenosis using fractional flow reserve (FFR) and systematic evaluation of its clinical value. It could be shown that an FFR value below 0.75–0.80 defines a hemodynamically significant stenosis that should be treated by revascularization [1‐4]. However, a drawback of this method is its invasiveness. Here, a noninvasive approach to detect coronary stenosis is the emerging technique of coronary computed tomography angiography (CCTA). Meanwhile, CCTA has been developed as a well-established and cost-effective imaging modality for the evaluation of CAD, especially to exclude obstructive stenosis due to its high negative predictive value [5‐8]. Technical progress and the introduction of various optimized acquisition techniques and strategies allowed considerable radiation dose reduction—one of the most significant issues at the beginning—to sub-millisievert levels [9]. Recently, the development of post-processing procedures enabled the calculation of computed tomography fractional flow reserve (FFR_CT) values based on CCTA datasets using computational fluid dynamics or machine learning algorithms. Although good diagnostic accuracy of FFR_CT has been reported, a major issue remains the evaluation of the distal parts of the vessels, with a potentially limited specificity [10]. Due to physiological tapering of the coronary vessels, FFR_CT evaluation may yield values below 0.8 resulting in false-positive results.

However, the exact prevalence of this finding is unknown, especially in asymptomatic persons without signs of CAD who perform regular exercise which is known to have a positive impact on endothelial function. Therefore, the aim of this study was to evaluate FFR_CT in a collective of asymptomatic marathon runners without CAD who prospectively underwent CCTA for CAD screening purposes.

This study demonstrated that in an asymptomatic cohort of male marathon runners without clinical or visually assessable coronary artery stenosis, FFR_CT evaluation results in abnormal FFR_CT values (FFR_CT ≤ 0.8) in distal segments of coronary arteries in over one-third of subjects. This effect is independent from coronary artery dominance and only to some degree explainable by small distal vessel diameters. Isolated vessel diameter is one important but not the only factor influencing FFR_CT. This finding limits the use of the method in distal vessel segments.

This is the first systematic FFR_CT evaluation in an asymptomatic cohort of male marathon runners initially prospectively recruited at that time. Correct evaluation and grading of FFR_CT values are of utmost importance for the estimation of relevant coronary artery stenosis, since the appropriate use of CCTA has been reported to decrease, and not to increase the number of unnecessary invasive coronary angiographies [16]. CCTA alone can be considered an established diagnostic modality in patients with low or intermediate pre-test probability for the exclusion of CAD [17]. It was previously shown that FFR_CT can successfully be used in an acute chest pain setting for the decision or deferral of invasive angiography [18]. It was also shown that FFR_CT provides reliable results compared to invasive catheter-based measurements [10, 19‐24]. In a recent publication, it was demonstrated that also on-site FFR_CT might be able to change patient management and improve diagnostic efficiency in patients with obstructive CAD [25]. It was also shown that on-site FFR_CT combined with CCTA offers similar diagnostic accuracy compared to CT perfusion and CCTA [26]. Therefore, the main task for FFR_CT in CCTA is the evaluation not only of the anatomical significance but also of the hemodynamical relevance of a given stenosis. One approach is the application of the FFR_CT threshold of 0.8. However, our study results indicate that this threshold might not be applied for the evaluation of hemodynamic coronary stenosis in the distal parts of the vessels. Therefore, it is of crucial importance that CCTA and FFR_CT are regarded as complementary techniques instead of the isolated use of CCTA or FFR_CT to prevent false-positive findings.

The development and introduction of FFR_CT have been an important step over the last few years to not only visually grade the significance of coronary artery stenosis but also non-invasively get information about its hemodynamic and clinical relevance. Severe stenosis does not consistently result in hemodynamically relevant pressure gradients, and a significant percentage of intermediate stenosis does not even cause ischemia [27, 28] The calculation of FFR_CT values via post-processing of an existing CCTA dataset displayed a promising diagnostic tool without harming patients. Although many studies could demonstrate good sensitivity and specificity in comparison to invasive X-ray coronary angiography, it remains elusive if the same threshold can be applied to FFR_CT as for the invasive counterpart [10]. FFR_CT values were comparable with invasive X-ray coronary angiography values in previous studies focusing on patients with coronary stenosis [10, 19‐24]. However, there is so far no data about the reliability of FFR_CT in apparently healthy subjects. A common finding in FFR_CT is the constant decline of FFR values in the more distal parts of the vessels, most probably due to the physiological tapering of the vessels. Another explanation might be the presence of endothelial dysfunction affecting the hemodynamics of the coronary arteries. However, a constant decline in more distal parts would not be generally expected in patients with endothelial dysfunction. Other influencing factors might be coronary dominance or the presence of serial lesions, as well as compensation via collaterals.

The question arises of how far distally hemodynamically significant stenosis can reliably be detected, and at which level the high diagnostic accuracy of coronary CT turns into a rate of high false-positive (FFR_CT) findings, potentially causing harm to the patient by subsequent investigations or medication. The evaluation of the vessel diameters in participants without any coronary artery stenosis showed a significant difference in vessel size in the distal LAD and RCA depending on FFR_CT above or below 0.8. However, no clear cut-off can be defined.

Therefore, we propose FFR_CT should always be evaluated in addition to visual evaluation of the CCTA dataset so that pathologic FFR_CT values without any stenosis in CCTA can easily be interpreted as false positive, but probably as a sign of endothelial dysfunction. Nevertheless, in subjects with stenosis located proximal or midportion, values below 0.8 in the distal vessel might be the result of two amplifying mechanisms. Other likely reasons reported are diffuse CAD, serial lesions, small vessel size relative to myocardial mass, inadequate nitrate response, or technical misalignment [27]. This issue of falsely pathologic FFR_CT presumably affects a significant portion of CAD patients, since we found this effect in up to a third of our study participants without any coronary stenosis at all. Of course, clinical data and symptom presentation should also be taken into consideration. However, further studies are necessary to investigate the clinical relevance of FFR_CT measurements in distal vessel parts. FFR_CT may report pathological values so distal in the vessel that it could not be stented [29]. In this context, hemodynamically relevant stenosis also in proximal or midportion segments may be treated with initial conservative strategy in chronic coronary syndrome [30]. Decision-making based on pathological FFR_CT values in distal coronary artery segments should therefore be performed with the greatest caution and by a thorough consideration of visual assessment, clinical data, and patient symptoms.