Transthoracic Doppler echocardiography – noninvasive diagnostic window for coronary flow reserve assessment

This review focuses on transthoracic Doppler echocardiography as noninvasive method used to assess coronary flow reserve (CFR) in a wide spectrum of clinical settings. Transthoracic Doppler echocardiography is rapidly gaining appreciation as popular tool to measure CFR both in stenosed and normal epicardial coronary arteries (predominantly in left anterior descending coronary artery). Post-stenotic CFR measurement is helpful in: functional assessment of moderate stenosis, detection of significant or critical stenosis, monitoring of restenosis after revascularization. In the absence of stenosis in the epicardial coronary artery, decreased CFR enable to detect impaired microvascular vasodilatation in: reperfused myocardial infarct, arterial hypertension with or without left ventricular hypertrophy, diabetes mellitus, hypercholesterolemia, syndrome X, hypertrophic cardiomyopathy. In these diseases, noninvasive transthoracic Doppler echocardiography allows for serial CFR evaluations to explore the effect of various pharmacological therapies.


Introduction
Coronary flow reserve (CFR) is defined as a ratio of maximal (stimulated) to baseline (resting) coronary blood flow. CFR evaluation is important for the understanding of the pathophysiology of coronary circulation. CFR measurement is used both to assess epicardial coronary stenoses and to examine the integrity of microvascular circulation. An appreciation of coronary physiology is an integral part of clinical decision-making for cardiologists treating patients with coronary artery disease. In the absence of stenosis in epicardial coronary artery, the CFR may be decreased when coronary microvascular circulation is compromised by arterial hypertension with or without left ventricular hypertrophy, diabetes mellitus, hypercholesterolemia, syndrome X, hypertrophic cardiomyopathy or other diseases [1].

Methods to assess CFR
Several methods have been established for measuring CFR (table 1). However, these methods are either invasive (intracoronary Doppler flow wire), highly expensive and scarcely available (Positron Emission Tomography) or semi-invasive and scarcely feasible (transesophageal Doppler), thus their clinical use is limited. In addition, PET and intracoronary Doppler flow wire involve radiation exposure, with inherent risk, environmental impact and biohazard connected with use of ionizing testing [2].
Because of the clinical importance of CFR there is a need for a simple, non-invasive, repeatable and inexpensive tool capable of this functional evaluation. The value of absolute coronary blood flow may be substituted by the value of coronary blood flow velocity [3-6] measurable by Doppler technique not only invasively but also using a non-invasive approach (figure 1,2,3). The present review discusses the assessment of CFR using transthoracic Doppler echocardiography, a technique which has been validated in a series of clinical studies [1,5,[7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. Recently the usefulness of transthoracic Doppler echocardiography to assess CFR has been reported in various clinical settings in a large general referral population. The method provides reliable measurements of CFR in the distal or middle segment of left anterior descending coronary artery (LAD), using pulsed wave Doppler echocardiography under the guidance of color Doppler flow mapping. The development of the transthoracic imaging technique (exploring various transducer beam orientations) extended the possibilities of imaging blood flow in the circumflex coronary artery [1] and right coronary artery (RCA) [24][25][26]. As regards the transthoracic Doppler assessment of CFR in the RCA we are able to measure the coronary flow velocity in proximal RCA and in its distal branch i.e. right posterior descending artery. Due to the fact that most relevant RCA stenoses are located proximal to the crux cordis the assessment of CFR in the right posterior descending artery usually provide post-stenotic values. The feasibility of CFR measurement with transthoracic Doppler echocardiography is improved by contrast enhancement combined with second-harmonic imaging technique. Consequently, in some reports the feasibility of transthoracic Doppler echocardiography to assess CFR achieved 100% [7,9].

Clinical Application
There are two most relevant clinical application of transthoracic Doppler echocardiography to assess reduced CFR due to: stenosis of epicardial LAD and impairment of coronary microvascular vasodilatation.
Coronary angiography provides a limited insight into the physiological significance of coronary stenoses. Therefore, the CFR is a useful parameter in the several important clinical setting summarized in

Detection of critical stenosis (>90%)
Using transthoracic Doppler echocardiography it is possible to detect severe LAD stenosis >90%. The CFR <1, suggesting coronary steal may be a predictor of critical coronary stenosis [23]. Coronary steal is defined as a decrease of CFR to a certain vascular region in favor of another area during maximal coronary vasodilatation, that is, CFR <1.

Combined assessment of coronary flow and wall motion
The CFR findings is additive and complementary to the information provided by 2DE on regional wall motion abnormalities. Combined assessment of CFR and wall motion was performed dipyridamole echocardiographic stress test. According to data from Rigo et al. report [28] coronary flow and contractile function of myocardium can be complementary in terms of predicting underlying angiographic anatomy, because abnormal wall motion can include coronary artery disease, and negative CFR can exclude it. In this study, sensitivity for detecting LAD dis-    study of Colonna et al [42] it was shown that preconditioning due to preinfarction angina had a protective role on microvascular function as demonstrated by CFR preservation (>2,5) after myocardial infarct.

Assessment of coronary graft patency
Another application of transthoracic Doppler echocardiography is the assessment of the patency of internal mammary artery and saphenous vein to coronary artery grafts [12,43]. In the largest study [43] the identification rate for mammary artery grafts was 100%, for saphenous

Figure 3
Direct visualization of coronary artery stenosis. The portion of mid segment of LAD with color mosaic (a sign of high-velocity, turbulent flow) at stenotic site.

Impairment of coronary microvascular vasodilatation
The second application of transthoracic Doppler echocardiography is the detection of reduced CFR due to impaired microvascular vasodilatation despite angiographically normal epicardial coronary arteries. It is well known that several diseases such as hypertrophy (due to aortic stenosis, hypertrophic cardiomyopathy, hypertension), diabetes mellitus, smoking, menopause cause structural and/or functional abnormalities in the microcirculation. The invasive Doppler measurement of CFR is not routinely performed in patients with chest pain and normal coronary arteries. Therefore, the extent of such microvascular disease appears to be underestimated. Accordingly, recent studies [4,44]. have demonstrated that up to 50% of the patients with chest pain and normal or near normal coronary angiograms have reduced CFR. Noninvasive assessment of CFR using transthoracic Doppler echocardiography has been performed in patients with hypertrophic cardiomyopathy [45], aortic stenosis [46] and smokers (both active and passive) [17]. In these studies CFR was measured using adenosine (standard vasodilator to test endothelium-independent vasodilatation). In patients with hypertrophic cardiomyopathy additionally the vasomotor response to stressors testing endotheliumdependent vasomotion was studied [18][19][20][21][22]47]. Cold pressor test [20,21], handgrip [22,47] and pacing [19] was used as stressing stimuli. Importantly, the noninvasive approach provides an opportunity to assess asymptomatic patients [18,20] and to recruit healthy subjects to form adequate control groups [13,18,19,21,22], which is impossible in an invasive study. Additionally, the effect of physiological hypertrophy on CFR is measurable by transthoracic Doppler echocardiography [13], which could prove useful in differentiating athlete's hypertrophic heart -in which CFR is in normal to supranormal range -from hypertrophic cardiomyopathy, in which CFR is markedly attenuated.
Moreover, noninvasive transthoracic Doppler echocardiography allows for serial CFR evaluations to explore the effect of various pharmacological therapies [18] or to as- Table 3: Proposed scheme of application of transthoracic Doppler echocardiography (with or without wall motion assessment) in diagnosis of epicardial or microvascular coronary vessel disease Before coronary angiography (nondiagnostic or equivocal exercise stress ECG) • Suspected epicardial coronary stenosis (LAD, Cx, RCA) • Suspected microvascular abnormalities (young patients with chest pain despite no risk factor for epicardial CAD) 1. WM (LV global) assessment (if negative) CFR in LAD 2. CFR (regional assessment of LAD) The clinical applications of CFR measurement are summarized in table 3.

Choosing the appropriate stimuli
There are two pharmacological vasodilators: adenosine and dipyridamole used to recruit CFR. Both agents are compared in table 4. Both adenosine and dipyridamole have an advantage over exercise and dobutamine, which are submaximal stimuli for coronary flow reserve and are more technically demanding for imaging of CFR [1,48].

Limitations of transthoracic Doppler echocardiography measurement of CFR Absolute volumetric flow versus flow velocity
Although the left anterior descending artery was detected with combined Doppler and two-dimensional imaging, the images were not of sufficient clarity to allow for accurate measurement of the vessel diameter in a substantial portion of the examined subjects. Without estimation of the coronary artery diameter we can measure changes only in coronary blood flow velocity, but not changes in coronary blood flow. Therefore CFR assessment by transthoracic Doppler echocardiography is limited to measurements of coronary blood flow velocity in majority of studies. However, it has been shown that CFR measured using both parameters is closely correlated (1-4). Moreover, even in large invasive studies DEBATE [49] and DESTINI [31,33] the CFR derived from changes only in the velocity of coronary blood flow was accepted instead of the absolute coronary blood flow, which is measurable during invasive studies.
Regarding the accuracy of transthoracic Doppler measurement of CBFV, its comparison with intracoronary measurement provided a highly satisfying correlation between non-invasive and invasive measurements [7,14].

Contrast enhancement versus non-contrast study: learning curve and cost-effectiveness
Another limitation is the feasibility of transthoracic coronary blood flow velocity measurement. In assessment of coronary flow in LAD, the learning curve effect was seen in most centers in which contrast agents were not used. In studies by Shapiro and coworkers, which were initiated in the beginning of the 90s, the capacity of detecting coronary flow increased from 34% to 77% [10,46,50,51]. Voci and coworkers were able to increase the capacity of coronary blood flow imaging from 76% [52]  , which are however expensive. As regard costeffectiveness balance it was calculated [23] that using 90s noncontrast/adenosine vasodilator approach the cost of the test was 14 times less expense than 7-min contrast-enhanced approach. As regard vasodilator agents, dipyridamole is cheaper than adenosine and therefore the best cost-effectiveness profile is achieved with dipyridamole stress without contrast enhancement.
Pitfalls and trouble-shooting CFR must be measured distally to stenosis, because erroneous CFR assessment at stenosis site is underestimated due to increased baseline flow velocity. Additionally, the flow in LAD branches could be erroneously interpreted as the flow in LAD main trunk.

Conclusions
Transthoracic Doppler echocardiography is rapidly gaining appreciation as popular tool to measure CFR both in stenosed and normal epicardial coronary arteries (predominantly in left anterior descending coronary artery). Post-stenotic CFR measurement is helpful in: functional assessment of moderate stenosis, detection of significant Short action, short-lasting adverse effects prolonged action allow to assess CFR and wall motion abnormalities during single examination Disadvantage AV conduction delay (including complete heart block), Hyperventilation, hypotension, flushing, headache, possibility of antidote-resistance prolonged ischemia, hypotension, flushing, headache, hyperventilation, or critical stenosis, monitoring of restenosis after revascularization. In the absence of stenosis in the epicardial coronary artery, decreased CFR enable to detect impaired microvascular vasodilatation in: reperfused myocardial infarct, arterial hypertension with or without left ventricular hypertrophy, diabetes mellitus, hypercholesterolemia, syndrome X, hypertrophic cardiomyopathy. In these diseases, noninvasive transthoracic Doppler echocardiography allows for serial CFR evaluations to explore the effect of various pharmacological therapies.