- Email: [email protected]
Non-invasive evaluation of coronary flow reserve with transthoracic Doppler echocardiography predicts the presence of significant stenosis in coronary arteries
294
Letters to the Editor
References [1] Dominguez-Rodriguez A, Abreu-Gonzalez P. The link between sleep duration and inflammation: effects on cardiovascular disease. Int J Cardiol 2014;173(3):600–1.
[2] Cheng Y, Du CL, Hwang JJ, Chen IS, Chen MF, Su TC. Working hours, sleep duration and the risk of acute coronary heart disease: a case–control study of middle-aged men in Taiwan. Int J Cardiol 2014;171:419–22. [3] Kawada T. Working hours, sleep duration and risk of coronary heart disease. Int J Cardiol 2014;174(1):162.
0167-5273/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2014.06.077
Non-invasive evaluation of coronary flow reserve with transthoracic Doppler echocardiography predicts the presence of significant stenosis in coronary arteries Inger Haraldsson a,b,⁎, Li-Ming Gan a,c, Sara Svedlund a,c, Ann Wittfeldt a,b, Truls Råmunddal a,b, Oskar Angerås a,b, Per Albertsson a,b, Göran Matejka a,b, Elmir Omerovic a,b a b c
Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden Department of Clinical Physiology, Sahlgrenska University Hospital, Gothenburg, Sweden
a r t i c l e
i n f o
Article history: Received 30 April 2014 Accepted 29 June 2014 Available online 10 July 2014 Keywords: Coronary artery disease Coronary flow reserve Transthoracic Doppler echocardiography
Coronary flow reserve (CFR) is the ratio between maximum and resting blood flow and reflects the ability of coronary circulation to adapt to an increased metabolic demand [1–3]. Reduced CFR is associated with a higher risk of adverse cardiovascular events [4–10]. Patients with coronary artery disease (CAD) and CFR b1.5 evaluated with positron emission tomography had a six-fold higher risk of cardiac death [11]. CFR can also be measured non-invasively with transthoracic Doppler echocardiography, which is a more accessible and a less expensive method. Our aim was to evaluate whether CFR measured with transthoracic Doppler echocardiography predicts significant (N50% lumen reduction) CAD in patients who underwent coronary angiography in routine clinical practice. We studied the patients with chest pain referred for evaluation with single photon emission tomography (SPECT) at Sahlgrenska University Hospital in Gothenburg between February 2006 and April 2009. We included 152 patients investigated with both SPECT and coronary angiography (Fig. 1). Patient characteristics and angiographic findings were obtained from SCAAR (Swedish Coronary Angiography and Angioplasty Registry) [12] registry, patient charts and individual angiograms. We measured CFR in all three coronary arteries i.e. left anterior descending artery (LAD), left circumflex artery (LCx) and right coronary artery (RCA) using transthoracic Doppler echocardiography (Supplement). Coronary flow velocity was first measured at rest (Fig. 2) and then at maximal flow after induction of hyperemia by intravenous infusion of adenosine (140 μg/kg/min). We analyzed data using several
⁎ Corresponding author at: Department of Cardiology, Sahlgrenska University Hospital, 413 45 Göteborg, Sweden. Tel.: +46 31 342 75 76. E-mail address: [email protected] (I. Haraldsson).
statistical models based on propensity score adjusted logistic regression (Supplement). Median age was 64 years (range 46-81) and 36% were female (Table 1). Angiography showed no significant CAD in 38.8% while 32.9% had single-vessel and 28.3% had multi-vessel disease. Patients with significant CAD were 75% males, were older and had more hypertension, hyperlipidemia, previous MI, previous percutaneous coronary intervention (PCI) and previous coronary by-pass surgery (CABG) than patients without significant CAD. We found lower CFR in all three coronary arteries in patients with significant CAD (Table 1 and Fig. 3A). CFR in LAD (Fig. 3B) and LCx showed negative linear relationship with the severity of CAD. However, this relationship was not present in RCA (Fig. 4). Multivariable regression analyses have shown that CFR in LAD, LCx and RCA were independent predictors of significant CAD. The results from the several secondary models were congruent with the primary analysis (Table 2).
Fig. 1. Study flow-chart. The study population consisted of patients with suspected or known ischemic heart disease referred to the Sahlgrenska University Hospital in Gothenburg for evaluation of symptoms. Of 416 consequent patients, 152 underwent coronary angiography and were included in the study.
Letters to the Editor
295
Fig. 2. Examples of coronary flow reserve assessed by transthoracic Doppler of the mid-distal portion of LAD. Coronary flow reserve is calculated as the ratio of mean diastolic coronary flow velocity at hyperemia (induced by intravenous infusion of adenosine 140 mkg/kg) to that in the resting condition.A) The normal finding is characterized by high CFR associated with angiographically normal coronary arteries.B) CFR was substantially lower in the presence of significant stenosis of the LAD.C) CFR measured in LAD was low in patients with a significant stenosis in LCx but without significant stenosis in LAD. Note the diffuse atherosclerosis in LAD.
The most important findings are as follows. Firstly, CFR predicted significant CAD in patients with suspected or known CAD. Secondly, CFR measured in any of the three coronary arteries predicted significant CAD independently of anatomical localization and number of diseased arteries. One explanation for this might be that CAD, being a progressive and
systemic disease, affects at the same time both coronary arteries and microcirculation. When CAD advances, the regulation of coronary flow may be disturbed in the whole heart and not only in the most diseased vessel. This latter hypothesis is consistent with our finding that CFR from any of the three coronary arteries predicted the presence of significant
Table 1 Characteristics of the study population.
Age median (IQR) Female gender n (%) BMI mean (± SD) Tobacco use n (%) Diabetes n (%) Hypertension n (%) Hyperlipidemia n (%) Previous MI n (%) Previous PCI n (%) Previous CABG n (%) Extension of coronary artery disease No significant stenosis One-vessel disease Two-vessel disease Three vessel disease CFR LAD mean (± SD) CFR LCx mean (± SD) CFR RCA mean (± SD) Mean CFRa mean (±SD)
All N = 152
No CAD N = 59
CAD N = 93
Missing
P-value
64 (46–81) 54 (35.5) 28.3 (± 16.5) 8 (5.2) 25 (16.5) 84 (55.3) 104 (68.4) 37 (24.3) 53 (34.9) 29 (19.1)
63.0 (54.5–66.0) 32 (54.2) 30.9 (27.1) 5 (8.5) 6 (10.2) 26 (44.1) 34 (57.6) 6 (10.2) 13 (22.0) 3 (5.1)
66.5 (60.0–70.0) 22 (23.6) 26.8 (16.6) 3 (3.2) 19 (20.4) 58 (62.4) 70 (75.3) 31 (33.3) 40 (43.0) 26 (27.9)
– – 11 (7.2) – – – – – – –
0.003 b0.001 0.158 0.158 0.096 0.027 0.023 0.003 0.008 b0.001 b0.001
59 (38.8) 50 (32.9) 16 (10.5) 27 (17.8) 2.5 (± 1.05) 2.04 (± 0.66) 2.23 (± 0.71) 2.26 (± 0.65)
59 (100) – – – 2.96 (± 0.90) 2.31 (± 0.60) 2.62 (± 0.64) 2.55 (± 0.58)
0 (0) 50 (53.6) 16 (17.2) 27 (29.0) 2.32 (± 1.04) 1.92 (± 0.66) 2.07 (± 0.68) 2.07 (± 0.61)
– – – – 29 34 38 29
(19.1) (22.4) (25.0) (19.1)
IQR inter-quartile range; CAD significant coronary artery disease; BMI body mass index; MI myocardial infarction; UA unstable angina; CFR coronary flow reserve. a Calculated as an average value of all available CFRs measured in two or three coronary arteries per individual patient.
0.002 0.003 b0.001 b0.001
296
Letters to the Editor
Fig. 3. A) Box-and-whiskers plot with median (band inside the box) and inter quartile range (lower and upper box-line) with minimum and maximum values (lower and upper whisker respectively) for CFR measured in all three coronary arteries in patients without (no CAD) and with (CAD) significant CAD. On average, CFR in the same artery was lower in patients with significant CAD.B) Mean values for CFR measured in LAD in patients with increasing severity of coronary artery disease. The test for trend showed significant decrease in CFR with increasing severity of coronary artery disease i.e. CFR was highest in patients without significant narrowing and lowest in patients with three-vessel disease (three-VD).
CAD. In addition, CFR from a single coronary artery as well as the average value from all three arteries was equally predictive. Therefore one could limit the examination to LAD since it is technically less demanding, less time-consuming, and therefore more patient-friendly. Thirdly, there was significant correlation between CFR measured in LAD, LCx and RCA independently of location of lesions. Fourthly, CFR decreased with increasing severity of CAD in LAD and LCx but not in RCA. While this negative relationship in LAD and LCx is intuitive and in line with the current paradigm, the absence of it in RCA was unexpected and the reason is not clear. An intriguing detail in this context is that MI with RCA as the culprit artery has less negative prognostic effect than when the culprit is LAD or LCx [13,14]. Our data confirm the results from previous studies and provide some new hypothesis-generating insights. While earlier studies focused mostly on measuring CFR in LAD, we successfully evaluated CFR in all three coronary arteries. The regulation of coronary blood flow is the result of a complex interaction between many factors and endothelium has a central role. A large body of evidence supports the paradigm that endothelial dysfunction occurs in response to cardiovascular risk factors (e.g. hypertension, hyperlipidemia, smoking, diabetes mellitus, social stress, sedentary life style, genetic predisposition) and precedes the development of atherosclerosis [15,16]. Since normal coronary flow depends on the interplay between many known and possibly yet unknown physiological systems, CFR may contain integrated information about these complex biophysical and biochemical arrangements. The best example so far with regard to the value of CFR for clinical and research
Fig. 4. Correlation between CFR measured in all three coronary arteries. CFR values in all three coronary arteries showed significant correlation with each other.
purposes is the recent prospective study [17] based on 4000 patients with known or suspected CAD. This study showed that low CFR in LAD is a strong predictor of mortality. Therefore, we think that it is important to investigate whether this non-invasive and relatively inexpensive method may be a valuable tool for diagnosis and for treatment-decisions in patients with suspected or known CAD. A number of questions should be addressed. Could CFR be used for screening of high risk asymptomatic individuals? Could CFR be valuable, in addition to the established methods, in optimizing decision-making regarding which coronary lesions should be treated with PCI and which ones with CABG? Could CFR be a valid surrogate end-point in interventional studies evaluating the effects of pharmacological and other interventions on cardiovascular morbidity and mortality? Although our study is relatively small, the number of events was reasonably high which together with the adherence to the recommended statistical modeling provided adequate power for hypothesis-testing. We cannot exclude the possibility of selection bias as the patient population was not randomly chosen.
Letters to the Editor Table 2 Statistical modeling for evaluation of CFR as a predictor of significant coronary artery stenosis based on propensity score adjusted logistic regression. OR
95% CI
P-value
Primary modela CFR in LADb CFR in LCxb CFR in RCAb Mean CFRb,c
0.61 0.40 0.38 0.27
0.40–0.92 0.23–0.71 0.21–0.72 0.13–0.58
0.018 0.002 0.003 0.001
Secondary models Model 1 CFR in LAD Model 2 mean CFRc Model 3 mean CFRc Model 4 CFR in LAD Model 5 mean CFRc Model 6 CFR in LAD Model 7 mean CFRc
0.49 0.25 0.27 0.42 0.15 0.63 0.31
0.32–0.76 0.12–0.54 0.13–0.58 0.25–0.71 0.05–0.43 0.39–0.99 0.14–0.68
0.001 0.001 0.002 0.001 0.001 0.048 0.004
297
Supplementary data to this article can be found online at http:// dx.doi.org/10.1016/j.ijcard.2014.06.076.
References
OR odds ratio; CI confidence interval; LAD left anterior descending artery, LCx left circumflex artery; RCA right coronary artery; CFR coronary flow reserve. Models 1 and 2. Logistic regression with complete-case analysis adjusted for quintiles of propensity score. Model 3. Logistic regression with imputation of the missing data adjusted for quintiles of propensity score. Models 4 and 5. Sensitivity analysis only with patients who underwent Doppler evaluation of CFR before coronary angiography (N = 90). The model is based on logistic regression with imputation of the missing data adjusted for quintiles of propensity score. Models 6 and 7. Sensitivity analysis only with patients without previous myocardial infarction (N = 115). The model is based on logistic regression with imputation of the missing data adjusted for quintiles of propensity score. a Logistic regression adjusted with propensity score as continuous variable. b Odds ratio for CFR in LAD, LCx and RCA was obtained from the separate models in which CFR values were entered into the model for one artery at a time. c Mean CFR is calculated as an average value of all available CFR measurements obtained per individual patient.
In conclusion, CFR measured with transthoracic Doppler echocardiography was an independent predictor of significant CAD in any of the three coronary arteries. This inexpensive and accessible method is useful for the diagnostics of CAD.
0167-5273/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2014.06.076
[1] Gould KL, Lipscomb K, Hamilton GW. Physiologic basis for assessing critical coronary stenosis. Instantaneous flow response and regional distribution during coronary hyperemia as measures of coronary flow reserve. Am J Cardiol 1974;33:87–94. [2] Esper RJ, Nordaby RA, Vilarino JO, Paragano A, Cacharron JL, Machado RA. Endothelial dysfunction: a comprehensive appraisal. Cardiovasc Diabetol 2006;5:4. [3] Verma S, Anderson TJ. Fundamentals of endothelial function for the clinical cardiologist. Circulation 2002;105:546–9. [4] Cortigiani L, Rigo F, Galderisi M, et al. Diagnostic and prognostic value of Doppler echocardiographic coronary flow reserve on left anterior descending artery in hypertensive and normotensive patients. Heart 2011;97(21):1758–65. [5] Cortigiani L, Rigo F, Gherardi S, et al. Prognostic effect of coronary flow reserve in women versus men with chest pain syndrome and normal dipyridamole stress echocardiography. Am J Cardiol 2010;106:1703–8. [6] Cortigiani L, Rigo F, Gherardi S, Galderisi M, Sicari R, Picano E. Prognostic implications of coronary flow reserve on left anterior descending coronary artery in hypertrophic cardiomyopathy. Am J Cardiol 2008;102:1718–23. [7] Cortigiani L, Rigo F, Gherardi S, et al. Additional prognostic value of coronary flow reserve in diabetic and nondiabetic patients with negative dipyridamole stress echocardiography by wall motion criteria. J Am Coll Cardiol 2007;50:1354–61. [8] Cortigiani L, Bigi R, Sicari R, Rigo F, Bovenzi F, Picano E. Comparison of prognostic value of pharmacologic stress echocardiography in chest pain patients with versus without diabetes mellitus and positive exercise electrocardiography. Am J Cardiol 2007;100:1744–9. [9] Marks DS, Gudapati S, Prisant LM, et al. Mortality in patients with microvascular disease. J Clin Hypertens (Greenwich) 2004;6:304–9. [10] Albertal M, Voskuil M, Piek JJ, et al. Coronary flow velocity reserve after percutaneous interventions is predictive of periprocedural outcome. Circulation 2002;105:1573–8. [11] Murthy VL, Naya M, Foster CR, et al. Improved cardiac risk assessment with noninvasive measures of coronary flow reserve. Circulation 2011;124:2215–24. [12] Lagerqvist B, James SK, Stenestrand U, Lindback J, Nilsson T, Wallentin L. Long-term outcomes with drug-eluting stents versus bare-metal stents in Sweden. N Engl J Med 2007;356:1009–19. [13] Chen YL, Hang CL, Fang HY, et al. Comparison of prognostic outcome between left circumflex artery-related and right coronary artery-related acute inferior wall myocardial infarction undergoing primary percutaneous coronary intervention. Clin Cardiol 2011;34:249–53. [14] Stone PH, Raabe DS, Jaffe AS, et al. Prognostic-significance of location and type of myocardial-infarction — independent adverse outcome associated with anterior location. J Am Coll Cardiol 1988;11:453–63. [15] Ross R. Atherosclerosis — an inflammatory disease. N Engl J Med 1999;340:115–26. [16] Shimokawa H. Primary endothelial dysfunction: atherosclerosis. J Mol Cell Cardiol 1999;31:23–37. [17] Cortigiani L, Rigo F, Gherardi S, et al. Coronary flow reserve during dipyridamole stress echocardiography predicts mortality. JACC Cardiovasc Imaging 2012;5:1079–85.
Letters to the Editor
References [1] Dominguez-Rodriguez A, Abreu-Gonzalez P. The link between sleep duration and inflammation: effects on cardiovascular disease. Int J Cardiol 2014;173(3):600–1.
[2] Cheng Y, Du CL, Hwang JJ, Chen IS, Chen MF, Su TC. Working hours, sleep duration and the risk of acute coronary heart disease: a case–control study of middle-aged men in Taiwan. Int J Cardiol 2014;171:419–22. [3] Kawada T. Working hours, sleep duration and risk of coronary heart disease. Int J Cardiol 2014;174(1):162.
0167-5273/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2014.06.077
Non-invasive evaluation of coronary flow reserve with transthoracic Doppler echocardiography predicts the presence of significant stenosis in coronary arteries Inger Haraldsson a,b,⁎, Li-Ming Gan a,c, Sara Svedlund a,c, Ann Wittfeldt a,b, Truls Råmunddal a,b, Oskar Angerås a,b, Per Albertsson a,b, Göran Matejka a,b, Elmir Omerovic a,b a b c
Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden Department of Clinical Physiology, Sahlgrenska University Hospital, Gothenburg, Sweden
a r t i c l e
i n f o
Article history: Received 30 April 2014 Accepted 29 June 2014 Available online 10 July 2014 Keywords: Coronary artery disease Coronary flow reserve Transthoracic Doppler echocardiography
Coronary flow reserve (CFR) is the ratio between maximum and resting blood flow and reflects the ability of coronary circulation to adapt to an increased metabolic demand [1–3]. Reduced CFR is associated with a higher risk of adverse cardiovascular events [4–10]. Patients with coronary artery disease (CAD) and CFR b1.5 evaluated with positron emission tomography had a six-fold higher risk of cardiac death [11]. CFR can also be measured non-invasively with transthoracic Doppler echocardiography, which is a more accessible and a less expensive method. Our aim was to evaluate whether CFR measured with transthoracic Doppler echocardiography predicts significant (N50% lumen reduction) CAD in patients who underwent coronary angiography in routine clinical practice. We studied the patients with chest pain referred for evaluation with single photon emission tomography (SPECT) at Sahlgrenska University Hospital in Gothenburg between February 2006 and April 2009. We included 152 patients investigated with both SPECT and coronary angiography (Fig. 1). Patient characteristics and angiographic findings were obtained from SCAAR (Swedish Coronary Angiography and Angioplasty Registry) [12] registry, patient charts and individual angiograms. We measured CFR in all three coronary arteries i.e. left anterior descending artery (LAD), left circumflex artery (LCx) and right coronary artery (RCA) using transthoracic Doppler echocardiography (Supplement). Coronary flow velocity was first measured at rest (Fig. 2) and then at maximal flow after induction of hyperemia by intravenous infusion of adenosine (140 μg/kg/min). We analyzed data using several
⁎ Corresponding author at: Department of Cardiology, Sahlgrenska University Hospital, 413 45 Göteborg, Sweden. Tel.: +46 31 342 75 76. E-mail address: [email protected] (I. Haraldsson).
statistical models based on propensity score adjusted logistic regression (Supplement). Median age was 64 years (range 46-81) and 36% were female (Table 1). Angiography showed no significant CAD in 38.8% while 32.9% had single-vessel and 28.3% had multi-vessel disease. Patients with significant CAD were 75% males, were older and had more hypertension, hyperlipidemia, previous MI, previous percutaneous coronary intervention (PCI) and previous coronary by-pass surgery (CABG) than patients without significant CAD. We found lower CFR in all three coronary arteries in patients with significant CAD (Table 1 and Fig. 3A). CFR in LAD (Fig. 3B) and LCx showed negative linear relationship with the severity of CAD. However, this relationship was not present in RCA (Fig. 4). Multivariable regression analyses have shown that CFR in LAD, LCx and RCA were independent predictors of significant CAD. The results from the several secondary models were congruent with the primary analysis (Table 2).
Fig. 1. Study flow-chart. The study population consisted of patients with suspected or known ischemic heart disease referred to the Sahlgrenska University Hospital in Gothenburg for evaluation of symptoms. Of 416 consequent patients, 152 underwent coronary angiography and were included in the study.
Letters to the Editor
295
Fig. 2. Examples of coronary flow reserve assessed by transthoracic Doppler of the mid-distal portion of LAD. Coronary flow reserve is calculated as the ratio of mean diastolic coronary flow velocity at hyperemia (induced by intravenous infusion of adenosine 140 mkg/kg) to that in the resting condition.A) The normal finding is characterized by high CFR associated with angiographically normal coronary arteries.B) CFR was substantially lower in the presence of significant stenosis of the LAD.C) CFR measured in LAD was low in patients with a significant stenosis in LCx but without significant stenosis in LAD. Note the diffuse atherosclerosis in LAD.
The most important findings are as follows. Firstly, CFR predicted significant CAD in patients with suspected or known CAD. Secondly, CFR measured in any of the three coronary arteries predicted significant CAD independently of anatomical localization and number of diseased arteries. One explanation for this might be that CAD, being a progressive and
systemic disease, affects at the same time both coronary arteries and microcirculation. When CAD advances, the regulation of coronary flow may be disturbed in the whole heart and not only in the most diseased vessel. This latter hypothesis is consistent with our finding that CFR from any of the three coronary arteries predicted the presence of significant
Table 1 Characteristics of the study population.
Age median (IQR) Female gender n (%) BMI mean (± SD) Tobacco use n (%) Diabetes n (%) Hypertension n (%) Hyperlipidemia n (%) Previous MI n (%) Previous PCI n (%) Previous CABG n (%) Extension of coronary artery disease No significant stenosis One-vessel disease Two-vessel disease Three vessel disease CFR LAD mean (± SD) CFR LCx mean (± SD) CFR RCA mean (± SD) Mean CFRa mean (±SD)
All N = 152
No CAD N = 59
CAD N = 93
Missing
P-value
64 (46–81) 54 (35.5) 28.3 (± 16.5) 8 (5.2) 25 (16.5) 84 (55.3) 104 (68.4) 37 (24.3) 53 (34.9) 29 (19.1)
63.0 (54.5–66.0) 32 (54.2) 30.9 (27.1) 5 (8.5) 6 (10.2) 26 (44.1) 34 (57.6) 6 (10.2) 13 (22.0) 3 (5.1)
66.5 (60.0–70.0) 22 (23.6) 26.8 (16.6) 3 (3.2) 19 (20.4) 58 (62.4) 70 (75.3) 31 (33.3) 40 (43.0) 26 (27.9)
– – 11 (7.2) – – – – – – –
0.003 b0.001 0.158 0.158 0.096 0.027 0.023 0.003 0.008 b0.001 b0.001
59 (38.8) 50 (32.9) 16 (10.5) 27 (17.8) 2.5 (± 1.05) 2.04 (± 0.66) 2.23 (± 0.71) 2.26 (± 0.65)
59 (100) – – – 2.96 (± 0.90) 2.31 (± 0.60) 2.62 (± 0.64) 2.55 (± 0.58)
0 (0) 50 (53.6) 16 (17.2) 27 (29.0) 2.32 (± 1.04) 1.92 (± 0.66) 2.07 (± 0.68) 2.07 (± 0.61)
– – – – 29 34 38 29
(19.1) (22.4) (25.0) (19.1)
IQR inter-quartile range; CAD significant coronary artery disease; BMI body mass index; MI myocardial infarction; UA unstable angina; CFR coronary flow reserve. a Calculated as an average value of all available CFRs measured in two or three coronary arteries per individual patient.
0.002 0.003 b0.001 b0.001
296
Letters to the Editor
Fig. 3. A) Box-and-whiskers plot with median (band inside the box) and inter quartile range (lower and upper box-line) with minimum and maximum values (lower and upper whisker respectively) for CFR measured in all three coronary arteries in patients without (no CAD) and with (CAD) significant CAD. On average, CFR in the same artery was lower in patients with significant CAD.B) Mean values for CFR measured in LAD in patients with increasing severity of coronary artery disease. The test for trend showed significant decrease in CFR with increasing severity of coronary artery disease i.e. CFR was highest in patients without significant narrowing and lowest in patients with three-vessel disease (three-VD).
CAD. In addition, CFR from a single coronary artery as well as the average value from all three arteries was equally predictive. Therefore one could limit the examination to LAD since it is technically less demanding, less time-consuming, and therefore more patient-friendly. Thirdly, there was significant correlation between CFR measured in LAD, LCx and RCA independently of location of lesions. Fourthly, CFR decreased with increasing severity of CAD in LAD and LCx but not in RCA. While this negative relationship in LAD and LCx is intuitive and in line with the current paradigm, the absence of it in RCA was unexpected and the reason is not clear. An intriguing detail in this context is that MI with RCA as the culprit artery has less negative prognostic effect than when the culprit is LAD or LCx [13,14]. Our data confirm the results from previous studies and provide some new hypothesis-generating insights. While earlier studies focused mostly on measuring CFR in LAD, we successfully evaluated CFR in all three coronary arteries. The regulation of coronary blood flow is the result of a complex interaction between many factors and endothelium has a central role. A large body of evidence supports the paradigm that endothelial dysfunction occurs in response to cardiovascular risk factors (e.g. hypertension, hyperlipidemia, smoking, diabetes mellitus, social stress, sedentary life style, genetic predisposition) and precedes the development of atherosclerosis [15,16]. Since normal coronary flow depends on the interplay between many known and possibly yet unknown physiological systems, CFR may contain integrated information about these complex biophysical and biochemical arrangements. The best example so far with regard to the value of CFR for clinical and research
Fig. 4. Correlation between CFR measured in all three coronary arteries. CFR values in all three coronary arteries showed significant correlation with each other.
purposes is the recent prospective study [17] based on 4000 patients with known or suspected CAD. This study showed that low CFR in LAD is a strong predictor of mortality. Therefore, we think that it is important to investigate whether this non-invasive and relatively inexpensive method may be a valuable tool for diagnosis and for treatment-decisions in patients with suspected or known CAD. A number of questions should be addressed. Could CFR be used for screening of high risk asymptomatic individuals? Could CFR be valuable, in addition to the established methods, in optimizing decision-making regarding which coronary lesions should be treated with PCI and which ones with CABG? Could CFR be a valid surrogate end-point in interventional studies evaluating the effects of pharmacological and other interventions on cardiovascular morbidity and mortality? Although our study is relatively small, the number of events was reasonably high which together with the adherence to the recommended statistical modeling provided adequate power for hypothesis-testing. We cannot exclude the possibility of selection bias as the patient population was not randomly chosen.
Letters to the Editor Table 2 Statistical modeling for evaluation of CFR as a predictor of significant coronary artery stenosis based on propensity score adjusted logistic regression. OR
95% CI
P-value
Primary modela CFR in LADb CFR in LCxb CFR in RCAb Mean CFRb,c
0.61 0.40 0.38 0.27
0.40–0.92 0.23–0.71 0.21–0.72 0.13–0.58
0.018 0.002 0.003 0.001
Secondary models Model 1 CFR in LAD Model 2 mean CFRc Model 3 mean CFRc Model 4 CFR in LAD Model 5 mean CFRc Model 6 CFR in LAD Model 7 mean CFRc
0.49 0.25 0.27 0.42 0.15 0.63 0.31
0.32–0.76 0.12–0.54 0.13–0.58 0.25–0.71 0.05–0.43 0.39–0.99 0.14–0.68
0.001 0.001 0.002 0.001 0.001 0.048 0.004
297
Supplementary data to this article can be found online at http:// dx.doi.org/10.1016/j.ijcard.2014.06.076.
References
OR odds ratio; CI confidence interval; LAD left anterior descending artery, LCx left circumflex artery; RCA right coronary artery; CFR coronary flow reserve. Models 1 and 2. Logistic regression with complete-case analysis adjusted for quintiles of propensity score. Model 3. Logistic regression with imputation of the missing data adjusted for quintiles of propensity score. Models 4 and 5. Sensitivity analysis only with patients who underwent Doppler evaluation of CFR before coronary angiography (N = 90). The model is based on logistic regression with imputation of the missing data adjusted for quintiles of propensity score. Models 6 and 7. Sensitivity analysis only with patients without previous myocardial infarction (N = 115). The model is based on logistic regression with imputation of the missing data adjusted for quintiles of propensity score. a Logistic regression adjusted with propensity score as continuous variable. b Odds ratio for CFR in LAD, LCx and RCA was obtained from the separate models in which CFR values were entered into the model for one artery at a time. c Mean CFR is calculated as an average value of all available CFR measurements obtained per individual patient.
In conclusion, CFR measured with transthoracic Doppler echocardiography was an independent predictor of significant CAD in any of the three coronary arteries. This inexpensive and accessible method is useful for the diagnostics of CAD.
0167-5273/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2014.06.076
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