The diameter of a normal epicardial artery is determined

Transcription

1 Coronary Hemodynamics Pressure Diameter Relationship in Human Coronary Arteries Olivier Muller, MD, PhD; Stylianos A. Pyxaras, MD; Catalina Trana MD; Fabio Mangiacapra, MD, PhD; Emanuele Barbato, MD, PhD; William Wijns, MD, PhD; Charles A. Taylor, PhD; Bernard De Bruyne, MD, PhD Background To quantify the changes in arterial dimensions after the acute changes in pressure associated with percutaneous coronary intervention (PCI). Methods and Results Forty-eight patients with one angiographically moderate-to-severe stenosis were included in the study. The pressure proximal and distal to the stenosis and the arterial diameter proximal and distal to the stenosis were measured at baseline, after intracoronary nitrates, and after stent PCI. In addition, in 8 patients distal pressure and coronary diameter were assessed while graded, controlled stenoses were created in the stented segment by progressive inflation of a balloon catheter. The mean diameter of the proximal coronary segment was 2.75±0.08 mm, 2.92±0.08 mm (+7.4%), and 3.10±0.07 mm (+14.7%) at baseline, after nitrates and after PCI, respectively (P<0.001). The mean diameter of the distal coronary segment was 2.07±0.09 mm, 2.23±0.09 mm (+9.7%), and 2.5±0.07 mm (+28.4%) at baseline, after nitrates and after PCI, respectively (P<0.001). The increase in distal diameter correlated significantly with the increase in distal pressure after PCI (r 2 =0.57; P<0.001). When graded stenoses were created, a decrease in diameter of 18±4% was observed with a pressure drop of 43±5 mm Hg. Conclusions The diameter of coronary arteries markedly varies with their distending pressure. After re-establishment of a normal distending pressure by stenting of severe coronary stenoses, a proportional increase in vessel diameter is observed. This should be taken into account when choosing the stent diameter and is an argument to discourage direct stenting. (Circ Cardiovasc Interv. 2012;5: ) Key Words: angioplasty coronary disease stenosis vasodilation The diameter of a normal epicardial artery is determined by the mass supplied by that segment and is modulated by the degree of active vasoconstriction, by the blood flowinduced shear stress and by the distension pressure. 1 3 In atherosclerotic arteries, this relation persists even though the atherosclerotic process interferes with normal physiology. 2 During percutaneous coronary intervention, the diameter of the stent is chosen to fit vessel size. These dimensions are derived from subjective analysis (eyeballing) of the angiogram, sometimes from intravascular ultrasound, rarely from quantitative coronary angiography. Even when objective metrics are used, it is difficult to predict to what extent the placement of a stent will increase the vessel size. This is particularly the case in very tight stenoses where the distension pressure is expected to increase substantially after stent placement. Not taking this phenomenon into account may lead to stent undersizing, a predictor of clinical events. 4,5 The goal of this study is to investigate the influence of acute changes in coronary pressure on the dimensions of the epicardial coronary arteries. Coronary vasomotion was offset by administration of nitrates and resting coronary blood flow was assumed to remain constant. Methods Study Sample The study sample consisted of 48 patients scheduled for elective onevessel percutaneous coronary intervention. In addition, in 8 patients distal pressure and coronary diameter were assessed while graded, controlled stenoses were created in the stented segment by progressive inflation of a balloon catheter. The wall motion was normal in all territories depending on the stenoses under study and all vessels showed a thrombolysis in myocardial infarction grade III flow. All patients signed a written informed consent form in agreement with the prescriptions of the Ethics Committee of the OLV-Ziekenhuis in Aalst. Coronary Angiography Diagnostic left heart catheterization and coronary angiography were performed by a standard percutaneous femoral approach, then a 6F guiding catheter was introduced and an angiogram was repeated in the projection allowing the best possible alignment of the target segment. The optimal angiographic projection was used for all subsequent Received May 24, 2012; accepted October 2, From the Cardiovascular Centre Aalst, OLV-Clinic, Aalst, Belgium (O.M., S.A.P., C.T., F.M., E.B., W.W., B.D.B.); HeartFlow, Inc, Redwood City, CA (C.A.T.); and Department of Bioengineering, Stanford University, Stanford, CA (C.A.T.). Correspondence to Bernard De Bruyne, MD, PhD, Cardiovascular Center Aalst, OLV Hospital, Moorselbaan, 164, B-9300 Aalst, Belgium. bernard.de.bruyne@olvz-aalst.be 2012 American Heart Association, Inc. Circ Cardiovasc Interv is available at DOI: /CIRCINTERVENTIONS

2 792 Circ Cardiovasc Interv December 2012 WHAT IS KNOWN During percutaneous coronary intervention, the choice of the material to be implanted is based on coronary angiogram. An epicardial stenosis is responsible for a lower distal pressure as compared with the proximal pressure. Thus, the distension forces of the artery are smaller distal than proximal to the stenosis. WHAT THE STUDY ADDS The article quantifies for the first time in humans the variation in diameter according to intraluminal pressure. The study shows that the diameter of atherosclerotic arteries varies by almost 30% in patients with obstructive coronary artery disease. These findings should be taken into account in the field of physiological research on coronary vessel dimensions, and more practically by interventional cardiologists to optimize the size of stents to be implanted. The data provide a strong argument against the use of direct stenting in tight stenosis. coronary arteriograms. A complete quantitative analysis was performed on an optimally filled end-diastolic image of the artery. The measurements were obtained (1) in a clearly identifiable smooth segment 1 to 2 cm proximal to the stenosis; (2) at the level of the stenosis; and (3) in a clearly identifiable angiographically smooth segment about 1 to 2 cm distal to the stenosis. For quantitative coronary angiography, a computer-based analysis system (Siemens QuantCor quantitative coronary angiography ACOM.PC 5.01, Siemens Medical Systems Inc, Malvern, PA) based on the Cardiovascular Angiography Analysis II System (Pie Medical Imaging, Maastricht, the Netherlands) was used. 6 The contrast-filled catheter was used for calibration. In our laboratory, coronary artery diameter measurements performed with the ACOM.PC 5.01 system have an interobserver variability of 0.11 mm and an intraobserver variability of 0.08 mm for mean lumen diameter on repeated analysis of the same frame. 6 Pressure Measurements After administration of intravenous heparin 100 IU/kg, a pressure monitoring guide wire (PressureWire Certus, St Jude Medical, Uppsala, Sweden) was calibrated and introduced into the guiding catheter. The sensor was advanced up to the tip of the guiding catheter, and it was verified that the pressure measured by the pressure monitoring guide wire was equal to the pressure measured by the guiding catheter. Next, the wire was manipulated into the culprit coronary artery. Proximal coronary pressure was recorded 1 or 2 cm proximal to the stenosis; distal coronary pressure was recorded 1 or 2 cm distal to the stenosis. Study Protocols Two separate study protocols were conducted in different patients. Study protocol 1 (before and after percutaneous coronary intervention) was performed in 48 patients, scheduled for percutaneous coronary intervention of an isolated stenosis. All angiographic measurements (proximal segment, stenotic segment, and distal segment), as well as the pressure measurements (proximal and distal) were obtained in the 3 following conditions: (1) at baseline; (2) 3 minutes after administration of an intracoronary bolus of 200 μg isosorbide dinitrate; and (3) 3 minutes after optimal stent placement and re-administration of an intracoronary bolus of 200 μg isosorbide dinitrate. The measurements and their timing are illustrated in Figure 1. Study protocol 2 (graded controlled coronary stenoses) was performed in 8 patients. After successful stenting of an isolated stenosis, a pressure monitoring guide wire (PressureWire Certus, St Jude Medical) was positioned in the distal part of the artery. A short semicompliant balloon catheter was positioned over the pressure wire in the stented segment; then the balloon was inflated to create a controlled pressure gradient between the pressure in the aorta (P a ) and the pressure in the distal part of the artery (P d ). The inflation pressure in the balloon was adjusted to create a moderate pressure gradient (between 10 and 25 mm Hg) and, thereafter, a severe pressure gradient and finally deflated to allow the pressure to return to its baseline value. At these 4 stages (baseline 1, moderate gradient, severe gradient, and baseline 2) distal coronary pressure and angiography-derived average vessel diameter were obtained. Statistical Analysis All analyses were performed with Graphpad Prism software, version 5 and SPSS software version 16. Summary descriptive statistics are reported as mean (SD) or counts (%), as appropriate. Continuous variables were compared between the 2 groups by independent samples t tests and categorical variables were compared with Fisher exact or χ 2 tests, as appropriate. Differences between repeated measures were analyzed with linear mixed effects models with patient as a random effect and unstructured covariance. Results Baseline Clinical and Angiographic Characteristics Mean age was 65±10 years, 66% were male and 27% were diabetic (Table 1). By design, all patients had one-vesseldisease; global and regional left ventricular ejection fractions were normal. The right coronary artery was involved in 56% of patients (Table 2). Figure 1. Schematic of the study protocol 1. At baseline, the pressure wire was used to record the coronary pressure proximal to the stenosis. Then the coronary pressure wire was advanced until the pressure sensor was located distal to the stenosis. At this stage, a coronary angiogram was performed to perform a quantitative coronary angiogram proximal and distal to the stenosis. The same data were obtained after nitrates and after stenting. Timing between these procedural steps is provided.

3 Muller et al Coronary Distensibility 793 Table 1. Clinical Characteristics of the Patient Sample Sample (n=48) Age, y 65±10 Male sex, n (%) 33 (61) Hypertension, n (%) 28 (60) Diabetes mellitus, n (%) 13 (28) Dyslipidemia, n (%) 29 (62) Active smoker, n (%) 13 (28) LVEF (%) 67±18 β-blockers, n (%) 22 (47) ACE-i/ARB, n (%) 19 (40) Aspirin, n (%) 37 (79) Clopidogrel, n (%) 36 (77) ACE-i/ARB indicates angiotensin-converting enzyme inhibitors/angiotensin receptor blockers; LVEF, left ventricular ejection fraction. Coronary Artery Diameters at Baseline, After Nitrates, and After Stent Implantation The minimal luminal diameter increased from 0.65±0.37 mm to 0.75±0.43 mm and to 2.72±0.53 mm at baseline, after nitrates and after stenting, respectively. The diameter of the proximal coronary segment was 2.75±0.08 mm, 2.92±0.08 mm (+7.4%), and 3.10±0.07 mm (+14.7%) at baseline, after nitrates, and after stent implantation, respectively (P<0.001). The diameter of the distal coronary segment was 2.07±0.09 mm, 2.23±0.09 mm (+10.5%), and 2.5±0.07 mm (+28.4%) at baseline, after nitrates, and after stent implantation, respectively (P<0.001, Table 3 and Figure 2A). Coronary Artery Pressure There were no significant changes in coronary pressure in the proximal segment at baseline, after nitrates, and after stent implantation (94±2.3 mm Hg, 88.4±1.9 mm Hg, and 96.3±2.8 mm Hg, respectively, P=0.309, Figure 2B). In contrast, coronary pressure in the distal segment was significantly lower both at baseline and after nitrates than after stent implantation (59.7±2.9 mm Hg, 56.6±2.8 mm Hg, and 89.6±2.2 mm Hg, respectively, P<0.001, Figure 2B). Table 2. Angiographic and Procedural Characteristics of the Patient Sample Coronary artery involved Sample (n=48) LAD, n (%) 14 (29) LCx, n (%) 7 (15) RCA, n (%) 27 (56) Stent diameter, mm 3.2±0.5 Stent length, mm 19±5 Deployment pressure, atm 15±3 Percentage diameter stenosis pre-pci 73±16 Percentage diameter stenosis post-pci 10±8 LAD indicates left anterior descending; LCx, left circumflex; RCA, right coronary artery; and PCI, percutaneous coronary intervention. Table 3. Coronary Artery Diameters and Pressures Proximal and Distal to the Stenosis at Baseline, After Nitrates, and After Stent Implantation Proximal segment QCA, mm Coronary Pressure, mm Hg Baseline, mm 2.75±0.08* 94±2.3 After nitrates, mm 2.92±0.08* 88.4±1.9 After stent implantation, mm 3.10±0.07* 96.3±2.8 Distal segment Baseline, mm 2.07±0.09* 59.7±2.9* After nitrates, mm 2.23±0.09* 56.6±2.8* After stent implantation, mm 2.5±0.07* 89.6±2.2* QCA indicates quantitative coronary angiography. *P< Indicates nonsignificant. Minimal Luminal Diameter and Changes in Coronary Artery Diameter There was no correlation between the percent increase in proximal diameter (between postnitrates and poststenting) and minimal luminal diameter (r²=0.046, P=0.15). In contrast, there was a significant exponential relationship between the increase in distal diameter (between postnitrates and poststenting) and the increase in minimal luminal diameter (r 2 =0.57, P=0.0003). The more severe the initial stenosis, the larger the expected increase in distal diameter (Figure 3A). As shown in Figure 3B, arteries with an minimal luminal diameter of <0.46 mm showed a mean increase in distal diameter of 30.7% (between postnitrates and poststent). Distal Pressure and Changes in Coronary Artery Diameters There was no significant relationship between the increase in distal pressure and the changes in proximal diameter (r 2 =0.004; P=0.65). In contrast, there was a significant correlation between the increase in distal pressure after stenting and the changes in distal diameter (Figure 4A). The larger the increase in distension pressure, the larger the change in diameter. As shown in Figure 4B, there is a gradual increase in distal segment diameter with gradual increase of distal segment pressure. Graded, Controlled Coronary Stenoses and Arterial Diameter As shown in Table 4 and Figure 5, moderate stenoses associated with a mean pressure of 73±5 mm Hg did not induce a significant change in coronary diameter. However, severe stenoses associated with a mean pressure of 48±5 mm Hg did induce a decrease in arterial diameter of 2.1±0.7 mm (P<0.001). After release of the stenosis by deflation of the balloon catheter, vessel diameter returned to the baseline value. Discussion The present study investigates the influence of distension pressure on the diameter of atherosclerotic coronary arteries before and immediately after stenting by direct intracoronary pressure measurements. The results indicate that, after suppression of coronary vasomotor tone, the brisk increase in coronary pressure associated with stenting is associated with

4 794 Circ Cardiovasc Interv December 2012 % increase in diameter Proximal Segment Distal Segment 10.5% 7.4% 28.4% 14.7% % changes in pressure Proximal Segment Distal Segment Figure 2. Percent increase in coronary artery diameter (left) and pressure (right) proximal and distal to the stenosis. 0 Baseline Nitrates After stent 0-20 Baseline Nitrates Post Stent a proportional increase in the diameter of the distal part of the coronary arteries. In severe stenoses, this increase in diameter reaches almost one third of the initial diameter. The data identify and assess the role of distension pressure as one of the main mechanisms modulating the dimensions of epicardial arteries. Practically, the present data indicate that, in case of tight coronary stenoses, it is difficult to predict the exact size that the vessel will reach after stenting. Therefore, it is preferable to perform precise sizing of the artery and thus of the stent to be implanted after balloon predilatation of the stenosis and reassessment of the vessel size after restoration of a normal or near normal distension pressure. This is of particular importance when evaluating new generations of bioabsorbable coronary scaffolding systems. 7 Blood flow to tissue, including the myocardium, is proportional to mass through a power-law relationship. 8 Because blood vessels adapt to the amount of flow they carry, the diameter of epicardial arteries adapts according to the mass of myocardium to be supplied. An everyday observation is that the diameter of the proximal part of a vessel is larger than the distal part because the mass to be perfused is larger. In normal arteries, the diameter is related to mass perfused at the second power. In patients with coronary atherosclerosis, this relation is maintained but skewed suggesting that the increase in mass is not associated with the same increase in diameter as in normals. 2 Also, when myocardial mass increases as is the case in left ventricular hypertrophy, this is associated with a larger diameter of the epicardial arteries. 9 After aortic valve replacement, when left ventricular hypertrophy regresses, a decrease in the epicardial arterial size has been documented. 1 Autoregulation of wall shear stress provides the mechanisms to explain an observed power-law flow diameter relationship. 10 Blood vessels adapt to changes in flow within weeks. 11 In addition, to these flow-mediated structural alterations, shear stress plays a role in acute changes in diameter related through vasomotor tone. 12,13 The present data indicate and quantify the importance of distension pressure in the diameter of the coronary arteries. By selecting patients with normal wall motion in the territory supplied by the stenosis under study, one can assume that the resting flow and therefore the shear stress remained relatively constant. Several animal studies on the relationship between coronary flow and myocardial function indicated that a reduction in resting perfusion flow was almost immediately paralleled by a decrease in wall thickening. 14 One can therefore imply that normal wall motion is subtended by normal resting flow. Vasomotor tone was Figure 3. A, Correlation between the percentage increase in pressure (mm Hg) and percentage increase in diameter (mm) in the distal segment after stent implantation. B, There is a gradual increase in distal coronary artery diameter between the first tertile and third tertile of percentage increase in pressure in the distal segment.

5 Muller et al Coronary Distensibility 795 Figure 4. A, Correlation between the severity of the lesion as measured by minimal luminal diameter (mm) and the % increase in diameter (mm) after stent implantation (r 2 =0.55, P<0.05) in the distal segment. B, Correlation between the percentage increase in pressure (mm Hg) and percentage increase in diameter (mm) in the distal segment after stent implantation. abolished by the administration of nitrates, and therefore the response of the artery was passive and controlled by pressure. This is corroborated in the present study by the increase in diameter proportional with the increasing coronary pressure. Limitations A number of limitations should be taken into account. It is assumed that coronary resting blood flow was normal and thus equally influenced the proximal and the distal segment. Because resting left ventricular wall motion was normal, it is likely that coronary blood flow was not significantly decreased given the tight relation between subendocardial perfusion and wall thickening observed in conscious dogs. 15 Yet, because flow velocity was not measured this cannot be verified in this clinical setting. Data obtained in patients with an isolated stenosis in the proximal left anterior descending showed that left ventricular wall motion and positron emission tomography-derived myocardial perfusion remained normal despite distal pressures as low as 50 mm Hg (De Bruyne, unpublished observations). This is in agreement with data Table 4. Individual Data of Distal Coronary Pressure and Changes in Diameter of the Distal Coronary Artery in 8 Patients in Whom Controlled, Graded Coronary Stenoses Were Created by Progressive Balloon Inflation Baseline Moderate Decrease in P d Severe Decrease in P d Post-Balloon Deflation P d Δdiam,% P d Δdiam,% P d Δdiam, % P d Δdiam, % Patient Patient Patient Patient Patient Patient Patient Patient Δdiam, % indicates percent change in coronary artery diameter; and P d indicates coronary pressure distal to the induced stenosis. obtained in conscious dogs. Also, some tethering effect of the stented segment on the adjacent segment may be partially responsible for the increase in diameter of the artery. This mechanism is suggested by the fact that the diameter of the proximal segment further increases after stenting. Finally, in the present setting, it cannot be excluded that transient hyperemic episodes (contrast medium and transient balloon coronary occlusions) may be responsible for some flowmediated vasodilation. The latter is known to peak 1 or 2 minutes after maximal hyperemia and to persist when coronary blood flow has already returned to baseline values. 3 Yet, the relative and much larger increase in diameter of the distal segment compared with the proximal segment suggests that it is mainly driven by an increase in distending pressure. Finally, all patients had atherosclerosis. It is therefore likely that the effect of pressure on arterial diameter would have been more pronounced in strictly normal arteries. In contrast, none of the patients showed heavy calcification and it is likely that in these patients the effects of pressure on coronary diameter would have been less pronounced or absent. Clinical Implications The main practical implication of the present findings is that the optimal dimension of a stent should be chosen after reestablishment of the distal coronary pressure ie, after balloon predilation. The more severe the stenosis, the lower the distal pressure and the larger the underestimation will be of the poststent diameter. This might suggest an added value for self-expanding stents in acute coronary syndromes which are most often associated with very tight lesions. These results should also be taken into account when evaluating bioabsorbable scaffolds. After disappearance of the scaffolding properties, the segment likely recovers its normal compliance and can therefore be significantly influenced by the systemic pressure. Finally, these changes in vessel dimensions after reestablishment of the distal pressure should be accounted for when poststent fractional flow reserve is predicted by coronary computed tomography angiography based computational flow dynamics. 16

6 796 Circ Cardiovasc Interv December 2012 Figure 5. A, A schematic representation of graded controlled stenosis induced by inflation of a compliant balloon catheter in the stented segment. A typical example of the pressure recordings proximal and distal to the stenosis is shown in the (B). C, Percent changes in coronary artery diameter of the segment distal to the stenosis. Conclusions Variations in the intracoronary distending pressure have a significant impact on defining diameter changes in epicardial vasculature. Furthermore, an increase in vessel diameter is observed after re-establishment of a normal distending pressure by stenting of tight coronary stenoses. These findings should be considered for proper stent sizing and is an argument to discourage direct stenting. None. Disclosures References 1. Villari B, Hess OM, Meier C, Pucillo A, Gaglione A, Turina M, Krayenbuehl HP. Regression of coronary artery dimensions after successful aortic valve replacement. Circulation. 1992;85: Seiler C, Kirkeeide RL, Gould KL. Basic structure-function relations of the epicardial coronary vascular tree. Basis of quantitative coronary arteriography for diffuse coronary artery disease. Circulation. 1992;85: Hintze TH, Vatner SF. Reactive dilation of large coronary arteries in conscious dogs. Circ Res. 1984;54: Cook S, Windecker S. Early stent thrombosis: past, present, and future. Circulation. 2009;119: van Werkum JW, Heestermans AA, Zomer AC, Kelder JC, Suttorp MJ, Rensing BJ, Koolen JJ, Brueren BR, Dambrink JH, Hautvast RW, Verheugt FW, ten Berg JM. Predictors of coronary stent thrombosis: the Dutch Stent Thrombosis Registry. J Am Coll Cardiol. 2009;53: Hamilos M, Muller O, Cuisset T, Ntalianis A, Chlouverakis G, Sarno G, Nelis O, Bartunek J, Vanderheyden M, Wyffels E, Barbato E, Heyndrickx GR, Wijns W, De Bruyne B. Long-term clinical outcome after fractional flow reserve-guided treatment in patients with angiographically equivocal left main coronary artery stenosis. Circulation. 2009;120: Serruys PW, Onuma Y, Ormiston JA, de Bruyne B, Regar E, Dudek D, Thuesen L, Smits PC, Chevalier B, McClean D, Koolen J, Windecker S, Whitbourn R, Meredith I, Dorange C, Veldhof S, Miquel-Hebert K, Rapoza R, García-García HM. Evaluation of the second generation of a bioresorbable everolimus drug-eluting vascular scaffold for treatment of de novo coronary artery stenosis: six-month clinical and imaging outcomes. Circulation. 2010;122: Choy JS, Kassab GS. Scaling of myocardial mass to flow and morphometry of coronary arteries. J Appl Physiol. 2008;104: Villari B, Hess OM, Moccetti D, Vassalli G, Krayenbuehl HP. Effect of progression of left ventricular hypertrophy on coronary artery dimensions in aortic valve disease. J Am Coll Cardiol. 1992;20: Kamiya A, Togawa T. Adaptive regulation of wall shear stress to flow change in the canine carotid artery. Am J Physiol. 1980;239:H14 H Zarins CK, Zatina MA, Giddens DP, Ku DN, Glagov S. Shear stress regulation of artery lumen diameter in experimental atherogenesis. J Vasc Surg. 1987;5: Hamilos M, Sarma J, Ostojic M, Cuisset T, Sarno G, Melikian N, Ntalianis A, Muller O, Barbato E, Beleslin B, Sagic D, De Bruyne B, Bartunek J, Wijns W. Interference of drug-eluting stents with endothelium-dependent coronary vasomotion: evidence for device-specific responses. Circ Cardiovasc Interv. 2008;1: Davies PF, Dewey CF, Jr, Bussolari SR, Gordon EJ, Gimbrone MA, Jr. Influence of hemodynamic forces on vascular endothelial function. In vitro studies of shear stress and pinocytosis in bovine aortic cells. J Clin Invest. 1984;73: Canty JM, Jr. Coronary pressure-function and steady-state pressureflow relations during autoregulation in the unanesthetized dog. Circ Res. 1988;63: Canty JM, Jr, Giglia J, Kandath D. Effect of tachycardia on regional function and transmural myocardial perfusion during graded coronary pressure reduction in conscious dogs. Circulation. 1990;82: Koo BK, Erglis A, Doh JH, Daniels DV, Jegere S, Kim HS, Dunning A, DeFrance T, Lansky A, Leipsic J, Min JK. Diagnosis of ischemia-causing coronary stenoses by noninvasive fractional flow reserve computed from coronary computed tomographic angiograms. Results from the prospective multicenter DISCOVER-FLOW (Diagnosis of Ischemia-Causing Stenoses Obtained Via Noninvasive Fractional Flow Reserve) study. J Am Coll Cardiol. 2011;58: