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. Author manuscript; available in PMC: 2009 Jul 28.
Published in final edited form as: J Nucl Cardiol. 2007;14(5):688–697. doi: 10.1016/j.nuclcard.2007.06.120

Diagnostic Value of PET-Measured Heterogeneity in Myocardial Blood Flows during CPT for the Identification of Coronary Vasomotor Dysfunction

Thomas H Schindler †,*, Xiao-Li Zhang *, Gabriella Vincenti †, Leila Mhiri †, Rene Nkoulou †, Hanjoerg Just ‡, Osman Ratib †, Francois Mach †, Magnus Dahlbom *, Heinrich R Schelbert *
PMCID: PMC2716693  NIHMSID: NIHMS30258  PMID: 17826322

Abstract

Background

To evaluate the diagnostic value of a PET-measured heterogeneity in longitudinal myocardial blood flow (MBF) during cold pressor testing (CPT) and global MBF response to CPT from rest (ΔMBF) for identification of coronary vasomotor dysfunction.

Methods and Results

In 35 patients, CPT-induced alterations in epicardial luminal area were determined with quantitative angiography as reference. MBF was assessed over the whole left ventricle as global MBF, and regionally in the mid and mid-distal myocardium as MBF difference or MBF heterogeneity with 13N-ammonia and PET. The sensitivity and specifity of a longitudinal MBF difference in the identification of epicardial vasomotor dysfunction was significantly higher than the global ΔMBF to CPT, respectively (88% vs. 79% and 82% vs. 64%, p<0.05). Combining both parameters resulted in an optimal sensitivity of 100% at the expense of an intermediate specifity of 73%. The diagnostic accuracy was highest for the combined analysis, than those for the MBF difference or global ΔMBF alone (91 vs. 86% and 74%, respectively, p<0.05).

Conclusions

The combined evaluation of a CPT-induced heterogeneity in longitudinal MBF and the change in global MBF from rest may emerge as a new promising analytic approach to further optimize the identification and characterization of coronary vasomotor dysfunction.

Keywords: Blood flow, cold pressor test, coronary vasomotion, endothelium, PET

Introduction

PET-measurements of global left-ventricular (LV) myocardial blood flow (MBF) at rest and during sympathetic stimulation with cold pressor testing (CPT) are increasingly applied to assess endothelium-related coronary vasomotor function.1-8 Such non-invasively obtained information on endothelium-dependent coronary vasomotor function is considered to carry important diagnostic and prognostic information.9-12 Of particular interest are recent findings findings of the effects of medical preventive intervention on vasomotor dysfunction in the peripheral circulation in patients with acute coronary syndrome and in hypertensive postmenopausal women.13, 14 In these patients, the institution of medical therapy led to an improvement of endothelium-dependent vasomotor function, which was also associated with an improved cardiovascular outcome, but not in those individuals who failed to improve. Conceptually, primary or secondary preventive medical intervention, as regards the development and progression of coronary artery disease (CAD), could be successfully monitored according to the findings of abnormal coronary vasomotor function in response to CPT 1, 15, 16 and/or to pharmacologic vasodilation.8, 17-19 Global left-ventricular (LV) MBF responses to CPT in the individual, however, may underlie some variability owing to daily temporal fluctuations of coronary circulatory (dys)function and/or inter-individual differences in hemodynamic responses to CPT.1, 3-5, 20-23 Thus, although group responses of global LV MBFs to CPT in persons with coronary risk factors are commonly reduced, a clear identification of coronary vasomotor dysfunction in the individual person sometimes may remain uncertain.

Emerging evidence suggests that the assessment of a longitudinal, base-to-apex decrease in myocardial perfusion or MBF during pharmacologically-stimulated hyperemia or during CPT may identify an impairment of flow-mediated and, thus, endothelium-dependent coronary vasodilation.24-27 With this in mind, we hypothesized that, apart from the conventional evaluation of CPT-induced change in global MBF (ΔMBF to CPT), the additional analysis of a heterogeneity in longitudinal MBF during sympathetic stress27 could further improve the non-invasive identification of coronary vasomotor dysfunction.

Accordingly, we aimed to determine the diagnostic value of a PET-measured heterogeneity in longitudinal MBF during CPT and the global ΔMBF to CPT for the identification of coronary vasomotor dysfunction in individuals with coronary risk factors but with normal coronary angiograms.

Methods

Patient Population

Thirty-five patients (men 12, women 23; mean age 57±9 years) without angiographic evidence for coronary artery disease (CAD) were studied (Table 1). They were classified into two groups according to presence or absence of various coronary risk factors. Twenty-five study participants with coronary risk factors were assigned to the “at risk” group, while eleven age-matched healthy individuals without traditional coronary risk factors served as control group. In the “at-risk” group, 10 pts. had hypertension (≥140/90 mmHg), eight had hypercholesterolemia (total cholesterol ≥240mg/dL; LDL cholesterol ≥ 160 mg/dL), and six were chronic smokers (>10 pack-years). Quantitative coronary angiography (QCA) at baseline and during CPT to establish flow-mediated vasoreactivity of epicardial coronary artery was performed as described previously.28 Within 20 days of coronary angiography, regional MBF at rest and in response to CPT was measured in each participant in ml/g/min with 13N-ammonia and PET.2, 29 All study participants had normal wall motion on angiographic evaluation. Each patient was screened by a complete history, physical examination, and blood chemistry. Exclusion criteria included a history of cardiovascular, liver, renal, endocrine or inflammatory disease. Only individuals not on vasoactive medication, such as angiotensin-converting enzyme inhibitors, calcium channel blockers, or statins were recruited. All smokers refrained from smoking ≥12 hours before QCA and PET studies, respectively. Routine blood chemistry analysis included total cholesterol, HDL and LDL cholesterol, very LDL cholesterol, triglycerides and glucose. The study was approved by the local Ethics Committee of the University of Freiburg, and written, informed consent was obtained from all individuals.

Table 1. Characteristics of Study population.

Control Group At-Risk Group
Number, n 11 24
Age (years) 58±7 57±10
Sex (F/M) 7/4 16/8
Body mass index (kg/m2) 24±4 25±3
Hypertension 0 10
Hypercholesterolemia 0 8
Smoking 0 6
Fasting plasma concentrations
Total cholesterol (mg/dl) 164±33 222±35*
LDL cholesterol (mg/dl) 96±25 152±25*
HDL cholesterol (mg/dl) 56±9 52±13
Triglycerides (mg/dl) 120±30 138±50*
Glucose (mg/dl) 86±6 98±14
Epicardial LA (mm2)
At rest 5.2±1.3 5.5±1.1
During CPT 6.1±1.0 4.5±0.9*
Δ Change to CPT 0.88±0.36 -1.02±0.85*
Global MBF (ml/g/min)
At rest 0.61±0.17 0.57±0.13
During CPT 0.90±0.16 0.63±0.25*
Δ Change to CPT 0.29±0.10 0.05±0.21*
MBF Difference (ml/g/min)
At rest 0.001±0.05 0.001±0.07
During CPT 0.05±0.02 0.15±0.08*
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Values are mean ± SD; HDL, high density lipoprotein; LDL, low density lipoprotein.

*

<0.0001 vs. control group

Quantitative Coronary Angiography

All patients underwent routine diagnostic coronary angiography for evaluation of chest pain using a biplane, isocentrique multidirectional digital angiographic system (BICOR-HICOR, Siemens, Erlangen, Germany).28 End-diastolic images of coronary arteries were evaluated quantitatively with automatic contour detection as described previously.28 In all individuals with normal coronary angiograms, as defined by smooth luminal surface of the coronary vessel without diffuse diameter reduction or stenoses, quantitative measurements were performed biplane in a selected, distinct 4- to 8-mm-long, relatively straight proximal left anterior descending coronary artery (LAD) segment (n=18) or left circumflex coronary artery (LCx) segment (n=17). Estimation of the luminal area assumed an elliptical shape at baseline and during CPT.28, 30 Calculation of the radiological magnification factor of the measured segment was used for scaling of the data from pixels to millimetres.28 Thus, the epicardial luminal area (LA) was determined at baseline and during CPT and the epicardial vasomotor response quantified.

Evaluation and Measurement of MBF

Positron Emission Tomography

MBF was measured noninvasively by using intravenous 13N–ammonia, serial image acquisition with PET (ECAT EXACT HR +, CTI / Siemens) and a two- compartment tracer kinetic model, as described previously.29 Transmission images were recorded first for 20 minutes. Beginning with each intravenous 13N-ammonia injection (555-740 MBq), serial transaxial, attenuation-corrected images were acquired for 19 min (16 frames: 12×10s, 2×30s, 1×60s, 1×15 min). MBF measurements were performed at baseline and during CPT. For the CPT, study participants immersed the left hand in ice water for 60 seconds, 13N-ammonia was injected again while CPT continued for another 60 seconds. Between MBF measurements, 45 minutes were allowed for physical decay of 13N-ammonia. From the last 15-min transaxial image, reoriented short- and long-axis myocardial slices and the corresponding polar map were submitted to visual and semi-quantitative analysis.2 The inter- and intraobserver reproducibility of PET-measured MBFs at rest and during CPT have been reported recently.31, 32 Heart rate (HR), blood pressure (BP), and a 12-lead ECG were recorded continuously during each MBF measurement. From the average of HR and BP during the first 2 minutes of each image acquisition, the rate pressure product (RPP) was determined as an index of cardiac work.

Quantitative Evaluation of Myocardial Blood Flow

On the polar map of the last 15 min image set, regions of interest (ROI) were assigned to myocardial territories of the three coronary arteries (Fig. 1). As also illustrated in Figure 1, two circumferential ROIs were assigned to the mid and the mid-distal portion of the LV. In addition, a 25mm2 ROI was assigned to the LV blood pool on the most basal short axis slice for deriving the arterial tracer input function. The ROIs were then copied to the serial polar maps acquired during the first 2 min after tracer injection. The time activities curves derived from these ROIs were fitted with a two-compartment tracer kinetic model and regional MBF values in ml/g/min were obtained.29 MBFs in the three coronary artery territories were averaged and mean global MBF was derived. Changes in MBF from rest to CPT were defined in ml/g/min as global ΔMBF. Further, a decrease in MBF from mid to mid-distal LV myocardium was defined as MBF difference (in ml/g/min) or heterogeneity in longitudinal MBF as indicative of a perfusion gradient.27

Fig. 1.

Fig. 1

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Schematic representation of polar maps of MBFs and assignment of regions of interest (ROI). A, three coronary artery territories; B, circumferential ROIs for mid (B) and mid-distal (A) portion of LV. LAD indicates left anterior descending; LCx, left circumflex and RCA, right coronary artery.

Data Analysis

Data are presented as mean ± SD for quantitative and absolute frequencies for qualitative variables. For comparison of differences, appropiate Wilcoxon rank sum tests for independent or paired samples were used (Statistical Analysis Software Institute, Cary, North Carolina). A comparison of CPT-induced change in global MBF and MBF difference between the different groups was performed by two-way analysis of variance (ANOVA), followed by Scheffe's multiple comparison test. Correlations between selected variables were estimated by Spearman correlation coefficients. Sensitivities, specifities, and diagnostic accuracies were calculated. All test procedures were two-sided with a p value ≤ 0.05, indicating statistical significance.

Results

Clinical Characteristics

Table 1 summarizes the characteristics of the two study groups. Total cholesterol, LDL cholesterol and triglyceride levels were significantly higher in the “at risk” group than in the control group, while HDL cholesterol tended to be lower. Glucose levels and body mass index did not differ significantly between the study groups.

Hemodynamic Parameters

Hemodynamic parameters during angiographic assessment of epicardial coronary vasomotion and during PET measurements of MBF at baseline and during CPT are listed in Table 2. The rate-pressure product (RPP; heart rate × systolic blood pressure) was used as index of cardiac work and as measure of the effectiveness of sympathetic stimulation with CPT. Heart rate and blood pressure were comparable at rest and during CPT between QCA and PET studies. CPT-induced a significant increase in heart rate, systolic and diastolic blood pressure. Consequently, the RPP increased significantly from rest to CPT. Notably, there was no significant difference between the RPP at rest and during CPT at the time of the QCA and of the PET study. In addition, when evaluating the change of the RPP during CPT from rest (ΔRPP) no significant difference was found between QCA and PET evaluation of MBF, indicating comparable myocardial workload on both study days.

Table 2. Hemodynamics in QCA and PET Studies at rest and during CPT.

QCA PET
Test Rest CPT Rest CPT
HR (bpm) 62±7 67±7* 62±7 66±7*
SBP (mmHg) 128±16 152±18* 130±15 149±16*
DBP (mmHg) 73±8 77±8* 72±7 77±7*
RPP (mmHg/min) 8096±1348 10183±1574* 8056±1380 9880±1476*
ΔRPP 2086±778* 1823±1012*
MAP (mmHg) 92±9 102±9* 91±9 101±8*
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*

p≤0.0001, CPT vs. rest for each corresponding hemodynamic parameter in QCA and PET study evaluation, respectively. P=NS, for each corresponding hemodynamic parameter between QCA and PET study evaluation. HR, heart rate (beat per minute); SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, mean arterial blood pressure; RPP, rate- pressure product (heart rate × systolic blood pressure, bpm × mmHg); ΔRPP, change of RPP from rest to CPT. Values are mean ± SD.

Findings on Quantitative Angiography

Table 1 denotes the mean changes of epicardial luminal area (LA) to CPT in the control group and in the “at risk” group. At baseline, the mean epicardial LA did not differ significantly between both groups. In the “at risk” group, the LA abnormally decreased from 5.5±1.1 to 4.5±0.9 mm2 by CPT (p<0.0001), reflecting a mean change in LA (ΔLA) of -1.02±0.85 mm2. Conversely, normal controls showed a significant flow-mediated increase of LA from 5.2±1.3 to 6.1±1.0 mm2 (p<0.0001), that represented a mean ΔLA of 0.88±0.36 mm2. The group comparison of a CPT-induced decrease of mean LA in the “at risk” group was significant when compared with blood flow-mediated increase of the mean LA in the control group (p<0.0001 by ANOVA).

MBF Response to CPT

Quantitative assessment of global MBF at rest was comparable between both study groups (Table 1). Global MBF during CPT in the “at risk” group was significantly lower than in the control group. Thus, the change of mean MBF to CPT from rest (ΔMBF) was significantly impaired in the “at risk” group when compared to the control group (Table 1). The group comparison of ΔMBF to CPT in the at “at-risk” group was significant when compared with the control group (p≤0.0001 by ANOVA).

The comparison of regional MBFs at rest in the mid and mid-distal direction demonstrated similar values for the mid and mid-distal LV sections in both groups (Controls: 0.64±0.15 and 0.62±0.16 ml/g/min and at risk: 0.61±0.11 and 0.61±0.14 ml/g/min; P=NS, respectively) (Fig. 2). In the control group, CPT induced a homogeneous increase in MBF with comparable mid and mid-distal LV MBFs (0.89±0.16 and 0.92±0.15 ml/g/min, p=NS) (Fig. 2). In the “at risk”, however, the MBF response to CPT in the mid LV was significantly lower as those in the control group (p<0.001). Moreover, sympathetic stimulation with CPT resulted in MBF heterogeneities in the “at risk” group. MBF increased to 0.77±0.24 ml/g/min in the mid LV myocardium, but only to 0.62±0.24 ml/g/min in the mid-distal LV myocardium (Fig. 2). This resulted in a MBF difference of 0.15±0.08 ml/g/min during CPT between the mid and mid-distal LV myocardium (Table 1). No such difference between the mid and mid-distal LV MBF was observed in the control group (0.05±0.02 ml/g/min, p=NS) (Table 1). The group comparison of the CPT-induced MBF difference between the “at risk” and control group was significantly different (p<0.0001 by ANOVA). Moreover, the CPT-induced MBF differences in the 2 coronary territories supplied by the vessel not evaluated on quantitative angiography in the “at risk” group were similar to the MBF differences in coronary territories subtended by coronary vessels and submitted to quantitative analysis. The MBF differences during CPT were comparable (0.13±0.12 vs. 0.15±0.08 ml/g/min; p=NS), suggesting that the MBF difference in “at risk” individuals to occur homogenously in the entire coronary circulation.

Fig. 2.

Fig. 2

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MBFs at rest and during CPT mid and mid-distal portions of the LV myocardium for the two study groups.

Correlation between CPT-induced Changes in Epicardial LA and MBF gradient

In order to evaluate a possible association between CPT-induced alterations of the epicardial artery and the relative decrease in MBF from the mid to mid-distal left-ventricular myocardium, the change in epicardial LA was compared with the MBF difference during CPT. For the entire study group, there was a significant correlation between the change in epicardial LA (ΔLA) to CPT and the MBF difference during CPT between the mid and mid-distal left-ventricular myocardium (r=0.90, p<0.0001). When looking at the risk group alone, then as Fig. 3 illustrates the CPT-induced decrease in epicardial LA and the MBF gradient were also significantly correlated (r=0.77, p<0.0001). These findings emphasize that the MBF difference is indeed related to functional alterations of the epicardial conduit vessels during CPT.

Fig. 3.

Fig. 3

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Correlation between (A) MBF difference and change in LA (ΔLA) during CPT.

Diagnostic Accuracy of Global ΔMBF to CPT and the CPT-Related MBF Difference in the Detection of Coronary Vasomotor Dysfunction

The receiver-operating curve (ROC) for the detection of epicardial vasomotor dysfunction by the MBF difference during CPT and global ΔMBF to CPT yielded an optimal cutoff point of >0.071 and ≤0.216 ml/g/min, respectively. Using this ROC-defined threshold, the sensitivity, specifity, NPV, PPV and diagnostic accuracy of MBF difference during CPT, global ΔMBF to CPT and the combined analysis of both parameters for the detection of coronary vasomotor dysfunction are given in Table 3 and Fig. 4. The sensitivity of the MBF difference to identify abnormal epicardial vasomotion was significantly higher than with the change in global MBF from rest to CPT (ΔMBF) (88% vs. 79%; p<0.05) (Fig. 4), while combining both parameters resulted in an optimal sensitivity of 100%. As regards the specifity, it was high for the MBF difference and relatively low for the ΔMBF (82% vs. 64%; p<0.05). Applying both parameters resulted in an intermediate specifity of 73% that was significantly lower than for the MBF difference with 82% (p<0.05), while still higher than for the ΔMBF with 64% but non-significantly. The diagnostic accuracy of the CPT-related MBF difference for evaluation of coronary vasomotor dysfunction was non-significantly higher as compared to ΔMBF to CPT (86% vs. 74%). The combined analysis of both parameters, however, yielded the highest diagnostic accuracy, that was significantly higher than those for the MBF difference or ΔMBF alone (91% vs. 86% and 74%, p<0.05).

Table 3. Diagnostic Accuracy of PET-measured MBF Alterations during CPT in the Detection of Coronary Vasomotor Function as determined by QCA.

ΔMBF to CPT MBF Difference during CPT Combined
Sensitivity 19/24 (79%) 21/24 (88%) 24/24 (100%)
Specifity 7/11 (64%) 9/11 (82%) 8/11 (73%)
PPV 19/23 (83%) 21/23 (91%) 24/27 (88%)
NPV 7/12 (58%) 9/12 (75%) 8/8 (100%)
Diagnostic Accuracy 26/35 (74%) 30/35 (86%) 32/35 (91)
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Values are n (%). MBF, myocardial blood flow; CPT, cold pressor test

Fig. 4.

Fig. 4

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Schematic representation of the sensitivity, specifity and diagnostic accuracy of PET-measured MBF alterations during CPT in the identification of epicardial vasomotor dysfunction.

Discussion

The current study is unique in that it demonstrates a close association between CPT-induced alterations in the lumen area of the epicardial artery and a heterogenous response of regional MBF from the mid to mid-distal LV myocardium, as indicative for a MBF gradient. This finding provide direct angiographic evidence that functional alterations, such as a sympathetically-mediated paradoxical vasoconstriction of the epicardial artery, may indeed account for a heterogeneity in longitudinal MBF during CPT as also observed in previous investigations with PET.24-27 In particular, the assessment of a CPT-related heterogeneity in longitudinal MBF appears to be superior to the change in global MBF to CPT from rest (ΔMBF) in identifying coronary vasomotor dysfunction. The combined analysis of both parameters, however, yielded the highest diagnostic accuracy of the non-invasive detection of coronary vasomotor dysfunction. Thus, the additional evaluation of a heterogeneity in longitudinal MBF during CPT, apart from the conventional global ΔMBF to CPT, may emerge as another reliable parameter to optimize the identification and characterization of coronary vasomotor dysfunction.

Coronary Vasomotor Function and Heterogene ity in Longitudinal MBF

The regulation and modulation of the coronary blood flow underlies a complex metabolic and autonomic control to meet the nutrition - and oxygen-requirements of the heart.33, 34 While the epicardial coronary arteries mediate more or less a conductance function, the coronary arteriolar vessels predominantly determine the coronary vascular resistance and, thus, the increase in MBF during times of increases in metabolic oxygen demand.33 Notably, the integrity of the coronary arteriolar resistance vessels reflects an important determinant in mediating anti-atherosclerotic effects.9, 10 This is, because increases in coronary flow owing to a metabolically-induced decrease in vascular resistance of the coronary arteriolar vessels leads to a flow-mediated vasodilation via endothelium-dependent release of nitric oxide, which also implicates nitric-oxide related antithrombotic and antiatherosclerotic effects.35, 36 37 Coronary flow increases during pharmacologically-induced hyperemia or during sympathetic stimulation with CPT, therefore, may be seen as a cumulative assessment of both the epicardial coronary arteries and the coronary arteriolar resistance vessels, rather than a reflection of the role of the coronary microcirculation alone.38 Early CAD-related functional and/or structural alterations of the arterial wall, however, may disturb the flow-mediated coronary vasodilatory capacity.33, 38 In regard of the latter, diffuse luminal narrowing and/or functional alterations of the epicardial coronary arteries,24, 26, 39 associated with an impairment of flow-mediated coronary vasodilatory function, have been proposed to account for a previously observed longitudinal, base-to-apex myocardial perfusion gradient or a heterogeneity in left-ventricular MBF during pharmacologically-stimulated hyperemia in patients with diffuse CAD or with coronary risk factors.19, 24, 26, 40 The mechanism underlying a MBF heterogeneity during hyperemic flow increases may be best described by the Hagen-Poiseuille equation.26, 39, 41 According to the latter, the resistance to flow depends on the length of the tube, the flow velocity and, importantly, inversely on the fourth power of the vessel diameter.24, 41 Normally, increases in intracoronary flow velocity induce a flow-mediated vasodilation of the coronary artery that compensates for the velocity-related increase in coronary resistance in order to keep the resistance low.42, 43 Conversely, an impairment of the flow-mediated vasodilation, due to presence of endothelial dysfunction and/or CAD-induced diffuse epicardial luminal narrowing, may impede the coronary artery to dilate during higher coronary flows.30, 43 As coronary angiographic investigations have shown,39 an impairment of a flow-mediated coronary vasodilation leads to an increases in intravascular resistance during hyperemic flows with a progressive decline in intracoronary pressure along the coronary artery. This progressive proximal to distal decline in intracoronary pressure during hyperemic coronary flow increases39 has been put forward as cause for the perfusion or MBF heterogeneity during pharmacologic vasodilation.24, 26, 39 Direct confirmation through comparative studies between PET flow measurements and quantitative angiography are still missing or are incomplete. A Recently performed investigation24 provides some first evidence of an association between the manifestation of a myocardial perfusion heterogeneity during dipyridamole-stimulated flow increases and the presence of CAD-induced diffuse arterial narrowing. As current study and recent investigations demonstrate,27 a heterogeneity in longitudinal MBF may also occur during sympathetic stimulation with CPT in individuals with coronary risk factors. Importantly, the current observations indicate that a heterogeneity in longitudinal MBF during CPT is indeed related to sympathetically-mediated functional alterations of the epicardial artery. Thus, these findings and previous investigations19, 24, 26, 27 support the evolving concept, as raised first by Gould et al.,24 that the assessment of a myocardial perfusion gradient and/or a longitudinal heterogeneity in MBF by means of PET could serve as an important tool to noninvasively identify early functional and/or structural alterations of the epicardial coronary artery.24, 26, 27, 40 Such a non-invasive measure of early stages of the development of CAD may also provide important predictive information on future cardiovascular events.18, 19

The endothelium-related global ΔMBF to CPT in healthy individuals have been reported to range between 30 and 50% and, thus, reveal some variability.1-5 The reason for this variability is uncertain and may be related to differences in daily temporal fluctuations of coronary circulatory (dys)function and/or inter-individual differences in hemodynamic responses to CPT.1, 3-5, 20-23, 44 Further, there is also an intrinsic variability of the severity of endothelium-dependent vasomotor dysfunction in the individual, despite the presence of similar risk profile, which has to be taken into consideration.11, 37 Another explanation is that, the extent of a diminished global MBF response to CPT, as indicative for coronary endothelial dysfunction,45 is also determined by a α-adrenergically-mediated constriction of the vascular smooth muscle cells, which is closely related to the degree of sympathetic stimulation during CPT as reported recently.27 Thus, interindividual differences in sympathetic stimulation of the vascular smooth muscle cells are likely to add some variability to the abnormal global MBF responses during CPT. Notably, the assessment of a heterogeneity in longitudinal MBF during pharmacologically-stimulated hyperemia or during CPT may evolve as another promising quantitative index to identify an impairment of flow-mediated and, thus, endothelium-dependent coronary vasodilation.26, 27 Such an approach might also overcome the aferomentioned limitations of the evaluation of the global ΔMBF to CPT and, thereby, could lead to a further improvement in the diagnostic accuracy of the detection of coronary vasomotor dysfunction. Tresholds for a heterogeneity in longitudinal MBF during CPT and a diminished increase in global ΔMBF to CPT were derived from a ROC analysis and validated in this group of patients who underwent coronary angiography within 20 days before the PET study. In this validation study, abnormal endothelium-dependent vasomotion was defined as an absent vasodilation or vasoconstriction of the epicardial artery during CPT.30, 46 Such an impairment of epicardial vasomotor function during CPT has been demonstrated to extent to the site of the coronary arteriolar resistance vessels.1, 3, 5 Using the epicardial vasomotor response to CPT as reference, we performed a ROC-analysis to define the optimal treshold for the identification of coronary vasomotor dysfunction by a heterogeneity in longitudinal MBF during CPT and the global ΔMBF to CPT. Relying exclusively on the heterogeneity in longitudinal MBF during CPT and on CPT-induced global ΔMBF with a ROC-defined treshold of >0.071 and ≤0.216 ml/g/min, respectively, to distinguish between abnormal and normal coronary vasomotor function. Using these tresholds, the sensitivity and specifity of the MBF heterogeneity during CPT were significantly higher as compared to the global ΔMBF to CPT (88% vs. 79% and 82% vs. 64%, respectively). This also resulted in a higher diagnostic accuracy to detect coronary vasomotor dysfunction with 86% for the heterogeneity in longitudinal MBF as compared to 74% of global ΔMBF to CPT. Furthermore, when we integrated both quantitative measures from the PET flow study, considering the vasomotor abnormality to be significant when detected on one of the two approaches, the diagnostic accuracy was significantly increased to 91%. In this regard, the sensitivity increased to 100% on the expense of a lower specifity of 73%. Thus, the current results indicate that the assessment of a heterogeneity in longitudinal MBF may be more sensitive in identifying coronary vasomotor dysfunction than the global ΔMBF to CPT. Nevertheless, the combined analysis of both parameters yielded the highest accuracy in the evaluation of coronary vasomotor function than the separate analysis of the MBF heterogeneity during CPT or the global MBF response to CPT. It follows then, that combining both quantitative measures of endothelium-related changes in MBF to CPT could be the preferred approach in the evaluation of coronary vasomotor function.

Limitations

There are shortcomings of the current study worthy to be considered in the interpretation of the data. First, coronary intravascular ultrasound was not employed in the current study protocol. Thus, we cannot rule out the presence of CAD-induced structural alterations of the arterial wall 24 that might have contributed to the manifestation of the MBF heterogeneity during CPT. Second, because the sample size of the study population was relatively small, larger prospective investigations in patients without or with diffuse CAD are desirable to draw more definite conclusions. Finally, as we did not assess the hyperemic MBF increases to pharmacologic vasodilation, which is clinically more widely used, further prospective angiographic studies are necessary to investigate the diagnostic accuracy of the heterogeneity in longitudinal MBF during pharmacologic vasodilation to identify an impairment of flow-mediated coronary vasomotor function.

Conclusions

While the assessment of a heterogeneity in longitudinal MBF during CPT appears to be more sensitive than the CPT-induced change in global MBF in identifying coronary vasomotor dysfunction, the combined analysis of both parameters yields the highest diagnostic accuracy of the non-invasive evaluation of coronary vasomotor function. Combining both quantitative measures of MBF responses to CPT may emerge as a new promising analytic approach to further optimize the non-invasive identification and characterization of coronary vasomotor dysfunction.

Acknowledgments

The authors are indebted to the nurses of the Cardiac Catheterization and PET-Cyclotron Unit of the Albert Ludwig University, Freiburg, for their invaluable support.

Research Grants: This work was supported in part by NIH grant HL 33177 from the National Heart, Lung and Blood Institute and by a grant from the government of Baden-Wuerttemberg for the “Center of Clinical Research II: Cardiovascular Diseases: Analysis and Integration of Form and Function” at the Albert-Ludwig-University Freiburg (Project THS - A1/A2).

Footnotes

Conflict of interest disclosure: The authors do not have any conflict of interest to disclose.

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References

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