Myocardial blood flow in patients with dilated cardiomyopathy: quantitative assessment with velocity-encoded cine magnetic resonance imaging of the coronary sinus

PURPOSE: To quantify global myocardial perfusion using magnetic resonance imaging (MRI) in patients with heart failure due to idiopathic dilated cardiomyopathy (IDC) and to compare myocardial perfusion and microvascular reactivity with healthy subjects. MATERIALS AND METHODS: A total of 19 subjects (healthy volunteers (N = 12) and IDC patients (N = 7)) were studied using cine MRI to measure left ventricular (LV) mass and a velocity-encoded cine MRI technique to measure coronary sinus flow at rest and after dipyridamole-induced hyperemia. Absolute values of total myocardial blood flow (MBF) were calculated from coronary sinus flow and LV mass. RESULTS: At baseline, MBF was not significantly different in patients with IDC (0.48 +/- 0.07 mL/minute/g) and healthy subjects (0.55 +/- 0.19 mL/minute/g, P= 0.41). After dipyridamole administration, MBF in IDC patients increased to a level significantly less than that in normal volunteers (1.05 +/- 0.35 mL/minute/g vs. 1.99 +/- 1.05 mL/minute/g, P < 0.05). Consequently, MBF reserve was impaired in patients with IDC (2.19 +/- 0.77) compared to that in healthy subjects (3.51 +/- 1.29, P < 0.05). A moderate correlation was found between MBF reserve and LV ejection fraction (r = 0.48, P < 0.05). CONCLUSION: MBF reserve is reduced in patients with IDC, indicating that coronary microcirculatory flow is impaired. This integrated MRI approach allows quantitative measurement of global MBF in humans and may have the potential to study the effects of pharmacological interventions on myocardial perfusion.     

Assessment of the reproducibility of baseline and hyperemic myocardial blood flow measurements with 15O-labeled water and PET.

PET with 15O-labeled water allows noninvasive quantification of myocardial blood flow (MBF) at baseline and during pharmacologically induced hyperemia to assess the coronary vasodilator reserve (CVR = hyperemic/baseline MBF). Despite widespread use of PET, its reproducibility during one study session has not been tested. Intravenous adenosine (Ado), a powerful coronary vasodilator with a very short decay time, is commonly used for the induction of hyperemia. However, it is not known whether Ado can induce tachyphylaxis after short-term repetitive administration. In this study, we aimed to test the reproducibility of PET assessment of CVR during Ado-induced hyperemia. METHODS: In 21 healthy volunteer men, baseline and Ado MBF were measured twice using PET with 15O-labeled water to obtain two CVR assessments within 1 h. RESULTS: There was no significant difference between the two baselines (0.89 +/- 0.14 versus 0.99 +/- 0.15 mL/min/g, mean difference 13% +/- 11%) or between the two hyperemic MBFs (3.51 +/- 0.45 versus 3.83 +/- 0.49 mL/min/g, mean difference 10% +/- 14%), resulting in comparable values of CVR (4.05 +/- 0.75 versus 3.93 +/- 0.72, mean difference 2% +/- 15%). The repeatability coefficient for MBF was 0.17 mL/min/g at baseline and 0.94 mL/min/g during hyperemia. The repeatability coefficient of the rate pressure product (RPP) was lower at baseline (1,304 mm Hg x beat/min) than during hyperemia (3,448 mm Hg x beat/min). CONCLUSION: Repeated measurements of MBF and CVR during the same study session were not significantly different, demonstrating the validity of the technique. The larger variability of hyperemic flow, as indicated by the larger repeatability coefficient, was paralleled by a greater variability of the RPP. This could mean that the greater variability of MBF during stress is more likely due to a variable response to Ado rather than to a measurement error.     

Assessment of myocardial perfusion by dynamic N-13 ammonia PET imaging: Comparison of 2 tracer kinetic models

BACKGROUND: Measurement of myocardial blood flow (MBF) by dynamic nitrogen 13 ammonia (NH(3)) positron emission tomography (PET) uses tracer kinetic modeling to analyze time-activity curves. We compared 2 commonly used models with 2 compartments (2C) and 3 compartments (3C) for quantification of MBF and coronary flow reserve (CFR). METHODS AND RESULTS: Seventy-seven patients underwent NH(3) PET at rest and during hyperemia. Time-activity curves for blood pool and myocardial segments were obtained from short-axis images of dynamic sequences. Model fitting of the 2C and 3C models was performed to estimate regional MBF. MBF values calculated by 2C and 3C models were 0.98 +/- 0.31 mL.min(-1).g(-1) and 1.11 +/- 0.37 mL.min(-1).g(-1), respectively, at rest (P < .0001) and 2.79 +/- 1.18 mL.min(-1).g(-1) and 2.46 +/- 1.02 mL.min(-1).g(-1), respectively, during hyperemia (P < .01), resulting in a CFR of 3.02 +/- 1.31 and 2.39 +/- 1.15 (P < .0001), respectively. Significant correlation was observed between the 2 models for calculation of resting MBF (r = 0.78), hyperemic MBF (r = 0.68), and CFR (r = 0.68). CONCLUSION: Measurements of MBF and CFR by 2C and 3C models are significantly related. However, quantification of MBF and CFR significantly differs between the methods. This difference needs to be considered when normal values are established or when measurements obtained with different methods need to be compared.     

Beta-adrenergic blockade and myocardial perfusion in coronary artery disease: differential effects in stenotic versus remote myocardial segments.

Beta-adrenergic blocking agents are widely used in coronary artery disease (CAD), although their impact on myocardial blood flow (MBF) and coronary flow reserve (CFR) remains unclear. We studied the effect of long-term beta-blocker treatment (carvedilol or metoprolol) on coronary microcirculation in CAD patients using PET. METHODS: Regional and global resting and adenosine-induced hyperemic MBF and CFR were measured with 13N-ammonia and PET in 36 CAD patients before and after 12 wk of oral therapy with either carvedilol, 50 mg/d, or metoprolol, 100 mg/d. RESULTS: Beta-blockade decreased global resting MBF in proportion to cardiac work (from 0.86 +/- 0.20 to 0.77 +/- 0.14 mL/min/g, P < 0.05) without affecting global hyperemic flow. Hyperemic MBF was significantly lower in stenosis-dependent segments than in remote segments (1.76 +/- 0.64 vs. 2.04 +/- 0.67 mL/min/g, P < 0.05) at baseline but was comparable in both after treatment (2.02 +/- 0.68 vs. 1.90 +/- 0.78 mL/min/g, P = not statistically significant [NS]), resulting in a significant CFR increase in stenotic segments (+15%, P < 0.05) but not in remote segments (+9%, P = NS). CONCLUSION: The beneficial effect of beta-adrenergic blockade can be explained by the reduction in oxygen consumption (= decreased demand) but also by a modest improvement in vasodilator capacity (= increased supply). The improvement in CFR is found predominantly in stenosis-dependent rather than remote segments.     

Bicycle exercise stress in PET for assessment of coronary flow reserve: repeatability and comparison with adenosine stress.

PET allows absolute measurements of myocardial blood flow (MBF). The aim of the present study was to evaluate the feasibility and repeatability of supine bicycle exercise stress, compared with standard adenosine stress, in PET. METHODS: In 11 healthy volunteers, MBF was assessed at rest, during adenosine-induced (140 microg/kg/min over 7 min) hyperemia, and immediately after supine bicycle exercise (mean workload, 130 W, which is 70% of the predicted value) using PET and (15)O-H(2)O. The assessment was then repeated after 20 min. Coronary flow reserve (CFR) was calculated as hyperemic/resting MBF for adenosine stress and exercise stress. Repeatability was evaluated according to the method of Bland and Altman. RESULTS: No significant differences were found between the paired resting MBF (1.22 +/- 0.16 vs. 1.26 +/- 0.21 mL/min/g; mean difference, 3% +/- 11%) and the hyperemic MBF with adenosine stress (5.13 +/- 0.74 vs. 4.97 +/- 1.05; mean difference, -4% +/- 14%) or exercise stress (2.35 +/- 0.66 vs. 2.25 +/- 0.61; mean difference, -4% +/- 19%). CFR was reproducible with adenosine stress (4.23 +/- 0.62 vs. 4.05 +/- 1.06, P = not statistically significant; mean difference, -5% +/- 19%) and exercise stress (1.91 +/- 0.46 vs. 1.80 +/- 0.44, P = not statistically significant; mean difference, -5% +/- 15%). Repeatability coefficients for MBF were 0.26 (rest), 1.34 (adenosine stress), and 0.82 (exercise stress) mL/min/g. CONCLUSION: Assessment of CFR with (15)O-H(2)O and PET using bicycle exercise in the PET scanner is feasible and at least as repeatable as using adenosine stress.     

Quantification of subendocardial and subepicardial blood flow using 15O-labeled water and PET: experimental validation.

The purpose of this study was to assess the feasibility and accuracy of quantifying subendocardial and subepicardial myocardial blood flow (MBF) and the relative coronary flow reserves (CFR) using (15)O-labeled water (H(2)(15)O) and 3-dimensional-only PET. METHODS: Eight pigs were scanned with H(2)(15)O and (15)O-labeled carbon monoxide (C(15)O) after partially occluding the circumflex (n = 3) or the left anterior descending (n = 5) coronary artery, both at rest and during hyperemia induced by intravenous dipyridamole. Radioactive microspheres were injected during each of the H(2)(15)O scans. RESULTS: In a total of 256 paired measurements of MBF, ranging from 0.30 to 4.46 mL.g(-1).min(-1), microsphere and PET MBF were fairly well correlated. The mean difference between the 2 methods was -0.01 +/- 0.52 mL.g(-1).min(-1) with 95% of the differences lying between the limits of agreement of -1.02 and 1.01 mL.g(-1).min(-1). CFR was significantly reduced (P < 0.05) in the ischemic subendocardium (PET = 1.12 +/- 0.45; microspheres = 1.09 +/- 0.50; P = 0.86) and subepicardium (PET = 1.2 +/- 0.35; microspheres = 1.32 +/- 0.5; P = 0.39) in comparison with remote subendocardium (PET = 1.7 +/- 0.62; microspheres = 1.64 +/- 0.61; P = 0.68) and subepicardium (PET = 1.79 +/- 0.73; microspheres = 2.19 +/- 0.86; P = 0.06). CONCLUSION: Dynamic measurements using H(2)(15)O and a 3-dimensional-only PET tomograph allow regional estimates of the transmural distribution of MBF over a wide flow range, although transmural flow differences were underestimated because of the partial-volume effect. PET subendocardial and subepicardial CFR were in good agreement with the microsphere values.     

Comparison of myocardial blood flow induced by adenosine triphosphate and dipyridamole in patients with coronary artery disease

Myocardial perfusion imaging with adenosine triphosphate (ATP) has been used increasingly to diagnose coronary artery disease (CAD) and assess risk for this disease. This study compared absolute myocardial blood flow (MBF) and myocardial flow reserve index (MFR) with ATP and dipyridamole (DIP) in patients with CAD. MBF was quantified by 15O-H2O PET in 21 patients with CAD (17 male, 4 female), aged 55 to 81 years. MBF was measured at rest, during intravenous injection of ATP (0.16 mg/kg/min), and again after DIP infusion (0.56 mg/kg). Regions of interest were drawn in nonischemic and ischemic segments based on findings from thallium-201 (201T1) scintigraphy and coronary angiography (CAG). Absolute MBF values and indexes of MFR were calculated in nonischemic and ischemic segments. Intravenous injection of ATP and DIP significantly increased MBF in nonischemic (2.4 +/- 0.9 and 2.1 +/- 0.8 ml/g/min, respectively; p < 0.01, for both) and in ischemic segments (1.3 +/- 0.4 and 1.5 +/- 0.4 ml/g/min, respectively; p < 0.01, for both). There was a significant difference in MBF values between ATP and DIP in nonischemic segments (p < 0.05), which was not observed in ischemic segments. In nonischemic segments, ATP produced higher MFR than DIP (2.1 +/- 0.8 and 1.8 +/- 0.7, respectively; p < 0.05), while no significant difference was observed in ischemic segments (1.5 +/- 0.6 and 1.7 +/- 0.3, respectively). ATP produced a greater hyperemia than DIP between the ischemic and nonischemic myocardium in patients with CAD. ATP is as effective as DIP for the diagnosis of CAD.     

Assessment of the long-term reproducibility of baseline and dobutamine-induced myocardial blood flow in patients with stable coronary artery disease.

Although physical exercise is the preferred stimulus for cardiac stress testing, pharmacologic agents are useful in patients who are unable to exercise. Previous studies have demonstrated short-term repeatability of exercise and adenosine stress, but little data exist regarding dobutamine (Dob) stress or the long-term reproducibility of pharmacologic stressors in coronary artery disease (CAD) patients. PET allows accurate, noninvasive quantification of myocardial blood flow (MBF) and coronary flow reserve (CFR). The aim of the study was to investigate the long-term reproducibility of Dob stress on MBF and CFR in CAD patients using PET. METHODS: Fifteen patients with chronic stable angina and angiographically proven CAD (>70% stenosis in at least 1 major coronary artery) underwent PET with (15)O-labeled water and Dob stress at baseline (time [t] = 0) and after 24 wk (t = 24). MBF at rest and MBF during Dob stress were calculated for the whole left ventricle, the region subtended by the most severe coronary artery stenosis (Isc), and remote myocardium subtended by arteries with minimal or no disease (Rem). Reproducibility was assessed using the Bland-Altman (BA) repeatability coefficient and was also expressed as a percentage of the mean value of the 2 measurements (%BA). RESULTS: Dob dose (30 +/- 11 vs. 031 +/- 11 microg/kg/min; P = not significant [ns]) and peak Dob rate.pressure product (20,738 +/- 3,947 vs. 20,047 +/- 3,455 mm Hg x beats/min; P = ns) were comparable at t = 0 and t = 24. There was no significant difference in resting or Dob MBF (mL/min/g) between t = 0 and t = 24 for the whole left ventricle (1.03 +/- 0.19 vs. 1.10 +/- 0.20 and 2.02 +/- 0.44 vs. 2.09 +/- 0.57; P = ns for both), Isc (1.05 +/- 0.24 vs. 1.10 +/- 0.26 and 1.79 +/- 0.53 vs. 1.84 +/- 0.62; P = ns for both), or Rem (1.03 +/- 0.23 vs. 1.10 +/- 0.26 and 2.27 +/- 0.63 vs. 2.26 +/- 0.63; P = ns for both) territories. Global (1.98 +/- 0.40 vs. 1.90 +/- 0.46; P = ns) and regional CFR (Isc: 1.65 +/- 0.40 vs. 1.67 +/- 0.47, and Rem: 2.25 +/- 0.57 vs. 2.06 +/- 0.51; P = ns) were reproducible. The BA repeatability coefficients (and %BA) for MBF in ischemic and remote territories were 0.3 (28%) and 0.26 (24%) at rest and 0.49 (27%) and 0.58 (26%) during Dob stress. CONCLUSION: In patients with clinically stable CAD, Dob induces reproducible changes in both global and regional MBF and CFR over a time interval of 24 wk. The reproducibility of MBF and CFR with Dob was comparable with the short-term repeatability reported for adenosine and physical exercise in healthy subjects.     

Variability of myocardial blood flow measurements by magnetic resonance imaging in the multi-ethnic study of atherosclerosis

OBJECTIVE: Magnetic resonance imaging (MRI) allows the noninvasive assessment of absolute myocardial blood flow (MBF) in mL/min/g during rest, and hyperemia induced by intravenous adenosine, a powerful coronary vasodilator with short decay time. The longitudinal variability in healthy volunteers of the hemodynamic response to adenosine, and of the MBF response, remain largely unknown. The purpose of this study was to assess the longitudinal variability for resting and hyperemic MBFs in the Multi-Ethnic Study of Atherosclerosis. MATERIALS AND METHODS: Thirty participants (19 women, 11 men, mean age 63.2 +/- 9.6; range 45-79 years) underwent 2 MRI exams with an average separation of 334 +/- 158 days (range: 20-645) between the 2 exams, using a rapid, multislice T1-weighted gradient-echo imaging technique at rest and during maximal vasodilation with intravenous adenosine. RESULTS: The absolute repeatability coefficient, corresponding to the 95% confidence intervals of the within subject differences, was 0.29 mL/min/g for rest studies, and 1.13 mL/min/g for hyperemic MBF. The relative repeatability coefficients, expressed as a percentage of the mean blood flow, averaged 30% at rest, and 41% during hyperemia. Differences in resting MBF between the 2 exams from 1.01 +/- 0.22 to 0.91 +/- 0.18 mL/min/g (P = 0.001) were associated with changes in hemodynamic conditions, but no such association was observed for hyperemic MBFs, which averaged 2.84 +/- 0.87 mL/min/g in the first examination, and 2.69 +/- 0.65 mL/min/g at follow-up. Over approximately 1 year of aging between perfusion studies there was no observable decline of the hyperemic response, but the variability of the hyperemic MBF response increased with the lag between baseline and follow-up measurements. CONCLUSIONS: The repeatability of MBF measurements by MRI at rest was similar to results from previous studies with positron emission tomography.     

Effect of caffeine intake on myocardial hyperemic flow induced by adenosine triphosphate and dipyridamole.

The aims of this study were (a). to compare absolute myocardial blood flow (MBF) during adenosine triphosphate (ATP) infusion with that after dipyridamole administration without caffeine intake and (b). to evaluate the effect of caffeine intake on the hyperemic flow induced by these coronary vasodilator agents. METHODS: MBF was quantified with (15)O-labeled water and PET at rest, during ATP infusion (0.16 mg/kg/min for 9 min), and after dipyridamole administration (0.56 mg/kg over 4 min) after a 24-h abstinence from caffeine (baseline evaluation) in 10 healthy volunteers. Within 2 wk, the same PET studies were repeated after caffeine intake to evaluate the effect of caffeine on the hyperemic flow induced by these pharmacologic agents (caffeine study). Myocardial flow reserve (MFR), defined as the ratio of hyperemic to resting blood flow, was also evaluated. RESULTS: Resting MBF in baseline and caffeine studies did not differ significantly (0.79 +/- 0.29 vs. 0.75 +/- 0.31 mL/min/g, P = 0.88). Without caffeine intake, MBF during ATP infusion was significantly higher than that after dipyridamole administration (3.70 +/- 0.67 vs. 3.00 +/- 0.79 mL/min/g, P = 0.003), whereas there was no significant difference in MFR between ATP and dipyridamole stress (5.15 +/- 1.64 vs. 4.11 +/- 1.44, P = 0.07). After caffeine intake, the hyperemic flows induced by ATP and dipyridamole were not significantly different (1.68 +/- 0.37 vs. 1.52 +/- 0.40 mL/min/g, P = 0.50). MFR estimated by ATP and dipyridamole also did not differ significantly in the caffeine studies (2.44 +/- 0.88 vs. 2.25 +/- 0.94, P = 0.73). MBF during ATP infusion and after dipyridamole administration were significantly lower in the caffeine studies than that in the baseline evaluation (1.68 +/- 0.37 vs. 3.70 +/- 0.67 mL/min/g, P < 0.0001, and 1.52 +/- 0.40 vs. 3.00 +/- 0.79 mL/min/g, P < 0.0001, respectively). CONCLUSION: This study demonstrates that ATP has the potential to induce greater hyperemia than dipyridamole, whereas hyperemic responses to ATP and dipyridamole are similarly attenuated after caffeine intake. These findings suggest that abstinence from caffeine before ATP stress testing may be needed.     

Coronary flow and coronary flow reserve measurements in humans with breath-held magnetic resonance phase contrast velocity mapping

Objective evidence for coronary lesion significance can be obtained with ischemic stress testing. Since flow-limiting stenoses have already undergone compensatory vasodilatation to maintain flow, the response to vasoactive stimulation is dampened. The degree of response limitation is reflected by the coronary flow reserve (CFR). Absolute volume flow rates can be accurately and noninvasively measured with MRI techniques. The purpose was to assess the ability to measure coronary volume flow rate noninvasively, and characterize the effect of pharmacologic stress on coronary flow quantitatively by using ultrafast, breath-held segmented k-space phasecontrast-MR imaging (PC-MRI). Ten healthy volunteers were examined by using ultrafast breath-held PC-MRI. Coronary volume flow rates were measured in the anterior descending coronary artery (LAD) at rest and following intravenous administration of dipyridamole. CFR was determined based on these data. Mean LAD volume flow rates increased from 38 ± 11 ml/min before application of dipyridamole to 169 ± 42 ml/min. The mean CFR amounted to 5.0 ± 2.6 (median = 4.15). This study demonstrates the feasibility of breath-held PC-MRI to noninvasively quantify coronary volume flow rates over the cardiac cycle. Pharmacologically induced changes in volume flow rate and thus CFR can be quantitated.     

Chronic heart failure: global left ventricular perfusion and coronary flow reserve with velocity-encoded cine MR imaging: initial results

PURPOSE: To quantify and compare global left ventricular (LV) perfusion and coronary flow reserve (CFR) in patients with chronic heart failure and in healthy volunteers by measuring coronary sinus flow with velocity-encoded cine (VEC) magnetic resonance (MR) imaging. MATERIALS AND METHODS: MR measurements were performed in 10 consecutive patients with chronic heart failure due to coronary artery disease and in 10 volunteers. Global LV perfusion was quantified by measuring coronary sinus flow in an oblique imaging plane perpendicular to the coronary sinus with non-breath-hold VEC MR imaging. LV mass was measured by means of cine imaging that encompassed the heart. LV perfusion was calculated from coronary sinus flow and mass. CFR was measured from LV perfusion at rest and that after infusion of dipyridamole. Analysis of covariance was used to determine differences between groups. Differences within groups were analyzed by means of the Student t test for paired data. Regression analysis was used to determine correlation between CFR and LV ejection fraction. RESULTS: At rest, LV perfusion was not significantly different in patients with chronic heart failure (0.46 mL/min/g +/- 0.19) and volunteers (0.52 mL/min/g +/- 0.21, P =.54). After administration of dipyridamole, LV perfusion was less than half in patients with chronic heart failure compared with that in volunteers (1.07 mL/min/g +/- 0.64 vs 2.19 mL/min/g +/- 0.98) (P =.03). CFR was severely reduced in patients with chronic heart failure compared with that in volunteers (2.3 +/- 0.9 vs 4.2 +/- 1.5, P =.01). A moderate but significant correlation was found between CFR and LV ejection fraction (r = 0.54, P =.02) CONCLUSION: Combined cine and VEC MR imaging revealed that patients with chronic heart failure have normal LV perfusion at rest but severely depressed LV perfusion after vasodilation. Impaired CFR may contribute to progressive decline in LV function in patients with chronic heart failure.     

Reduction of coronary flow reserve in areas with and without ischemia on stress perfusion imaging in patients with coronary artery disease: A study using oxygen 15-labeled water PET

BACKGROUND: Myocardial perfusion single photon emission computed tomography (SPECT) occasionally fails to detect coronary stenosis in patients with coronary artery disease (CAD). We evaluated coronary flow reserve (CFR) using oxygen 15-labeled water in areas with and without ischemia on technetium 99m tetrofosmin stress perfusion SPECT in patients with angiographically documented CAD. METHODS AND RESULTS: Twenty-seven patients with CAD and eleven age-matched normal subjects were studied. Baseline myocardial blood flow (MBF) and MBF during hyperemia induced by intravenous adenosine triphosphate infusion (0.16 mg. kg(-1). min(-1)) were determined with the use of O-15-labeled water positron emission tomography, and the CFR was calculated. Tc-99m tetrofosmin stress/rest SPECT was performed for comparison. On the basis of the results of coronary angiography and SPECT, coronary segments were divided into 3 types: segments with coronary stenosis and a perfusion abnormality on stress SPECT imaging (group A, n = 16), segments with coronary stenosis without a perfusion abnormality (group B, n = 42), and remote segments with no coronary stenosis or perfusion abnormality (group C, n = 18). Baseline MBF values were similar among the 3 groups. CFR in group A was lower (1.82 +/- 0.54) than in group B (2.22 +/- 0.87, P <.05), in group C (2.92 +/- 1.21, P <.01), and in normal segments (3.86 +/- 1.24, P <.001). CFR in group B was lower than in group C (P <.02) and in normal segments (P <.001). CFR in group C was lower than in normal segments (P <.02). CONCLUSIONS: Areas with a perfusion abnormality on stress SPECT had reduced CFR. In the areas without a perfusion abnormality and with coronary stenosis, lowering of CFR was intermediate between the areas with a perfusion abnormality and remote segments. Moreover, CFR was slightly, but significantly, lower in remote segments in patients with CAD compared with normal segments.     

Determinants of myocardial blood flow response to cold pressor testing and pharmacologic vasodilation in healthy humans

Purpose Response of myocardial blood flow (MBF) to sympathetic stimulation with cold is modulated by endothelium-related factors and is typically altered in the presence of coronary risk factors. Determinants of flow response to cold pressor testing (CPT) in normal volunteers at low risk for CAD remain less well defined, especially relative to baseline conditions such as hemodynamics and MBF, plasma substrate and lipid levels, and total pharmacologically stimulated vasodilator capacity. Methods In 50 normal volunteers (42±13 years; 31 women) without coronary risk factors, insulin resistance, or family history of diabetes/premature CAD, MBF was measured with ¹³N-ammonia and PET at baseline, during CPT, and during pharmacologic hyperemia. Results Sympathetic stimulation with CPT raised heart rate and blood pressure and thus MBF (ΔMBF=0.23±0.09 ml/min/g). MBF response, defined in absolute flow units as the difference between CPT and baseline, was independent of age, gender, heart rate, and blood pressure and rate–pressure product (RPP) at baseline as well as plasma substrate and lipid levels with the exception of an association with HDL cholesterol (ρ=0.40, p=0.005) but depended on the change in RPP from rest (ρ=0.33, p=0.019). Finally, changes in coronary vascular resistance in response to CPT were associated with changes in pharmacologic vasodilation (ρ=0.56, p<0.0001). Conclusion MBF response to sympathetic stimulation with cold (NO-mediated endothelium-dependent vasomotion), reflecting the functional state of the coronary endothelium, was independent of gender, age, and resting heart conditions. It was modulated by HDL cholesterol levels, even in healthy volunteers, and also related to pharmacologically stimulated vasodilator capacity at the coronary vascular resistance level.     

Effect of mental stress on myocardial blood flow and vasomotion in patients with coronary artery disease.

In patients with coronary artery disease (CAD), mental stress may provoke ischemic electrocardiograph changes and abnormalities in regional and global left ventricular function. However, little is known about the underlying myocardial blood flow response (MBF) in these patients. METHODS: We investigated the hemodynamic, neurohumoral, and myocardial blood flow responses to mental stress in 17 patients with CAD and 17 healthy volunteers of similar age. Mental stress was induced by asking individuals to solve mathematic subtractions in a progressively challenging sequence; MBF was quantified at rest and during mental stress using 13N ammonia PET. RESULTS: Mental stress induced significant (P < 0.01) and comparable increases in rate-pressure product, measured in beats per minute x mm Hg, in both patients (from 7826 +/- 2006 to 10586 +/- 2800) and healthy volunteers (from 8227 +/- 1272 to 10618 +/- 2468). Comparable increases also occurred in serum epinephrine (58% in patients versus 52% in healthy volunteers) and norepinephrine (22% in patients versus 27% in healthy volunteers). Although MBF increased in patients (from 0.67 +/- 0.15 to 0.77 +/- 0.18 mL/min/g, P < 0.05) and healthy volunteers (from 0.73 +/- 0.13 to 0.95 +/- 0.22 mL/min/g, P < 0.001), the magnitude of flow increase was smaller in patients (14% +/- 17%) than in healthy volunteers (29% +/- 14%) (P = 0.01). The increase in MBF during mental stress correlated significantly with changes in cardiac work in healthy volunteers (r = 0.77; P < 0.001) but not in patients. CONCLUSION: Despite similar increases in cardiac work and comparable sympathetic stimulation in CAD patients and healthy volunteers, CAD patients exhibit an attenuated blood flow response to mental stress that may contribute to mental stress-induced ischemic episodes in daily life.     

Assessing coronary sinus blood flow in patients with coronary artery disease: a comparison of phase-contrast MR imaging with positron emission tomography

OBJECTIVE: This study was performed to determine whether MR imaging can be used to reliably measure global myocardial blood flow and coronary flow reserve in patients with coronary artery disease as compared with such measurements obtained by positron emission tomography (PET). SUBJECTS AND METHODS: We measured myocardial blood flow first at baseline and then after dipyridamole-induced hyperemia in 20 patients with coronary artery disease. Myocardial blood flow as revealed by MR imaging was calculated by dividing coronary sinus flow by the left ventricular mass. Coronary flow reserve was calculated by dividing the rate of hyperemic flow by the rate of baseline flow. RESULTS: Using MR imaging, myocardial blood flow at baseline was 0.73 +/- 0.23 mL x min(-1) x g(-1), and at hyperemia the blood flow was 1.43 +/- 0.37 mL x min(-1) x g(-1), yielding an average coronary flow reserve of 1.99 +/- 0.47. Using PET, myocardial blood flow was 0.89 +/- 0.21 mL x min(-1) x g(-1) at baseline and 1.56 +/- 0.42 mL x min(-1) x g(-1) at hyperemia, yielding an average coronary flow reserve of 1.77 +/- 0.36. The correlation of myocardial blood flow and coronary flow reserve measurements for these two methods was an r of 0.80 (p < 0.01) and an r of 0.50 (p < 0.05), respectively. CONCLUSION: This study shows that myocardial blood flow measurements obtained using MR imaging have a good correlation with corresponding PET measurements. Coronary flow reserve measurements obtained using MR imaging had only moderate correlation with PET-obtained measurements. Our results suggest that MR imaging flow quantification could potentially be used for measuring global myocardial blood flow in patients in whom interventional treatment for coronary artery disease is being evaluated.     

Reproducibility of measurements of regional myocardial blood flow in a model of coronary artery disease: Comparison of H215O and 13NH3 PET techniques.

PET absolute myocardial blood flow (MBF) with H(2)15O and 13NH3 are widely used in clinical and research settings. However, their reproducibility with a 16-myocardial segment model has not been examined in chronic coronary artery disease (CAD). We examined the short-term reproducibility of PET H(2)15O MBF and PET 13NH3 MBF in an animal model of chronic CAD. METHODS: Twelve swine (mean weight +/- SD, 38 +/- 5 kg) underwent percutaneous placement of a copper stent in the mid circumflex coronary artery, resulting in an intense inflammatory fibrotic reaction with luminal stenosis at 4 wk. Each animal underwent repeated resting MBF measurements by PET H(2)15O and PET 13NH3. Attenuation-corrected images were analyzed using commercial software to yield absolute MBF (mL/min/g) in 16 myocardial segments. MBF was also normalized to the rate.pressure product (RPP). RESULTS: By Bland-Altman reproducibility plots, the mean difference was 0.01 +/- 0.18 mL/min/g and 0.01 +/- 0.11 mL/min/g, with confidence limits of +/-0.36 and +/-0.22 mL/min/g for uncorrected regional PET H(2)15O MBF and for uncorrected regional PET 13NH3 MBF, respectively. The repeatability coefficient ranged from 0.09 to 0.43 mL/min/g for H(2)15O and from 0.09 to 0.18 mL/min/g for 13NH3 regional MBF. RPP correction did not improve reproducibility for either PET H(2)15O or PET 13NH3 MBF. The mean difference in PET H(2)15O MBF was 0.03 +/- 0.14 mL/min/g and 0.02 +/- 0.19 mL/min/g for infarcted and remote regions, respectively, and in PET 13NH3 MBF was 0.03 +/- 0.11 mL/min/g and 0.00 +/- 0.09 mL/min/g for infarcted and remote regions, respectively. CONCLUSION: PET H(2)15O and PET 13NH3 resting MBF showed excellent reproducibility in a closed-chest animal model of chronic CAD. Resting PET 13NH3 MBF was more reproducible than resting PET H(2)15O MBF. A high level of reproducibility was maintained in areas of lower flow with infarction for both isotopes.     

Validation of myocardial perfusion reserve measurements using regularized factor images of H(2)(15)O dynamic PET scans.

The use of H(2)(15)O PET scans for the measurement of myocardial perfusion reserve (MPR) has been validated in both animal models and humans. Nevertheless, this protocol requires cumbersome acquisitions such as C(15)O inhalation or (18)F-FDG injection to obtain images suitable for determining myocardial regions of interest. Regularized factor analysis is an alternative method proposed to define myocardial contours directly from H(2)(15)O studies without any C(15)O or FDG scan. The study validates this method by comparing the MPR obtained by the regularized factor analysis with the coronary flow reserve (CFR) obtained by intracoronary Doppler as well as with the MPR obtained by an FDG acquisition. METHODS: Ten healthy volunteers and 10 patients with ischemic cardiopathy or idiopathic dilated cardiomyopathy were investigated. The CFR of patients was measured sonographically using a Doppler catheter tip placed into the proximal left anterior descending artery. The mean velocity was recorded at baseline and after dipyridamole administration. All subjects underwent PET imaging, including 2 H(2)(15)O myocardial perfusion studies at baseline and after dipyridamole infusion, followed by an FDG acquisition. Dynamic H(2)(15)O scans were processed by regularized factor analysis. Left ventricular cavity and anteroseptal myocardial regions of interest were drawn independently on regularized factor images and on FDG images. Myocardial blood flow (MBF) and MPR were estimated by fitting the H(2)(15)O time-activity curves with a compartmental model. RESULTS: In patients, no significant difference was observed among the 3 methods of measurement-Doppler CFR, 1.73 +/- 0.57; regularized factor analysis MPR, 1.71 +/- 0.68; FDG MPR, 1.83 +/- 0.49-using a Friedman 2-way ANOVA by ranks. MPR measured with the regularized factor images correlated significantly with CFR (y = 1.17x - 0.30; r = 0.97). In the global population, the regularized factor analysis MPR and FDG MPR correlated strongly (y = 0.99x; r = 0.93). Interoperator repeatability on regularized factor images was 0.126 mL/min/g for rest MBF, 0.38 mL/min/g for stress MBF, and 0.34 for MPR (19% of mean MPR). CONCLUSION: Regularized factor analysis provides well-defined myocardial images from H(2)(15)O dynamic scans, permitting an accurate and simple measurement of MPR. The method reduces exposure to radiation and examination time and lowers the cost of MPR protocols using a PET scanner.     

Changes in human cerebral blood flow and myocardial blood flow during mental stress measured by dual positron emission tomography

Mental stress causes a substantial sympathetic response, thus increasing myocardial blood flow (MBF). However, the effects of mental stress on global CBF have not been elucidated. In this study, changes in CBF and MBF in relation to mental stress were measured by a dual positron emission tomography system that can measure CBF and MBF simultaneously. CBF and MBF were measured in 10 healthy men with O-15 labeled water at rest (baseline) and during the performance of a mental task that required subtraction of 7s serially from a four-digit number. Baseline global CBF and values obtained during the mental activity were 0.42 +/- 0.05 and 0.45 +/- 0.06 ml/ml/min (mean +/- SD), respectively. Baseline MBF and values obtained during mental activity were 0.61 +/- 0.12 and 1.09 +/- 0.58 ml/ml/min, respectively. Percent changes in CBF and MBF during mental stress were 6 +/- 11% and 78 +/- 73%, respectively. No significant difference was observed in PaCO2 level between the mental stress and baseline conditions. MBF, blood pressure, heart rate, and plasma concentrations of adrenaline and noradrenaline increased significantly during mental stress. Sympathetic stimulation is reported to cause cerebral vasoconstriction and reduce CBF in animals. Although such a sympathetic response was observed in relation to mental stress, no significant change in CBF was observed in our subjects.     

Comparison of myocardial blood flow and coronary flow reserve during dobutamine and adenosine stress: implications for pharmacologic stress testing in coronary artery disease

BACKGROUND: Mechanistic differences between pharmacologic stressors may offer different clinical benefits. Therefore the effects of dobutamine and adenosine on absolute myocardial blood flow (MBF) and coronary flow reserve (CFR) were compared. METHODS AND RESULTS: We divided 36 patients (mean age, 61 +/- 8 years) with coronary artery disease into 2 groups based on stenosis severity as follows: greater than 50% but less than 75% (n = 16) and greater than 75% (n = 20). In addition, 18 normal volunteers (mean age, 46 +/- 7 years) served as control subjects. Groups of equal sizes received either dobutamine or adenosine. MBF at rest and peak MBF were measured by use of positron emission tomography in territories subtended by the stenosis (ischemic) and remote myocardium (remote), whereas left ventricular MBF was used in control subjects. CFR was calculated as peak MBF divided by MBF at rest. CFR was significantly greater with adenosine than with dobutamine stress in control subjects and remote CFR. Ischemic CFR was blunted to a similar degree with each stressor. Therefore adenosine achieved flow heterogeneity across all coronary stenosis severities greater than 50%. However, dobutamine achieved flow heterogeneity only in the presence of a severe coronary stenosis greater than 75% despite provoking a greater ischemic stimulus. CONCLUSION: Adenosine stress demonstrated a higher sensitivity and dobutamine demonstrated a higher specificity with quantitative perfusion imaging. Therefore adenosine is superior for diagnostic perfusion imaging, whereas dobutamine is better suited in combination with visual imaging and in the functional assessment of a known coronary stenosis.