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1.  Improved Cardiac Risk Assessment with Non-Invasive measures of Coronary flow reserve 
Circulation  2011;124(20):2215-2224.
Impaired vasodilator function is an early manifestation of coronary artery disease and may precede angiographic stenosis. It is unknown whether non-invasive assessment of coronary vasodilator function in patients with suspected or known coronary artery disease (CAD) carries incremental prognostic significance.
Methods and Results
2783 consecutive patients referred for rest/stress PET were followed for a median of 1.4 years (inter-quartile range: 0.7–3.2 years). The extent and severity of perfusion abnormalities were quantified by visual evaluation of myocardial perfusion images (MPI). Rest and stress myocardial blood flow (MBF) were calculated using factor analysis and a 2-compartment kinetic model, and were used to compute coronary flow reserve (CFR=stress/rest MBF). The primary endpoint was cardiac death. Overall 3-year cardiac mortality was 8.0%. The lowest tertile of CFR (<1.5) was associated with a 5.6-fold increase in the risk of cardiac death (95%CI 2.5–12.4, p<0.0001) compared to the highest tertile. Incorporation of CFR into cardiac death risk assessment models resulted in an increase in the c-index from 0.82 (95%CI 0.78–0.86) to 0.84 (95%CI 0.80–0.87, p=0.02) and in a net reclassification improvement (NRI) of 0.098 (95%CI 0.025–0.180). Addition of CFR resulted in correct reclassification of 34.8% of intermediate risk patients (NRI=0.487, 95%CI 0.262–0.731). Corresponding improvements in risk assessment for mortality from any cause were also demonstrated.
Non-invasive quantitative assessment of coronary vasodilator function using PET is a powerful, independent predictor of cardiac mortality in patients with known or suspected CAD and provides meaningful incremental risk stratification over clinical and gated MPI variables.
PMCID: PMC3495106  PMID: 22007073
coronary disease; blood flow; imaging; atherosclerosis; ischemia
2.  Quantitative Relation between Coronary Calcium Content and Coronary Flow Reserve as Assessed by Integrated PET-CT Imaging 
Coronary artery calcium (CAC) is a marker of atherosclerosis. Whether epicardial calcium reflects more widespread atherosclerosis affecting coronary vascular function is unknown.
We evaluated 136 consecutive patients without known coronary disease (age 62 ±12 years, 68 % females) undergoing vasodilator stress 82Rb PET and CAC scoring based on clinical grounds. Patients with normal myocardial perfusion on standard semi-quantitative analysis were included. The Agatston CAC score, rest and stress myocardial blood flow (MBF), coronary flow reserve (CFR) and coronary vascular resistance (CVR) were quantified and analyzed on a per patient and per vascular territory basis.
Global and regional CAC scores showed modest but significant correlation with hyperemic MBF (r= −0.31 and r= −0.26, p≤0.0002, respectively), CFR (r= −0.28 and r= −0.2, p≤0.001, respectively), and CVR during peak hyperemia (r=0.32 and r= 0.26, p≤0.0002, respectively). There was a modest stepwise decline of mean CFR with increasing CAC score on per patient analysis (1.8 ±0.5 vs 1.7 ±0.5 vs 1.5±0.4, p=0.048 with total CAC= 0, 1-400 and >400 respectively) and per vessel analysis (1.8 ±0.6 vs 1.6 ±0.4 vs 1.5 ±0.5 vs 1.5 ±0.5, p=0.004 with vessel CAC score= 0, 1-100, 101-400 and >400 respectively). In multivariable modeling only body mass index (p=0.005), CAC score (p =0.04) and hypertension (p=0.05) remained predictive.
In patients without overt CAD, there is a modest but statistically significant inverse relationship between CAC content and coronary vasodilator function, which persists after adjusting for the effect of coronary risk factors.
PMCID: PMC3117296  PMID: 19387640
coronary calcifications; coronary flow reserve; coronary atherosclerosis; positron emission tomography
3.  Quantitative relationship between coronary artery calcium score and hyperemic myocardial blood flow as assessed by hybrid 15O-water PET/CT imaging in patients evaluated for coronary artery disease 
Journal of Nuclear Cardiology  2011;19(2):256-264.
The incremental value of CAC over traditional risk factors to predict coronary vasodilator dysfunction and inherent myocardial blood flow (MBF) impairment is only scarcely documented (MBF). The aim of this study was therefore to evaluate the relationship between CAC content, hyperemic MBF, and coronary flow reserve (CFR) in patients undergoing hybrid 15O-water PET/CT imaging.
We evaluated 173 (mean age 56 ± 10, 78 men) patients with a low to intermediate likelihood for coronary artery disease (CAD), without a documented history of CAD, undergoing vasodilator stress 15O-water PET/CT and CAC scoring. Obstructive coronary artery disease was excluded by means of invasive (n = 44) or CT-based coronary angiography (n = 129).
91 of 173 patients (52%) had a CAC score of zero. Of those with CAC, the CAC score was 0.1-99.9, 100-399.9, and ≥400 in 31%, 12%, and 5% of patients, respectively. Global CAC score showed significant inverse correlation with hyperemic MBF (r = −0.32, P < .001). With increasing CAC score, there was a decline in hyperemic MBF on a per-patient basis [3.70, 3.30, 2.68, and 2.53 mL · min−1 · g−1, with total CAC score of 0, 0.1-99.9, 100-399.9, and ≥400, respectively (P < .001)]. CFR showed a stepwise decline with increasing levels of CAC (3.70, 3.32, 2.94, and 2.93, P < .05). Multivariate analysis, including age, BMI, and CAD risk factors, revealed that only age, male gender, BMI, and hypercholesterolemia were associated with reduced stress perfusion. Furthermore, only diabetes and age were independently associated with CFR.
In patients without significant obstructive CAD, a greater CAC burden is associated with a decreased hyperemic MBF and CFR. However, this association disappeared after adjustment for traditional CAD risk factors. These results suggest that CAC does not add incremental value regarding hyperemic MBF and CFR over established CAD risk factors in patients without obstructive CAD.
PMCID: PMC3313028  PMID: 22076826
Coronary artery calcium; hyperemic myocardial blood flow; coronary risk factors
4.  Diagnostic Value of PET-Measured Heterogeneity in Myocardial Blood Flows during CPT for the Identification of Coronary Vasomotor Dysfunction 
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).
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.
PMCID: PMC2716693  PMID: 17826322
Blood flow; cold pressor test; coronary vasomotion; endothelium; PET
5.  Caffeine Impairs Myocardial Blood Flow Response to Physical Exercise in Patients with Coronary Artery Disease as well as in Age-Matched Controls 
PLoS ONE  2009;4(5):e5665.
Caffeine is one of the most widely consumed pharmacologically active substances. Its acute effect on myocardial blood flow is widely unknown. Our aim was to assess the acute effect of caffeine in a dose corresponding to two cups of coffee on myocardial blood flow (MBF) in coronary artery disease (CAD).
Methodology/Principal Findings
MBF was measured with 15O-labelled H2O and Positron Emission Tomography (PET) at rest and after supine bicycle exercise in controls (n = 15, mean age 58±13 years) and in CAD patients (n = 15, mean age 61±9 years). In the latter, regional MBF was assessed in segments subtended by stenotic and remote coronary arteries. All measurements were repeated fifty minutes after oral caffeine ingestion (200 mg). Myocardial perfusion reserve (MPR) was calculated as ratio of MBF during bicycle stress divided by MBF at rest. Resting MBF was not affected by caffeine in both groups. Exercise-induced MBF response decreased significantly after caffeine in controls (2.26±0.56 vs. 2.02±0.56, P<0.005), remote (2.40±0.70 vs. 1.78±0.46, P<0.001) and in stenotic segments (1.90±0.41 vs. 1.38±0.30, P<0.001). Caffeine decreased MPR significantly by 14% in controls (P<0.05 vs. baseline). In CAD patients MPR decreased by 18% (P<0.05 vs. baseline) in remote and by 25% in stenotic segments (P<0.01 vs. baseline).
We conclude that caffeine impairs exercise-induced hyperaemic MBF response in patients with CAD to a greater degree than age-matched controls.
PMCID: PMC2682574  PMID: 19479069
6.  Automatic generation of absolute myocardial blood flow images using [15O]H2O and a clinical PET/CT scanner 
Parametric imaging of absolute myocardial blood flow (MBF) using [15O]H2O enables determination of MBF with high spatial resolution. The aim of this study was to develop a method for generating reproducible, high-quality and quantitative parametric MBF images with minimal user intervention.
Nineteen patients referred for evaluation of MBF underwent rest and adenosine stress [15O]H2O positron emission tomography (PET) scans. Ascending aorta and right ventricular (RV) cavity volumes of interest (VOIs) were used as input functions. Implementation of a basis function method (BFM) of the single-tissue model with an additional correction for RV spillover was used to generate parametric images. The average segmental MBF derived from parametric images was compared with MBF obtained using nonlinear least-squares regression (NLR) of VOI data. Four segmentation algorithms were evaluated for automatic extraction of input functions. Segmental MBF obtained using these input functions was compared with MBF obtained using manually defined input functions.
The average parametric MBF showed a high agreement with NLR-derived MBF [intraclass correlation coefficient (ICC) = 0.984]. For each segmentation algorithm there was at least one implementation that yielded high agreement (ICC > 0.9) with manually obtained input functions, although MBF calculated using each algorithm was at least 10% higher. Cluster analysis with six clusters yielded the highest agreement (ICC = 0.977), together with good segmentation reproducibility (coefficient of variation of MBF <5%).
Parametric MBF images of diagnostic quality can be generated automatically using cluster analysis and a implementation of a BFM of the single-tissue model with additional RV spillover correction.
Electronic supplementary material
The online version of this article (doi:10.1007/s00259-011-1730-3) contains supplementary material, which is available to authorized users.
PMCID: PMC3070081  PMID: 21271246
Myocardial perfusion; PET/CT; Segmentation; Parametric images
7.  Reproducibility and Accuracy of Quantitative Myocardial Blood Flow Using 82Rb-PET: Comparison with 13N-Ammonia 
82Rb cardiac PET allows the assessment of myocardial perfusion using a column generator in clinics that lack a cyclotron. We and others have previously shown that quantitation of myocardial blood flow (MBF) and coronary flow reserve (CFR) is feasible using dynamic 82Rb PET and factor and compartment analyses. The aim of the present work was to determine the intra- and inter-observer variability of MBF estimation using 82Rb PET as well as the reproducibility of our generalized factor + compartment analyses methodology to estimate MBF and assess its accuracy by comparing, in the same subjects, 82Rb estimates of MBF to those obtained using 13N-ammonia.
Twenty-two subjects were included in the reproducibility and twenty subjects in the validation study. Patients were injected with 60±5mCi of 82Rb and imaged dynamically for 6 minutes at rest and during dipyridamole stress Left and right ventricular (LV+RV) time-activity curves were estimated by GFADS and used as input to a 2-compartment kinetic analysis that estimates parametric maps of myocardial tissue extraction (K1) and egress (k2), as well as LV+RV contributions (fv,rv).
Our results show excellent reproducibility of the quantitative dynamic approach itself with coefficients of repeatability of 1.7% for estimation of MBF at rest, 1.4% for MBF at peak stress and 2.8% for CFR estimation. The inter-observer reproducibility between the four observers that participated in this study was also very good with correlation coefficients greater than 0.87 between any two given observers when estimating coronary flow reserve. The reproducibility of MBF in repeated 82Rb studies was good at rest and excellent at peak stress (r2=0.835). Furthermore, the slope of the correlation line was very close to 1 when estimating stress MBF and CFR in repeated 82Rb studies. The correlation between myocardial flow estimates obtained at rest and during peak stress in 82Rb and 13N-ammonia studies was very good at rest (r2=0.843) and stress (r2=0.761). The Bland-Altman plots show no significant presence of proportional error at rest or stress, nor a dependence of the variations on the amplitude of the myocardial blood flow at rest or stress. A small systematic overestimation of 13N-ammonia MBF was observed with 82Rb at rest (0.129 ml/g/min) and the opposite, i.e., underestimation, at stress (0.22 ml/g/min).
Our results show that absolute quantitation of myocardial bloof flow is reproducible and accurate with 82Rb dynamic cardiac PET as compared to 13N-ammonia. The reproducibility of the quantitation approach itself was very good as well as inter-observer reproducibility.
PMCID: PMC3133618  PMID: 19525467
82Rb cardiac 2D PET; 13N-ammonia cardiac PET; Quantitation of myocardial blood flow
8.  Coronary microvascular dysfunction in male patients with Anderson‐Fabry disease and the effect of treatment with α galactosidase A 
Heart  2005;92(3):357-360.
To measure coronary flow reserve (CFR), an index of microvascular function, in Anderson‐Fabry disease (AFD) at baseline and after enzyme replacement therapy (ERT).
Methods and results
Mean (SD) myocardial blood flow (MBF) at rest and during hyperaemia (adenosine 140 μg/kg/min) was measured in 10 male, non‐smoking patients (53.8 (10.9) years, cholesterol 5.5 (1.3) mmol/l) and in 24 age matched male, non‐smoking controls (52.0 (7.6) years, cholesterol 4.5 (0.6) mmol/l) by positron emission tomography (PET). Resting and hyperaemic MBF and CFR (hyperaemic/resting MBF) were reduced in patients compared with controls (0.99 (0.17) v 1.17 (0.25) ml/g/min, p < 0.05; 1.37 (0.32) v 3.44 (0.78) ml/g/min, p < 0.0001; and 1.41 (0.39) v 3.03 (0.85), p < 0.0001, respectively). This coronary microvascular dysfunction was independent of cholesterol concentrations. PET was repeated in five patients after 10.1 (2.3) months of ERT; resting and hyperaemic MBF and CFR were unchanged after ERT (0.99 (0.16) v 0.99 (0.16) ml/g/min; 1.56 (0.29) v 1.71 (0.3) ml/g/min; and 1.6 (0.37) v 1.74 (0.28), respectively; all not significant).
The results of the present study show that patients with AFD have very abnormal coronary microvascular function. These preliminary data suggest that ERT has no effect on coronary microvascular dysfunction. Further work is necessary to determine whether treatment at an earlier stage in the course of the disease may improve coronary microvascular function in patients with AFD.
PMCID: PMC1860797  PMID: 16085718
cardiomyopathy; coronary circulation; myocardial blood flow; myocardial ischaemia; cardiac imaging
9.  Comparison and Effectiveness of Regadenoson versus Dipyridamole on Stress Electrocardiographic Changes during Positron Emission Tomography Evaluation of Patients with Hypertrophic Cardiomyopathy 
The American journal of cardiology  2012;110(7):1033-1039.
Dipyridamole (Dip) is the most common vasodilator employed with positron emission tomography (PET) for the evaluation of individuals with hypertrophic cardiomyopathy (HC). The aim of this study was to evaluate whether PET quantification of regional myocardial perfusion (rMP), myocardial blood flow (MBF) and coronary flow reserve (CFR) are comparable between Dip and the newer vasodilator agent, Regadenoson (Reg) in HC. An additional aim was to evaluate the association between vasodilator-induced ST segment depression on ECG and myocardial flow in HC. N-13 ammonia PET was performed in 57 symptomatic HC patients at rest and during vasodilator stress (peak) with either Dip (0.56 mg/kg during 4-min infusion) or Reg (0.4 mg fixed bolus dose) for assessment of ECG, rMP (17 AHA-summed difference score [SDS]), MBF and CFR. The Dip and Reg groups consisted of 28 and 29 patients respectively. Baseline characteristics, including resting MBF (0.92 ± 0.22 vs. 0.89 ± 0.23 ml/min/g; P = 0.6) were similar between the Dip and Reg groups. During stress, the presence and severity of abnormal rMP (SDS 5.5 ± 5.5 vs. 5.8 ± 6.7, P=0.8), peak MBF (1.81 ± 0.44 vs. 1.82 ± 0.50 ml/min/g; P = 0.9) and CFR (2.02 ± 0.53 vs. 2.12 ± 0.12; P = 0.5) were comparable between Dip and Reg. Fewer patients exhibited side effects with Reg (2 vs.7; p=0.06). Vasodilator-induced ST segment depression showed a high specificity (~92%) but low sensitivity (~34%) to predict abnormal rMP (SDS ≥ 2). In conclusion, measurement of rMP and quantitative flow with PET is similar between Regadenoson and Dipyridamole in patients with symptomatic HC. Regadenoson is tolerated better than Dipyridamole and is easier to administer. Vasodilator-induced ST segment depression is a specific but non-sensitive marker for prediction of abnormal rMP in HC.
PMCID: PMC3439569  PMID: 22748357
PET; hypertrophic cardiomyopathy; Regadenoson; ECG
10.  T2 Preparation Method for Measuring Hyperemic Myocardial O2 Consumption: In Vivo Validation by Positron Emission Tomography 
To validate a new T2-prepared method for the quantification of regional myocardial O2 consumption during pharmacologic stress with positron emission tomography (PET).
Materials and Methods
A T2 prepared gradient-echo sequence was modified to measure myocardial T2 within a single breath-hold. Six beagle dogs were randomly selected for the induction of coronary artery stenosis. Magnetic resonance imaging (MRI) experiments were performed with the T2 imaging and first-pass perfusion imaging at rest and during either dobutamine- or dipyridamole-induced hyperemia. Myocardial blood flow (MBF) was quantified using a previously developed model-free algorithm. Hyperemic myocardial O2 extraction fraction (OEF) and consumption (MVO2) were calculated using a two-compartment model developed previously. PET imaging using 11C-acetate and 15O-water was performed in the same day to validate OEF, MBF, and MVO2 measurements.
The T2-prepared mapping sequence measured regional myocardial T2 with a repeatability of 2.3%. By myocardial segment-basis analysis, MBF measured by MRI is closely correlated with that measured by PET (R2 = 0.85, n = 22). Similar correlation coefficients were observed for hyperemic OEF (R2 = 0.90, n = 9, mean difference of PET − MRI = −2.4%) and MVO2 (R2 = 0.83, n = 7, mean difference = 4.2%).
The T2-prepared imaging method may allow quantitative estimation of regional myocardial oxygenation with relatively good accuracy. The precision of the method remains to be improved.
PMCID: PMC3773230  PMID: 21274973
BOLD; T2; myocardial oxygen consumption; myocardial perfusion reserve; hyperemia
11.  Quantitative Cardiac Positron Emission Tomography: The Time Is Coming! 
Scientifica  2012;2012:948653.
In the last 20 years, the use of positron emission tomography (PET) has grown dramatically because of its oncological applications, and PET facilities are now easily accessible. At the same time, various groups have explored the specific advantages of PET in heart disease and demonstrated the major diagnostic and prognostic role of quantitation in cardiac PET. Nowadays, different approaches for the measurement of myocardial blood flow (MBF) have been developed and implemented in user-friendly programs. There is large evidence that MBF at rest and under stress together with the calculation of coronary flow reserve are able to improve the detection and prognostication of coronary artery disease. Moreover, quantitative PET makes possible to assess the presence of microvascular dysfunction, which is involved in various cardiac diseases, including the early stages of coronary atherosclerosis, hypertrophic and dilated cardiomyopathy, and hypertensive heart disease. Therefore, it is probably time to consider the routine use of quantitative cardiac PET and to work for defining its place in the clinical scenario of modern cardiology.
PMCID: PMC3820449  PMID: 24278760
12.  Roles of myocardial blood volume and flow in coronary artery disease: an experimental MRI study at rest and during hyperemia 
European radiology  2010;20(8):2005-2012.
To validate fast perfusion mapping techniques in a setting of coronary artery stenosis, and to further assess the relationship of absolute myocardial blood volume (MBV) and blood flow (MBF) to global myocardial oxygen demand.
A group of 27 mongrel dogs were divided into 10 controls and 17 with acute coronary stenosis. On 1.5-T MRI, first-pass perfusion imaging with a bolus injection of a blood-pool contrast agent was performed to determine myocardial perfusion both at rest and during either dipyridamole-induced vasodilation or dobutamine-induced stress. Regional values of MBF and MBV were quantified by using a fast mapping technique. Color microspheres and 99mTc-labeled red blood cells were injected to obtain respective gold standards.
Microsphere-measured MBF and 99mTc-measured MBV reference values correlated well with the MR results. Given the same changes in MBF, changes in MBV are twofold greater with dobutamine than with dipyridamole. Under dobutamine stress, MBV shows better association with total myocardial oxygen demand than MBF. Coronary stenosis progressively reduced this association in the presence of increased stenosis severity.
MR first-pass perfusion can rapidly estimate regional MBF and MBV. Absolute quantification of MBV may add additional information on stenosis severity and myocardial viability compared with standard qualitative clinical evaluations of myocardial perfusion.
PMCID: PMC2900455  PMID: 20182731
Coronary stenosis; Myocardial blood flow; Myocardial blood volume
13.  Coronary Vascular Dysfunction and Prognosis in Patients with Chronic Kidney Disease 
JACC. Cardiovascular imaging  2012;5(10):1025-1034.
To evaluate whether impaired vasodilator function, an early manifestation of coronary artery disease which precedes angiographic stenosis, accounts for increased risk among patients with moderate to severe renal dysfunction.
Patients with renal dysfunction are at increased risk of adverse cardiac outcomes, even in the absence of overt myocardial ischemia or infarction.
We included 866 consecutive patients with moderate to severe renal dysfunction referred for rest and stress myocardial perfusion PET and followed them for a median of 1.28 years (inter-quartile range: 0.64–2.34). Regional myocardial perfusion abnormalities were assessed by semiquantitative visual analysis of PET images. Rest and stress myocardial blood flow (MBF) were calculated using factor analysis and a 2-compartment kinetic model, and were used to compute coronary flow reserve (stress/rest MBF). The primary endpoint was cardiac death.
Overall 3-year cardiac mortality was 16.2%. After adjusting for clinical risk, left ventricular ejection fraction, as well as the magnitude of scar and/or ischemia, coronary flow reserve below the median (<1.5) was associated with a 2.1-fold increase in the risk of cardiac death (95%CI 1.3–3.5, P= 0.004). Incorporation of coronary flow reserve into cardiac death risk assessment models resulted in an increase in the c-index from 0.75 to 0.77 (P=0.05) and in a net reclassification improvement (NRI) of 0.142 (95%CI 0.076–0.219). Among patients at intermediate risk based on all data other than coronary flow reserve, the NRI was 0.489 (95%CI 0.192–0.836). Corresponding improvements in risk assessment for mortality from any cause were also demonstrated.
The presence of coronary vascular dysfunction in patients with moderate to severe renal dysfunction, as assessed by PET, is a powerful, independent predictor of cardiac mortality and provides meaningful incremental risk stratification over conventional markers of clinical risk.
PMCID: PMC3471090  PMID: 23058070
coronary artery disease; chronic kidney disease; blood flow; imaging; atherosclerosis; ischemia
14.  Coronary risk factors and myocardial blood flow in patients evaluated for coronary artery disease: a quantitative [15O]H2O PET/CT study 
There has been increasing interest in quantitative myocardial blood flow (MBF) imaging over the last years and it is expected to become a routinely used technique in clinical practice. Positron emission tomography (PET) using [15O]H2O is the established gold standard for quantification of MBF in vivo. A fundamental issue when performing quantitative MBF imaging is to define the limits of MBF in a clinically suitable population. The aims of the present study were to determine the limits of MBF and to determine the relationship among coronary artery disease (CAD) risk factors, gender and MBF in a predominantly symptomatic patient cohort without significant CAD.
A total of 128 patients (mean age 54 ± 10 years, 50 men) with a low to intermediate pretest likelihood of CAD were referred for noninvasive evaluation of CAD using a hybrid PET/computed tomography (PET/CT) scanner. MBF was quantified with [15O]H2O at rest and during adenosine-induced hyperaemia. Obstructive CAD was excluded in these patients by means of invasive or CT-based coronary angiography.
Global average baseline MBF values were 0.91 ± 0.34 and 1.09 ± 0.30  ml·min−1·g−1 (range 0.54–2.35  and 0.59–2.75 ml·min−1·g−1) in men and women, respectively (p < 0.01). However, no gender-dependent difference in baseline MBF was seen following correction for rate–pressure product (0.98 ± 0.45 and 1.09 ± 0.30 ml·min−1·g−1 in men and women, respectively; p = 0.08). Global average hyperaemic MBF values were 3.44 ± 1.20 ml·min−1·g−1 in the whole study population, and 2.90 ± 0.85 and 3.78 ± 1.27 ml·min−1·g−1 (range 1.52–5.22 and 1.72–8.15 ml·min−1·g−1) in men and women, respectively (p < 0.001). Multivariate analysis identified male gender, age and body mass index as having an independently negative impact on hyperaemic MBF.
Gender, age and body mass index substantially influence reference values and should be corrected for when interpreting hyperaemic MBF values.
PMCID: PMC3227802  PMID: 22005845
Myocardial blood flow; Positron emission tomography; Non-obstructive CAD; CAD risk factors; Gender
15.  Feasibility Study of Myocardial Perfusion and Oxygenation by Non-Contrast MRI: Comparison with PET Study in a Canine Model 
Magnetic resonance imaging  2007;26(1):11-19.
The purpose of this study was to examine the feasibility of quantifying myocardial blood flow (MBF) and rate of myocardial oxygen consumption (MVO2) during pharmacologically induced stress without using a contrast agent. The former was measured by the arterial spin labeling (ASL) method and the later was obtained by measuring the oxygen extraction fraction (OEF) with the magnetic resonance imaging (MRI) blood oxygenation level-dependent (BOLD) effect and Fick's law. The MRI results were compared with the established positron emission tomography (PET) methods. Six mongrel dogs with induced acute moderate left coronary artery stenosis were scanned using a clinical PET and a 1.5T MRI system, in the same day. Regional MBF, myocardial OEF, and MVO2 were measured with both imaging modalities. Correlation coefficients (R2) of the three myocardial indexes (MBF, OEF, and MVO2) between MRI and PET methods ranged from 0.70 to 0.93. Bland-Altman statistics demonstrated that the estimated precision of the limits of agreement between MRI and PET measurements varied from 18% (OEF), to 37% (MBF), and 45% (MVO2). The detected changes in these indexes, at rest and during dobutamine stress, were similar between two image modalities. The proposed non-contrast MRI technique is a promising method to quantitatively assess myocardial perfusion and oxygenation.
PMCID: PMC2230634  PMID: 17566684
MRI; PET; myocardial blood flow; oxygen consumption; non-contrast; comparative studies
16.  Assessment of intravascular and extravascular mechanisms of myocardial perfusion abnormalities in obstructive hypertrophic cardiomyopathy by myocardial contrast echocardiography 
Heart  2007;93(10):1204-1212.
To assess mechanisms of myocardial perfusion impairment in patients with hypertrophic cardiomyopathy (HCM).
Fourteen patients with obstructive HCM (mean (SD) age 53 (10) years, 11 men) underwent intravenous adenosine myocardial contrast echocardiography (MCE), positron emission tomography (PET) and cardiac catheterisation. Fourteen healthy volunteers (mean age 31 (4) years, 11 men) served as controls. Relative myocardial blood volume (rBV), exchange flow velocity (β), myocardial blood flow (MBF), MBF reserve (MFR) and endocardial‐to‐subepicardial (endo‐to‐epi) MBF ratio were measured from the steady state and contrast replenishment time–intensity curves.
Patients with HCM had lower rest MBF (for LVRPP‐corrected)—mean (SD) (0.92 (0.12) vs 1.13 (0.25) ml/min/g, p<0.01)—and hyperaemic MBF—(2.56 (0.49) vs 4.34 (0.78) ml/min/g, p<0.01) than controls. Resting rBV was lower in patients with HCM (0.094 (0.016) vs 0.138 (0.014) ml/ml), and during hyperaemia (0.104 (0.018) ml/ml vs 0.185 (0.024) ml/ml) (all p<0.001) than in controls. β tended to be higher in HCM at rest (9.4 (4.6) vs 7.7 (4.2) ml/min) and during hyperaemia (25.8 (6.4) vs 23.1 (6.2) ml/min) than in controls. Septal endo‐to‐epi MBF decreased during hyperaemia (0.86 (0.15) to 0.64 (0.18), p<0.01). rBV was inversely correlated with left ventricular (LV) mass index (p<0.05). Both hyperaemic and endo‐to‐epi MBF were inversely correlated with LV end‐diastolic pressure, LV mass index, and LV outflow tract pressure gradient (all p<0.05). MCE‐derived MBF correlated well with PET at rest (r = 0.84) and hyperaemia (r = 0.87) (all p<0.001).
In patients with HCM, LV end‐diastolic pressure, LV outflow tract pressure gradient, and LV mass index are independent predictors of rBV and hyperaemic MBF.
PMCID: PMC2000941  PMID: 17488767
myocardial perfusion; hypertrophic obstructive cardiomyopathy; myocardial contrast echocardiography; positron emission tomography
17.  Coronary Artery Calcification and Myocardial Perfusion in Asymptomatic Adults: The MESA (Multi-Ethnic Study of Atherosclerosis) 
This study assessed the cross-sectional association between coronary artery calcification (CAC) and myocardial perfusion in an asymptomatic population.
Clinical studies showed that the prevalence of stress-induced ischemia increased with CAC burden among patients with coronary heart disease (CHD). Whether an association between CAC and myocardial perfusion exists in subjects without a history of CHD remains largely unknown.
A total of 222 men and women, ages 45 to 84 years old and free of CHD diagnosis, in the Minnesota field center of the MESA (Multi-Ethnic Study of Atherosclerosis) were studied. Myocardial blood flow (MBF) was measured using magnetic resonance imaging during rest and adenosine-induced hyperemia. Perfusion reserve was calculated as the ratio of hyperemic to resting MBF. Agatston CAC score was determined from chest multidetector computed tomography.
Mean values of hyperemic MBF and perfusion reserve, but not resting MBF, were monotonically lower across increasing CAC levels. After adjusting for age and gender, odds ratios (95% confidence intervals) of reduced perfusion reserve (<2.5) for subjects with CAC scores of 0, 0.1 to 99.9, 100 to 399, and ≥400 were 1.00 (reference), 2.16 (0.96 to 4.84), 2.81 (1.04 to 7.58), and 4.99 (1.73 to 14.4), respectively. Further adjustment for other coronary risk factors did not substantially modify the association. However, the inverse association between perfusion reserve and CAC attenuated with advancing age (p for interaction < 0.05).
Coronary vasodilatory response was associated inversely with the presence and severity of CAC in asymptomatic adults. Myocardial perfusion could be impaired by or manifest the progression to subclinical coronary atherosclerosis in the absence of clinical CHD.
PMCID: PMC1853335  PMID: 16949496
18.  Feasibility of subendocardial and subepicardial myocardial perfusion measurements in healthy normals with 15O-labeled water and positron emission tomography 
Journal of Nuclear Cardiology  2011;18(4):650-656.
Positron emission tomography (PET) enables robust and reproducible measurements of myocardial blood flow (MBF). However, the relatively limited resolution of PET till recently prohibited distinction between the subendocardial and the subepicardial layers in non-hypertrophied myocardium. Recent developments in hard- and software, however, have enabled to identify a transmural gradient difference in animal experiments. The aim of this study is to determine the feasibility of subendocardial and subepicardial MBF in normal human hearts assessed with 15O-labeled water PET.
Twenty-seven healthy subjects (mean age 41 ± 13 years; 11 men) were studied with 15O-labeled water PET to quantify resting and hyperaemic (adenosine) MBF at a subendocardial and subepicardial level. In addition, cardiac magnetic resonance imaging was performed to determine left ventricular (LV) volumes and function.
Mean rest MBF was 1.46 ± 0.49 in the subendocardium, and 1.14 ± 0.342 mL · min−1 · g−1 in the subepicardium (P < .001). MBF during vasodilation was augmented to a greater extent at the subepicardial level (subendocardium vs subepicardium: 3.88 ± 0.86 vs 4.14 ± 0.88 mL · min−1 · g−1, P = .013). The endocardial-to-epicardial MBF ratio decreased significantly during hyperaemia (1.35 ± 0.23 to 1.12 ± 0.20, P < .001). Hyperaemic transmural MBF was inversely correlated with left ventricular end-diastolic volume index (LVEDVI) (r2 = 0.41, P = .0003), with greater impact however at the subendocardial level.
15O-labeled water PET enables MBF measurements with distinction of the subendocardial and subepicardial layers in the normal human heart and correlates with LVEDVI. This PET technique may prove useful in evaluating patients with signs of ischaemia due to coronary artery disease or microvascular dysfunction.
PMCID: PMC3143328  PMID: 21519976
Positron emission tomography; imaging; coronary microcirculation; myocardial blood flow; subendocardial
19.  Voxel-wise quantification of myocardial blood flow with cardiovascular magnetic resonance: effect of variations in methodology and validation with positron emission tomography 
Quantitative assessment of myocardial blood flow (MBF) from cardiovascular magnetic resonance (CMR) perfusion images appears to offer advantages over qualitative assessment. Currently however, clinical translation is lacking, at least in part due to considerable disparity in quantification methodology. The aim of this study was to evaluate the effect of common methodological differences in CMR voxel-wise measurement of MBF, using position emission tomography (PET) as external validation.
Eighteen subjects, including 9 with significant coronary artery disease (CAD) and 9 healthy volunteers prospectively underwent perfusion CMR. Comparison was made between MBF quantified using: 1. Calculated contrast agent concentration curves (to correct for signal saturation) versus raw signal intensity curves; 2. Mid-ventricular versus basal-ventricular short-axis arterial input function (AIF) extraction; 3. Three different deconvolution approaches; Fermi function parameterization, truncated singular value decomposition (TSVD) and first-order Tikhonov regularization with b-splines. CAD patients also prospectively underwent rubidium-82 PET (median interval 7 days).
MBF was significantly higher when calculated using signal intensity compared to contrast agent concentration curves, and when the AIF was extracted from mid- compared to basal-ventricular images. MBF did not differ significantly between Fermi and Tikhonov, or between Fermi and TVSD deconvolution methods although there was a small difference between TSVD and Tikhonov (0.06 mL/min/g). Agreement between all deconvolution methods was high. MBF derived using each CMR deconvolution method showed a significant linear relationship (p < 0.001) with PET-derived MBF however each method underestimated MBF compared to PET (by 0.19 to 0.35 mL/min/g).
Variations in more complex methodological factors such as deconvolution method have no greater effect on estimated MBF than simple factors such as AIF location and observer variability. Standardization of the quantification process will aid comparison between studies and may help CMR MBF quantification enter clinical use.
PMCID: PMC3904701  PMID: 24460930
Cardiovascular magnetic resonance; Coronary artery disease; Myocardial blood flow; Positron emission tomography; Quantification
20.  In vivo characterization of rodent cyclic myocardial perfusion variation at rest and during adenosine-induced stress using cine-ASL cardiovascular magnetic resonance 
Assessment of cyclic myocardial blood flow (MBF) variations can be an interesting addition to the characterization of microvascular function and its alterations. To date, totally non-invasive in vivo methods with this capability are still lacking. As an original technique, a cine arterial spin labeling (ASL) cardiovascular magnetic resonance approach is demonstrated to be able to produce dynamic MBF maps across the cardiac cycle in rats.
High-resolution MBF maps in left ventricular myocardium were computed from steady-state perfusion-dependent gradient-echo cine images produced by the cine-ASL sequence. Cyclic changes of MBF over the entire cardiac cycle in seven normal rats were analyzed quantitatively every 6ms at rest and during adenosine-induced stress.
The study showed a significant MBF increase from end-systole (ES) to end-diastole (ED) in both physiological states. Mean MBF over the cardiac cycle within the group was 5.5 ± 0.6 mL g-1 min-1 at rest (MBFMin = 4.7 ± 0.8 at ES and MBFMax = 6.5 ± 0.6 mL g-1 min-1 at ED, P = 0.0007). Mean MBF during adenosine-induced stress was 12.8 ± 0.7mL g-1 min-1 (MBFMin = 11.7±1.0 at ES and MBFMax = 14.2 ± 0.7 mL g-1 min-1 at ED, P = 0.0007). MBF percentage relative variations were significantly different with 27.2 ± 9.3% at rest and 17.8 ± 7.1% during adenosine stress (P = 0.014). The dynamic analysis also showed a time shift of peak MBF within the cardiac cycle during stress.
The cyclic change of myocardial perfusion was examined by mapping MBF with a steady-pulsed ASL approach. Dynamic MBF maps were obtained with high spatial and temporal resolution (6ms) demonstrating the feasibility of non-invasively mapping cyclic myocardial perfusion variation at rest and during adenosine stress. In a pathological context, detailed assessment of coronary responses to infused vasodilators may give valuable complementary information on microvascular functional defects in disease models.
PMCID: PMC3937054  PMID: 24548535
Myocardial blood flow; Microcirculation; Adenosine; Perfusion; Rat heart
21.  Resting myocardial perfusion quantification with CMR arterial spin labeling at 1.5 T and 3.0 T 
The magnetic resonance technique of arterial spin labeling (ASL) allows myocardial perfusion to be quantified without the use of a contrast agent. This study aimed to use a modified ASL technique and T1 regression algorithm, previously validated in canine models, to calculate myocardial blood flow (MBF) in normal human subjects and to compare the accuracy and repeatability of this calculation at 1.5 T and 3.0 T. A computer simulation was performed and compared with experimental findings.
Eight subjects were imaged, with scans at 3.0 T showing significantly higher T1 values (P < 0.001) and signal-to-noise ratios (SNR) (P < 0.002) than scans at 1.5 T. The average MBF was found to be 0.990 ± 0.302 mL/g/min at 1.5 T and 1.058 ± 0.187 mL/g/min at 3.0 T. The repeatability at 3.0 T was improved 43% over that at 1.5 T, although no statistically significant difference was found between the two field strengths. In the simulation, the accuracy and the repeatability of the MBF calculations were 61% and 38% higher, respectively, at 3.0 T than at 1.5 T, but no statistically significant differences were observed. There were no significant differences between the myocardial perfusion data sets obtained from the two independent observers. Additionally, there was a trend toward less variation in the perfusion data from the two observers at 3.0 T as compared to 1.5 T.
This suggests that this ASL technique can be used, preferably at 3.0 T, to quantify myocardial perfusion in humans and with further development could be useful in the clinical setting as an alternative method of perfusion analysis.
PMCID: PMC2654036  PMID: 19014709
22.  Computational Fluid Dynamics Simulations of Contrast Agent Bolus Dispersion in a Coronary Bifurcation: Impact on MRI-Based Quantification of Myocardial Perfusion 
Contrast-enhanced first-pass magnetic resonance imaging (MRI) in combination with a tracer kinetic model, for example, MMID4, can be used to determine myocardial blood flow (MBF) and myocardial perfusion reserve (MPR). Typically, the arterial input function (AIF) required for this methodology is estimated from the left ventricle (LV). Dispersion of the contrast agent bolus might occur between the LV and the myocardial tissue. Negligence of bolus dispersion could cause an error in MBF determination. The aim of this study was to investigate the influence of bolus dispersion in a simplified coronary bifurcation geometry including one healthy and one stenotic branch on the quantification of MBF and MPR. Computational fluid dynamics (CFD) simulations were combined with MMID4. Different inlet boundary conditions describing pulsatile and constant flows for rest and hyperemia and differing outflow conditions have been investigated. In the bifurcation region, the increase of the dispersion was smaller than inside the straight vessels. A systematic underestimation of MBF values up to −16.1% for pulsatile flow and an overestimation of MPR up to 7.5% were found. It was shown that, under the conditions considered in this study, bolus dispersion can significantly influence the results of quantitative myocardial MR-perfusion measurements.
PMCID: PMC3600257  PMID: 23533541
23.  Indirect Radionuclide Coronary Angiography to Evaluate Gradients of Myocardial Blood Flow and Flow Reserve Through Coronary Stenosis Using N-13 Ammonia PET/CT 
Chonnam Medical Journal  2013;49(2):69-74.
Although quantitative evaluation of myocardial blood flow (MBF) and myocardial flow reserve (MFR) has been perceived as an attractive advantage of positron emission tomography (PET) over other cardiac imaging technologies, application of the information to specific coronary lesions is a difficult task for nuclear cardiologists. We hypothesized that changes in MBF and MFR over a coronary lesion could be identified by use of a hybrid technology of CT coronary angiography (CTCA) and N-13 ammonia PET. To evaluate this hypothesis, we measured the gradient of MBF and MFR through coronary stenosis in seven patients (M:F=3:4, median age 56 years) with coronary artery disease who underwent N-13 ammonia PET, CTCA, and interventional coronary angiography. Two patients had proximal left anterior descending (LAD) coronary artery disease and five patients had mid to distal LAD disease. Mean global stress and rest MBF were 2.62±0.58 and 1.03±0.19 ml/min/g, respectively. Mean global MFR was 2.6±0.73. Regional stress and rest MBF in the LAD territory were 2.36±0.75 and 0.96±0.21 ml/min/g, respectively. Regional MFR in the LAD territory was 2.55±0.83 ml/min/g. Stress MBF changed dramatically according to the location of coronary stenosis. It dropped acutely in proximal lesions, whereas it diminished gradually in mid to distal lesions. In conclusion, by use of a hybrid technology of CTCA and PET, it was feasible to make a direct correlation of coronary lesions with the gradient of MFR and CFR through coronary stenosis, which indicated the severity of the coronary lesion. We named this technique indirect radionuclide coronary angiography.
PMCID: PMC3759685  PMID: 24010069
Radionuclide imaging; Coronary angiography; Mycocardium
24.  Quantitative Relationship Between Coronary Vasodilator Reserve Assessed by Rubidium-82 PET Imaging and Coronary Artery Stenosis Severity 
The relationship between myocardial blood flow (MBF) and stenosis severity has been determined previously using cyclotron-produced radiotracers such as 15O-H2O and 13N-ammonia. An attractive alternative to overcome the limitations related to the use of cyclotron might be to use the generator-produced Rubidium-82 as a flow tracer. The current study was undertaken to investigate the relationship between MBF and coronary vasodilator reserve (CVR) as measured by Rubidium-82 positron emission tomography (PET) and the percent diameter stenosis as defined by quantitative coronary arteriography.
We prospectively evaluated 22 individuals: 15 patients (60±11 years of age) with angiographically documented coronary artery disease (CAD) and seven age-matched (56±9 years) asymptomatic individuals without risk factors for CAD. Dynamic Rubidium-82 PET was performed at rest and after dipyridamole vasodilation. MBF, CVR and an index of “minimal coronary resistance” (MCR) were assessed in each of the three main coronary territories.
Rest and stress MBF in regions subtended by vessels with <50% diameter stenosis was similar to that of the individuals with no risk factors for CAD. As a result, CVR was also similar in the two groups (1.9, interquartile [IQ] range from 1.7 to 2.7 vs. 2.2, IQ range from 2 to 3.4 respectively, p=0.09)). CVR successfully differentiated coronary lesions with stenosis severity 70% to 89% from those with 50% to 69% stenosis (1, IQ range from 1 to 1.3 vs. 1.7, IQ range from 1.4 to 2), respectively, p=0.001. In addition, hyperaemic MBF (r2=.74, p<0.001), CVR (r2=.69, p<0.001), and MCR (r2=.78, p<0.001) measurements were inversely and non-linearly correlated to the percent diameter stenosis on angiography.
MBF and CVR are inversely and non-linearly correlated to stenosis severity. Quantitative Rubidium-82 PET can be a clinically useful tool for an accurate functional assessment of CAD.
PMCID: PMC3124702  PMID: 18425513
Myocardial blood flow; Positron Emission Tomography; Rubidium-82
25.  Effects of coronary revascularisation on myocardial blood flow and coronary vasodilator reserve in hibernating myocardium 
Heart  2001;85(2):208-212.
OBJECTIVE—Previous studies have suggested that resting myocardial blood flow is within normal limits in most chronically dysfunctional left ventricular segments which improve function after coronary artery revascularisation (hibernating myocardium). The aim of this study was to assess myocardial blood flow and coronary vasodilator reserve in hibernating myocardium before and after coronary revascularisation.
PATIENTS AND METHODS— 30 patients with multivessel coronary disease undergoing coronary revascularisation (21 patients with bypass grafting and nine with coronary angioplasty), and 21 age and sex matched healthy volunteers (controls). Myocardial blood flow (MBF, ml/min/g) was measured by positron emission tomography using oxygen-15 water at rest and after dipyridamole (MBFdip, 0.56 mg/kg in four minutes). Coronary vasodilator reserve was calculated as MBFdip/MBF. Regional wall motion was assessed with echocardiography.
RESULTS—Before revascularisation there were 48 remote and 275 dysfunctional myocardial segments, of which 163 (59%) improved function after revascularisation (hibernating). In hibernating segments coronary vasodilator reserve before revascularisation was significantly lower than in remote segments (1.97 (0.7), p < 0.0001) and controls (3.2 (1.5), p < 0.0001). In hibernating segments, myocardial blood flow remained unchanged after revascularisation (0.94 (0.3) v 0.95 (0.3) ml/min/g, p = 0.3) while coronary vasodilator reserve increased (1.47 (0.7) v 1.98 (1.0), p < 0.0001). Myocardial blood flow was similar in remote, hibernating segments before and after revascularisation and in controls.
CONCLUSIONS—This study confirms that myocardial blood flow at rest in hibernating myocardium is within normal limits in most segments, and that hibernating myocardium is characterised by an impaired coronary vasodilator reserve which improves significantly after coronary revascularisation.

Keywords: hibernating myocardium; myocardial blood flow; heart failure; positron emission tomography
PMCID: PMC1729621  PMID: 11156674

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