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1.  Changes of Coronary Blood Flow in Vasospastic Angina under Cold Stimulation by Transthoracic Doppler Echocardiography 
Journal of Korean Medical Science  2005;20(2):204-208.
This study was done to evaluate changes of microvascular function under cold stimulation by measuring coronary flow velocities (CFVs) in vasospastic angina (VA) patients using transthoracic Doppler echocardiography (TTDE). 14 patients with VA and 15 healthy controls were included. CFVs were measured at the distal left anterior descending coronary artery by TTDE at baseline and under cold stimulation. Hyperemia was induced by intravenous adenosine infusion (140 µg/kg/min). At baseline, CFVs and coronary flow reserve (CFR) were not different between controls and VA patients. Under cold stimulation, the degree of increment of CFV with adenosine was lower in VA patients than in controls. Comparing baseline with cold stimulation, coronary flow reserve (CFR) increased (3.1±0.7 to 3.8±1.0, p=0.06) in controls. In contrast, in VA patients, CFR was decreased (2.8±0.9 to 2.6±0.7, p=0.05) and coronary vascular resistance index markedly increased (0.35 to 0.43, p=0.01). Throughout the study, no patient experienced chest pain or ECG changes. In VA patients, CFR was preserved at baseline, but coronary blood flow increase in response to cold stimulation was blunted and CFR was decreased. These findings suggest that endothelial dependent vasodilation is impaired at the coronary microvascular and the epicardial artery level in VA under cold stimulation.
PMCID: PMC2808592  PMID: 15831987
Angina Pectoris, Variant; Coronary Vasospasm; Cold Stimulation; Regional Blood Flow; Microvascular Function; Echocardiography, Doppler
2.  Non-invasive evaluation of myocardial reperfusion by transthoracic Doppler echocardiography and single-photon emission computed tomography in patients with anterior acute myocardial infarction 
The study was designed to evaluate whether the preserved coronary flow reserve (CFR) 72 hours after reperfused acute myocardial infarction (AMI) is associated with less microvascular dysfunction and is predictive of left ventricular (LV) functional recovery and the final infarct size at follow-up.
In our study, CFR was assessed by transthoracic Doppler echocardiography (TDE) in 44 patients after the successful percutaneous coronary intervention during the acute AMI phase. CFR was correlated with contractile reserve assessed by low-dose dobutamine echocardiography and with the total perfusion defect measured by single-photon emission computed tomography 72 hours after reperfusion and at 5 months follow-up. The ROC analysis was performed to determine test sensitivity and specificity based on CFR. Categorical data were compared by an χ2 analysis, continuous variables were analysed with the independent Student's t test. In order to analyse correlation between CFR and the parameters of LV function and perfusion, the Pearson correlation analysis was conducted. The linear regression analysis was used to assess the relationship between CFR and myocardial contractility as well as the final infarct size.
We estimated the CFR cut-off value of 1.75 as providing the maximal accuracy to distinguish between patients with preserved and impaired CFR during the acute AMI phase (sensitivity 91.7%, specificity 75%). Wall motion score index was better in the subgroup with preserved CFR as compared to the subgroup with reduced CFR: 1.74 (0.29) vs. 1.89 (0.17) (p < 0.001) during the acute phase and 1.47 (0.30) vs. 1.81 (0.20) (p < 0.001) at follow-up, respectively. LV ejection fraction was 47.78% (8.99) in preserved CFR group vs. 40.79% (7.25) in impaired CFR group (p = 0.007) 72 hours after reperfusion and 49.78% (8.70) vs. 40.36% (7.90) (p = 0.001) after 5 months at follow-up, respectively. The final infarct size was smaller in patients with preserved as compared to patients with reduced CFR: 5.26% (6.14) vs. 23.28% (12.19) (p < 0.001) at follow-up.
The early measurement of CFR by TDE can be of high value for the assessment of successful reperfusion in AMI and can be used to predict LV functional recovery, myocardial viability and the final infarct size.
PMCID: PMC3123269  PMID: 21619676
Myocardial infarction; contractile function; coronary flow reserve; reperfusion
3.  Association between Cardiac Troponin Level and Coronary Flow Reserve in Patients without Coronary Artery Disease: Insight from a Thermodilution Technique Using an Intracoronary Pressure Wire 
Korean Circulation Journal  2014;44(3):141-147.
Background and Objectives
Cardiac troponins are associated with increased mortality, even among patients with no coronary artery disease. Elevated cardiac troponin levels are frequently observed in patients without significant coronary lesions, although the mechanism underlying this finding is unclear. The aim of our study was to evaluate the association between the levels of cardiac troponin and coronary flow reserve (CFR).
Subjects and Methods
We evaluated serum cardiac troponin-I in 19 patients (9 female; age 61.9±10.9 year-old). All patients had an ejection fraction >40% and angiographically normal coronary arteries. Simultaneous measurements of fractional flow reserve (FFR), the index of microcirculatory resistance (IMR), and CFR measurements using an intracoronary temperature- and pressure-sensing guidewire under basal conditions and during maximal hyperemia were performed in three vessels: the left anterior descending artery (LAD), left circumflex artery (LCX) and right coronary artery (RCA).
All patients were followed for a median of 13 months. FFR, IMR, and CFR measurements were performed successfully in all subjects. Mean CFRs of LAD, LCX, and RCA were 1.98±1.20, 2.75±2.11, and 4.44±2.51, respectively. Mean IMRs of LAD, LCX and RCA were 33.28±18.78, 29.11±26.70, and 30.55±23.65, respectively. There was a poor correlation between CFR and troponin-I values in each vessel. In selecting the lowest value of CFR in each patient as the corresponding value, the lowest CFR was not associated with troponin-I levels (r=-0.219, p=0.367).
In patients without significant coronary lesions, the correlation between CFR and troponin-I level was not significant using a thermodilution technique. Further study of a larger population with longer-term follow-up may be needed to more fully understand microvascular dysfunction.
PMCID: PMC4037635  PMID: 24876854
Myocardiol coronary flow reserve; Troponin; Vascular resistance; Microvessels
4.  Predicting Myocardial Functional Recovery After Acute Myocardial Infarction: Relationship Between Myocardial Strain and Coronary Flow Reserve 
Korean Circulation Journal  2010;40(12):639-644.
Background and Objectives
The purpose of this study was to evaluate the relationship between myocardial strain and coronary flow reserve (CFR) in the prediction of myocardial functional recovery after acute myocardial infarction (AMI).
Subjects and Methods
Consecutive patients with anterior ST elevation AMI were analyzed. Left ventricular (LV) strain, determined by 2-dimensional speckle tracking imaging and CFR, determined by intracoronary flow measurement, were obtained on the same day, 3-5 days after primary percutaneous coronary intervention. A-strain was defined as the mean systolic longitudinal strain of 11 LV segments (out of 18) assumed to be supplied by the left anterior descending coronary artery (LAD). Functional recovery was defined as improved wall motion >1 grade seen in at least 2 contiguous dysfunctional segments by echocardiography at the 6-month follow-up.
Of 20 patients, 8 patients had preserved CFR (>2.0) and 12 patients had impaired CFR (≤2.0). There were no differences between the 2 CFR groups in LV ejection fractions and wall motion score indices in the LAD territory. However, A-strain was greater in patients with preserved CFR than in patients with impaired CFR (-6.4±2.0% vs. -4.6±1.4%, p=0.03). A-strain and CFR correlated well with each other (r=-0.49, p=0.03). Ten of 20 patients showed functional recovery at 6 months. Of clinical and echocardiographic parameters, A-strain was the only predictor of recovery (odds ratio 2.02, 95% confidence interval=1.03-3.97, p=0.04). For predicting recovery, the sensitivity and specificity were 80.0% and 80.0%, respectively, for CFR (cutoff=1.60), and 60.0% and 90.0%, respectively, for A-strain (cutoff=-6.13%).
Myocardial strain correlates well with the extent of microvascular integrity and can be used as a noninvasive method for predicting recovery after AMI.
PMCID: PMC3025337  PMID: 21267386
Myocardial infarction; Strains
5.  Association of haematological indices with the degree of microvascular injury in patients with acute anterior wall myocardial infarction treated with primary percutaneous coronary intervention 
Heart  2006;93(3):313-318.
In acute myocardial infarction (AMI), increased neutrophil count has been associated with more severe coronary artery disease and larger infarct size. Increased mean platelet volume (MPV) is also associated with poor clinical outcome and impaired angiographic reperfusion in patients with AMI. However, the associations of neutrophil count and MPV with the indices of tissue level reperfusion were not fully elucidated.
To elucidate the relationship between baseline neutrophil count and MPV on presentation and microvascular injury in patients with anterior AMI treated with primary percutaneous coronary intervention (pPCI).
41 patients with anterior wall AMI treated successfully with pPCI were included. The leucocyte count, neutrophil count and MPV were obtained on admission, and the percentage of neutrophils was calculated. After PCI thrombolysis in myocardial infarction, grade 3 flow was established in all patients. The coronary flow velocity pattern (diastolic deceleration time (DDT)) was examined with transthoracic echocardiography and measured intracoronary pressures with fibreoptic pressure–temperature sensor‐tipped guidewire in the left anterior descending artery within 48 h after pPCI. Thermodilution‐derived coronary flow reserve (CFR) was calculated. Index of microvascular resistance (IMR) was defined as simultaneously measured distal coronary pressure divided by the inverse of the thermodilution‐derived hyperaemic mean transit time. Subsequently, a short compliant balloon was placed in the stented segment and inflated to measure coronary wedge pressure (CWP).
Higher neutrophil counts were strongly associated with higher IMR (r = 0.86, p<0.001), lower CFR (r = −0.60, p<0.001), shorter DDT (r = −0.73, p<0.001) and higher CWP (r = 0.73, p<0.001). Likewise, there were significant correlations among the percentage of neutrophils and CFR (r = −0.34, p = 0.02), IMR (r = 0.46, p = 0.002), DDT (r = −0.36, p = 0.01) and CWP (r = 0.49, p = 0.001). Relationships among leucocyte count and IMR (r = 0.38, p = 0.01), CFR (r = −0.33, p =  0.03), DDT (r = −0.36, p = 0.01) and CWP (r = 0.32, p = 0.026) were slightly significant. Higher neutrophil count remained independently associated with indices of microvascular perfusion in multivariable models controlling for age, smoking habits and time to treatment. Also, higher MPV on admission was strongly associated with higher IMR (r = 0.89, p<0.001), steeper DDT (r = −0.64, p<0.001), lower CFR (r = −0.43, p = 0.004) and higher CWP (r = 0.77, p<0.001).
Absolute and relative neutrophilia and higher MPV on admission were independently associated with impaired microvascular perfusion in patients with anterior AMI treated with pPCI. It is possible that neutrophilia and high MPV are simple surrogate markers of worse microvascular injury in patients with AMI.
PMCID: PMC1861446  PMID: 16940390
6.  Aldosterone and Myocardial Extracellular Matrix Expansion in Type 2 Diabetes Mellitus 
Myocardial extracellular matrix expansion and reduced coronary flow reserve (CFR) occur in patients with type 2 diabetes mellitus without heart failure or coronary artery disease. Because aldosterone is implicated in the pathophysiology of cardiac fibrosis and vascular injury, the aim of this study was to test the hypothesis that aldosterone is associated with extracellular matrix expansion and reduced CFR in type 2 diabetes mellitus. Patients with type 2 diabetes mellitus without evidence of coronary artery disease were recruited. Blood pressure, lipid management, and glycemic control were optimized over 3 months. Cardiac magnetic resonance imaging with T1 mapping was used to measure myocardial extracellular volume (ECV). Cardiac positron emission tomography was used to assess CFR. On a liberal, 250 mEq/day sodium diet, 24-hour urinary aldosterone and change in serum aldosterone with angiotensin II stimulation were measured. Fifty-three participants with type 2 diabetes (68% men, mean age 53 ± 7 years, mean body mass index 32.2 ± 4.3 kg/m2, mean glycosylated hemoglobin 6.8 ± 0.7%, mean systolic blood pressure 126 ± 14 mm Hg) without infarction or ischemia by cardiac magnetic resonance and positron emission tomography were studied. Subjects had impaired CFR (2.51 ± 0.83) and elevated ECV (0.36 ± 0.05), despite normal echocardiographic diastolic function and normal left ventricular function. Myocardial ECV, but not CFR, was positively associated with 24-hour urinary aldosterone excretion (r = 0.37, p = 0.01) and angiotensin II–stimulated aldosterone increase (r = 0.35, p = 0.02). In a best-overall multivariate model (including age, gender, body mass index, glycosylated hemoglobin, and blood pressure), 24-hour urinary aldosterone was the strongest predictor of myocardial ECV (p = 0.004). In conclusion, in patients with type 2 diabetes mellitus without coronary artery disease, aldosterone is associated with myocardial extracellular matrix expansion. These results implicate aldosterone in early myocardial remodeling in type 2 diabetes mellitus.
PMCID: PMC3957437  PMID: 23597770
7.  Coronary Flow Reserve in Pregnant Rats with Increased Left Ventricular Afterload 
PLoS ONE  2014;9(7):e102147.
Coronary flow reserve (CFR) is used as a measure of coronary endothelial function. We investigated the effect of increased afterload on CFR of pregnant and non-pregnant rats.
Afterload increase in Wister rats (both pregnant and non-pregnant) was achieved by the infusion of angiotensin II (Ang II) for ∼10 days or by subjecting them to transverse aortic constriction (TAC) for ∼14 days. Control groups were infused with 0.9% NaCl or had sham surgery, respectively. In pregnant rats, the experiments were performed close to term gestation. Doppler velocity waveforms of the left main coronary artery were recorded using a high resolution ultrasound imaging system (Vevo 770, VisualSonics, Canada) at baseline while the animals were anesthetized with 1.5% inhaled isoflurane, and during maximal coronary dilatation obtained by the inhalation of 3.5% of isoflurane. CFR was calculated as the ratio between the peak coronary flow velocities (CFRpeak) and the velocity-time integrals (CFRVTI) recorded at hyperemia and at baseline.
CFR could be calculated in 60 of 75 (80%) animals. There were no differences in CFR between intervention and control groups irrespective of whether afterload was increased by Ang II or TAC. In the TAC-study CFRpeak (1.54±0.07 vs 1.85±0.17; p = 0.03) was decreased in pregnant compared to non-pregnant shams. When sham animals from both studies were pooled together both CFRpeak (1.42±0.07 vs 1.86±0.16; p = 0.005) as well as CFRVTI (1.45±0.07 vs 1.78±0.12; p = 0.03) were significantly lower in pregnant rats compared to non-pregnant.
CFR can be measured non-invasively in rats using Doppler echocardiography and high concentrations of inhaled isoflurane as a coronary vasodilator. In pregnant rats, CFR is reduced close to term. CFR is not affected by increased left ventricular afterload caused by chronic Ang II infusion or TAC.
PMCID: PMC4089919  PMID: 25007056
8.  The relationship between ischemia-induced left ventricular dysfunction, coronary flow reserve, and coronary steal on regadenoson stress-gated 82Rb PET myocardial perfusion imaging 
Gated rubidium-82 (82Rb) positron emission tomography (PET) imaging studies are acquired both at rest and during pharmacologic stress. Stress-induced ischemic left ventricular dysfunction (LVD) can produce a significant decrease in left ventricular ejection fraction (LVEF) from rest to stress. We determined the prevalence on PET of stress LVD with reduced ejection fraction (EF) and its association with absolute global and regional coronary flow reserve (CFR), and with relative perfusion defect summed difference score (SDS).
Methods and Results
We studied 205 patients with known or suspected coronary disease (120 M, 75 F, age 69 ± 13 years) who had clinically indicated rest/regadenoson stress 82Rb PET/CT studies. Data were acquired in dynamic gated list mode. Global and 17-segment regional CFR values were computed from first-pass flow data using a 2-compartment model and factor analysis applied to auto-generated time-activity curves. Rest and stress LVEF and SDS were quantified from gated equilibrium myocardial perfusion tomograms using Emory Cardiac Toolbox software. LVD was defined as a change in LVEF of ≤−5% from rest to stress. A subgroup of 109 patients also had coronary angiography. Stress LVD developed in 32 patients (16%), with mean EF change of −10 ± 5%, vs +6 ± 7% for patients without LVD (P < .0001). EF was similar at rest in patients with and without stress LVD (57 ± 18% vs 56 ± 16%, P = .63), but lower during stress for patients with LVD (47 ± 20% vs 61 ± 16%, P = .0001). CFR was significantly lower in patients with LVD (1.61 ± 0.67 vs 2.21 ± 1.03, Wilcoxon P = .002), and correlated significantly with change in EF (r = 0.35, P < .0001), but not with SDS (r = −0.13, P = .07). The single variable most strongly associated with high risk of CAD (i.e., left main stenosis ≥50%, LAD % stenosis ≥70%, and/or 3-vessel disease) was stress EF (χ2 = 17.3, P < .0001). There was a higher prevalence of patients with territorial CFR values ≤1.0, consistent with coronary steal, in the LVD group than in the non-LVD group (39% vs 12%, P = .001).
LVD developed in 16% of patients undergoing 82Rb PET myocardial perfusion imaging, and was associated with multivessel coronary artery disease. There was a significant relationship between LVD and coronary blood flow during stress, with LVD corresponding to a low CFR. Territorial CFR ≤1.0 was more common in patients with LVD than those without, suggesting that coronary steal is an important pathophysiologic mechanism contributing to pharmacologic stress-induced LVD.
PMCID: PMC4209719  PMID: 24092270
PET/CT; left ventricular dysfunction; myocardial perfusion imaging; PET; coronary flow reserve; quantification; rubidium isotopes
9.  Target heart rate to determine the normal value of coronary flow reserve during dobutamine stress echocardiography 
The determination of coronary flow reserve (CFR) is an essential concept at the moment of decision-making in ischemic heart disease. There are several direct and indirect tests to evaluate this parameter. In this sense, dobutamine stress echocardiography is one of the pharmacological method most commonly used worldwide. It has been previously demonstrated that CFR can be determined by this technique. Despite our wide experience with dobutamine stress echocardiography, we ignored the necessary heart rate to consider sufficient the test for the analysis of CFR. For this reason, our main goal was to determine the velocity of coronary flow in each stage of dobutamine stress echocardiography and the heart rate value necessary to double the baseline values of coronary flow velocity in the territory of the left anterior descending (LAD) coronary artery.
A total of 33 consecutive patients were analyzed. The patients included had low risk for coronary artery disease. All the participants underwent dobutamine stress echocardiography and coronary artery flow velocity was evaluated in the distal segment of LAD coronary artery using transthoracic color-Doppler echocardiography.
The feasibility of determining CFR in the territory of the LAD during dobutamine stress echocardiography was high: 31/33 patients (94%). Mean CFR was 2.67 at de end of dobutamine test.
There was an excellent concordance between delta HR (difference between baseline HR and maximum HR) and the increase in the CFR (correlation coefficient 0.84). In this sense, we found that when HR increased by 50 beats, CFR was ≥ 2 (CI 93-99.2%). In addition, 96.4% of patients reached a CFR ≥ 2 (IC 91.1 - 99%) at 75% of their predicted maximum heart rate.
We found that the feasibility of dobutamine stress echocardiography to determine CFR in the territory of the LAD coronary artery was high. In this study, it was necessary to achieve a difference of 50 bpm from baseline HR or at least 75% of the maximum predicted heart rate to consider sufficient the test for the analysis of CFR.
PMCID: PMC3080796  PMID: 21457582
10.  Transthoracic coronary flow reserve and dobutamine derived myocardial function: a 6-month evaluation after successful coronary angioplasty 
After percutaneous transluminal coronary angioplasty (PTCA), stress-echocardiography and gated single photon emission computerized tomography (g-SPECT) are usually performed but both tools have technical limitations. The present study evaluated results of PTCA of left anterior descending artery (LAD) six months after PTCA, by combining transthoracic Doppler coronary flow reserve (CFR) and color Tissue Doppler (C-TD) dobutamine stress.
Six months after PTCA of LAD, 24 men, free of angiographic evidence of restenosis, underwent standard Doppler-echocardiography, transthoracic CFR of distal LAD (hyperemic to basal diastolic coronary flow ratio) and C-TD at rest and during dobutamine stress to quantify myocardial systolic (Sm) and diastolic (Em and Am, Em/Am ratio) peak velocities in middle posterior septum. Patients with myocardial infarction, coronary stenosis of non-LAD territory and heart failure were excluded. According to dipyridamole g-SPECT, 13 patients had normal perfusion and 11 with perfusion defects. The 2 groups were comparable for age, wall motion score index (WMSI) and C-TD at rest. However, patients with perfusion defects had lower CFR (2.11 ± 0.4 versus 2.87 ± 0.6, p < 0.002) and septal Sm at high-dose dobutamine (p < 0.01), with higher WMSI (p < 0.05) and stress-echo positivity of LAD territory in 5/11 patients. In the overall population, CFR was related negatively to high-dobutamine WMSI (r = -0.50, p < 0.01) and positively to high-dobutamine Sm of middle septum (r = 0.55, p < 0.005).
In conclusion, even in absence of epicardial coronary restenosis, stress perfusion imaging reflects a physiologic impairment in coronary microcirculation function whose magnitude is associated with the degree of regional functional impairment detectable by C-TD.
PMCID: PMC539289  PMID: 15581428
Percutaneous coronary angioplasty; Coronary flow reserve; Color Tissue Doppler; Stress-echo
11.  Prognostic Interplay of Coronary Artery Calcification and Underlying Vascular Dysfunction in Patients With Suspected Coronary Artery Disease 
This study sought to evaluate the interrelation of atherosclerotic burden, as assessed by coronary artery calcium (CAC) score and coronary vascular function, as assessed by quantitative estimates of coronary flow reserve (CFR), with respect to prediction of clinical outcomes.
The contribution of coronary vascular dysfunction, atherosclerotic burden, and the 2 combined to cardiac events is unknown.
A total of 901 consecutive patients underwent 82Rubidium myocardial perfusion imaging (MPI) positron emission tomography (PET) and CAC scan. All patients had normal MPI. The primary endpoint was a composite of major adverse cardiac events (MACE) including cardiac death, nonfatal myocardial infarction, late revascularization, and admission for heart failure.
At baseline, CFR decreased (2.15 ± 0.72, 2.02 ± 0.65, and 1.88 ± 0.64, p < 0.0001) with increasing levels of CAC (0, 1 to 399, and ≥400). Over a median of 1.53 years (interquartile range: 0.77 to 2.44), there were 57 MACE. Annual risk-adjusted MACE rates were higher for patients with CFR <2.0 compared with ≥2.0 (1.9 vs. 5.5%/year, p = 0.0007) but were only borderline associated with CAC (3.1%, 3.4%, and 6.2%/year for CAC of 0, 1 to 399, and ≥400, respectively; p = 0.09). Annualized adjusted MACE was increased in the presence of impaired CFR even among patients with CAC = 0 (1.4% vs. 5.2%, p = 0.03). Cox proportional hazards analysis revealed that CFR improved model fit, risk discrimination, and risk reclassification over clinical risk, whereas CAC only modestly improved model fit without improving risk discrimination or reclassification.
In symptomatic patients with normal MPI, global CFR but not CAC provides significant incremental risk stratification over clinical risk score for prediction of major adverse cardiac events.
PMCID: PMC3753576  PMID: 23524053
atherosclerotic burden; coronary artery calcium; coronary flow reserve; hybrid PET/CET; prognosis
12.  Transthoracic measurement of left coronary artery flow reserve improves the diagnostic value of routine dipyridamole-atropine stress echocardiogram 
We hypothesized that coronary flow reserve (CFR) in the left anterior descending artery (LAD) can be effectively measured during an accelerated dipyridamole-atropine stress echocardiography (DASE) protocol to improve the diagnostic performance of the test.
Material and methods
In 64 patients with suspected or known coronary artery disease scheduled for coronary angiography DASE with concomitant CFR measurement in LAD was performed.
Coronary flow reserve measurement and calculation were feasible in 83% of patients. The positive predictive value of undetectable LAD flow was 81% for severe LAD disease. Measured values of CFR were in the range 1.3–4.1 (mean: 2.2 ±0.7). Significantly lower CFR was found in patients with LAD disease (1.97 ±0.62 vs. 2.55 ±0.57, p = 0.0015). The optimal cutoff for detecting ≥ 50% stenosis was CFR ≤ 2.1 (ROC AUC 0.776), corresponding with 68% sensitivity and 84% specificity. In patients with negative DASE results 67% of patients with LAD disease had abnormal CFR, whereas in patients with a positive DASE result 92% of patients with normal LAD had normal CFR. The DASE diagnostic accuracy for the detection of coronary artery disease (CAD) increased from 75% to 85% when CFR measurement was added to wall motion abnormality (WMA) analysis. No test with both abnormalities was false positive for the detection of coronary disease.
Incorporation of CFR measurement into WMA-based stress echocardiography is feasible even in an accelerated DASE protocol and can be translated into an approximate gain of 10% in overall test accuracy.
PMCID: PMC3832825  PMID: 24273560
coronary circulation; cardiac ultrasound; stress echocardiography
13.  Remote ischemic conditioning improves coronary microcirculation in healthy subjects and patients with heart failure 
Remote ischemic conditioning (RIC) is a treatment modality that suppresses inflammation and improves endothelial function, which are factors involved in the pathogenesis of heart failure (HF) with reduced left ventricular ejection fraction. Coronary flow reserve (CFR) is a physiological index of coronary microcirculation and is noninvasively measured by transthoracic Doppler echocardiography (TTDE). This study aimed to investigate the effects of RIC on CFR in healthy subjects and patients with HF, through the assessment by TTDE.
Ten patients with HF with left ventricular ejection fraction of less than 40%, and ten healthy volunteers were enrolled in this study. RIC treatment was performed twice a day for 1 week. Our custom-made RIC device was programmed to automatically conduct 4 cycles of 5 minutes inflation and 5 minutes deflation of a blood pressure cuff to create intermittent arm ischemia. CFR measurements and laboratory tests were examined before, and after 1 week of RIC treatment.
One week of RIC treatment was well tolerated in both groups. RIC treatment increased CFR from 4.0±0.9 to 4.6±1.3 (mean ± standard deviation) in healthy subjects (P=0.02), and from 1.9±0.4 to 2.3±0.7 in patients with HF (P=0.03), respectively. Systolic blood pressure in healthy subjects, and heart rate in HF patients decreased after RIC treatment (both P<0.01).
This study demonstrated that a 1 week course of RIC treatment improved coronary microcirculation in healthy subjects and patients with HF associated with reduced left ventricular ejection fraction.
PMCID: PMC4154883  PMID: 25210440
echocardiography; coronary flow reserve; heart failure; preconditioning; rehabilitation
14.  Non‐invasive coronary flow reserve is correlated with microvascular integrity and myocardial viability after primary angioplasty in acute myocardial infarction 
Heart  2006;92(8):1113-1118.
To test whether preserved coronary flow reserve (CFR) two days after reperfused acute myocardial infarction (AMI) is associated with less microvascular dysfunction (“ no‐reflow” phenomenon) and is predictive of myocardial viability.
24 patients with anterior AMI underwent CFR assessment in the left anterior descending coronary artery (LAD) with transthoracic echocardiography and myocardial contrast echocardiography (MCE) 48 h after primary angioplasty in the LAD (mean 4 (SD 2) and 3 (1) days, respectively). Low‐dose dobutamine echocardiography was performed 6 (3) days after AMI and follow‐up echocardiography at three months.
No‐reflow extent was greater in patients with impaired CFR (< 2.5) than in those with preserved CFR (> 2.5) (55 (35)% v 11 (25)%, p < 0.001). MCE reflow was more common in patients with preserved CFR (8/12) than in those with reduced CFR (1/12, p < 0.05). Wall motion score index in the LAD territory (A‐WMSI) was similar at the first echocardiography (2.14 (0.39) v 2.32 (0.47), NS), although it was better in patients with preserved CFR at dobutamine (1.38 (0.45) v 1.97 (0.67), p < 0.05) and follow‐up echocardiography (1.36 (0.40) v 1.97 (0.64), p < 0.05). An inverse correlation was found between CFR and A‐WMSI at dobutamine and follow‐up echocardiography (r  =  −0.49, p  =  0.016 and r  =  −0.55, p  =  0.005) and between MCE and A‐WMSI at dobutamine and follow‐up echocardiography (r  =  −0.75, p < 0.001 and r  =  −0.75, p < 0.001). By multivariate analysis MCE reflow remained the only predictor of recovery at both dobutamine and follow‐up echocardiography (odds ratio 1.06, 95% CI 1 to 1.1, p  =  0.009).
CFR is inversely correlated with the extent of microvascular dysfunction at MCE two days after reperfused AMI. CFR and MCE reflow early after AMI are correlated with myocardial viability at follow up.
PMCID: PMC1861096  PMID: 16449513
15.  Coronary Flow Reserve in the Remote Myocardium Predicts Left Ventricular Remodeling Following Acute Myocardial Infarction 
Yonsei Medical Journal  2014;55(4):904-911.
Coronary flow reserve (CFR) in the non-infarcted myocardium is often impaired following acute myocardial infarction (AMI). However, the clinical significance of CFR in the non-infarcted myocardium is not fully understood. The objective of the present study was to assess whether a relationship exists between CFR and left ventricular remodeling following AMI.
Materials and Methods
We enrolled 18 consecutive patients undergoing coronary intervention. Heart function was analyzed using real-time myocardial contrast echocardiography at one week and six months after coronary angioplasty. Ten subjects were enrolled as the control group and were examined using the same method at the same time to assess CFR. Cardiac troponin I (cTnI) levels were routinely analyzed to estimate peak concentration.
CFR was 1.55±0.11 in the infarcted zone and 2.05±0.31 in the remote zone (p<0.01) at one week following AMI. According to CFR values in the remote zone, all patients were divided into two groups: Group I (CFR <2.05) and Group II (CFR >2.05). The levels of cTnI were higher in Group I compared to Group II on admission (36.40 vs. 21.38, p<0.05). Furthermore, left ventricular end diastolic volume was higher in Group I compared to Group II at six months following coronary angioplasty.
Microvascular dysfunction is commonly observed in the remote myocardium. The CFR value accurately predicts adverse ventricular remodeling following AMI.
PMCID: PMC4075393  PMID: 24954317
Myocardial infarction; microvascular dysfunction; left ventricular remodeling
16.  Association Between Coronary Vascular Dysfunction and Cardiac Mortality in Patients with and without Diabetes Mellitus 
Circulation  2012;126(15):1858-1868.
Diabetes increases the risk of adverse cardiac outcomes and is considered a coronary artery disease (CAD) equivalent. We examined whether coronary vascular dysfunction, an early manifestation of CAD, accounts for increased risk among patients with diabetes compared to non-diabetics.
Methods and Results
2783 consecutive patients (1172 diabetics and 1611 non-diabetics) underwent quantification of coronary flow reserve (CFR=stress divided by rest myocardial blood flow) by PET and were followed for a median of 1.4 years (Q1–Q3: 0.7–3.2). The primary endpoint was cardiac death. Impaired CFR (below the median) was associated with an adjusted 3.2 and 4.9-fold increase in the rate of cardiac death for diabetics and non-diabetics, respectively (p=0.0004). Addition of CFR to clinical and imaging risk models improved risk discrimination both diabetics and non-diabetics (c-index: 0.77 to 0.79, p=0.04, and 0.82 to 0.85, p=0.03, respectively). Diabetic patients without known CAD with impaired CFR experienced a rate of cardiac death comparable to that for non-diabetic patients with known CAD (2.8 vs 2.0%/year, P=0.33). Conversely, diabetics without known CAD and preserved CFR had very low annualized cardiac mortality, which was similar to patients without known CAD or diabetes and normal stress perfusion and systolic function (0.3 vs. 0.5%/year, P=0.65).
Coronary vasodilator dysfunction is a powerful, independent correlate of cardiac mortality among both diabetics and non-diabetics and provides meaningful incremental risk stratification. Among diabetic patients without CAD, those with impaired CFR have event rates comparable to patients with prior CAD while those with preserved CFR have event rates comparable to non-diabetics.
PMCID: PMC3495105  PMID: 22919001
coronary disease; diabetes mellitus; imaging; myocardial perfusion imaging
17.  Effect of Phosphodiesterase Type 5 Inhibition on Microvascular Coronary Dysfunction in Women: A Women’s Ischemia Syndrome Evaluation (WISE) Ancillary Study 
Clinical cardiology  2011;34(8):483-487.
Microvascular coronary dysfunction (MCD) is associated with symptoms, signs of ischemia, and adverse outcomes in women without macrovascular obstructive coronary artery disease (M-CAD). Although, MCD can be quantified using coronary flow reserve (CFR), treatment is poorly defined.
Phosphodiesterase type 5 (PDE-5) inhibition acutely improves MCD in these women.
The subjects were 23 symptomatic women (age 54±11 years) participating in an ancillary study of the Women’s Ischemia Syndrome Evaluation (WISE) with baseline CFR ≤3.0 (Doppler flow wire and intracoronary adenosine) and without M-CAD. CFR was re-measured 45 minutes after PDE-5 inhibition (100 mg oral sildenafil). The primary measure of interest was change in CFR adjusted for baseline variables.
The relationship between log2 transformed CFR post–PDE-5 inhibition (adjusted) and baseline was different from the line of identity (slope: 0.55 vs. 1.0, P=0.008; intercept: 0.73 vs. 0.0, P=0.01), indicating that PDE-5 inhibition improves CFR and the lower the baseline CFR, the greater the response. Among women with baseline CFR ≤2.5 (N=11), CFR increased from 2.1±0.2 to 2.7±0.6 (P=0.006). For women with baseline CFR >2.5 (N=12), CFR did not change (3.1±0.3 to 3.0±0.6; P=0.70).
For women with symptoms and signs of ischemia and no M-CAD, PDE-5 inhibition is associated with acute improvement in CFR and the effect concentrates among those with CFR ≤2.5. If these acute effects are sustained, then PDE-5 inhibition would provide a rational strategy for management of MCD in symptomatic women without M-CAD. The longer-term effects warrant study in a randomized trial using a sustained acting PDE-5 inhibitor.
PMCID: PMC3151010  PMID: 21780138
Women; Microvascular coronary dysfunction; Coronary flow reserve; Phosphodiesterase type 5 inhibition
18.  Number and Function of Bone-Marrow Derived Angiogenic Cells and Coronary Flow Reserve in Women without Obstructive Coronary Artery Disease: A Substudy of the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) 
PLoS ONE  2013;8(12):e81595.
In women with ischemia and no obstructive coronary artery disease, the Women's Ischemic Syndrome Evaluation (WISE) observed that microvascular coronary dysfunction (MCD) is the best independent predictor of adverse cardiovascular events. Since coronary microvascular tone is regulated in part by endothelium, we hypothesized that circulating endothelial cells (CEC), which reflect endothelial injury, and the number and function of bone-marrow derived angiogenic cells (BMDAC), which could help repair damaged endothelium, may serve as biomarkers for decreased coronary flow reserve (CFR) and MCD.
We studied 32 women from the WISE cohort. CFR measurements in response to intracoronary adenosine were taken as an index of MCD. We enumerated BMDAC colonies and CEC in peripheral blood samples. BMDAC function was assessed by assay of migration of CD34+ cells toward SDF-1 and measurement of bioavailable nitric oxide (NO). These findings were compared with a healthy reference group and also entered into a multivariable model with CFR as the dependent variable.
Compared with a healthy reference group, women with MCD had lower numbers of BMDAC colonies [16 (0, 81) vs. 24 (14, 88); P = 0.01] and NO [936 (156, 1875) vs. 1168 (668, 1823); P = 0.02]. Multivariable regression analysis showed strong correlation of CFR to the combination of BMDAC colony count and CD34+ cell function (migration and NO) (R2 = 0.45; P<0.05).
The BMDAC function and numbers of BMDAC colonies are decreased in symptomatic women with MCD and are independently associated with CFR. These circulating cells may provide mechanistic insights into MCD in women with ischemia.
PMCID: PMC3846855  PMID: 24312563
19.  Relationship between coronary flow reserve evaluated by phase-contrast cine cardiovascular magnetic resonance and serum eicosapentaenoic acid 
Long-term intake of long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs), especially eicosapentaenoic acid (EPA) is associated with a low risk for cardiovascular disease. Phase-contrast cine cardiovascular magnetic resonance (PC cine CMR) can assess coronary flow reserve (CFR). The present study investigates the relationship between CFR evaluated by PC cine CMR and the serum EPA.
We studied 127 patients (male, 116 (91%); mean age, 72.2 ± 7.4 years) with known or suspected coronary artery disease (CAD). X-ray coronary angiography revealed no significant coronary arterial stenoses (defined as luminal diameter reduction ≥50% on quantitative coronary angiogram (QCA) analysis) in all study participants. Breath-hold PC cine CMR images of the coronary sinus (CS) were acquired to assess blood flow of the CS both at rest and during adenosine triphosphate (ATP) infusion. We calculated CFR as CS blood flow during ATP infusion divided by that at rest. Patients were allocated to groups according to whether they had high (n = 64, EPA ≥ 75.8 μg/mL) or low (n = 63, EPA < 75.8 μg/mL) median serum EPA.
CFR was significantly lower in the low, than in the high EPA group (2.54 ± 1.00 vs. 2.91 ± 0.98, p = 0.038). Serum EPA positively correlated with CFR (R = 0.35, p < 0.001). We defined preserved CFR as > 2.5, which is the previously reported lower limit of normal flow reserve without obstructive CAD. Multivariate analysis revealed that EPA is an independent predictor of CFR > 2.5 (odds ratio, 1.01; 95% confidence interval, 1.00 – 1.02, p = 0.008).
The serum EPA is significantly correlated with CFR in CAD patients without significant coronary artery stenosis.
PMCID: PMC3878179  PMID: 24359564
20.  Nebivolol improves coronary flow reserve in patients with idiopathic dilated cardiomyopathy 
Heart  2006;93(3):319-324.
Impaired coronary flow reserve (CFR) is a significant predictor of poor prognosis in patients with idiopathic dilated cardiomyopathy (IDC). Nebivolol reduces mortality and morbidity in patients with heart failure and left ventricular dysfunction, including cases caused by IDC.
To assess the effects of nebivolol on CFR in patients with IDC.
CFR was measured in 21 clinically stable patients with IDC (mean (SD) ejection fraction 35.7 (6.2)) at baseline and after 1 month of treatment with nebivolol once daily. A control group of apparently healthy subjects who were matched for age and sex was used for comparison. Resting and hyperaemic coronary flows were measured using transthoracic second‐harmonic Doppler echocardiography. None of the subjects had any systemic disease.
After 1 month of treatment, heart rate was reduced significantly (p<0.001). The blood pressure was decreased significantly (p<0.001). The left ventricular end‐diastolic diameter and stroke volume were not changed significantly, but end‐systolic diameter was decreased significantly (p<0.05). Resting rate–pressure product was lower after treatment with nebivolol, but dipyridamole‐induced change was not influenced by the treatment. Nebivolol treatment reduced significantly coronary velocities at rest (p<0.02) and also caused a significant increase in coronary velocities after dipyridamole (p<0.02), leading to a greater CFR (2.02 (0.35) vs 2.61 (0.43), p<0.001). Nebivolol induced an absolute increase of 6% in the CFR in 17 of 21 patients (80.9%).
In patients with IDC, 1 month of treatment with nebivolol induces a marked increase in CFR.
PMCID: PMC1861460  PMID: 17065184
21.  Inflammation is Related to Coronary Flow Reserve Detected by Positron Emission Tomography in Asymptomatic Male Twins 
To examine the relationship between inflammation and coronary microvascular function in asymptomatic individuals using positron emission tomography (PET) and assessment of coronary flow reserve (CFR).
Coronary microvascular dysfunction is an early precursor of coronary artery disease (CAD) thought to result from endothelial cell activation and inflammation, but data are limited.
We examined 268 asymptomatic male monozygotic and dizygotic twins. Plasma biomarkers of inflammation and endothelial cell activation included C-reactive protein (CRP), interleukin-6 (IL-6), white blood cell count (WBC), vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). Blood flow quantitation was obtained with [13N] ammonia PET at rest and after adenosine stress. CFR was measured as the ratio of maximum flow to baseline flow at rest; abnormal CFR was defined as a ratio <2.5. A summed stress score for visible perfusion defects was calculated.
In within-pair analyses, all biomarkers, except VCAM-1, were higher in twins with lower CFR than their brothers with higher CFR (p<0.05). This was observed in the entire sample, as well as within pairs discordant for a CFR of <2.5. Associations persisted after adjusting for summed stress score and CAD risk factors. In contrast no biomarker, except IL-6, was related to the summed stress score of visible defects.
Even in asymptomatic subjects, a decrease in coronary microvascular function is accompanied by a systemic inflammatory response, independent of CAD risk factors. Our results, using a controlled twin design, highlight the importance of coronary microvascular function in the early phases of CAD.
PMCID: PMC3073445  PMID: 21392641
circulation; imaging; inflammation; coronary disease; endothelium
22.  Coronary artery flow reserve in diabetics with erectile dysfunction using sildenafil 
Diabetics with erectile dysfunction have a high prevalence of microvascular disturbance of the coronary circuit as measured by coronary flow reserve (CFR).
We aimed to evaluate the effects of the phosphodiesterase 5 inhibitor sildenafil on CFR in diabetics with erectile dysfunction.
Diabetics seeking diabetes refinement therapy were screened for vascular or neurogenic erectile dysfunction which was confirmed in 43 patients. No ischemic ECG changes were found in any of the ECG stress tests at the 100 W level. Cardiologic examinations raised suspicion of coronary artery disease in 16 patients; coronary angiography confirmed severe coronary artery lesions in 12, who were excluded from further analysis. CFR measurements were not possible in 10 participants. The 21 diabetics eligible for CFR measurements aged 60 years (50–69) had known diabetes for 11 years (3–30) and a BMI of 27 kg/m2 (24–36). CFR of the left anterior descending artery was assessed at baseline and 1 hour after 50 mg sildenafil, using transthoracic Doppler echocardiography.
Baseline CFR was at the lower level of the normal range (median 245%, range 210 – 490%). After sildenafil administration, CFR decreased insignificantly (ΔCFR -10%, p = 0.3). Patients with a BMI > 25 kg/m2 and left ventricular hypertrophy exhibited the highest reduction of CFR after sildenafil. No decrease of CFR below 200 % was observed. Systemic blood pressure dropped from 130/80 mmHg to 120/72 mmHg (p < 0.002).
Diabetics with erectile dysfunction exhibit a CFR in the lower normal range indicating severe microvascular disturbance. Sildenafil did not alter CFR in those patients. A high prevalence of severe coronary macroangiopathy was identified in asymptomatic diabetic patients screened for contraindications for sildenafil.
PMCID: PMC194431  PMID: 12952551
Coronary flow reserve; Diabetes mellitus; sildenafil.
23.  Coronary microcirculatory vasodilator function in relation to risk factors among patients without obstructive coronary disease and low to intermediate Framingham score 
European Heart Journal  2009;31(8):936-942.
The study aim was to evaluate the relation between the Framingham risk score (FRS) and the presence of coronary risk factors to coronary microcirculatory vasodilator function in patients with early coronary atherosclerosis.
Methods and results
We evaluated 1063 patients (age: 50 ± 12 years, 676 (64%) females) without significant narrowing (<30%) on coronary angiography who underwent invasive assessment of coronary endothelial function. Coronary blood flow (CBF) in response to the endothelium-dependent vasodilator acetylcholine was evaluated as well as the microvascular (endothelium-independent) coronary flow reserve (CFR) in response to intracoronary adenosine. Coronary blood flow and CFR were analysed in relation to the FRS and the presence of traditional and novel risk factors. The estimated 10 years risk in this group was 5.4 ± 5.2%. Higher FRS was associated with lower CBF in men (P = 0.008), and was a univariate predictor of lower CFR (P = 0.012) in all patients. Multivariable analysis identified a higher FRS (P < 0.001), female sex (P < 0.001) and a positive family history of coronary disease (P = 0.043) as independent predictors of reduced CFR.
In patients without obstructive coronary disease, a higher FRS was an independent predictor of reduced CFR. The current study provides insight into the relation between cardiac risk profile and coronary microcirculatory function, and suggests that impaired microcirculatory vasodilator function may be present even in patients with a low to intermediate Framingham score.
PMCID: PMC2854505  PMID: 19897496
Coronary atherosclerosis; Female; Framingham risk score; Endothelial function; Microcirculation
24.  The Relationship between Endothelial Progenitor Cell Populations and Epicardial and Microvascular Coronary Disease—A Cellular, Angiographic and Physiologic Study 
PLoS ONE  2014;9(4):e93980.
Endothelial progenitor cells (EPCs) are implicated in protection against vascular disease. However, studies using angiography alone have reported conflicting results when relating EPCs to epicardial coronary artery disease (CAD) severity. Moreover, the relationship between different EPC types and the coronary microcirculation is unknown. We therefore investigated the relationship between EPC populations and coronary epicardial and microvascular disease.
Thirty-three patients with a spectrum of isolated left anterior descending artery disease were studied. The coronary epicardial and microcirculation were physiologically interrogated by measurement of fractional flow reserve (FFR), index of microvascular resistance (IMR) and coronary flow reserve (CFR). Two distinct EPC populations (early EPC and late outgrowth endothelial cells [OECs]) were isolated from these patients and studied ex vivo.
There was a significant inverse relationship between circulating OEC levels and epicardial CAD severity, as assessed by FFR and angiography (r = 0.371, p = 0.04; r = -0.358, p = 0.04; respectively). More severe epicardial CAD was associated with impaired OEC migration and tubulogenesis (r = 0.59, p = 0.005; r = 0.589, p = 0.004; respectively). Patients with significant epicardial CAD (FFR<0.75) had lower OEC levels and function compared to those without hemodynamically significant stenoses (p<0.05). In contrast, no such relationship was seen for early EPC number and function, nor was there a relationship between IMR and EPCs. There was a significant relationship between CFR and OEC function.
EPC populations differ in regards to their associations with CAD severity. The number and function of OECs, but not early EPCs, correlated significantly with epicardial CAD severity. There was no relationship between EPCs and severity of coronary microvascular disease.
PMCID: PMC3988011  PMID: 24736282
25.  Absolute Myocardial Flow Quantification with 82Rb PET/CT: Comparison of Different Software Packages and Methods 
European journal of nuclear medicine and molecular imaging  2013;41(1):10.1007/s00259-013-2537-1.
In clinical cardiac 82Rb PET, globally impaired coronary flow reserve (CFR) is a relevant marker for predicting short-term cardiovascular events. However, there is limited data on the impact of different software and methods for estimation of myocardial blood flow (MBF) and CFR. Our objective was to compare quantitative results obtained from previously validated software tools.
We retrospectively analyzed cardiac 82Rb PET/CT data from 25 subjects (group 1; 62 ± 11 yrs) with low-to-intermediate probability of coronary artery disease (CAD) and 26 patients (group 2; 57 ± 10 yrs; P = 0.07) with known CAD. Resting and vasodilator-stress MBF and CFR were derived using three software applications: 1) Corridor4DM (4DM), which is based on factor analysis (FA) and kinetic modeling according to Yoshida, 2) with a second option based on region-of-interest (ROI) and kinetic modeling according to Lortie, 3) MunichHeart (MH), which uses a simplified ROI-based-retention model approach and 4) FlowQuant (FQ) based on ROI and compartmental modeling with constant distribution volume (DV).
Rest (1.47 ± 0.59, 1.16 ± 0.51, 0.91 ± 0.39, 0.90 ± 0.44; P <0.001), and stress (3.05 ± 1.66, 2.26 ± 1.01, 1.90 ± 0.82, 1.83 ± 0.81; P < 0.001) MBF were significantly different between methods (4DM-FA, 4DM-ROI, FQ, and MH respectively). However there was no statistically significant difference of CFR values (2.15 ± 1.08, 2.05 ± 0.83, 2.23 ± 0.89, and 2.21 ± 0.90; P=0.17) between software tools. Regional MBF and CFR according to vascular territories showed similar results. Linear correlation coefficient for global CFR varied between 0.71 (MH vs. 4DM-ROI) and 0.90 (FQ vs. 4DM-ROI). Using a cutoff of 2.0 for abnormal CFR, the agreement among software programs ranged between 76% (MH vs. FQ) and 90% (FQ vs. 4DM-ROI). Interobserver agreement was in general excellent with all software packages.
Quantitative assessment of resting and stress MBF with 82Rb PET is dependent on the software and methods used, whereas CFR appears to be more comparable. Follow-up and treatment assessment should be done with the same software and method.
PMCID: PMC3849220  PMID: 23982454
82Rb; cardiac PET/CT; myocardial blood flow; coronary flow reserve; kinetic modeling

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