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.
Pericardial fat is a localized fat depot associated with coronary artery calcium and myocardial infarction. We hypothesized that genetic loci would be associated with pericardial fat independent of other body fat depots. Pericardial fat was quantified in 5,487 individuals of European ancestry from the Framingham Heart Study (FHS) and the Multi-Ethnic Study of Atherosclerosis (MESA). Genotyping was performed using standard arrays and imputed to ∼2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of pericardial fat adjusted for age, sex, weight, and height. A weighted z-score meta-analysis was conducted, and validation was obtained in an additional 3,602 multi-ethnic individuals from the MESA study. We identified a genome-wide significant signal in our primary meta-analysis at rs10198628 near TRIB2 (MAF 0.49, p = 2.7×10-08). This SNP was not associated with visceral fat (p = 0.17) or body mass index (p = 0.38), although we observed direction-consistent, nominal significance with visceral fat adjusted for BMI (p = 0.01) in the Framingham Heart Study. Our findings were robust among African ancestry (n = 1,442, p = 0.001), Hispanic (n = 1,399, p = 0.004), and Chinese (n = 761, p = 0.007) participants from the MESA study, with a combined p-value of 5.4E-14. We observed TRIB2 gene expression in the pericardial fat of mice. rs10198628 near TRIB2 is associated with pericardial fat but not measures of generalized or visceral adiposity, reinforcing the concept that there are unique genetic underpinnings to ectopic fat distribution.
Pericardial fat is a localized fat depot associated with coronary artery calcium and myocardial infarction. To test whether genetic loci are associated with pericardial fat independent of other body fat depots, we measured pericardial fat in 5,487 individuals of European ancestry. After performing an unbiased screen using genome-wide association, we identified a genome-wide significant signal in our primary meta-analysis at rs10198628 near TRIB2 (MAF 0.49, p = 2.7×10-08). This SNP was not associated with visceral fat (p = 0.17) or body mass index (p = 0.38). Our findings were robust among multi-ethnic participants from the MESA study, with a combined p-value of 5.4E-14. We observed TRIB2 gene expression in the pericardial fat of mice. rs10198628 near TRIB2 is associated with pericardial fat but not measures of generalized or visceral adiposity, reinforcing the concept that there are unique genetic underpinnings to ectopic fat distribution.
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.
coronary calcifications; coronary flow reserve; coronary atherosclerosis; positron emission tomography
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.
myocardial perfusion; hypertrophic obstructive cardiomyopathy; myocardial contrast echocardiography; positron emission tomography
Background and Aims
Arterial stiffness is a prominent feature of vascular aging and a risk factor for cardiovascular disease (CVD). Fat around the heart and blood vessels (i.e. pericardial fat, Pfat) may contribute to arterial stiffness via a local paracrine effect of adipose tissue on the surrounding vasculature. Thus, we determined the association between Pfat and carotid stiffness in 5,770 participants (mean age 62 yrs, 53% female, 25% African American, 24% Hispanic, and 13% Chinese) from the Multi-Ethnic Study of Atherosclerosis.
Methods and Results
Pfat was measured by computed tomography, and ultrasonography of the common carotid artery was used to calculate the distensibility coefficient (DC) and young’s modulus (YM). Lower DC and higher YM values indicate stiffer arteries. Pfat quartile was highly associated with demographic, behavioral, anthropometric, hemodynamic, metabolic, and disease variables in both men and women. After adjusting for height, clinical site, CVD risk factors, and medications, a 1-standard deviation (41.91 cm3) increment in Pfat was associated with a 0.00007±0.00002 1/mmHg lower DC (p=0.0002) in men and a 48.1±15.1 mmHg/mm higher YM in women (p=0.002). Additional adjustment for C-reactive protein, coronary artery calcification, and carotid intima-media thickness had only modest effects. More importantly, adjusting for body mass index and waist circumference did not significantly change the overall results.
Higher Pfat is associated with higher carotid stiffness, independent of traditional CVD risk factors and obesity.
pericardial fat; arterial stiffness; distensibility; carotid artery
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.
The aim of this study was to evaluate fully quantitative myocardial blood flow (MBF) at a pixel level based on contrast-enhanced first-pass cardiac magnetic resonance (CMR) imaging in dogs and patients.
Microspheres can quantify MBF in subgram regions of interest but CMR perfusion imaging may be able to quantify MBF and differentiate blood flow at much higher resolution.
First-pass CMR perfusion imaging was performed in a dog model with local hyperemia induced by intracoronary adenosine. Fluorescent microspheres were the reference standard for MBF validation. CMR perfusion imaging was also performed on patients with significant coronary artery disease (CAD) by invasive coronary angiography. Myocardial time-signal intensity curves of the images were quantified on a pixel-by-pixel basis using a model-constrained deconvolution analysis.
Qualitatively, color CMR perfusion pixel maps were comparable to microsphere MBF bull’s-eye plots in all animals. Pixel-wise CMR MBF estimates correlated well against subgram (0.49 ± 0.14 g) microsphere measurements (r=0.87 to 0.90) but showed minor underestimation of MBF. To reduce bias due to misregistration and minimize issues related to repeated measures, one hyperemic and one remote sector per animal were compared to the microsphere MBF which improved the correlation (r=0.97 to 0.98) and the bias was close to zero. Sector-wise and pixel-wise CMR MBF estimates also correlated well (r=0.97). In patients, color CMR stress perfusion pixel maps showed regional blood flow decreases and transmural perfusion gradients in territories served by stenotic coronary arteries. MBF estimates in endocardial versus epicardial subsectors, and ischemic versus remote sectors, were all significantly different (p<0.001 and p<0.01).
Myocardial blood flow can be quantified at the pixel level (~32 microliters of myocardium) on CMR perfusion images and results compared well with microsphere measurements. High-resolution pixel-wise CMR perfusion maps can quantify transmural perfusion gradients in patients with CAD.
cardiac magnetic resonance imaging; myocardial perfusion; gadolinium; myocardial ischemia
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.
Myocardial blood flow; Positron Emission Tomography; Rubidium-82
We evaluated the association between pericardial fat and myocardial ischemia for risk stratification.
Pericardial fat volume (PFV) and thoracic fat volume (TFV) measured from noncontrast computed tomography (CT) performed for calculating coronary calcium score (CCS) are associated with increased CCS and risk for major adverse cardiovascular events.
From a cohort of 1,777 consecutive patients without previously known coronary artery disease (CAD) with noncontrast CT performed within 6 months of single photon emission computed tomography (SPECT), we compared 73 patients with ischemia by SPECT (cases) with 146 patients with normal SPECT (controls) matched by age, gender, CCS category, and symptoms and risk factors for CAD. TFV was automatically measured. Pericardial contours were manually defined within which fat voxels were automatically identified to compute PFV. Computer-assisted visual interpretation of SPECT was performed using standard 17-segment and 5-point score model; perfusion defect was quantified as summed stress score (SSS) and summed rest score (SRS). Ischemia was defined by: SSS – SRS ≥4. Independent relationships of PFV and TFV to ischemia were examined.
Cases had higher mean PFV (99.1 ± 42.9 cm3 vs. 80.1 ± 31.8 cm3, p = 0.0003) and TFV (196.1 ± 82.7 cm3 vs. 160.8 ± 72.1 cm3, p = 0.001) and higher frequencies of PFV >125 cm3 (22% vs. 8%, p = 0.004) and TFV >200 cm3 (40% vs. 19%, p = 0.001) than controls. After adjustment for CCS, PFV and TFV remained the strongest predictors of ischemia (odds ratio [OR]: 2.91, 95% confidence interval [CI]: 1.53 to 5.52, p = 0.001 for each doubling of PFV; OR: 2.64, 95% CI: 1.48 to 4.72, p = 0.001 for TFV. Receiver operating characteristic analysis showed that prediction of ischemia, as indicated by receiver-operator characteristic area under the curve, improved significantly when PFV or TFV was added to CCS (0.75 vs. 0.68, p = 0.04 for both).
Pericardial fat was significantly associated with myocardial ischemia in patients without known CAD and may help improve risk assessment.
computed tomography; ischemia; pericardial fat; SPECT; thoracic fat
Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in the United States. Recent studies suggest that pericardial adipose tissue (PCAT) secretes inflammatory factors that contribute to the development of CVD. To better characterize the role of PCAT in the pathogenesis of disease, we performed a large-scale unbiased analysis of the transcriptional differences between PCAT and subcutaneous adipose tissue, analysing 53 microarrays across 19 individuals. As it was unknown whether PCAT-secreted factors are produced by adipocytes or cells in the supporting stromal fraction, we also sought to identify differentially expressed genes in isolated pericardial adipocytes vs. isolated subcutaneous adipocytes. Using microarray analysis, we found that: 1) pericardial adipose tissue and isolated pericardial adipocytes both overexpress atherosclerosis-promoting chemokines and 2) pericardial and subcutaneous fat depots, as well as isolated pericardial adipocytes and subcutaneous adipocytes, express specific patterns of homeobox genes. In contrast, a core set of lipid processing genes showed no significant overlap with differentially expressed transcripts. These depot-specific homeobox signatures and transcriptional profiles strongly suggest different functional roles for the pericardial and subcutaneous adipose depots. Further characterization of these inter-depot differences should be a research priority.
to determine the prevalence of asymptomatic ischemic heart disease (IHD) in HIV patients by myocardial perfusion scintigraphy (MPS) and to determine the value of coronary artery calcium score (CACS), carotid intima-media thickness (cIMT) and pericardial fat volume as screening tools for detection of IHD in subjects with HIV.
Patients with HIV seem prone to early development of IHD.
105 consecutive HIV patients (mean age 47.4 years; mean duration of HIV 12.3 years; mean CD4+ cell count 636×106/L; all receiving antiretroviral therapy) and 105 controls matched for age, gender and smoking status, without history of IHD were recruited. MPS, CACS, cIMT, pericardial fat volume, and cardiovascular risk scores were measured.
HIV patients demonstrated higher prevalence of perfusion defects than controls (18% vs. 0%; p<0.001) despite similar risk scores. Of HIV patients with perfusion defects, 42% had a CACS = 0. CACS and cIMT were similar in HIV patients and controls. HIV patients on average had 35% increased pericardial fat volume and increased concentration of biomarkers of atherosclerosis in the blood. HIV patients with myocardial perfusion defects had increased pericardial fat volume compared with HIV patients without perfusion defects (314±43 vs. 189±12 mL; p<0.001).
HIV patients had an increased prevalence of silent IHD compared to controls as demonstrated by MPS. The finding was strongly associated with pericardial fat volume, whereas cardiovascular risk scores, cIMT and CACS seem less useful as screening tools for detection of myocardial perfusion defects in HIV patients.
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.
BOLD; T2; myocardial oxygen consumption; myocardial perfusion reserve; hyperemia
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.
PET; hypertrophic cardiomyopathy; Regadenoson; ECG
By taking advantage of its high spatial resolution, noninvasive and nontoxic nature first-pass perfusion cardiovascular magnetic resonance (CMR) has rendered an indispensable tool for the noninvasive detection of reversible myocardial ischemia. A potential advantage of perfusion CMR is its ability to quantitatively assess perfusion reserve within a myocardial segment, as expressed semi- quantitatively by myocardial perfusion reserve index (MPRI) and fully- quantitatively by absolute myocardial blood flow (MBF). In contrast to the high accuracy and reliability of CMR in evaluating cardiac function and volumes, perfusion CMR is adversely affected by multiple potential reasons during data acquisition as well as post-processing. Various image acquisition techniques, various contrast agents and doses as well as variable blood flow at rest as well as variable reactions to stress all influence the acquired data. Mechanisms underlying the variability in perfusion CMR post processing, as well as their clinical significance, are yet to be fully elucidated. The development of a universal, reproducible, accurate and easily applicable tool in CMR perfusion analysis remains a challenge and will substantially enforce the role of perfusion CMR in improving clinical care.
Stress cardiac magnetic resonance (CMR) imaging; quantitative analysis; reproducibility
Dynamic first pass contrast-enhanced myocardial perfusion is the standard CMR method for the estimation of myocardial blood flow (MBF) and MBF reserve in man, but it is challenging in rodents because of the high temporal and spatial resolution requirements. Hyperemic first pass myocardial perfusion CMR during vasodilator stress in mice has not been reported.
Five C57BL/6 J mice were scanned on a clinical 3.0 Tesla Achieva system (Philips Healthcare, Netherlands). Vasodilator stress was induced via a tail vein catheter with an injection of dipyridamole. Dynamic contrast-enhanced perfusion imaging (Gadobutrol 0.1 mmol/kg) was based on a saturation recovery spoiled gradient echo method with 10-fold k-space and time domain undersampling (k-t PCA). One week later the mice underwent repeat anaesthesia and LV injections of fluorescent microspheres at rest and at stress. Microspheres were analysed using confocal microscopy and fluorescence-activated cell sorting.
Mean MBF at rest measured by Fermi-function constrained deconvolution was 4.1 ± 0.5 ml/g/min and increased to 9.6 ± 2.5 ml/g/min during dipyridamole stress (P = 0.005). The myocardial perfusion reserve was 2.4 ± 0.54. The mean count ratio of stress to rest microspheres was 2.4 ± 0.51 using confocal microscopy and 2.6 ± 0.46 using fluorescence. There was good agreement between cardiovascular magnetic resonance CMR and microspheres with no significant difference (P = 0.84).
First-pass myocardial stress perfusion CMR in a mouse model is feasible at 3 Tesla. Rest and stress MBF values were consistent with existing literature and perfusion reserve correlated closely to microsphere analysis. Data were acquired on a 3 Tesla scanner using an approach similar to clinical acquisition protocols, potentially facilitating translation of imaging findings between rodent and human studies.
Cardiovascular magnetic resonance imaging; Myocardial perfusion; Murine
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).
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.
Carotid intima-media thickness (IMT) is a sub-clinical marker of atherosclerosis and a strong predictor of stroke. Pericardial fat (PF), the fat depot around the heart, has been associated with several atherosclerosis risk factors. We sought to examine the association between carotid IMT and PF, and to examine whether such an association is independent from common atherosclerosis risk factors including measures of overall adiposity.
Unadjusted and multivariable adjusted linear regression analysis was used to examine associations between common (CCA-IMT) and internal (ICA-IMT) carotid IMT with PF in a random sample of 996 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who underwent carotid ultrasound and chest CT at baseline examination.
A significant positive correlation was observed between PF and CCA-IMT (r =0.27, P<0.0001) and ICA-IMT (r =0.17, P<0.0001). In an unadjusted sex-specific linear regression analysis, there was a significant association between PF (1-SD difference) and CCA-IMT (mm) in both women (β coefficient (95% CI): 0.06 (0.04, 0.08), P<0.0001) and men (0.03 (0.01, 0.05), P<0.0002), an association that persisted after further adjusting for age and ethnicity (0.02 (+0.00, 0.04), P=0.0120 for women, and 0.02 (+0.00, 0.03), P=0.0208 for men). However, after additional adjustment for atherosclerosis risk factors and either BMI or waist circumference, these relations were no longer significant in either sex. In similar analyses, PF was significantly associated with ICA-IMT in both men (0.11 (0.06, 0.15), P<0.0001) and women (0.08 (0.02, 0.13), P=041). These relations were no longer significant in women in multivariable adjusted models, but persisted in men in all models except after adjusting for age, ethnicity and waist circumference.
In the general population PF is associated with carotid IMT, an association that possibly not independent from markers of overall adiposity or common atherosclerosis risk factors.
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.
cardiomyopathy; coronary circulation; myocardial blood flow; myocardial ischaemia; cardiac imaging
Pericardial fat volume (PFV) and thoracic fat volume (TFV) can be routinely measured from noncontrast CT (NCT) performed for calculating coronary calcium score (CCS) and may predict major adverse cardiovascular event (MACE) risk.
From a registry of 2751 asymptomatic patients without known CAD and 4-year follow-up for MACE (cardiac death, myocardial infarction, stroke, late revascularization) after NCT, we compared 58 patients with MACE (“EVENTS”) to 174 same-sex event-free controls matched by a propensity score to account for age, risk factors, and CCS. TFV was automatically calculated, and PFV was calculated with manual assistance in defining the pericardial contour, within which fat voxels were automatically identified. Independent relationships of PFV and TFV to MACE were evaluated using conditional multivariable logistic regression.
EVENTS had higher mean PFV (101.8±49.2 cm3 vs. 84.9±37.7 cm3, p=0.007) and TFV (204.7±90.3 cm3 vs. 177±80.3 cm3, p=0.029) and higher frequencies of PFV>125 cm3 (33% vs. 14%, p=0.002) and TFV>250 cm3 (31% vs. 17%, p=0.025). After adjusting for Framingham Risk Score, CCS, and body-mass-index, PFV and TFV were significantly associated with MACE (odds ratio (OR) 1.74, 95%CI 1.03–2.95 for each doubling of PFV; OR 1.78, 95%CI 1.01–3.14 for TFV). Areas-under-the-curve from receiver operating characteristic analyses showed a trend of improved MACE prediction when PFV was added to FRS and CCS (0.73 vs 0.68, p=0.058). Addition of PFV, but not TFV, to FRS and CCS improved estimated specificity (0.72 vs 0.66, p=0.008) and overall accuracy (0.70 vs 0.65, p=0.009) in predicting MACE.
Asymptomatic patients who experience MACE exhibit greater PFV on pre-MACE NCT when compared to event-free controls with similar cardiovascular risk profiles. Our preliminary findings suggest that PFV may help improve prediction of MACE.
Pericardial fat; computed tomography; prognosis; cardiovascular events
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.
Myocardial perfusion; PET/CT; Segmentation; Parametric images
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.
coronary disease; blood flow; imaging; atherosclerosis; ischemia
Pericardial and intra-thoracic fat depots may represent novel risk factors for obesity-related cardiovascular disease. We sought to determine the prevalence, distribution and risk factor correlates of high pericardial and intra-thoracic fat deposits.
Methods and Results
Participants from the Framingham Heart Study (n=3312; mean age 52 years, 48% women) underwent multi-detector CT imaging in 2002–2005; high pericardial and high intra-thoracic fat were defined based on the sex-specific 90th percentile for these fat depots in a healthy reference sample. For men and women, the prevalence of high pericardial fat was 29.3% and 26.3%, respectively, and high intra-thoracic fat was 31.4% and 35.3%, respectively. Overall, 22.1% of the sample was discordant for pericardial and intra-thoracic fat depots: 8.3% had high pericardial but normal intra-thoracic fat, and 13.8% had high intra-thoracic but normal pericardial fat. Higher body mass index, higher waist circumference (WC) and increased prevalence of metabolic syndrome were more likely in participants with high intra-thoracic fat depots than with high pericardial fat (p<0.05 for all comparisons). High abdominal visceral adipose tissue was more frequent in participants with high intra-thoracic adipose tissue compared to those with high pericardial fat (p<0.001). Intra-thoracic fat, but not WC, was more highly correlated with VAT (r=0.76 and 0.78 in men and women, respectively; p<0.0001) than with SAT (r=0.46 and 0.54 in men and women, respectively; p<0.0001).
Although prevalence of pericardial fat and intra-thoracic fat were comparable at 30%, intra-thoracic fat correlated more closely with metabolic risk and visceral fat. Intra-thoracic fat may be a potential marker of metabolic risk and visceral fat on thoracic imaging.
pericardial fat; obesity; epidemiology
Nutritional status is assessed by measuring BMI or percent body fat (%fat). BMI can misclassify persons who carry more weight as fat-free mass and %fat can be misleading in cases of malnutrition or in disease states characterized by wasting of lean tissue. The fat-free mass index (FFMI) is proposed to assess body composition in individuals who have a similar body composition but differ in height allowing identification of those suffering from malnutrition, wasting or those that possess a relatively high muscle mass. The purpose was to determine whether the FFMI differs in a group of racially/ethnically diverse adults.
Subjects were a multi-ethnic sample (Caucasian, CA; African American, AA; Hispanic, HIS and Asian, AS) of 1339 healthy males (n = 480) and females (n = 859) ranging in age from 18–110 years. Total body fat, total fat-free mass and bone mineral density were estimated using dual energy X-ray absorptiometry.
FFMI differed among the four ethnic groups (P ≤ 0.05) for both genders. A curvilinear relationship was found between age and FFMI for both genders although the coefficients in the quadratic model differed between genders (P ≤ 0.001) indicating the rate of change in FFMI differed between genders. The estimated turning point where FFMI started to decline was in the mid 20s for male and mid 40s for female participants. An age × gender interaction was found such that the rate of decline was greater in male than female participants (P ≤ 0.001). For both genders, FFMI was greatest in AA and the least in AS (P ≤ 0.001). There was no significant interaction between race and age or age2 (P = 0.06). However, male participants consistently had a greater FFMI than female participants (P ≤ 0.001).
These findings have clinical implications for identifying individuals who may not be recognized as being malnourished based on their BMI or %fat but whose fat-free mass corrected for height is relatively low.
fat-free mass index; fat-free mass; body mass index (BMI); percent body fat; nutritional assessment
Cardiac tamponade is the phenomenon of hemodynamic compromise caused by a pericardial effusion. Following a myocardial infarction, the most common causes of pericardial fluid include early pericarditis, Dressler's syndrome, and hemopericardium secondary to a free wall rupture. On transthoracic echocardiography, pericardial fluid appears as an echo-free space in between the visceral and parietal layers of the pericardium. Pericardial fat has a similar appearance on echocardiography and it may be difficult to discern the two entities. We present a case of a post-MI patient demonstrating pseudo tamponade physiology in the setting of excessive pericardial fat.
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.
82Rb cardiac 2D PET; 13N-ammonia cardiac PET; Quantitation of myocardial blood flow