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1.  Coronary Artery Calcification and Myocardial Perfusion in Asymptomatic Adults: The MESA (Multi-Ethnic Study of Atherosclerosis) 
OBJECTIVES
This study assessed the cross-sectional association between coronary artery calcification (CAC) and myocardial perfusion in an asymptomatic population.
BACKGROUND
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.
METHODS
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.
RESULTS
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).
CONCLUSIONS
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.
doi:10.1016/j.jacc.2006.04.089
PMCID: PMC1853335  PMID: 16949496
2.  Genome-Wide Association of Pericardial Fat Identifies a Unique Locus for Ectopic Fat 
PLoS Genetics  2012;8(5):e1002705.
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.
Author Summary
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.
doi:10.1371/journal.pgen.1002705
PMCID: PMC3349742  PMID: 22589742
3.  Assessment of intravascular and extravascular mechanisms of myocardial perfusion abnormalities in obstructive hypertrophic cardiomyopathy by myocardial contrast echocardiography 
Heart  2007;93(10):1204-1212.
Objectives
To assess mechanisms of myocardial perfusion impairment in patients with hypertrophic cardiomyopathy (HCM).
Methods
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.
Results
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).
Conclusions
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.
doi:10.1136/hrt.2006.110460
PMCID: PMC2000941  PMID: 17488767
myocardial perfusion; hypertrophic obstructive cardiomyopathy; myocardial contrast echocardiography; positron emission tomography
4.  Pericardial Fat is Associated with Carotid Stiffness in the Multi-Ethnic Study of Atherosclerosis 
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.
Conclusion
Higher Pfat is associated with higher carotid stiffness, independent of traditional CVD risk factors and obesity.
doi:10.1016/j.numecd.2009.10.010
PMCID: PMC2929306  PMID: 20153618
pericardial fat; arterial stiffness; distensibility; carotid artery
5.  Quantitative Relation between Coronary Calcium Content and Coronary Flow Reserve as Assessed by Integrated PET-CT Imaging 
Background
Coronary artery calcium (CAC) is a marker of atherosclerosis. Whether epicardial calcium reflects more widespread atherosclerosis affecting coronary vascular function is unknown.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1007/s00259-009-1121-1
PMCID: PMC3117296  PMID: 19387640
coronary calcifications; coronary flow reserve; coronary atherosclerosis; positron emission tomography
6.  Increased Pericardial Fat Volume Measured From Noncontrast CT Predicts Myocardial Ischemia by SPECT 
JACC. Cardiovascular imaging  2010;3(11):1104-1112.
OBJECTIVES
We evaluated the association between pericardial fat and myocardial ischemia for risk stratification.
BACK GROUND
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.
METHODS
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.
RESULTS
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).
CONCLUSIONS
Pericardial fat was significantly associated with myocardial ischemia in patients without known CAD and may help improve risk assessment.
doi:10.1016/j.jcmg.2010.07.014
PMCID: PMC3057558  PMID: 21070997
computed tomography; ischemia; pericardial fat; SPECT; thoracic fat
7.  Silent Ischemic Heart Disease and Pericardial Fat Volume in HIV-Infected Patients: A Case-Control Myocardial Perfusion Scintigraphy Study 
PLoS ONE  2013;8(8):e72066.
Objectives
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.
Background
Patients with HIV seem prone to early development of IHD.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1371/journal.pone.0072066
PMCID: PMC3743817  PMID: 23967275
8.  Quantitative Relationship Between Coronary Vasodilator Reserve Assessed by Rubidium-82 PET Imaging and Coronary Artery Stenosis Severity 
The relationship between myocardial blood flow (MBF) and stenosis severity has been determined previously using cyclotron-produced radiotracers such as 15O-H2O and 13N-ammonia. An attractive alternative to overcome the limitations related to the use of cyclotron might be to use the generator-produced Rubidium-82 as a flow tracer. The current study was undertaken to investigate the relationship between MBF and coronary vasodilator reserve (CVR) as measured by Rubidium-82 positron emission tomography (PET) and the percent diameter stenosis as defined by quantitative coronary arteriography.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1007/s00259-008-0793-2
PMCID: PMC3124702  PMID: 18425513
Myocardial blood flow; Positron Emission Tomography; Rubidium-82
9.  Epicardial and thoracic fat - Noninvasive measurement and clinical implications 
Epicardial fat, the local visceral fat depot enclosed by the visceral pericardial sac, surrounds the coronary arteries for most of their course, and may contribute to the development of coronary atherosclerosis through local production of inflammatory cytokines. Several studies which measured epicardial fat volume noninvasively have shown a relationship of increased epicardial fat volume with coronary artery disease, with the presence and progression of coronary plaque, major adverse cardiovascular events, myocardial ischemia and atrial fibrillation. Quantitative measurement of epicardial fat volume from noninvasive imaging modalities such as CT and MRI are feasible, and may play a clinical role in cardiovascular risk assessment. The evidence to date warrants larger studies with follow-up to further investigate the role of epicardial fat as an imaging marker with prognostic importance.
doi:10.3978/j.issn.2223-3652.2012.04.03
PMCID: PMC3839150  PMID: 24282702
Epicardial and thoracic fat; noninvasive measurement; coronary artery disease; clinical implications
10.  Computational Fluid Dynamics Simulations of Contrast Agent Bolus Dispersion in a Coronary Bifurcation: Impact on MRI-Based Quantification of Myocardial Perfusion 
Contrast-enhanced first-pass magnetic resonance imaging (MRI) in combination with a tracer kinetic model, for example, MMID4, can be used to determine myocardial blood flow (MBF) and myocardial perfusion reserve (MPR). Typically, the arterial input function (AIF) required for this methodology is estimated from the left ventricle (LV). Dispersion of the contrast agent bolus might occur between the LV and the myocardial tissue. Negligence of bolus dispersion could cause an error in MBF determination. The aim of this study was to investigate the influence of bolus dispersion in a simplified coronary bifurcation geometry including one healthy and one stenotic branch on the quantification of MBF and MPR. Computational fluid dynamics (CFD) simulations were combined with MMID4. Different inlet boundary conditions describing pulsatile and constant flows for rest and hyperemia and differing outflow conditions have been investigated. In the bifurcation region, the increase of the dispersion was smaller than inside the straight vessels. A systematic underestimation of MBF values up to −16.1% for pulsatile flow and an overestimation of MPR up to 7.5% were found. It was shown that, under the conditions considered in this study, bolus dispersion can significantly influence the results of quantitative myocardial MR-perfusion measurements.
doi:10.1155/2013/513187
PMCID: PMC3600257  PMID: 23533541
11.  T2 Preparation Method for Measuring Hyperemic Myocardial O2 Consumption: In Vivo Validation by Positron Emission Tomography 
Purpose
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.
Results
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%).
Conclusion
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.
doi:10.1002/jmri.22322
PMCID: PMC3773230  PMID: 21274973
BOLD; T2; myocardial oxygen consumption; myocardial perfusion reserve; hyperemia
12.  Caffeine Impairs Myocardial Blood Flow Response to Physical Exercise in Patients with Coronary Artery Disease as well as in Age-Matched Controls 
PLoS ONE  2009;4(5):e5665.
Background
Caffeine is one of the most widely consumed pharmacologically active substances. Its acute effect on myocardial blood flow is widely unknown. Our aim was to assess the acute effect of caffeine in a dose corresponding to two cups of coffee on myocardial blood flow (MBF) in coronary artery disease (CAD).
Methodology/Principal Findings
MBF was measured with 15O-labelled H2O and Positron Emission Tomography (PET) at rest and after supine bicycle exercise in controls (n = 15, mean age 58±13 years) and in CAD patients (n = 15, mean age 61±9 years). In the latter, regional MBF was assessed in segments subtended by stenotic and remote coronary arteries. All measurements were repeated fifty minutes after oral caffeine ingestion (200 mg). Myocardial perfusion reserve (MPR) was calculated as ratio of MBF during bicycle stress divided by MBF at rest. Resting MBF was not affected by caffeine in both groups. Exercise-induced MBF response decreased significantly after caffeine in controls (2.26±0.56 vs. 2.02±0.56, P<0.005), remote (2.40±0.70 vs. 1.78±0.46, P<0.001) and in stenotic segments (1.90±0.41 vs. 1.38±0.30, P<0.001). Caffeine decreased MPR significantly by 14% in controls (P<0.05 vs. baseline). In CAD patients MPR decreased by 18% (P<0.05 vs. baseline) in remote and by 25% in stenotic segments (P<0.01 vs. baseline).
Conclusions
We conclude that caffeine impairs exercise-induced hyperaemic MBF response in patients with CAD to a greater degree than age-matched controls.
doi:10.1371/journal.pone.0005665
PMCID: PMC2682574  PMID: 19479069
13.  A Fully Quantitative Pixel-Wise Measurement of Myocardial Blood Flow Using Contrast-Enhanced First-Pass Cardiac Magnetic Resonance Perfusion Imaging: Microsphere Validation in Dogs and Feasibility Study in Humans 
JACC. Cardiovascular imaging  2012;5(2):154-166.
Objectives
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.
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1016/j.jcmg.2011.07.013
PMCID: PMC3460374  PMID: 22340821
cardiac magnetic resonance imaging; myocardial perfusion; gadolinium; myocardial ischemia
14.  A Case of Partial Congenital Pericardial Defect Presenting as Acute Coronary Syndrome 
Korean Circulation Journal  2013;43(12):845-848.
Congenital pericardial defects are rare and asymptomatic for both partial and complete defects. However, some patients can experience syncope, arrhythmia, and chest pain. When a patient experiences a symptom, it may be caused by herniation and dynamic compression or torsion of a heart structure including the coronary arteries. Diagnosis of a congenital pericardial defect may be difficult, especially in old patients with concomitant coronary artery disease. The clinical importance of congenital pericardial defect has not been stressed and congenital pericardial defects are regarded as benign, but in this case, pericardial defect was responsible for myocardial ischemia. The authors report a case of partial congenital pericardial defect causing herniation and dynamic compression of the coronary arteries, presenting as an acute coronary syndrome in an old man, with an emphasis on the unique features of the coronary angiogram that support the diagnosis of partial pericardial defects.
doi:10.4070/kcj.2013.43.12.845
PMCID: PMC3875704  PMID: 24385999
Heart defects, congenital; Pericardium; Coronary artery disease
15.  Pericardial fat burden on ECG-gated noncontrast CT in asymptomatic patients who subsequently experience adverse cardiovascular events on 4-year follow-up: A case-control study 
JACC. Cardiovascular imaging  2010;3(4):352-360.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1016/j.jcmg.2009.12.013
PMCID: PMC2946639  PMID: 20394896
Pericardial fat; computed tomography; prognosis; cardiovascular events
16.  Association Between Carotid Intima-Media Thickness and Pericardial Fat in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Introduction
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.jstrokecerebrovasdis.2009.03.008
PMCID: PMC2817960  PMID: 20123228
17.  Pattern Specification and Immune Response Transcriptional Signatures of Pericardial and Subcutaneous Adipose Tissue 
PLoS ONE  2011;6(10):e26092.
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.
doi:10.1371/journal.pone.0026092
PMCID: PMC3191160  PMID: 22022522
18.  Coronary microvascular dysfunction in male patients with Anderson‐Fabry disease and the effect of treatment with α galactosidase A 
Heart  2005;92(3):357-360.
Objective
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).
Conclusions
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.
doi:10.1136/hrt.2004.054015
PMCID: PMC1860797  PMID: 16085718
cardiomyopathy; coronary circulation; myocardial blood flow; myocardial ischaemia; cardiac imaging
19.  In vivo characterization of rodent cyclic myocardial perfusion variation at rest and during adenosine-induced stress using cine-ASL cardiovascular magnetic resonance 
Background
Assessment of cyclic myocardial blood flow (MBF) variations can be an interesting addition to the characterization of microvascular function and its alterations. To date, totally non-invasive in vivo methods with this capability are still lacking. As an original technique, a cine arterial spin labeling (ASL) cardiovascular magnetic resonance approach is demonstrated to be able to produce dynamic MBF maps across the cardiac cycle in rats.
Method
High-resolution MBF maps in left ventricular myocardium were computed from steady-state perfusion-dependent gradient-echo cine images produced by the cine-ASL sequence. Cyclic changes of MBF over the entire cardiac cycle in seven normal rats were analyzed quantitatively every 6ms at rest and during adenosine-induced stress.
Results
The study showed a significant MBF increase from end-systole (ES) to end-diastole (ED) in both physiological states. Mean MBF over the cardiac cycle within the group was 5.5 ± 0.6 mL g-1 min-1 at rest (MBFMin = 4.7 ± 0.8 at ES and MBFMax = 6.5 ± 0.6 mL g-1 min-1 at ED, P = 0.0007). Mean MBF during adenosine-induced stress was 12.8 ± 0.7mL g-1 min-1 (MBFMin = 11.7±1.0 at ES and MBFMax = 14.2 ± 0.7 mL g-1 min-1 at ED, P = 0.0007). MBF percentage relative variations were significantly different with 27.2 ± 9.3% at rest and 17.8 ± 7.1% during adenosine stress (P = 0.014). The dynamic analysis also showed a time shift of peak MBF within the cardiac cycle during stress.
Conclusion
The cyclic change of myocardial perfusion was examined by mapping MBF with a steady-pulsed ASL approach. Dynamic MBF maps were obtained with high spatial and temporal resolution (6ms) demonstrating the feasibility of non-invasively mapping cyclic myocardial perfusion variation at rest and during adenosine stress. In a pathological context, detailed assessment of coronary responses to infused vasodilators may give valuable complementary information on microvascular functional defects in disease models.
doi:10.1186/1532-429X-16-18
PMCID: PMC3937054  PMID: 24548535
Myocardial blood flow; Microcirculation; Adenosine; Perfusion; Rat heart
20.  Variability in quantitative cardiac magnetic resonance perfusion analysis 
Journal of Thoracic Disease  2013;5(3):357-359.
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.
doi:10.3978/j.issn.2072-1439.2013.06.08
PMCID: PMC3698280  PMID: 23825774
Stress cardiac magnetic resonance (CMR) imaging; quantitative analysis; reproducibility
21.  Hyperemic stress myocardial perfusion cardiovascular magnetic resonance in mice at 3 Tesla: initial experience and validation against microspheres 
Background
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1186/1532-429X-15-62
PMCID: PMC3750232  PMID: 23870734
Cardiovascular magnetic resonance imaging; Myocardial perfusion; Murine
22.  Roles of myocardial blood volume and flow in coronary artery disease: an experimental MRI study at rest and during hyperemia 
European radiology  2010;20(8):2005-2012.
Objective
To validate fast perfusion mapping techniques in a setting of coronary artery stenosis, and to further assess the relationship of absolute myocardial blood volume (MBV) and blood flow (MBF) to global myocardial oxygen demand.
Methods
A group of 27 mongrel dogs were divided into 10 controls and 17 with acute coronary stenosis. On 1.5-T MRI, first-pass perfusion imaging with a bolus injection of a blood-pool contrast agent was performed to determine myocardial perfusion both at rest and during either dipyridamole-induced vasodilation or dobutamine-induced stress. Regional values of MBF and MBV were quantified by using a fast mapping technique. Color microspheres and 99mTc-labeled red blood cells were injected to obtain respective gold standards.
Results
Microsphere-measured MBF and 99mTc-measured MBV reference values correlated well with the MR results. Given the same changes in MBF, changes in MBV are twofold greater with dobutamine than with dipyridamole. Under dobutamine stress, MBV shows better association with total myocardial oxygen demand than MBF. Coronary stenosis progressively reduced this association in the presence of increased stenosis severity.
Conclusions
MR first-pass perfusion can rapidly estimate regional MBF and MBV. Absolute quantification of MBV may add additional information on stenosis severity and myocardial viability compared with standard qualitative clinical evaluations of myocardial perfusion.
doi:10.1007/s00330-010-1740-8
PMCID: PMC2900455  PMID: 20182731
Coronary stenosis; Myocardial blood flow; Myocardial blood volume
23.  Fat-free mass index: changes and race/ethnic differences in adulthood 
Objective
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.
Design
Cross-sectional.
Subjects
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.
Results
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).
Conclusions
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.
doi:10.1038/ijo.2010.111
PMCID: PMC3306818  PMID: 20531353
fat-free mass index; fat-free mass; body mass index (BMI); percent body fat; nutritional assessment
24.  Quantitative Cardiac Positron Emission Tomography: The Time Is Coming! 
Scientifica  2012;2012:948653.
In the last 20 years, the use of positron emission tomography (PET) has grown dramatically because of its oncological applications, and PET facilities are now easily accessible. At the same time, various groups have explored the specific advantages of PET in heart disease and demonstrated the major diagnostic and prognostic role of quantitation in cardiac PET. Nowadays, different approaches for the measurement of myocardial blood flow (MBF) have been developed and implemented in user-friendly programs. There is large evidence that MBF at rest and under stress together with the calculation of coronary flow reserve are able to improve the detection and prognostication of coronary artery disease. Moreover, quantitative PET makes possible to assess the presence of microvascular dysfunction, which is involved in various cardiac diseases, including the early stages of coronary atherosclerosis, hypertrophic and dilated cardiomyopathy, and hypertensive heart disease. Therefore, it is probably time to consider the routine use of quantitative cardiac PET and to work for defining its place in the clinical scenario of modern cardiology.
doi:10.6064/2012/948653
PMCID: PMC3820449  PMID: 24278760
25.  Improvement in coronary vascular dysfunction produced with euglycaemic control in patients with type 2 diabetes 
Heart  2006;93(3):345-349.
Objective
To determine the effect of plasma glucose lowering on coronary circulatory function in type 2 diabetes mellitus.
Methods
Twenty patients with type 2 diabetes and 18 weight‐matched controls were studied. At baseline, myocardial blood flow (MBF) was measured with [13N]ammonia and positron emission tomography at rest, during cold pressor testing (CPT), and during adenosine hyperaemia. In diabetic patients, MBF and blood chemistry were analysed again after 3 months of glucose‐lowering treatment with glyburide and metformin.
Results
Although hyperaemic MBF did not differ significantly between the patients and controls (1.81 (0.38) v 1.97 (0.43) ml/min/g; mean (SD)), the CPT‐induced MBF increase (ΔMBF) was significantly less in diabetic patients than in controls (0.07 (0.07) v 0.25 (0.12) ml/min/g; p<0.001). Treatment with glyburide and metformin significantly decreased plasma glucose concentrations from 207 (76) to 134 (52) mg/dl (p<0.001). This decrease in plasma glucose was paralleled by a significant increase in ΔMBF in response to CPT (0.20 (0.16) from 0.07 (0.07) ml/min/g; p<0.001), which tended to be lower than in controls at baseline (0.20 (0.16) v 0.25 (0.12) ml/min/g; p  =  NS). The decrease in plasma glucose concentrations correlated significantly with the improvement in ΔMBF in response to CPT (r = 0.67, p<0.01).
Conclusions
Type 2 diabetes mellitus is associated with abnormal MBF response to CPT, which can be significantly improved by euglycaemic control with glyburide and metformin. The close association between the decrease in plasma glucose concentration and the improvement in coronary vasomotor function in response to CPT suggests a direct adverse effect of raised plasma glucose concentration on diabetes‐related coronary vascular disease.
doi:10.1136/hrt.2006.094128
PMCID: PMC1861464  PMID: 16940388
coronary disease; cold pressor testing; type 2 diabetes; endothelium; myocardial blood flow; positron emission tomography

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