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.
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
Pericardial fat has a higher secretion of inflammatory cytokines than subcutaneous fat. Cytokines released from pericardial fat around coronary arteries may act locally on the adjacent cells.
We examined the relationship between pericardial fat and calcified coronary plaque.
Participants in the community-based Multi-Ethnic Study of Atherosclerosis underwent a computed tomography scan for the assessment of calcified coronary plaque in 2001/02. We measured the volume of pericardial fat using these scans in 159 whites and blacks without symptomatic coronary heart disease from Forsyth County, NC, aged 55–74 years.
Calcified coronary plaque was observed in 91 participants (57%). After adjusting for height, a one standard deviation increment in pericardial fat was associated with an increased odds of calcified coronary plaque (odds ratio (95% confidence interval): 1.92 (1.27, 2.90)). With further adjustment of other cardiovascular factors, pericardial fat was still significantly associated with calcified coronary plaque. This relationship did not differ by gender and ethnicity. On the other hand, body mass index and height-adjusted waist circumference were not associated with calcified coronary plaque.
Pericardial fat is independently associated with calcified coronary plaque.
coronary heart disease; body mass index; waist circumference
Microvascular dysfunction in HCM has been associated with adverse clinical outcomes. Advances in quantitative cardiovascular magnetic resonance (CMR) perfusion imaging now allow myocardial blood flow to be quantified at the pixel level. We applied these techniques to investigate the spectrum of microvascular dysfunction in hypertrophic cardiomyopathy (HCM) and to explore its relationship with fibrosis and wall thickness.
CMR perfusion imaging was undertaken during adenosine-induced hyperemia and again at rest in 35 patients together with late gadolinium enhancement (LGE) imaging. Myocardial blood flow (MBF) was quantified on a pixel-by-pixel basis from CMR perfusion images using a Fermi-constrained deconvolution algorithm. Regions-of-interest (ROI) in hypoperfused and hyperemic myocardium were identified from the MBF pixel maps. The myocardium was also divided into 16 AHA segments.
Resting MBF was significantly higher in the endocardium than in the epicardium (mean ± SD: 1.25 ± 0.35 ml/g/min versus 1.20 ± 0.35 ml/g/min, P < 0.001), a pattern that reversed with stress (2.00 ± 0.76 ml/g/min versus 2.36 ± 0.83 ml/g/min, P < 0.001). ROI analysis revealed 11 (31%) patients with stress MBF lower than resting values (1.05 ± 0.39 ml/g/min versus 1.22 ± 0.36 ml/g/min, P = 0.021). There was a significant negative association between hyperemic MBF and wall thickness (β = −0.047 ml/g/min per mm, 95% CI: −0.057 to −0.038, P < 0.001) and a significantly lower probability of fibrosis in a segment with increasing hyperemic MBF (odds ratio per ml/g/min: 0.086, 95% CI: 0.078 to 0.095, P = 0.003).
Pixel-wise quantitative CMR perfusion imaging identifies a subgroup of patients with HCM that have localised severe microvascular dysfunction which may give rise to myocardial ischemia.
Hypertrophic cardiomyopathy; Perfusion; Cardiovascular magnetic resonance; Microvascular dysfunction; Sudden cardiac death
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.
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
Myocardial blood flow (MBF) varies throughout the cardiac cycle in response to phasic changes in myocardial tension. The aim of this study was to determine if quantitative myocardial perfusion imaging with cardiovascular magnetic resonance (CMR) can accurately track physiological variations in MBF throughout the cardiac cycle.
30 healthy volunteers underwent a single stress/rest perfusion CMR study with data acquisition at 5 different time points in the cardiac cycle (early-systole, mid-systole, end-systole, early-diastole and end-diastole). MBF was estimated on a per-subject basis by Fermi-constrained deconvolution. Interval variations in MBF between successive time points were expressed as percentage change. Maximal cyclic variation (MCV) was calculated as the percentage difference between maximum and minimum MBF values in a cardiac cycle.
At stress, there was significant variation in MBF across the cardiac cycle with successive reductions in MBF from end-diastole to early-, mid- and end-systole, and an increase from early- to end-diastole (end-diastole: 4.50 ± 0.91 vs. early-systole: 4.03 ± 0.76 vs. mid-systole: 3.68 ± 0.67 vs. end-systole 3.31 ± 0.70 vs. early-diastole: 4.11 ± 0.83 ml/g/min; all p values <0.0001). In all cases, the maximum and minimum stress MBF values occurred at end-diastole and end-systole respectively (mean MCV = 26 ± 5%). There was a strong negative correlation between MCV and peak heart rate at stress (r = −0.88, p < 0.001). The largest interval variation in stress MBF occurred between end-systole and early-diastole (24 ± 9% increase). At rest, there was no significant cyclic variation in MBF (end-diastole: 1.24 ± 0.19 vs. early-systole: 1.28 ± 0.17 vs.mid-systole: 1.28 ± 0.17 vs. end-systole: 1.27 ± 0.19 vs. early-diastole: 1.29 ± 0.19 ml/g/min; p = 0.71).
Quantitative perfusion CMR can be used to non-invasively assess cyclic variations in MBF throughout the cardiac cycle. In this study, estimates of stress MBF followed the expected physiological trend, peaking at end-diastole and falling steadily through to end-systole. This technique may be useful in future pathophysiological studies of coronary blood flow and microvascular function.
Cardiovascular magnetic resonance imaging; Myocardial perfusion imaging; Myocardial blood flow
Body mass index (BMI) may not accurately or adequately reflect body composition or its role in the development of cardiovascular disease (CVD). Ectopic adipose depots may provide a more refined representation of the role of adiposity in CVD. Thus, we examined the association of pericardial and intra-thoracic fat with coronary artery calcium (CAC). Nearly 600 white men and women, as well as Filipina women and African-American women, all without known CVD, had abdominal and chest computed tomography (CT) scans at two time points about four years apart from which CAC presence, severity and progression, as well as pericardial and intra-thoracic fat volumes were obtained. Logistic and linear regression models with staged adjustment were used to assess associations of pericardial and intra-thoracic fat with CAC presence, severity and progression. After adjustment for age, BMI, sex/ethnic group, ever smoking, and lipids, each standard deviation higher increment of intra-thoracic fat, but not pericardial fat, was significantly associated with 3.84-fold higher odds of prevalent CAC (95% CI (1.54, 9.58), p=0.004) and a 38.4% higher CAC score (95% CI (3.5%, 90.0%), p=0.03). Neither pericardial nor intra-thoracic fat were associated with CAC progression. Contrary to previous reports, pericardial fat was not associated with the presence, severity or progression of CAC. We did, however, demonstrate a significant association between intra-thoracic fat and both the presence and severity of CAC. Studies measuring fat in the thoracic cavity may consider defining intra-thoracic fat as a separate entity from pericardial fat.
There has been increasing interest in quantitative myocardial blood flow (MBF) imaging over the last years and it is expected to become a routinely used technique in clinical practice. Positron emission tomography (PET) using [15O]H2O is the established gold standard for quantification of MBF in vivo. A fundamental issue when performing quantitative MBF imaging is to define the limits of MBF in a clinically suitable population. The aims of the present study were to determine the limits of MBF and to determine the relationship among coronary artery disease (CAD) risk factors, gender and MBF in a predominantly symptomatic patient cohort without significant CAD.
A total of 128 patients (mean age 54 ± 10 years, 50 men) with a low to intermediate pretest likelihood of CAD were referred for noninvasive evaluation of CAD using a hybrid PET/computed tomography (PET/CT) scanner. MBF was quantified with [15O]H2O at rest and during adenosine-induced hyperaemia. Obstructive CAD was excluded in these patients by means of invasive or CT-based coronary angiography.
Global average baseline MBF values were 0.91 ± 0.34 and 1.09 ± 0.30 ml·min−1·g−1 (range 0.54–2.35 and 0.59–2.75 ml·min−1·g−1) in men and women, respectively (p < 0.01). However, no gender-dependent difference in baseline MBF was seen following correction for rate–pressure product (0.98 ± 0.45 and 1.09 ± 0.30 ml·min−1·g−1 in men and women, respectively; p = 0.08). Global average hyperaemic MBF values were 3.44 ± 1.20 ml·min−1·g−1 in the whole study population, and 2.90 ± 0.85 and 3.78 ± 1.27 ml·min−1·g−1 (range 1.52–5.22 and 1.72–8.15 ml·min−1·g−1) in men and women, respectively (p < 0.001). Multivariate analysis identified male gender, age and body mass index as having an independently negative impact on hyperaemic MBF.
Gender, age and body mass index substantially influence reference values and should be corrected for when interpreting hyperaemic MBF values.
Myocardial blood flow; Positron emission tomography; Non-obstructive CAD; CAD risk factors; Gender
The incremental value of CAC over traditional risk factors to predict coronary vasodilator dysfunction and inherent myocardial blood flow (MBF) impairment is only scarcely documented (MBF). The aim of this study was therefore to evaluate the relationship between CAC content, hyperemic MBF, and coronary flow reserve (CFR) in patients undergoing hybrid 15O-water PET/CT imaging.
We evaluated 173 (mean age 56 ± 10, 78 men) patients with a low to intermediate likelihood for coronary artery disease (CAD), without a documented history of CAD, undergoing vasodilator stress 15O-water PET/CT and CAC scoring. Obstructive coronary artery disease was excluded by means of invasive (n = 44) or CT-based coronary angiography (n = 129).
91 of 173 patients (52%) had a CAC score of zero. Of those with CAC, the CAC score was 0.1-99.9, 100-399.9, and ≥400 in 31%, 12%, and 5% of patients, respectively. Global CAC score showed significant inverse correlation with hyperemic MBF (r = −0.32, P < .001). With increasing CAC score, there was a decline in hyperemic MBF on a per-patient basis [3.70, 3.30, 2.68, and 2.53 mL · min−1 · g−1, with total CAC score of 0, 0.1-99.9, 100-399.9, and ≥400, respectively (P < .001)]. CFR showed a stepwise decline with increasing levels of CAC (3.70, 3.32, 2.94, and 2.93, P < .05). Multivariate analysis, including age, BMI, and CAD risk factors, revealed that only age, male gender, BMI, and hypercholesterolemia were associated with reduced stress perfusion. Furthermore, only diabetes and age were independently associated with CFR.
In patients without significant obstructive CAD, a greater CAC burden is associated with a decreased hyperemic MBF and CFR. However, this association disappeared after adjustment for traditional CAD risk factors. These results suggest that CAC does not add incremental value regarding hyperemic MBF and CFR over established CAD risk factors in patients without obstructive CAD.
Coronary artery calcium; hyperemic myocardial blood flow; coronary risk factors
Gender-specific differences in cardiovascular risk are well known, and current evidence supports an existing role of endothelium in these differences. The purpose of this study was to assess non invasively coronary endothelial function in male and female young volunteers by myocardial blood flow (MBF) measurement using coronary sinus (CS) flow quantification by velocity encoded cine cardiovascular magnetic resonance (CMR) at rest and during cold pressor test (CPT).
Twenty-four healthy volunteers (12 men, 12 women) underwent CMR in a 3 Tesla MR imager. Coronary sinus flow was measured at rest and during CPT using non breath-hold velocity encoded phase contrast cine-CMR. Myocardial function and morphology were acquired using a cine steady-state free precession sequence.
At baseline, mean MBF was 0.63 ± 0.23 mL·g-1·min-1 in men and 0.79 ± 0.21 mL·g-1·min-1 in women. During CPT, the rate pressure product in men significantly increased by 49 ± 36% (p < 0.0001) and in women by 52 ± 22% (p < 0.0001). MBF increased significantly in both men and women by 0.22 ± 0.19 mL·g-1·min-1 (p = 0.0022) and by 0.73 ± 0.43 mL·g-1·min-1 (p = 0.0001), respectively. The increase in MBF was significantly higher in women than in men (p = 0.0012).
CMR coronary sinus flow quantification for measuring myocardial blood flow revealed a higher response of MBF to CPT in women than in men. This finding may reflect gender differences in endothelial-dependent vasodilatation in these young subjects. This non invasive rest/stress protocol may become helpful to study endothelial function in normal physiology and in physiopathology.
cold pressor test; coronary sinus flow; endothelium; myocardial blood flow
Pericardial fat has been implicated in the pathogenesis of obesity-related cardiovascular disease. Whether the associations of pericardial fat and measures of cardiac structure and function are independent of the systemic effects of obesity and visceral adiposity has not been fully explored.
Methods and Results
Participants from the Framingham Heart Study (n=997, 54.4% women) underwent chest and abdominal CT and cardiovascular MRI (CMR) between 2002 and 2005. Pericardial fat, intrathoracic fat, and visceral adipose tissue (VAT) quantified from multidetector computed tomography, along with BMI and waist circumference, were examined in relation to CMR measures of left ventricular (LV) mass, LV end diastolic volume (LVEDV), and left atrial dimension. In women, pericardial fat (r=0.20 to 0.35, p<0.001), intrathoracic fat (r=0.25 to 0.37, p<0.001), VAT (r=0.24 to 0.45, p<0.001), BMI (r=0.36 to 0.53, p<0.001), and waist circumference (r=0.30 to 0.48, p<0.001) were directly correlated with LV mass, LVEDV, and left atrial dimension. In men, pericardial fat (r=0.19 to 0.37, p<0.001), intrathoracic fat (r=0.17 to 0.31, p<0.001), VAT (r=0.19 to 0.36, p<0.001), BMI (r=0.32 to 0.44, p<0.001), and waist circumference (r=0.34 to 0.44, p<0.001) were directly correlated with LV mass and left atrial dimension, but LVEDV was not consistently associated with adiposity measures. Associations persisted after multivariable adjustment, but not after additional adjustment for body weight and VAT, with the exception of pericardial fat and left atrial dimension in men.
Pericardial fat is correlated with CMR measures, but the association is not independent of or stronger than other ectopic fat stores or proxy measures of visceral adiposity. An important exception is left atrial dimension in men. These results suggest that the systemic effects of obesity on cardiac structure and function may outweigh the local pathogenic effects of pericardial fat.
pericardial fat; visceral fat; left ventricular mass; left atrial size; obesity; epidemiology; risk factors
Paraoxonase 1 [PON1] is recognized as a protective enzyme against LDL oxidation, and PON1 polymorphism has been described as a factor influencing coronary heart disease [CHD] free survival. As coronary vasoreactivity is a surrogate of future cardiovascular events, we aimed at assessing the respective effect of the PON1 genotype and activity on coronary vasoreactivity in a population of type 2 diabetic patients.
Nineteen patients with type 2 diabetes mellitus underwent 82Rb cardiac PET/CT to quantify myocardial blood flow [MBF] at rest, during cold pressor testing [CPT], and during adenosine-induced hyperaemia to compute myocardial flow reserve [MFR]. They were allocated according to Q192R and L55M polymorphisms into three groups (wild-type and LM/QR heterozygotes, MM homozygotes, and RR homozygotes) and underwent a measurement of plasmatic PON1 activity. Relations between rest-MBF, stress-MBF, MFR, and MBF response to CPT and PON1 genotypes and PON1 activity were assessed using Spearman's correlation and multivariate linear regression analysis.
Although PON1 activity was significantly associated with PON1 polymorphism (p < 0.0001), there was no significant relation between the PON1 genotypes and the rest-MBF, stress-MBF, or MBF response to CPT (p ≥ 0.33). The PON1 activity significantly correlated with the HDL plasma level (ρ = 0.63, p = 0.005), age (ρ = -0.52, p = 0.027), and MFR (ρ = 0.48, p = 0.044). Moreover, on multivariate analysis, PON1 activity was independently associated with MFR (p = 0.037).
Our study supports an independent association between PON1 activity and MFR. Whether PON1 contributes to promote coronary vasoreactivity through its antioxidant activity remains to be elucidated. This putative mechanism could be the basis of the increased risk of CHD in patients with low PON1 activity.
paraoxonase; myocardial flow reserve; diabetes; rubidium-82
Two-dimensional (2D) perfusion cardiovascular magnetic resonance (CMR) remains limited by a lack of complete myocardial coverage. Three-dimensional (3D) perfusion CMR addresses this limitation and has recently been shown to be clinically feasible. However, the feasibility and potential clinical utility of quantitative 3D perfusion measurements, as already shown with 2D-perfusion CMR and positron emission tomography, has yet to be evaluated. The influence of systolic or diastolic acquisition on myocardial blood flow (MBF) estimates, diagnostic accuracy and image quality is also unknown for 3D-perfusion CMR. The purpose of this study was to establish the feasibility of quantitative 3D-perfusion CMR for the detection of coronary artery disease (CAD) and to compare systolic and diastolic estimates of MBF.
Thirty-five patients underwent 3D-perfusion CMR with data acquired at both end-systole and mid-diastole. MBF and myocardial perfusion reserve (MPR) were estimated on a per patient and per territory basis by Fermi-constrained deconvolution. Significant CAD was defined as stenosis ≥70% on quantitative coronary angiography.
Twenty patients had significant CAD (involving 38 out of 105 territories). Stress MBF and MPR had a high diagnostic accuracy for the detection of CAD in both systole (area under curve [AUC]: 0.95 and 0.92, respectively) and diastole (AUC: 0.95 and 0.94). There were no significant differences in the AUCs between systole and diastole (p values >0.05). At stress, diastolic MBF estimates were significantly greater than systolic estimates (no CAD: 3.21 ± 0.50 vs. 2.75 ± 0.42 ml/g/min, p < 0.0001; CAD: 2.13 ± 0.45 vs. 1.98 ± 0.41 ml/g/min, p < 0.0001); but at rest, there were no significant differences (p values >0.05). Image quality was higher in systole than diastole (median score 3 vs. 2, p = 0.002).
Quantitative 3D-perfusion CMR is feasible. Estimates of MBF are significantly different for systole and diastole at stress but diagnostic accuracy to detect CAD is high for both cardiac phases. Better image quality suggests that systolic data acquisition may be preferable.
Cardiovascular magnetic resonance; Perfusion, 3-dimensional; Myocardial perfusion imaging; Ischemic heart disease; Myocardial blood flow
The aim of this study was to assess whether pericardial fat, intrathoracic fat, and visceral abdominal adipose tissue (VAT) are associated with the prevalence of cardiovascular disease (CVD).
Methods and results
Participants from the Framingham Heart Study Offspring cohort underwent abdominal and chest multidetector computed tomography to quantify volumes of pericardial fat, intrathoracic fat, and VAT. Relations between each fat depot and CVD were assessed using logistic regression. The analysis of 1267 participants (mean age 60 years, 53.8% women, 9.7% with prevalent CVD) demonstrated that pericardial fat [odds ratio (OR) 1.32, 95% confidence interval (CI) 1.11–1.57; P = 0.002] and VAT (OR 1.35, 95% CI 1.11–1.57; P = 0.003), but not intrathoracic fat (OR 1.14, 95% CI 0.93–1.39; P = 0.22), were significantly associated with prevalent CVD in age–sex-adjusted models and after adjustment for body mass index and waist circumference. After multivariable adjustment, associations were attenuated (P > 0.14). Only pericardial fat was associated with prevalent myocardial infarction after adjusting for conventional measures of adiposity (OR 1.37, 95% CI 1.03–1.82; P = 0.03).
Pericardial fat and VAT, but not intrathoracic fat, are associated with CVD independent of traditional measures of obesity but not after further adjustment for traditional risk factor. Taken together with our prior work, these findings may support the hypothesis that pericardial fat contributes to coronary atherosclerosis.
Pericardial fat; Visceral abdominal fat; Cardiovascular disease; Framingham Heart Study; Epidemiology
Obesity is associated with altered atrial electrophysiology and a prominent risk factor for atrial fibrillation. Body mass index, the most widely used adiposity measure, has been related to atrial electrical remodeling. We tested the hypothesis that pericardial fat is independently associated with electrocardiographic measures of atrial conduction.
Methods and Results
We performed a cross‐sectional analysis of 1946 Framingham Heart Study participants (45% women) to determine the relation between pericardial fat and atrial conduction as measured by P wave indices (PWI): PR interval, P wave duration (P‐duration), P wave amplitude (P‐amplitude), P wave area (P‐area), and P wave terminal force (P‐terminal). We performed sex‐stratified linear regression analyses adjusted for relevant clinical variables and ectopic fat depots. Each 1‐SD increase in pericardial fat was significantly associated with PR interval (β=1.7 ms, P=0.049), P‐duration (β=2.3 ms, P<0.001), and P‐terminal (β=297 μV·ms, P<0.001) among women; and P‐duration (β=1.2 ms, P=0.002), P‐amplitude (β=−2.5 μV, P<0. 001), and P‐terminal (β=160 μV·ms, P=0.002) among men. Among both sexes, pericardial fat was significantly associated with P‐duration in analyses additionally adjusting for visceral fat or intrathoracic fat; a similar but non‐significant trend existed with P‐terminal. Among women, pericardial fat was significantly associated with P wave area after adjustment for visceral and intrathoracic fat.
Pericardial fat is associated with atrial conduction as quantified by PWI, even with adjustment for extracardiac fat depots. Further studies are warranted to identify the mechanisms through which pericardial fat may modify atrial electrophysiology and promote subsequent risk for arrhythmogenesis.
atrium; conduction; electrocardiography; epidemiology; obesity
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
Obesity represents an important risk factor for atrial fibrillation (AF). We tested the hypothesis that pericardial fat, a unique fat deposit in close anatomic proximity to cardiac structures and autonomic fibers, is associated with prevalent AF.
Methods and Results
Participants from the Framingham Heart Study underwent multi-detector computed tomography from 2002–2005. We estimated the association between quantitative pericardial, intra-thoracic and visceral adipose tissue volumes (per standard deviation [SD] of volume) with prevalent AF adjusting for established AF risk factors (age, sex, systolic blood pressure, blood pressure treatment, PR interval and clinically significant valvular disease). Of the 3217 eligible participants (mean age 50.6±10.1 years, 48% women), 54 had a confirmed diagnosis of AF. Pericardial fat, but not intra-thoracic or visceral abdominal fat, was associated with prevalent AF in multivariable-adjusted models (Odds Ratio [OR] per SD of pericardial fat volume 1.28, 95% confidence intervals [CI] 1.03–1.58). Further adjustments for body mass index, heart failure, myocardial infarction and intra-thoracic fat volume did not materially change the association between pericardial fat and AF.
Pericardial fat was associated with prevalent AF even after adjustment for AF risk factors, including body mass index. If this association is replicated, further investigations into the mechanisms linking pericardial fat to AF are merited.
Atrial fibrillation; pericardial; adipose tissue; obesity; epidemiology; risk factor
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
Quantitative assessment of myocardial blood flow (MBF) from cardiovascular magnetic resonance (CMR) perfusion images appears to offer advantages over qualitative assessment. Currently however, clinical translation is lacking, at least in part due to considerable disparity in quantification methodology. The aim of this study was to evaluate the effect of common methodological differences in CMR voxel-wise measurement of MBF, using position emission tomography (PET) as external validation.
Eighteen subjects, including 9 with significant coronary artery disease (CAD) and 9 healthy volunteers prospectively underwent perfusion CMR. Comparison was made between MBF quantified using: 1. Calculated contrast agent concentration curves (to correct for signal saturation) versus raw signal intensity curves; 2. Mid-ventricular versus basal-ventricular short-axis arterial input function (AIF) extraction; 3. Three different deconvolution approaches; Fermi function parameterization, truncated singular value decomposition (TSVD) and first-order Tikhonov regularization with b-splines. CAD patients also prospectively underwent rubidium-82 PET (median interval 7 days).
MBF was significantly higher when calculated using signal intensity compared to contrast agent concentration curves, and when the AIF was extracted from mid- compared to basal-ventricular images. MBF did not differ significantly between Fermi and Tikhonov, or between Fermi and TVSD deconvolution methods although there was a small difference between TSVD and Tikhonov (0.06 mL/min/g). Agreement between all deconvolution methods was high. MBF derived using each CMR deconvolution method showed a significant linear relationship (p < 0.001) with PET-derived MBF however each method underestimated MBF compared to PET (by 0.19 to 0.35 mL/min/g).
Variations in more complex methodological factors such as deconvolution method have no greater effect on estimated MBF than simple factors such as AIF location and observer variability. Standardization of the quantification process will aid comparison between studies and may help CMR MBF quantification enter clinical use.
Cardiovascular magnetic resonance; Coronary artery disease; Myocardial blood flow; Positron emission tomography; Quantification
To examine the correlations between intra-hepatic and intra-thoracic (total, epicardial, and pericardial) fat deposition with cardiovascular disease (CVD) risk factors and subclinical atherosclerosis burden in healthy, recently postmenopausal women.
Women screened for the Kronos Early Estrogen Prevention Study (mean age 52.9 years) who underwent electron beam or multidetector computed tomography (CT) imaging for the quantification of intra-hepatic fat and thoracic adipose tissue, and coronary artery calcification (CAC) were included (n= 650).
Higher levels of intra-hepatic and thoracic fat were each associated with CVD risk markers. After adjustment for BMI, the associations for intra-hepatic fat with hs-CRP and insulin persisted (r= 0.21 and 0.19, respectively; P<0.001), while those between thoracic fat indices and lipids persisted (r for total thoracic fat with HDL, LDL, and triglycerides= −0.16, 0.11, and 0.11, respectively, P<0.05). Total thoracic fat was associated with CAC after initial multivariable adjustment (odds ratio [OR] of 2nd, 3rd, and 4th vs. 1st quartile and [95% confidence intervals]: 0.8 [0.4–1.6], 1.5 [0.8–2.9], and 1.8 [1.0–3.4]; P for linear trend=0.017) and was only slightly attenuated after additional adjustment for BMI. Associations between total thoracic fat and CVD risk markers and CAC appeared due slightly more to associations with epicardial than pericardial fat.
While hepatic fat is related to hs-CRP and insulin, cardiac fat is associated with subclinical atherosclerosis as demonstrated by CAC. Cardiac fat may represent a useful marker for increased CVD risk beyond the standard adiposity measures of BMI and WC.
coronary calcification; ectopic fat; cardiac fat; hepatic fat; risk factors; women
The objective of this study was to determine whether systemic inflammatory and oxidative stress marker concentrations correlate with pericardial and intrathoracic fat volumes. Participants of the Framingham Offspring Study (n=1175; 53% women; mean age 59±9 years) had pericardial and intrathoracic fat volumes assessed by multidetector computed tomography (MDCT) scans, and provided fasting blood and urine samples to measure concentrations of fourteen inflammatory markers: C-reactive protein (CRP); interleukin-6; monocyte chemoattractant protein-1 (MCP-1); CD40 ligand; fibrinogen; intracellular adhesion molecule-1; lipoprotein-associated phospholipase A2 activity and mass; myeloperoxidase; osteoprotegerin; P-selectin; tumor necrosis factor-alpha; tumor necrosis factor receptor 2; and urinary isoprostanes. Multivariable linear regression models were used to determine the association of log-transformed inflammatory marker concentrations with fat volumes, using fat volume as the dependent variable. Due to smaller sample sizes, models were rerun after adding urinary isoprostanes (n=961) and tumor necrosis factor-alpha (n=813) to the marker panel. Upon backward elimination, four of the biomarkers correlated positively with each fat depot: CRP (P<0.0001 for each fat depot); interleukin-6 (P<0.05 for each fat depot); MCP-1 (P<0.01 for each fat depot); and urinary isoprostanes (P<0.01 for pericardial fat; P<0.001 for intrathoracic fat). Even after adjusting for body mass index, waist circumference, and abdominal visceral fat, CRP (P=0.0001) and urinary isoprostanes (P=0.02) demonstrated significant positive associations with intrathoracic fat, but not with pericardial fat. Multiple markers of inflammation and oxidative stress correlated with pericardial and intrathoracic fat volumes, extending the known association between regional adiposity and inflammation and oxidative stress.
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.
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