Reproducibility of rest and exercise stress contrast-enhanced calf perfusion magnetic resonance imaging in peripheral arterial disease.

BACKGROUND: The purpose was to determine the reproducibility and utility of rest, exercise, and perfusion reserve (PR) measures by contrast-enhanced (CE) calf perfusion magnetic resonance imaging (MRI) of the calf in normal subjects (NL) and patients with peripheral arterial disease (PAD). METHODS: Eleven PAD patients with claudication (ankle-brachial index 0.67 ±0.14) and 16 age-matched NL underwent symptom-limited CE-MRI using a pedal ergometer. Tissue perfusion and arterial input were measured at rest and peak exercise after injection of 0.1 mM/kg of gadolinium-diethylnetriamine pentaacetic acid (Gd-DTPA). Tissue function (TF) and arterial input function (AIF) measurements were made from the slope of time-intensity curves in muscle and artery, respectively, and normalized to proton density signal to correct for coil inhomogeneity. Perfusion index (PI) = TF/AIF. Perfusion reserve (PR) = exercise TF/ rest TF. Intraclass correlation coefficient (ICC) was calculated from 11 NL and 10 PAD with repeated MRI on a different day. RESULTS: Resting TF was low in NL and PAD (mean ± SD 0.25 ± 0.18 vs 0.35 ± 0.71, p = 0.59) but reproducible (ICC 0.76). Exercise TF was higher in NL than PAD (5.5 ± 3.2 vs. 3.4 ± 1.6, p = 0.04). Perfusion reserve was similar between groups and highly variable (28.6 ± 19.8 vs. 42.6 ± 41.0, p = 0.26). Exercise TF and PI were reproducible measures (ICC 0.63 and 0.60, respectively). CONCLUSION: Although rest measures are reproducible, they are quite low, do not distinguish NL from PAD, and lead to variability in perfusion reserve measures. Exercise TF and PI are the most reproducible MRI perfusion measures in PAD for use in clinical trials.

Arterial spin labeling MR imaging reproducibly measures peak-exercise calf muscle perfusion: a study in patients with peripheral arterial disease and healthy volunteers.

OBJECTIVES: This study hypothesized that arterial spin labeling (ASL) magnetic resonance (MR) imaging at 3-T would be a reliable noncontrast technique for measuring peak exercise calf muscle blood flow in both healthy volunteers and patients with peripheral arterial disease (PAD) and will discriminate between these groups. BACKGROUND: Prior work demonstrated the utility of first-pass gadolinium-enhanced calf muscle perfusion MR imaging in patients with PAD. However, patients with PAD often have advanced renal disease and cannot receive gadolinium. METHODS: PAD patients had claudication and an ankle brachial index of 0.4 to 0.9. Age-matched normal subjects (NL) had no PAD risk factors and were symptom-free with exercise. All performed supine plantar flexion exercise in a 3-T MR imaging scanner using a pedal ergometer until exhaustion or limiting symptoms and were imaged at peak exercise with 15 averaged ASL images. Peak perfusion was measured from ASL blood flow images by placing a region of interest in the calf muscle region with the greatest signal intensity. Perfusion was compared between PAD patients and NL and repeat testing was performed in 12 subjects (5 NL, 7 PAD) for assessment of reproducibility. RESULTS: Peak exercise calf perfusion of 15 NL (age: 54 ± 9 years) was higher than in 15 PAD patients (age: 64 ± 5 years, ankle brachial index: 0.70 ± 0.14) (80 ± 23 ml/min - 100 g vs. 49 ± 16 ml/min/100 g, p < 0.001). Five NL performed exercise matched to PAD patients and again demonstrated higher perfusion (84 ± 25 ml/min - 100 g, p < 0.002). As a measure of reproducibility, intraclass correlation coefficient between repeated studies was 0.87 (95% confidence interval [CI]: 0.61 to 0.96). Interobserver reproducibility was 0.96 (95% CI: 0.84 to 0.99). CONCLUSIONS: ASL is a reproducible noncontrast technique for quantifying peak exercise blood flow in calf muscle. Independent of exercise time, ASL discriminates between NL and PAD patients. This technique may prove useful for clinical trials of therapies for improving muscle perfusion, especially in patients unable to receive gadolinium.

Elevated circulating fibrocyte levels in patients with hypertensive heart disease.

OBJECTIVE: Autopsy and biopsy studies have shown that there is significantly more fibrosis in hearts of patients with hypertensive heart disease compared to normal hearts. Fibrocytes, a population of circulating bone marrow-derived cells, have been shown to home to tissues and promote scar formation in several diseases, but their role in human hypertensive heart disease has not been investigated to date. Our objective was to determine whether fibrocyte levels are elevated in individuals with hypertensive heart disease. METHODS: We measured peripheral blood fibrocyte levels and their activated phenotypes in 12 individuals with hypertensive heart disease as determined by increased left ventricular mass on noninvasive imaging and compared them to fibrocyte levels from 19 healthy normal controls and correlated them to cardiac MRI findings. RESULTS: Compared to normal controls, individuals with hypertensive heart disease had significantly higher circulating levels of total fibrocytes [median (interquartile range); 149000 (62200-220000) vs. 564500 (321000-1.2900e(+006)), P < 0.0001, respectively] as well as activated fibrocytes [15700 (6380-19800) vs. 478500 (116500-1.2360e(+006)) P < 0.0001]. Moreover, the fibrocyte subsets expressing the chemokine markers CXCR4 (P < 0.0001), CCR2 (P < 0.0001), CCR7 (P < 0.0001) and coexpression of both CXCR4 and CCR2 (P < 0.0001) were significantly elevated in patients with hypertensive heart disease compared to controls. Lastly, in patients with hypertensive heart disease there was a strong correlation between left ventricular mass index and total fibrocytes (r = 0.65, P = 0.037) and activated fibrocytes (r = 0.70, P = 0.016). CONCLUSION: Our data suggest that bone marrow-derived circulating fibrocytes are associated with the presence and extent of left ventricular hypertrophy in patients with hypertensive heart disease.

Low-density lipoprotein lowering does not improve calf muscle perfusion, energetics, or exercise performance in peripheral arterial disease.

OBJECTIVES: We hypothesized that low-density lipoprotein (LDL) reduction regardless of mechanism would improve calf muscle perfusion, energetics, or walking performance in peripheral arterial disease (PAD) as measured by magnetic resonance imaging and magnetic resonance spectroscopy. BACKGROUND: Statins improve cardiovascular outcome in PAD, and some studies suggest improved walking performance. METHODS: Sixty-eight patients with mild to moderate symptomatic PAD (age 65 ± 11 years; ankle-brachial index [ABI] 0.69 ± 0.14) were studied at baseline and annually for 2 years after beginning simvastatin 40 mg (n = 20) or simvastatin 40 mg/ezetimibe 10 mg (n = 18) if statin naïve, or ezetimibe 10 mg (n = 30) if taking a statin. Phosphocreatine recovery time was measured by (31)P magnetic resonance spectroscopy immediately after symptom-limited calf exercise on a 1.5-T scanner. Calf perfusion was measured using first-pass contrast-enhanced magnetic resonance imaging with 0.1 mM/kg gadolinium at peak exercise. Gadolinium-enhanced magnetic resonance angiography was graded. A 6-min walk and a standardized graded Skinner-Gardner exercise treadmill test with peak Vo(2) were performed. A repeated-measures model compared changes over time. RESULTS: LDL reduction from baseline to year 2 was greater in the simvastatin 40 mg/ezetimibe 10 mg group (116 ± 42 mg/dl to 56 ± 21 mg/dl) than in the simvastatin 40 mg group (129 ± 40 mg/dl to 90 ± 30 mg/dl, p < 0.01). LDL also decreased in the ezetimibe 10 mg group (102 ± 28 mg/dl to 79 ± 27 mg/dl, p < 0.01). Despite this, there was no difference in perfusion, metabolism, or exercise parameters between groups or over time. Resting ABI did improve over time in the ezetimibe 10 mg group and the entire study group of patients. CONCLUSIONS: Despite effective LDL reduction in PAD, neither tissue perfusion, metabolism, nor exercise parameters improved, although rest ABI did. Thus, LDL lowering does not improve calf muscle physiology or functional capacity in PAD. (Comprehensive Magnetic Resonance of Peripheral Arterial Disease; NCT00587678).

The effect of ezetimibe on peripheral arterial atherosclerosis depends upon statin use at baseline.

BACKGROUND: Both statins and ezetimibe lower LDL-C, but ezetimibe's effect on atherosclerosis is controversial. We hypothesized that lowering LDL-C cholesterol by adding ezetimibe to statin therapy would regress atherosclerosis measured by magnetic resonance imaging (MRI) in the superficial femoral artery (SFA) in peripheral arterial disease (PAD). METHODS: Atherosclerotic plaque volume was measured in the proximal 15-20 cm of the SFA in 67 PAD patients (age 63 ± 10, ABI 0.69 ± 0.14) at baseline and annually × 2. Statin-naïve patients (n=34) were randomized to simvastatin 40 mg (S, n=16) or simvastatin 40 mg+ezetimibe 10mg (S+E, n=18). Patients already on statins but with LDL-C >80 mg/dl had open-label ezetimibe 10mg added (E, n=33). Repeated measures models estimated changes in plaque parameters over time and between-group differences. RESULTS: LDL-C was lower at year 1 in S+E (67 ± 7 mg/dl) than S (91 ± 8 mg/dl, p<0.05), but similar at year 2 (68 ± 10 mg/dl vs. 83 ± 11 mg/dl, respectively). Plaque volume did not change from baseline to year 2 in either S+E (11.5 ± 1.4-10.5 ± 1.3 cm(3), p=NS) or S (11.0 ± 1.5-10.5 ± 1.4 cm(3), p=NS). In E, plaque progressed from baseline to year 2 (10.0 ± 0.8-10.8 ± 0.9, p<0.01) despite a 22% decrease in LDL-C. CONCLUSIONS: Statin initiation with or without ezetimibe in statin-naïve patients halts progression of peripheral atherosclerosis. When ezetimibe is added to patients previously on statins, peripheral atherosclerosis progressed. Thus, ezetimibe's effect on peripheral atherosclerosis may depend upon relative timing of statin therapy.