Craig H. Meyer

Multifactorial Determinants of Functional Capacity in Peripheral Arterial Disease: Uncoupling of Calf Muscle Perfusion and Metabolism

OBJECTIVESnWe aimed to investigate the pathophysiology of peripheral arterial disease (PAD) by examining magnetic resonance imaging (MRI) and spectroscopic (MRS) correlates of functional capacity.nnnBACKGROUNDnDespite the high prevalence, morbidity, and cost of PAD, its pathophysiology is incompletely understood.nnnMETHODSnEighty-five patients (age 68 +/- 10 years) with mild-to-moderate PAD (ankle-brachial index 0.69 +/- 0.14) had their most symptomatic leg studied by MRI/MRS. Percent wall volume in the superficial femoral artery was measured with black blood MRI. First-pass contrast-enhanced MRI calf muscle perfusion and (31)P MRS phosphocreatine recovery time constant (PCr) were measured at peak exercise in calf muscle. All patients underwent magnetic resonance angiography (MRA), treadmill testing with maximal oxygen consumption measurement, and a 6-min walk test.nnnRESULTSnMean MRA index of number and severity of stenoses was 0.84 +/- 0.68 (normal 0), % wall volume 74 +/- 11% (normal 46 +/- 7%), tissue perfusion 0.039 +/- 0.015 s(-1) (normal 0.065 +/- 0.013 s(-1)), and PCr 87 +/- 54 s (normal 34 +/- 16 s). MRA index, % wall volume, and ankle-brachial index correlated with most functional measures. PCr was the best correlate of treadmill exercise time, whereas calf muscle perfusion was the best correlate of 6-min walk distance. No correlation was noted between PCr and tissue perfusion.nnnCONCLUSIONSnFunctional limitations in PAD are multifactorial. As measured by MRI and spectroscopy, atherosclerotic plaque burden, stenosis severity, tissue perfusion, and energetics all play a role. However, cellular metabolism is uncoupled from tissue perfusion. These findings suggest a potential role for therapies that regress plaque, increase tissue perfusion, and/or improve cellular metabolism. (Comprehensive Magnetic Resonance of Peripheral Arterial Disease; NCT00587678).

Calf Muscle Perfusion at Peak Exercise in Peripheral Arterial Disease: Measurement by First-Pass Contrast-Enhanced Magnetic Resonance Imaging

To develop a contrast‐enhanced magnetic resonance (MR) technique to measure skeletal muscle perfusion in peripheral arterial disease (PAD).

Reproducibility and Reliability of Atherosclerotic Plaque Volume Measurements in Peripheral Arterial Disease with Cardiovascular Magnetic Resonance

A high resolution, noninvasive approach to quantify atherosclerotic plaque in the peripheral vasculature could have significant clinical and research utility. Seventeen patients with peripheral arterial disease (PAD) were studied in a 1.5T CMR scanner. Atherosclerotic plaque volume in the superficial femoral artery was measured and interobserver, intraobserver, and test-retest variability determined. Nineteen vessels were studied with mean acquisition time of 13.1 minutes per vessel. Mean plaque volume was 7.27 +/- 3.73 cm3. Intra-observer intraclass correlation was R = 0.997, inter-observer was R = 0.987, and test-retest reproducibility was R = 0.996. Thus, high resolution measurement of plaque volume in PAD is reliable and reproducible.

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

OBJECTIVESnThis 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.nnnBACKGROUNDnPrior 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.nnnMETHODSnPAD 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.nnnRESULTSnPeak 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).nnnCONCLUSIONSnASL 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.

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

BACKGROUNDnBoth statins and ezetimibe lower LDL-C, but ezetimibes 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).nnnMETHODSnAtherosclerotic 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.nnnRESULTSnLDL-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.nnnCONCLUSIONSnStatin 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, ezetimibes effect on peripheral atherosclerosis may depend upon relative timing of statin therapy.

Low-Density Lipoprotein Lowering Does Not Improve Calf Muscle Perfusion, Energetics, or Exercise Performance in Peripheral Arterial Disease

OBJECTIVESnWe 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.nnnBACKGROUNDnStatins improve cardiovascular outcome in PAD, and some studies suggest improved walking performance.nnnMETHODSnSixty-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.nnnRESULTSnLDL 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.nnnCONCLUSIONSnDespite 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).

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

BackgroundThe 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).MethodsEleven 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)u2009=u2009TF/AIF. Perfusion reserve (PR)u2009=u2009exercise TF/ rest TF. Intraclass correlation coefficient (ICC) was calculated from 11 NL and 10 PAD with repeated MRI on a different day.ResultsResting TF was low in NL and PAD (meanu2009±u2009SD 0.25u2009±u20090.18 vs 0.35u2009±u20090.71, pu2009=u20090.59) but reproducible (ICC 0.76). Exercise TF was higher in NL than PAD (5.5u2009±u20093.2 vs. 3.4u2009±u20091.6, pu2009=u20090.04). Perfusion reserve was similar between groups and highly variable (28.6u2009±u200919.8 vs. 42.6u2009±u200941.0, pu2009=u20090.26). Exercise TF and PI were reproducible measures (ICC 0.63 and 0.60, respectively).ConclusionAlthough 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 perfusion cardiovascular magnetic resonance of the calf in peripheral arterial disease: cuff occlusion hyperemia vs exercise

BackgroundAssessment of calf muscle perfusion requires a physiological challenge. Exercise and cuff-occlusion hyperemia are commonly used methods, but it has been unclear if one is superior to the other. We hypothesized that post-occlusion calf muscle perfusion (Cuff) with pulsed arterial spin labeling (PASL) cardiovascular magnetic resonance (CMR) at 3 Tesla (T) would yield greater perfusion and improved reproducibility compared to exercise hyperemia in studies of peripheral arterial disease (PAD).MethodsExercise and Cuff cohorts were independently recruited. PAD patients had an ankle brachial index (ABI) between 0.4-0.9. Controls (NL) had no risk factors and ABI 0.9-1.4. Subjects exercised until exhaustion (15 NL-Ex, 15 PAD-Ex) or had a thigh cuff inflated for 5 minutes (12 NL-Cuff, 11 PAD-Cuff). Peak exercise and average cuff (Cuffmean) perfusion were compared. Six participants underwent both cuff and exercise testing. Reproducibility was tested in 8 Cuff subjects (5 NL, 3 PAD).ResultsControls had greater perfusion than PAD independent of stressor (NL-Ex 74 ± 21 vs. PAD-Ex 43 ± 10, p = 0.01; NL-Cuffmean 109 ± 39 vs. PAD-Cuffmean 34 ± 17 ml/min-100 g, p < 0.001). However, there was no difference between exercise and Cuffmean perfusion within groups (p > 0.6). Results were similar when the same subjects had the 2 stressors performed. Cuffmean had superior reproducibility (Cuffmean ICC 0.98 vs. Exercise ICC 0.87) and area under the receiver operating characteristic curve (Cuffmean 0.992 vs. Exercise 0.905).ConclusionsCuff hyperemia differentiates PAD patients from controls, as does exercise stress. Cuffmean and exercise calf perfusion values are similar. Cuff occlusion hyperemia has superior reproducibility and thus may be the preferred stressor.

Percutaneous intervention in peripheral artery disease improves calf muscle phosphocreatine recovery kinetics: A pilot study

We hypothesized that percutaneous intervention in the affected lower extremity artery would improve calf muscle perfusion and cellular metabolism in patients with claudication and peripheral artery disease (PAD) as measured by magnetic resonance imaging (MRI) and spectroscopy (MRS). Ten patients with symptomatic PAD (mean ± SD: age 57 ± 9 years; ankle–brachial index (ABI) 0.62 ± 0.17; seven males) were studied 2 months before and 10 months after lower extremity percutaneous intervention. Calf muscle phosphocreatine recovery time constant (PCr) in the revascularized leg was measured by 31P MRS immediately after symptom-limited exercise on a 1.5-T scanner. Calf muscle perfusion was measured using first-pass gadolinium-enhanced MRI at peak exercise. A 6-minute walk and treadmill test were performed. The PCr recovery time constant improved significantly following intervention (91 ± 33 s to 52 ± 34 s, p < 0.003). Rest ABI also improved (0.62 ± 0.17 to 0.93 ± 0.25, p < 0.003). There was no difference in MRI-measured tissue perfusion or exercise parameters, although the study was underpowered for these endpoints. In conclusion, in this pilot study, successful large vessel percutaneous intervention in patients with symptomatic claudication, results in improved ABI and calf muscle phosphocreatine recovery kinetics.

Adenosine Stress Cardiovascular Magnetic Resonance With Variable Density Spiral Pulse Sequences Accurately Detects Coronary Artery Disease: Initial Clinical Evaluation

Background—Adenosine stress cardiovascular magnetic resonance perfusion imaging can be limited by motion-induced dark-rim artifacts, which may be mistaken for true perfusion abnormalities. A high-resolution variable-density spiral pulse sequence with a novel density compensation strategy has been shown to reduce dark-rim artifacts in first-pass perfusion imaging. We aimed to assess the clinical performance of adenosine stress cardiovascular magnetic resonance using this new perfusion sequence to detect obstructive coronary artery disease. Methods and Results—Cardiovascular magnetic resonance perfusion imaging was performed during adenosine stress (140 &mgr;g/kg per minute) and at rest on a Siemens 1.5-T Avanto scanner in 41 subjects with chest pain scheduled for coronary angiography. Perfusion images were acquired during injection of 0.1 mmol/kg Gadolinium-diethylenetriaminepentacetate at 3 short-axis locations using a saturation recovery interleaved variable-density spiral pulse sequence. Significant stenosis was defined as >50% by quantitative coronary angiography. Two blinded reviewers evaluated the perfusion images for the presence of adenosine-induced perfusion abnormalities and assessed image quality using a 5-point scale (1 [poor] to 5 [excellent]). The prevalence of obstructive coronary artery disease by quantitative coronary angiography was 68%. The average sensitivity, specificity, and accuracy were 89%, 85%, and 88%, respectively, with a positive predictive value and negative predictive value of 93% and 79%, respectively. The average image quality score was 4.4±0.7, with only 1 study with more than mild dark-rim artifacts. There was good inter-reader reliability with a &kgr; statistic of 0.67. Conclusions—Spiral adenosine stress cardiovascular magnetic resonance results in high diagnostic accuracy for the detection of obstructive coronary artery disease with excellent image quality and minimal dark-rim artifacts.