Alirocumab and plaque volume, calf muscle blood flow, and walking performance in peripheral artery disease: A randomized clinical trial.

BACKGROUND: The distal superficial femoral artery (SFA) is most commonly affected in peripheral artery disease (PAD). The effects of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab added to statin therapy on SFA atherosclerosis, downstream flow, and walking performance are unknown. METHODS: Thirty-five patients with PAD on maximally tolerated statin therapy were recruited. Patients were randomized to alirocumab 150 mg subcutaneously (n = 18) or matching placebo (n = 17) therapy every 2 weeks for 1 year. The primary outcome was change in SFA plaque volume by black blood magnetic resonance imaging (MRI). Secondary outcomes were changes in calf muscle perfusion by cuff/occlusion hyperemia arterial spin labeling MRI, 6-minute walk distance (6MWD), low-density lipoprotein (LDL) cholesterol, and other biomarkers. RESULTS: Age (mean ± SD) was 64 ± 8 years, 20 (57%) patients were women, 17 (49%) were Black individuals, LDL was 107 ± 36 mg/dL, and the ankle-brachial index 0.71 ± 0.20. The LDL fell more with alirocumab than placebo (mean [95% CI]) (-49.8 [-66.1 to -33.6] vs -7.7 [-19.7 to 4.3] mg/dL; p < 0.0001). Changes in SFA plaque volume and calf perfusion showed no difference between groups when adjusted for baseline (+0.25 [-0.29 to 0.79] vs -0.04 [-0.47 to 0.38] cm3; p = 0.37 and 0.22 [-8.67 to 9.11] vs 3.81 [-1.45 to 9.08] mL/min/100 g; p = 0.46, respectively), nor did 6MWD. CONCLUSION: In this exploratory study, the addition of alirocumab therapy to statins did not alter SFA plaque volume, calf perfusion or 6MWD despite significant LDL lowering. Larger studies with longer follow up that include plaque characterization may improve understanding of the effects of intensive LDL-lowering therapy in PAD (ClinicalTrials.gov Identifier: NCT02959047).

Arterial spin labeling perfusion cardiovascular magnetic resonance of the calf in peripheral arterial disease: cuff occlusion hyperemia vs exercise.

BACKGROUND: Assessment 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). METHODS: Exercise 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 (Cuff mean ) perfusion were compared. Six participants underwent both cuff and exercise testing. Reproducibility was tested in 8 Cuff subjects (5 NL, 3 PAD). RESULTS: Controls had greater perfusion than PAD independent of stressor (NL-Ex 74 ± 21 vs. PAD-Ex 43 ± 10, p = 0.01; NL-Cuff mean 109 ± 39 vs. PAD-Cuff mean 34 ± 17 ml/min-100 g, p < 0.001). However, there was no difference between exercise and Cuff mean perfusion within groups (p > 0.6). Results were similar when the same subjects had the 2 stressors performed. Cuff mean had superior reproducibility (Cuff mean ICC 0.98 vs. Exercise ICC 0.87) and area under the receiver operating characteristic curve (Cuff mean 0.992 vs. Exercise 0.905). CONCLUSIONS: Cuff hyperemia differentiates PAD patients from controls, as does exercise stress. Cuff mean and exercise calf perfusion values are similar. Cuff occlusion hyperemia has superior reproducibility and thus may be the preferred stressor.

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.

A nonpeptide angiotensin II type 2 receptor agonist does not attenuate postmyocardial infarction left ventricular remodeling in mice.

Cardiac overexpression of the angiotensin II type 2 receptor (AT2 R) attenuates left ventricular (LV) remodeling after myocardial infarction (MI) in transgenic mice. We hypothesized that a novel nonpeptide AT2 R agonist, compound 21 (C21), would attenuate post-MI LV remodeling. Fifty-nine mice were studied for 28 days after 1-hour surgical occlusion-reperfusion of the left anterior descending coronary artery. Immediately thereafter, 23 mice received 0.3 mg·kg·d of C21 via Alzet osmotic minipump, 16 received 10 mg·kg·d of the AT1 R antagonist candesartan in drinking water, and 20 were untreated controls. Cardiac magnetic resonance imaging measured ejection fraction (EF), LV end-systolic, and end-diastolic volumes (ESVI and EDVI) indexed to weight serially post MI. Infarct size was measured on day 1 by late gadolinium-enhanced cardiac magnetic resonance imaging. At baseline, heart rate, blood pressure, EDVI, ESVI, and EF were similar between groups. Mean infarct size (42%-45% of LV mass) was similar between groups. C21-treated animals demonstrated adverse LV remodeling (increased EDVI and ESVI at all post-MI time points) compared with control. Candesartan therapy preserved left ventricular EF at day 28 compared with the C21-treated group. Thus, direct stimulation of the AT2 R by C21 at 0.3 mg·kg·d does not attenuate post-MI LV remodeling in reperfused MI in mice.

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.

Multifactorial determinants of functional capacity in peripheral arterial disease: uncoupling of calf muscle perfusion and metabolism.

OBJECTIVES: We aimed to investigate the pathophysiology of peripheral arterial disease (PAD) by examining magnetic resonance imaging (MRI) and spectroscopic (MRS) correlates of functional capacity. BACKGROUND: Despite the high prevalence, morbidity, and cost of PAD, its pathophysiology is incompletely understood. METHODS: Eighty-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. RESULTS: Mean 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. CONCLUSIONS: Functional 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).

Interaction between bradykinin subtype 2 and angiotensin II type 2 receptors during post-MI left ventricular remodeling.

Angiotensin II type 2 receptor (AT(2)R) overexpression (AT(2)TG) attenuates left ventricular remodeling in a mouse model of anterior myocardial infarction (MI). We hypothesized that the beneficial effects of cardiac AT(2)TG are mediated via the bradykinin subtype 2 receptor (B(2)R). Fourteen transgenic mice overexpressing the AT(2)R (AT(2)TG mice), 10 mice with a B(2)R deletion (B(2)KO mice), 13 AT(2)TG mice with B(2)R deletion (AT(2)TG/B(2)KO mice), and 11 wild-type (WT) mice were studied. All mice were on a C57BL/6 background. Mice were studied by cardiac magnetic resonance imaging at baseline and days 1, 7, and 28 after MI induced by 1 h of occlusion of the left anterior descending artery followed by reperfusion. Short-axis images from apex to base were used to compare ventricular volumes and ejection fraction (EF). At baseline, end-diastolic volume index (EDVI) and end-systolic volume index (ESVI) were lower and EF higher in AT(2)TG mice compared with the other three strains. Infarct size was similar between groups. No differences were observed in global remodeling parameters at day 28 between AT(2)TG and AT(2)TG/B(2)KO mice; however, EDVI and ESVI were lower and EF higher in both transgenic groups than in WT or B(2)KO mice. Both strains lacking B(2)R demonstrated increased collagen content and less hypertrophy in adjacent noninfarcted regions at day 28. Attenuation of postinfarct remodeling by overexpression of AT(2)R is not directly mediated via a B(2)R pathway. However, B(2)R does appear to have a role in the smaller cavity size and hyperdynamic function observed at baseline in AT(2)TG mice and in limiting collagen deposition during postinfarct remodeling.

Calf muscle perfusion at peak exercise in peripheral arterial disease: measurement by first-pass contrast-enhanced magnetic resonance imaging.

PURPOSE: To develop a contrast-enhanced magnetic resonance (MR) technique to measure skeletal muscle perfusion in peripheral arterial disease (PAD). MATERIALS AND METHODS: A total of 11 patients (age = 61 +/- 11 years) with mild to moderate symptomatic PAD (ankle-brachial index [ABI] = 0.75 +/- 0.08) and 22 normals were studied using an MR-compatible ergometer. PAD and normal(max) (Nl(max); N = 11) exercised to exhaustion. Nl(low) (N = 11) exercised to the same workload achieved by PAD. At peak exercise, 0.1 mm/kg of gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) was infused at 3-4 cm(3)/second followed by a saline flush at the same rate. A dual-contrast gradient echo (GRE) sequence enabled simultaneous acquisition of muscle perfusion and arterial input function (AIF). The perfusion index (PI) was defined as the slope of the time-intensity curve (TIC) in muscle divided by the arterial TIC slope. RESULTS: Median workload was 120 Joules in PAD, 210 Joules in Nl(low), and 698 Joules in Nl(max) (P < 0.001 vs. Nl(low) and PAD). Median PI was 0.29 in PAD (25th and 75th percentiles [%] = 0.20, 0.40), 0.48 in Nl(low) (25th, 75th % = 0.36, 0.62; P < 0.02 vs. PAD), and 0.69 in Nl(max) (25th, 75th % = 0.5, 0.77; P < 0.001 vs. PAD). Area under the ROC-curve for PI differentiating patients from Nl(max) was 0.95 (95% confidence interval [CI] = 0.77-0.99). CONCLUSION: Peak-exercise measurement of lower limb perfusion with dual-contrast, first-pass MR distinguishes PAD from normals. This method may be useful in the study of novel therapies for 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.

Dobutamine response and myocardial infarct transmurality: functional improvement after coronary artery bypass grafting--initial experience.

The Investigational Review Board approved the protocol, and all patients provided signed informed consent. The protocol was compliant with HIPAA. The purpose of the study was to prospectively test the hypothesis that addition of low-dose dobutamine and quantification of inotropic reserve in segments with 1%-50% infarct transmurality (IT) would improve the predictive value for functional recovery after revascularization in chronic infarction. Fifteen patients with multivessel coronary artery disease and left ventricular systolic dysfunction were enrolled prior to coronary artery bypass grafting (CABG). Late gadolinium-enhanced cardiac magnetic resonance (MR) imaging was used to assess IT. The percentage of wall thickening was measured with cine cardiac MR imaging at rest and during infusion of 10 (microg . kg(-1))/min dobutamine. Repeat cardiac MR imaging was performed 20 weeks +/- 4 (standard error) later. Functional parameters according to segment were compared before and after CABG by using F tests with repeated-measures models. In segments with 1%-50% IT, similar functional recovery was noted in those with 1%-25% or 26%-50% IT. However, in the same segments, those that improved with dobutamine to normal range demonstrated greater improvement in the percentage of wall thickening (22% +/- 4) after revascularization than those that did not (9% +/- 4) (P < .04). In 1%-50% IT, a normal dobutamine response helps differentiate segments with greater functional recovery after CABG.

The angiotensin II type 2 receptor and improved adjacent region function post-MI.

Angiotensin II type 2 receptor (AT2-R) overexpression in the mouse heart preserves left ventricular (LV) size and global LV function during post-MI remodeling. We hypothesized that CMR tagging would localize regional improvements in myocardial function during post-MI remodeling in AT2-R cardiac overexpressed transgenic mice (TG), which could explain the preservation of global LV function post-MI. Six male wild-type (WT) C57BL/6 mice and 10 TG mice were studied by CMR at baseline (day 0) and days 1, 7, and 28 post-MI. MI was induced by 1 hour occlusion of the LAD followed by reperfusion. On day 1 post-MI, gadolinium-DTPA was injected to assess infarct size. LV size and function was assessed by cine CMR. Mean % circumferential shortening (%CS) was calculated within infarcted, adjacent, and remote regions at each time point in WT and TG mice. Quantitative interstitial collagen and mean myocyte cross-sectional area was measured postmortem at day 28 post-MI. LV end-systolic volume was lower and ejection fraction higher at baseline in the TG group and these differences were maintained post-MI. Within infarcted and remote zones, although %CS was higher in TG mice at day 0, there was no difference by day 28 between groups. Within adjacent regions, while there was no difference at day 0 or 1 in TG vs. WT, %CS was significantly higher in TG mice by day 7, and these changes persisted out to day 28 post-MI. Regional interstitial collagen and myocyte size were similar between groups. Thus, myocardial tagging can detect regional differences in contractile function post-MI in TG mice, and AT2-R overexpression is associated with improved contractile function in adjacent noninfarcted myocardium.

Magnetic resonance imaging identifies the fibrous cap in atherosclerotic abdominal aortic aneurysm.

BACKGROUND: MRI can distinguish components of atherosclerotic plaque. We hypothesized that contrast enhancement with gadolinium-DTPA (Gd-DTPA) could aid in the differentiation of plaque components in abdominal aortic aneurysm (AAA). METHODS AND RESULTS: Twenty-three patients (19 males, age 70+/-8 years) with AAA underwent MRI on a 1.5-T clinical scanner 3+/-3 days before surgical grafting. T1- and T2-weighted (W) black blood spin echo imaging was performed in 1 axial slice, and the T1-W imaging was repeated after a Gd-DTPA-enhanced 3D magnetic resonance angiogram. A section of the aorta at the site of imaging was resected at surgery for histopathologic examination of tissue components and inflammatory cells. Signal-to-noise and contrast-to-noise ratios (CNR) were measured in visualized plaque components from multispectral MRI, and percent enhancement after contrast on T1-W imaging was calculated. The kappa value for agreement between pathology and MRI for the number of tissue components was 0.785. T2-W imaging identified thrombus as regions of high signal and lipid core as low signal, with a CNR of 6.43+/-3.41. Nine patients had a fibrous cap pathologically, which was visualized as a discrete area of uniform increased signal on T2-W imaging with a CNR of 4.52+/-1.93 compared with lipid core. Within the cap, the percent enhancement after Gd-DTPA on T1-W imaging was 91+/-63%. CONCLUSIONS: Higher signal on T2-W MRI identifies the fibrous cap and thrombus within AAA. Contrast enhancement improves delineation of the fibrous cap. The addition of contrast to MRI plaque imaging may enhance identification of vulnerable plaque.

Infarct involution and improved function during healing of acute myocardial infarction: the role of microvascular obstruction.

Delayed contrast-enhanced cardiac magnetic resonance imaging (ceCMR) delineates infarct size. The presence of hypoenhancement consistent with microvascular obstruction (MO) signifies larger infarcts with a worse prognosis. We hypothesized that the size of the contrast defect (CD) on ceCMR in acutely infarcted myocardium may change during infarct healing and depend upon the presence of MO. Twenty-five patients underwent CMR on weeks 1 and 8 after reperfused myocardial infarction. After short-axis cine CMR was performed, gadolinium was infused and ceCMR images and matched tagged cine MR images were obtained in the three most dysfunctional short-axis slices on cine CMR. The area and transmural extent of hyperenhancement (HE) with or without MO representing total CD size were planimetered. Between week 1 and week 8, the CD area fell from 1729+/-970 mm2 at week 1 to 1270+/-706 mm2 (p<0.001), as did the transmural extent of infarction (71+/-22% to 63+/-24%, p<0.001). The decline in CD trended to be higher in patients with MO (840+/-807 mm2) than in HE (312+/-485 mm2, p<0.07). In the patient group as a whole, ejection fraction (EF) improved (56+/-9% to 60+/-10%, p=0.002) between weeks 1 and 8, but patients with MO showed no increase in EF. Segments with some HE demonstrated partial functional improvement whereas no improvement was seen in HE+MO segments. In patients 8 weeks after reperfused myocardial infarction (MI), the size of infarction by ceCMR decreases compared to week 1 post-MI, especially in those with microvascular obstruction in whom there is little improvement in regional or global function.

Angiotensin II type 2 receptor overexpression preserves left ventricular function after myocardial infarction.

BACKGROUND: The role of the angiotensin II type 2 receptor (AT2-R) in left ventricular (LV) remodeling may depend on the underlying stimulus. We hypothesized that cardiac AT2-R overexpression in transgenic (TG) mice would attenuate remodeling after myocardial infarction (MI). METHODS AND RESULTS: Ten wild-type (WT) C57BL/6 mice and 12 TG mice that overexpress the AT2-R in the heart were studied by cardiac MRI at baseline and days 1, 7, and 28 post-MI induced by 1 hour of occlusion of the LAD followed by reperfusion. Short-axis imaging from apex to base was used to determine LV mass index, end-diastolic and end-systolic volume indices (EDVI, ESVI), regional wall thickness and thickening, and ejection fraction (EF). Gadolinium-DTPA was infused 20 minutes before day 1 imaging to assess infarct size. At baseline, heart rate, blood pressure, LV mass index, and EDVI were similar between groups. Baseline ESVI was lower (0.20+/-0.07 versus 0.45+/-0.15 microL/g, P<0.001) and EF higher (82.3+/-4.9% versus 67.7+/-5.3%, P<0.001) in TG than WT. Infarct size was similar (36.6+/-7.2% in WT, 34.0+/-7.8% in TG, P=NS). When controlled for baseline differences, ESVI was significantly less and EF significantly higher at all time points in TG versus WT. At day 28, ESVI was 1.05+/-0.32 microL/g in TG and 1.63+/-0.41 microL/g in WT, P<0.03, and EF was 47.3+/-5.8% versus 34.1+/-9.2%, P<0.003, respectively. Regional wall thickness and thickening were greater in TG both at baseline and at day 28. At day 28, blood pressure and LV dP/dt were higher in TG. CONCLUSIONS: Cardiac AT2-R overexpression improves LV systolic function at baseline and preserves function during post-MI remodeling.