Kathleen R. Harris

Magnetic Resonance Versus Radionuclide Pharmacological Stress Perfusion Imaging for Flow-Limiting Stenoses of Varying Severity

Background—Although magnetic resonance first-pass imaging (MRFP) has potential advantages in pharmacological stress perfusion imaging, direct comparisons of current MRFP and established radionuclide techniques are not available. Methods and Results—Graded regional differences in coronary flow were produced during global coronary vasodilation in chronically instrumented dogs by partially occluding the left circumflex artery. Regional differences in full-thickness flow quantified using microspheres were compared with regional differences obtained with MRFP and radionuclide SPECT imaging (99mTc-sestamibi and 201Tl). Relative regional flows (RRFs) derived from the initial areas under MRFP signal intensity-time curves were linearly related to reference microsphere RRFs over the full range of vasodilation (y= 0.93x+4.3; r2 = 0.77). Relationships between 99mTc-sestamibi and 201Tl RRFs and microsphere RRFs were curvilinear, plateauing as flows increased. The high spatial resolution of the MRI enabled transmural flow to be evaluated in 3 to 5 layers across the myocardial wall. Reductions in subendocardial flow were visually apparent in MRFP images for ≥50% reductions in full-thickness flow. Endocardial-to-epicardial gradients in MRFP flow increased progressively with stenosis severity, whereas transmural flow patterns in remote normally perfused myocardium remained normal. Flow reductions of ≥50% not identified by radionuclide imaging were apparent in MRFP full-thickness and transmural analyses. Conclusions—High-resolution MRFP can identify regional reductions in full-thickness myocardial blood flow during global coronary vasodilation over a wider range than current SPECT imaging. Transmural flow gradients can also be identified; their magnitude increases progressively as flow limitations become more severe and endocardial flow is compromised increasingly.

Myocardial perfusion imaging based on the blood oxygen level-dependent effect using T2-prepared steady-state free-precession magnetic resonance imaging

Background—The decision to perform coronary revascularization procedures may hinge on assessment of myocardial perfusion reserve. Blood oxygen level–dependent (BOLD) MRI is a potential method to detect the effects of regional variations in myocardial blood flow during vasodilation. Methods and Results—We imaged dogs (n=13) on a 1.5-T whole-body MRI scanner using a new T2-prepared steady-state free-precession (SSFP) MRI pulse sequence sensitive to BOLD contrast. Images (in-plane resolution ≈1 mm2) of 5 short-axis and 2 long-axis slices of the heart were acquired during graded levels of adenosine infusion via a surgically placed left circumflex (LCx) catheter (n=11) or via a right atrial catheter in animals with an LCx occluder (n=2). Relative myocardial perfusion was measured with the use of fluorescent microspheres. Signal intensity changes in myocardium subtended by the left anterior descending coronary artery were compared with those in the LCx region. Unprocessed T2-weighted images revealed changes in signal intensity corresponding to areas of regional vasodilation or reduced myocardial perfusion reserve during systemic vasodilation. At maximal vasodilation, the signal intensity ratio in the LCx versus left anterior descending territories increased by 33±4% compared with baseline, corresponding to a 3.8±0.3-fold increase in relative perfusion (P<0.01). MR intensity at progressive levels of vasodilation demonstrated good agreement with microsphere flow (R=0.80, P<0.01). Conclusions—T2-prepared SSFP BOLD imaging is a promising method to determine an index of myocardial perfusion reserve in this animal model.

Blockade of Nitric Oxide Synthesis Reduces Myocardial Oxygen Consumption In Vivo

BACKGROUND Although cardiac myocytes and coronary vascular endothelium are known to express a constitutive form of NO synthase, the in vivo effects of tonic endogenous production of NO on myocardial O2 consumption and contractile performance remain unclear. METHODS AND RESULTS The effects of blockade of NO synthase were determined in intact dogs. Myocardial O2 consumption decreased systematically over a wide range of hemodynamic demand after the systemic administration of N omega-nitro-L-arginine methyl ester (L-NAME) or N omega-nitro-L-arginine. Decreases after doses of 1 and 10 mg/kg L-NAME averaged 23 +/- 3.8% and 34 +/- 7.2% at a heart rate of 90 bpm in open-chest animals. Similar reductions occurred after the administration of L-NAME and N omega-nitro-L-arginine in chronically instrumented animals and were unaffected by beta-adrenergic blockade. Intracoronary infusion of L-NAME in chronically instrumented animals reduced both myocardial O2 consumption and regional segment shortening, even at a dose that did not increase systemic arterial pressure. CONCLUSIONS The blockade of NO synthesis reduces myocardial O2 consumption in vivo. The decrease in O2 consumption is accompanied by a decrease in segment shortening. It involves a direct myocardial action of NO, is unaffected by beta-blockade, and is consistent with in vitro studies indicating that low levels of NO augment contractile performance by inhibition of a cGMP-dependent phosphodiesterase.

Endothelium-derived relaxing factor (nitric oxide) has a tonic vasodilating action on coronary collateral vessels

OBJECTIVES We sought to determine whether endothelium-derived relaxing factor (nitric oxide) exerts a tonic vasodilating effect on coronary collateral channels developed in response to myocardial ischemia. BACKGROUND Although the coronary collateral circulation is known to react to several vasoactive agents, the role of endogenously produced nitric oxide is unclear. METHODS Coronary collateral channels were induced in the left circumflex artery bed of 12 chronically instrumented dogs by either ameroid implantation or repeated occlusion of the left circumflex coronary artery. With the native circumflex artery occluded, aortic and circumflex pressures and microsphere flows were measured before and after systemic administration of NG-nitro-L-arginine methyl ester, an arginine analogue known to block the synthesis of nitric oxide. RESULTS NG-nitro-L-arginine methyl ester increased mean aortic pressure from a mean +/- SEM of 92 +/- 4 to 114 +/- 4 mm Hg, whereas pressure in the occluded circumflex artery decreased from 61 +/- 4 to 55 +/- 4 mm Hg. The increase in aortic-circumflex pressure gradient (from 31 +/- 4 to 59 +/- 5 mm Hg) was accompanied by a decrease in flow in the circumflex bed (from 1.31 to +/- 0.14 to 1.09 +/- 0.15 ml/min per g), resulting in an increase in coronary collateral resistance averaging 173 +/- 37% (from 26 +/- 4 to 64 +/- 9 mm Hg/ml per min per g, p < 0.01). The increase in collateral resistance could be partially reversed by administration of L-arginine. CONCLUSIONS We conclude that nitric oxide normally exerts a substantial tonic dilating effect in coronary collateral vessels. Disease-induced alterations in endothelial function may limit collateral perfusion importantly.

Comparison of Two Different Methods for Inoculating VX2 Tumors in Rabbit Livers and Hind Limbs

PURPOSE To compare two methods to (a) propagate VX2 cell strain in rabbit hind limbs and (b) inoculate liver parenchymal tumors in rabbits. MATERIALS AND METHODS One hundred forty-two New Zealand white rabbits were used for this study (60 with hind limb tumor [donors] and 82 with liver tumors [recipients]). In the donor group, nine rabbits received frozen VX2 cell suspension and 51 were injected with freshly prepared VX2 cell suspension. In the recipient group, 32 rabbits were injected with VX2 tumor cells and 50 were implanted with a small tumor fragment in the liver parenchyma. Success rates in terms of tumor growth were compared by using chi(2) or Fisher exact tests, with alpha = .05. RESULTS Hind limb and liver tumors were successfully grown in 48 of the 60 rabbits in the donor group (80%) and 57 of the 82 rabbits in the recipient group (70%). The success rate of growing hind limb tumors increased from 33% (three of nine rabbits) to 88% (45 of 51 rabbits) when fresh VX2 cells instead of frozen were injected percutaneously (P < .0011). Similarly, the success rate for VX2 liver tumors almost doubled from 47% (15 of 32 rabbits) to 84% (42 of 50 rabbits) when a tumor fragment instead of VX2 cell suspension was used (P < .00036). This also significantly reduced the frequency of metastasis (P < .005). CONCLUSIONS The authors recommend (a) the use of fresh VX2 cell suspension for percutaneous injection in the hind limbs of rabbits to maintain the VX2 cell strain and (b) the surgical implantation of freshly harvested VX2 tumor fragment into the liver parenchyma to establish liver tumors.

Assessment of regional differences in myocardial blood flow using T2-weighted 3D BOLD imaging

The feasibility of detecting regional differences in myocardial blood flow based on the blood oxygen level‐dependent (BOLD) effect was evaluated in vivo in dogs (N = 9) using a 3D T2‐prepared segmented gradient‐echo sequence at 1.5 T. Regional differences in myocardial blood flow were created by administering adenosine through a catheter placed in the left circumflex coronary artery (LCX). The difference in the R2 (1/T2) relaxation rate between the left ventricular myocardial region supplied by the LCX and regions supplied by the left anterior descending coronary artery (LAD) or septal artery during adenosine administration was correlated to the corresponding regional myocardial blood flow difference determined using fluorescent microspheres. A correlation coefficient of 0.80 was found between the MR BOLD measurements and the myocardial flow assessment. Our results show that the sequence used in this study allows fast 3D BOLD imaging of the heart, and is a promising technique for detecting regional myocardial perfusion differences. Magn Reson Med 46:573–578, 2001.

Antirestenotic Effects of a Locally Delivered Caspase Inhibitor in a Balloon Injury Model

Background—The precise role of arterial barotrauma-mediated apoptosis in causing restenosis is unclear. The purpose of this study was to determine if a link exists between angioplasty-mediated medial smooth muscle cell apoptosis and subsequent neointimal hyperplasia. Methods and Results—Bilateral iliac artery angioplasty was performed in 25 male New Zealand White rabbits. Simultaneous with balloon injury, each artery was treated locally with either the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp(Ome)-fluoromethylketone (ZVAD-fmk) or control. In the acute cohort that was survived to 4 hours (n=10, 7 high dose and 3 low dose), an apoptotic index was calculated using the terminal deoxynucleotidyl TUNEL method. In the intermediate cohort that was survived to 2 weeks (n=5), luminal reendothelialization was measured via CD-31 staining. In the chronic cohort that was survived to 4 weeks (n=10), neointimal area was measured. In the acute cohort, there was a 40% reduction in the apoptotic index with high-dose ZVAD-fmk (P =0.008) and a 33% reduction with low-dose ZVAD-fmk (P =0.08). At 2 weeks, there was no significant difference in the degree of luminal reendothelialization. However, at 4 weeks, there was a 33% (0.33±0.23 versus 0.22±0.20 mm2) (P <0.005) reduction in neointimal area in ZVAD-fmk–treated arteries. Conclusions—The local delivery of ZVAD-fmk during balloon injury inhibits smooth muscle cell apoptosis. This corresponds to a significant reduction in neointimal proliferation seen at 4 weeks without a significant change in the degree of reendothelialization at 2 weeks.

Proportionate reversible decreases in systolic function and myocardial oxygen consumption after modest reductions in coronary flow: hibernation versus stunning.

OBJECTIVES This study sought to determine whether modest short-term reductions in coronary flow can produce subsequent proportionate reductions in myocardial function and O2 consumption compatible with myocardial hibernation. BACKGROUND Acute studies indicate that myocardial energy utilization can be downregulated during moderate flow reduction. Whether this apparently beneficial adjustment persists into the reperfusion period is unsettled because most postischemic contractile dysfunction has been presumed to represent stunned or irreversibly injured myocardium. METHODS Responses of regional myocardial function and O2 consumption were assessed in chronically instrumented dogs after approximately 50% reductions in flow for 2 h (n = 8) or repeated 2-min total coronary occlusions (n = 6). RESULTS When unrestricted perfusion was restored after sustained partial occlusions, regional function and O2 consumption stabilized at proportionate, systematically decreased levels ([mean +/- SEM] 80 +/- 3.1% and 81 +/- 5.1% of control values, both p < 0.05) and then returned to control values within 24 h. Similar proportionate reductions occurred after as few as five cycles of brief total occlusion (79 +/- 5.1% and 83 +/- 1.6% of control values, both again p < 0.05); these persisted with additional occlusions and then returned to baseline values within 3 h. The absence of irreversible injury was documented histologically in both series. Sham animals (n = 5) showed no changes in regional function or O2 consumption throughout similar experimental periods. CONCLUSIONS Moderate decreases in coronary flow or repeated brief coronary occlusions can be followed by proportionate reversible reductions in regional systolic function and O2 consumption compatible with the traditional definition of myocardial hibernation. These findings emphasize the complexity of myocardial responses to flow restriction and call attention to limitations in characterizing reversibly hypocontractile myocardium as simply hibernating or stunned.

Magnetic resonance imaging of myocardial infarction using a manganese-based contrast agent (EVP 1001-1): Preliminary results in a Dog model

To investigate the MRI characteristics of an intracellular manganese‐based contrast agent, EVP 1001‐1 (Eagle Vision Pharmaceutical Corp.), in a canine model of myocardial infarction.

Gadofluorine-Enhanced Magnetic Resonance Imaging of Carotid Atherosclerosis in Yucatan Miniswine

Objective:The aim of this study was to determine whether gadofluorine, a paramagnetic magnetic resonance imaging (MRI) contrast agent, selectively enhances carotid atherosclerotic plaques in Yucatan miniswine. Methods:Atherosclerotic plaques were induced in the left carotid arteries (LCA) of Yucatan miniswine (n = 3) by balloon denudation and high cholesterol diet. T1-weighted MRI was performed before and 24 hours after gadofluorine injection (at a dose of 100 &mgr;mol/kg) to assess the enhancement of the balloon-injured LCA wall relative to healthy, uninjured right carotid artery (RCA) wall. Histopathology was performed to verify the presence and composition of the atherosclerotic plaques imaged with MRI. Results:Gadofluorine was found to enhance LCA atherosclerotic lesions relative to RCA wall by 21% (P < 0.025) 24 hours after contrast injection. Enhancement of healthy LCA wall relative to healthy RCA wall was not observed. Conclusion:Gadofluorine selectively enhances carotid atherosclerotic plaques in Yucatan miniswine. Gadofluorine appears to be a promising MR contrast agent for detection of atherosclerotic plaques in vivo.