Limits of detection of regional differences in vasodilated flow in viable myocardium by first-pass magnetic resonance perfusion imaging.

BACKGROUND: Perfusion imaging techniques intended to identify regional limitations in coronary flow reserve in viable myocardium need to identify 2-fold differences in regional flow during coronary vasodilation consistently. This study evaluated the suitability of current first-pass magnetic resonance approaches for evaluating such differences, which are 1 to 2 orders of magnitude less than in myocardial infarction. METHODS AND RESULTS: Graded regional differences in vasodilated flow were produced in chronically instrumented dogs with either left circumflex (LCx) infusion of adenosine or partial LCx occlusion during global coronary vasodilation. First-pass myocardial signal intensity-time curves were obtained after right atrial injection of gadoteridol (0.025 mmol/kg) with an MRI inversion recovery true-FISP sequence. The area under the initial portion of the LCx curve was compared with that of a curve from a remote area of the ventricle. Relative LCx and remote flows were assessed simultaneously with microspheres. The ratio of LCx and remote MRI curve areas and the ratio of LCx and remote microsphere concentrations were highly correlated and linearly related over a 5-fold range of flow differences (y=0.96 x+/-0.07, P<0.0001, r(2)=0.87). The 95% confidence limits for individual MRI measurements were +/-35%. Regional differences of >/=2-fold were consistently apparent in unprocessed MR images. CONCLUSIONS: Clinically relevant regional reductions in vasodilated flow in viable myocardium can be detected with 95% confidence over the range of 1 to 5 times resting flow. This suggests that MRI can identify and quantify limitations in perfusion reserve that are expected to be produced by stenoses of >/=70%.

Myofibrillar disruption in hypocontractile myocardium showing perfusion-contraction matches and mismatches.

Chronically instrumented dogs underwent 2- or 5-h regional reductions in coronary flow that were followed, respectively, by balanced reductions in myocardial contraction and O(2) consumption ("hibernation") and persistently reduced contraction despite normal myocardial O(2) consumption ("stunning"). Previously unidentified myofibrillar disruption developed during flow reduction in both experimental models and persisted throughout the duration of reperfusion (2-24 h). Aberrant perinuclear aggregates that resembled thick filaments and stained positively with a monoclonal myosin antibody were present in 34 +/- 3.8% (SE) and 68 +/- 5.9% of "hibernating" and "stunned" subendocardial myocytes in areas subjected to flow reduction and in 16 +/- 2.5% and 44 +/- 7.4% of subendocardial myocytes in remote areas of the same ventricles. Areas of myofibrillar disruption also showed glycogen accretion and unusual heterochromatin clumping adjacent to the inner nuclear envelope. The degrees of flow reduction employed were sufficient to reduce regional myofibrillar creatine kinase activity by 25-35%, but troponin I degradation was not evident. The observed changes may reflect an early, possibly reversible, phase of the myofibrillar loss characteristic of hypocontractile myocardium in patients undergoing revascularization.

Coronary vascular responsiveness to adenosine is impaired additively by blockade of nitric oxide synthesis and a sulfonylurea.

OBJECTIVES: We sought to define effects of glibenclamide, a sulfonylurea known to block ATP-dependent potassium (KATP) channels, and Nomega-nitro-L-arginine methyl ester (L-NAME), an L-arginine analog known to block nitric oxide (NO) synthesis, on coronary vascular responsiveness to adenosine. BACKGROUND: The role of adenosine in coronary flow regulation becomes increasingly important when KATP channel function or NO synthesis is impaired. Both variables are potentially altered in patients with coronary artery disease taking a sulfonylurea. METHODS: Dose-response curves relating coronary conductance to plasma adenosine concentration were obtained by using intracoronary infusions of adenosine (10 to 1,000 microg/min) in chronically instrumented dogs. RESULTS: ED50, the plasma concentration of adenosine needed to produce 50% of the maximal increase in conductance under baseline conditions, increased threefold after either 1 or 10 mg/kg of L-NAME. ED50 also increased in response to glibenclamide in a dose-related fashion (5.7-fold increase per 1 mg/kg body weight of glibenclamide). Effects of combined blockade of KATP channels and NO synthesis were additive, with increases in ED50 as high as 15-fold. Both L-NAME and glibenclamide increased systemic pressure and reduced coronary conductance, confirming the roles of NO and KATP channels in regulating coronary and systemic vascular tone under rest conditions as well as during stress. CONCLUSIONS: Coronary vascular responsiveness to adenosine is blunted in vivo by both L-NAME and glibenclamide. Effects of the sulfonylurea and blockade of NO synthesis are additive and can limit coronary vasodilation as well as other responses involving KATP channels and NO.

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.

Comparison of apoptosis signaling through T cell receptor, fas, and calcium ionophore.

The SUP-T13 cell line, a human T leukemia, is susceptible to apoptosis by various inducers, including anti-TCR mAb, calcium ionophores, and anti-fas mAb. Induction of apoptosis by these three agents was investigated, and several differences were found. All three agents induced DNA fragmentation with a similar time course, but the kinetics of cell death were different for the three agents. Anti-TCR mAb-induced apoptosis, but not A23187- or anti-fas-induced apoptosis, was rescued by anti-CD3 mAb treatment. In contrast, only anti-fas mAb-mediated apoptosis was rescued by PKC activators such as PMA. These differences suggest that each of these three agents mediate apoptosis by unique signaling pathways. Nevertheless, two variant subclones of SUP-T13 were found to be resistant to all three apoptosis-inducing agents, suggesting a point(s) of common regulation between the different pathways. To determine whether this regulation occurred through bcl-2, p53, or c-myc, their expression in the parental and variant cells was determined. The three clones expressed approximately equal amounts of these proteins, and their levels did not change significantly upon treatment with anti-TCR or anti-TCR plus anti-CD3 mAb. Thus, although the proximal signaling by various apoptosis inducers were quite different, a common mediator(s) (as yet unknown) may still regulate apoptosis induced by these multiple agents.