Targeted imaging of the spatial and temporal variation of matrix metalloproteinase activity in a porcine model of postinfarct remodeling: relationship to myocardial dysfunction.

BACKGROUND: Matrix metalloproteinases (MMPs) are known to modulate left ventricular (LV) remodeling after a myocardial infarction (MI). However, the temporal and spatial variation of MMP activation and their relationship to mechanical dysfunction after MI remain undefined. METHODS AND RESULTS: MI was surgically induced in pigs (n = 23) and cine magnetic resonance (MR) and dual-isotope hybrid single-photon emission CT (SPECT)/CT imaging obtained using thallium-201 and a technetium-99m-labeled MMP targeted tracer ((99m)Tc-RP805) at 1, 2, and 4 weeks post-MI along with controls (n = 5). Regional myocardial strain was computed from MR images and related to MMP zymography and ex vivo myocardial (99m)Tc-RP805 retention. MMP activation as assessed by in vivo and ex vivo (99m)Tc-RP805 imaging and retention studies was increased nearly 4-fold within the infarct region at 1 week post-MI and remained elevated up to 1 month post-MI. The post-MI change in LV end-diastolic volumes was correlated with MMP activity (y = 31.34e(0.48x), P = 0.04). MMP activity was increased within the border and remote regions early post-MI, but declined over 1 month. There was a high concordance between regional (99m)Tc-RP805 uptake and ex vivo MMP-2 activity. CONCLUSIONS: A novel, multimodality, noninvasive hybrid SPECT/CT imaging approach was validated and applied for in vivo evaluation of MMP activation in combination with cine MR analysis of LV deformation. Increased (99m)Tc-RP805 retention was seen throughout the heart early post-MI and was not purely a reciprocal of thallium-201 perfusion. The (99m)Tc-RP805 SPECT/CT imaging may provide unique information regarding regional myocardial MMP activation and predict late post-MI LV remodeling.

Accuracy and reproducibility of absolute quantification of myocardial focal tracer uptake from molecularly targeted SPECT/CT: a canine validation.

UNLABELLED: Accurate and reproducible SPECT quantification of myocardial molecular processes remains a challenge because of the complication of heterogeneous background and extracardiac activity adjacent to the heart, which causes errors in the estimation of myocardial focal tracer uptake. Our aim in this study was to introduce a heuristic method for the correction of extracardiac activity into SPECT quantification and validate the modified quantification method for accuracy and reproducibility using a canine model. METHODS: Dual-isotope-targeted (99m)Tc and (201)Tl perfusion SPECT images were acquired using a hybrid SPECT/CT camera in 6 dogs at 2 wk after myocardial infarction. Images were reconstructed with and without CT-based attenuation correction, and the reconstructed SPECT images were filtered and quantified simultaneously with incorporation of extracardiac radioactivity correction, gaussian fitting, and total-count sampling. Absolute myocardial focal tracer uptake was quantified from SPECT images using 3 different normal limits (maximum entropy [ME], mean-squared-error minimization [MSEM], and global minimum [GM]). SPECT-quantified percentage injected dose (%ID) was calculated and compared with the well-counted radioactivity measured from the postmortem myocardial tissue. SPECT quantitative processing was performed by 2 different individuals with extensive experience in cardiac image processing, to assess reproducibility of the quantitative analysis. RESULTS: Correlations between SPECT-quantified and well-counted %IDs using 3 different normal limits were excellent (ME: r = 0.82, y = 0.932 x - 0.0102; MSEM: r = 0.73, y = 1.1413 x - 0.0052; and GM: r = 0.7, y = 1.2147 x - 0.0002). SPECT quantification using ME normal limits resulted in an underestimation of %ID, as compared with well-counted %ID. Myocardial focal tracer uptake quantified from SPECT images without CT-based attenuation correction was significantly lower than that with the attenuation correction. The %IDs quantified from attenuation-corrected SPECT images using MSEM and GM normal limits were not significantly different from well-counted %IDs. Reproducibility of the SPECT quantitative analysis was excellent (ME: r = 0.98, y = 0.9221 x + 0.0001; MSEM: r = 0.97, y = 0.9357 x + 0.0004; and GM: r = 0.96, y = 0.9026 x + 0.001). CONCLUSION: Our SPECT/CT quantification algorithm for the assessment of regional radioactivity may allow for accurate and reproducible serial noninvasive evaluation of molecularly targeted tracers in the myocardium.

Sleep architecture, cocaine and visual learning.

BACKGROUND: Disturbances in sleep associated with chronic cocaine use may underlie abstinence-related cognitive dysfunction. We hypothesized that sleep-related cognitive function would be impaired in chronic cocaine users, and that this impairment would be associated with abstinence-related changes in sleep architecture. METHODS: Twelve chronic cocaine users completed a 23-day in-patient study that included randomized, placebo-controlled, cocaine self-administration sessions. We report polysomnographic measurement of rapid eye-movement (REM) sleep and slow-wave activity, and performance on a visual texture discrimination task. FINDINGS: Progressive abstinence from cocaine was associated with characteristic changes in REM sleep. REM sleep was shortest on nights following cocaine use and rebounded in the first week of abstinence before diminishing with progressive abstinence, following a pattern opposite that of slow-wave activity. Overnight visual learning was observed over the first night following 3 consecutive days of laboratory cocaine use; however, learning was not observed at 3 days or 17 days of abstinence. Across all points of abstinence, early-night slow-wave activity was associated strongly with non-deterioration of visual performance overnight. Furthermore, overnight enhancement of visual performance was predicted by the co-occurrence of sufficient early-night slow-wave activity and late night REM sleep, similar to results from studies in healthy subjects. CONCLUSIONS: These results suggest that abstinence-associated sleep-dependent learning deficits are related to characteristic changes in sleep architecture, and promote the idea that treatments directed at sleep ('somno-tropic' treatments) could be helpful in offsetting physiological consequences of cocaine abstinence.

Sleep, sleep-dependent procedural learning and vigilance in chronic cocaine users: Evidence for occult insomnia.

Sleep disturbance has been implicated in cocaine use; however, the nature of the disturbance and its potential effects on cognition and learning are largely unknown. Twelve chronic cocaine users completed a 23-day inpatient study that included randomized, placebo-controlled, cocaine self-administration sessions. Six subjects received cocaine on each of days 4-6 and placebo on days 18-20, the other six received cocaine on each of days 18-20 and placebo on days 4-6. Sleep was measured by polysomnography, the Nightcap sleep monitor, and self-reported measures. Simple and vigilance reaction times were measured daily; a motor-sequence test of procedural learning was administered four times. Electrophysiological measures of sleep showed a different pattern than self-reported sleep across cocaine administration and abstinence: total sleep time and sleep latency were at their worst by 14-17 days of abstinence while self-reported sleep was at its best. Vigilance correlated positively with electrophysiologically measured sleep and negatively with self-reported measures. Similarly, sleep-dependent procedural learning correlated with total sleep time and was impaired at 17 days abstinence relative to 2- and 3-days abstinence. Slow-wave activity was lowest at days 4-9 of abstinence and highest during use and days 10-17 of abstinence. With sustained abstinence, chronic cocaine users exhibit decreased sleep, impaired vigilance and sleep-dependent procedural learning, and spectral activity suggestive of chronic insomnia. However, they report subjectively improving sleep, indicating they are unaware of this "occult" insomnia. These results suggest the possibility of homeostatic sleep drive dysregulation in chronic cocaine users.

Pacing does not improve hypotension in patients with severe orthostatic hypotension--a prospective randomized cross-over pilot study.

BACKGROUND: Tachypacing has been suggested to compensate for drop in blood pressure as a technique to improve symptoms in patients with severe orthostatic hypotension secondary to autonomic dysfunction. To date, however, no randomized controlled studies have been performed to validate the approach. METHODS AND RESULTS: Six patients with severe orthostatic hypotension and chronotropic incompetence secondary to autonomic dysfunction underwent a prospective randomized cross-over tilt table study with no pacing and with temporary DDD pacing at 90 and 110 bpm. Time to syncope or pre-syncopal symptoms, blood pressure changes, stroke volume and cardiac output were recorded using real time hemodynamic monitoring and echocardiography. All patients, except for one, had a drop in blood pressure and syncope or pre-syncopal symptoms during tilt regardless of whether they were paced or not. There was also no difference in any of the measured hemodynamic and vasomotor parameters with pacing. CONCLUSIONS: Pacing did not produce any benefits in terms of symptoms or in any of the measured hemodynamic variables during tilt for patients with severe orthostatic hypotension secondary to autonomic dysfunction in this limited pilot study.