Ventricular muscarinic receptor remodeling in patients with and without primary ventricular fibrillation. An imaging study.

BACKGROUND: Vagal innervation modulates the electrical stability of the left ventricle (LV) during ischemia. Thus, abnormal parasympathetic activity in myocardial infarction (MI) patients with primary ventricular fibrillation (FV) can account for their arrhythmic disorders. We evaluated LV muscarinic receptor density (B (max)) after MI in patients with (FV(G), n = 11) or without (nFV(G), n = 12) primary FV. METHODS AND RESULTS: The B (max) was measured by positron emission tomography and the specific antagonist [(11)C]methylquinuclidinyl benzilate ([(11)C]MQNB) in 23 patients 39 ± 19 days post-MI, and 10 volunteers. Myocardial damage was quantified by delayed contrast-enhanced magnetic resonance imaging. Three short-axis slices per subject were analyzed and six time-activity curves per slice were fitted to a 3-compartment ligand-receptor model. The B (max) in remote regions of the 23 patients (67 ± 36 pmol/mL · tissue; n = 139) was higher than in normal regions of volunteers (33 ± 16 pmol/mL · tissue; n = 171; P = .01). Receptor density in remote regions was similarly upregulated in nFV(G) (69 ± 31 pmol/mL · tissue, n = 73) and FV(G) (66 ± 40 pmol/mL · tissue, n = 66; P = .72). In damaged regions, the B (max) was reduced in both patient groups (44 pmol/mL · tissue). CONCLUSIONS: Chronically infarcted patients with or without primary FV share similar patterns of ventricular muscarinic receptor remodeling, characterized by receptor upregulation, in remote non-damaged territories.

Muscarinic receptor upregulation in patients with myocardial infarction: a new paradigm.

BACKGROUND: Despite the major role attributed to myocardial vagal activity in left ventricular arrhythmogenesis in chronic myocardial infarction, the impact of infarction on left ventricular muscarinic receptor density remains unknown. METHODS AND RESULTS: Left ventricular muscarinic receptor density was measured in vivo by positron emission tomography using the specific antagonist [(11)C]methylquinuclidinyl benzilate ([(11)C]MQNB) in 11 patients 43+/-20 days after myocardial infarction and 9 healthy volunteers. The extent of myocardial damage was quantified by delayed contrast-enhanced MRI. Three short-axis slices from each subject were analyzed in matched positron emission tomography and MRI images. A 2-injection positron emission tomography protocol was used; [(11)C]MQNB time-activity curves were obtained in 6 regions per slice and fitted to a 3-compartment ligand-receptor model. Four classes of myocardial regions were considered: normal (in volunteers); remote, supplied by healthy or <70% diameter reduction arteries and without MRI signs of damage; potentially damaged, supplied by infarct-related or >70% diameter reduction arteries and without signs of damage; and damaged, with damage. The muscarinic receptor density in remote (67+/-30 pmol/mL tissue; n=86) and potentially damaged (71+/-30 pmol/mL tissue; n=42) regions of patients was higher than in normal regions of volunteers (32+/-17 pmol/mL tissue; n=156; P<0.001). The muscarinic receptor density in damaged regions (42+/-21 pmol/mL tissue; n=58) was reduced compared with remote and potentially damaged regions (P<0.001) but was not significantly different from normal regions in volunteers (P=0.093). CONCLUSIONS: Vagal control in patients with chronic myocardial infarction involves muscarinic receptor upregulation in remote nondamaged left ventricular regions. Our results suggest that the receptor density remains within normal values in myocardial regions containing damaged tissue.

Mechanisms leading to reversible mechanical dysfunction in severe CAD: alternatives to myocardial stunning.

Patients with severe chronic coronary artery disease (CAD) exhibit a highly altered myocardial pattern of perfusion, metabolism, and mechanical performance. In this context, the diagnosis of stunning remains elusive not only because of methodological and logistic considerations, but also because of the pathophysiological characteristics of the myocardium of these patients. In addition, a number of alternative pathophysiological mechanisms may act by mimicking the functional manifestations usually attributed to stunning. The present review describes three mechanisms that could theoretically lead to reversible mechanical dysfunction in these patients: myocardial wall stress, the tethering effect, and myocardial expression and release of auto- and paracrine agents. Attention is focused on the role of these mechanisms in scintigraphically "normal" regions (i.e., regions usually showing normal perfusion, glucose metabolism, and cellular integrity as assessed by nuclear imaging techniques), in which stunning is usually considered, but these mechanisms could also operate throughout the viable myocardium. We hypothesize that reversion of these three mechanisms could partially explain the unexpected functional benefit after reperfusion recently highlighted by high-spatial-resolution imaging techniques.

Tagged MRI and PET in severe CAD: discrepancy between preoperative inotropic reserve and intramyocardial functional outcome after revascularization.

In severe coronary artery disease (CAD), it has been shown that intramyocardial inotropic reserve as assessed with tagged magnetic resonance imaging (MRI) is uniformly distributed among positron emission tomography (PET) patterns reflecting normal or concomitant reductions in perfusion and glucose metabolism. This preliminary study aimed to delineate the relationship between preoperative values of intramyocardial inotropic reserve (in different PET patterns of perfusion and glucose uptake) and intramyocardial functional outcome after surgical revascularization in severe CAD. Twelve patients underwent preoperative tagged MRI (baseline, 10 microg.kg(-1).min(-1) of dobutamine), H2 15O/[18F]fluorodeoxyglucose PET imaging, and postoperative resting tagged MRI. Regional midmyocardial circumferential shortening (Ecc, in %) and PET patterns (normal, match viable, mismatch viable, and infarcted) were assessed in three tagged MRI/PET short-axis slices. Ecc at baseline ranged from 12 +/- 6 to 8 +/- 5 and 4 +/- 4% in normal, match-viable, and infarcted regions, respectively (P <0.05) and was 8 +/- 5% in mismatch-viable regions. Of the 429 regions studied, 187 showed preoperative inotropic reserve with dobutamine, but 238 showed postoperative functional improvement. Postoperative functional improvement was less common in infarcted regions (41 vs. approximately 60% in the other PET patterns), but the extent of improvement was similar among PET patterns (approximately 6%). Postoperative functional improvement occurred in 53% of all (normal, match viable, and mismatch viable) regions without inotropic reserve. In severe CAD, revascularization affords greater intramyocardial functional benefit than expected from the evaluation of intramyocardial inotropic reserve with low-dose dobutamine. Postoperative functional improvement in PET-viable regions without inotropic reserve suggests that factors other than regionally enhanced perfusion contribute to such functional improvement.

Dobutamine-tagged MRI for inotropic reserve assessment in severe CAD: relationship with PET findings.

The impact of blood flow reductions on the intramyocardial inotropic reserve has not yet been established in coronary artery disease (CAD). We therefore evaluated in severe CAD the relationship between positron emission tomography (PET) patterns of perfusion and glucose uptake and the corresponding tagged magnetic resonance imaging (tagged MRI) values of midmyocardial strains under low-dose dobutamine. Eighteen patients underwent tagged MRI (at rest, with dobutamine) and H2(15)O/18F-fluorodeoxyglucose PET. Regional midmyocardial circumferential shortening (Ecc) and PET patterns (normal, match viable, mismatch viable, and infarcted) were assessed in three tagged MRI/PET short-axis slices. Regional Ecc at rest correlated with both perfusion (r = 0.49) and glucose uptake (r = 0.58). The presence of the inotropic reserve was similar in normal, match viable, and infarcted (approximately 40% of regions vs. 52% in mismatch viable, P < 0.05), but the extent of the increase after dobutamine was lower in infarcted regions (P = 0.06). Within each PET pattern, regions were grouped according to their Ecc values at rest into three categories (high, intermediate, and low contractile performance). In mismatch viable (hibernation), the inotropic reserve was similar among the three categories, but in the other PET patterns the presence and extent of the inotropic reserve was higher in those regions with lowest Ecc (without significant differences in perfusion). In severe CAD, the presence of the inotropic reserve assessed by midmyocardial changes under dobutamine does not relate to resting perfusion. At a similar level of perfusion, the presence of the inotropic reserve is inversely related to contractile performance at rest, but our results suggest that it may not be true for hibernating myocardium.

Myocardial perfusion and glucose uptake coupling in CAD patients.

PURPOSE: To evaluate coronary artery disease (CAD) patients regarding to their perfusion-glucose uptake relationship at rest for all myocardial regions and to determine whether this evaluation could typify patients with different positron emission tomography (PET)-pattern proportions and pathophysiological characteristics. METHODS: Rest/dipyridamole H(15)2O and 18FDG PET studies were performed in 23 patients with left ventricular dysfunction. Regional index (relative perfusion, %H(15)2O; relative glucose uptake, %18FDG) allowed to detect PERFUSION-metabolism mismatch (i.e. hibernation) and dipyridamole-induced reversible stress defects (RSD). RESULTS: The correlation (r) between %H(15)2O and % 18FDG at rest allowed definition of three groups: correlated (CORR; r > 0.7; n = 10), semicorrelated (SEMI; 0.5 < r < or = 0.7; n = 6) and uncorrelated (UNCO; r < or = 0.5; n = 7). In UNCO, 96% of regions had a %H(15)2O > or = 55% (p < 0.01 vs. 89 and 82% in SEMI and CORR) and 95% of regions had a %18FDG > or = 55% (p < 0.01 vs. 78 and 71% in SEMI and CORR). Mismatch proportions increased from CORR to SEMI and UNCO (11, 19 and 27%; p < 0.02) and proportion of regions with RSD was higher in UNCO and SEMI (25 and 24 vs. 6% in CORR; p < 0.01). Proportion of mismatch with RSD was at least three fold higher in UNCO (17/58) (p < 0.01 vs. 3/33 and 1/16 in SEMI and CORR). CONCLUSIONS: Analysis of perfusion and glucose uptake at rest allowed to typify three categories of CAD patients with different PET-patterns proportions, distinctive ranges of perfusion and glucose uptake and distinctive hyperemic response. Our results suggest that myocardial hibernation associated with defective hyperemic response is specific of patients with preserved perfusion and glucose uptake.

Cardiac retention of [11C]HED in genotyped long QT patients: a potential amplifier role for severity of the disease.

Although mutations in cardiac sodium and potassium channel genes are associated with congenital long QT syndrome (LQTS), a "modifier" role of the sympathetic nervous system was proposed to explain the distinct severity of the disease. We evaluated cardiac sympathetic innervation using [11C]hydroxyephedrine ([11C]HED) and positron emission tomography (PET) in genotyped LQTS patients. H215O and [11C]HED PET studies were performed in 11 patients (5 symptomatic) and 8 controls. Perfusion and [11C]HED images were depicted as 36-sector polar maps. Sectorial values of perfusion (H2O%), absolute (HEDRet) and relative retention (HED%Ret) of [11C]HED, and the ratio of HED%Ret to H2O% (HED%Ret/H2O%) were calculated. Normal databases were obtained from controls. Sectorial values below 2SD database values were defined as "outside sectors." Controls and patients showed similar sectorial perfusion. Sectorial HEDRet did not differ between groups, but means of HED%Ret were lower in three sectors for patients (P < 0.05). Three sectors from 3 controls had HED%Ret below 2SD, whereas 36 sectors in 9 patients were outside sectors (P < 0.01). In patients, average HED%Ret/H2O% was lower in 9 sectors (P < 0.05 vs. controls); 2 outside sectors were found in controls, but 43 outside sectors were found in patients (P < 0.01), 77% of them in the 5 symptomatic patients. Heterogeneous [11C]HED retention was localized in the septal, anterior, and lateral walls. Most LQTS patients showed a localized and decreased pattern of [11C]HED retention. The larger number of heterogeneous sectors in symptomatic patients suggests that sympathetic function could play an amplifier role for severity of the disease.

Factor analysis of medical image sequences improves evaluation of first-pass MR imaging acquisitions for myocardial perfusion.

RATIONALE AND OBJECTIVES: Factor analysis of medical image sequences (FAMIS) applied to gadolinium chelate-enhanced subsecond magnetic resonance (MR) imaging was evaluated as a postprocessing method for assessing myocardial perfusion in coronary artery disease (CAD). MATERIALS AND METHODS: To assess the accuracy of motion correction, five normal volunteers underwent MR imaging at rest. Thirteen patients with well-documented CAD and no myocardial infarction underwent MR imaging at rest and after dipyridamole administration. After motion correction, a single myocardial tissue factor (FAMISt) image was obtained with FAMIS for each raw MR imaging series acquisition. To evaluate how FAMIS could improve the analysis of these acquisitions, five readers visually assessed myocardial perfusion with FAMISt and raw MR images, and a multicase, multireader receiver operating characteristic analysis was performed. RESULTS: FAMISt images significantly improved detection of the perfusion defects when compared with raw MR images (P = .002). Areas under the receiver operating characteristic curves ranged from 0.84 to 0.93 with FAMISt images and from 0.48 to 0.85 with raw MR images. CONCLUSION: FAMIS applied to first-pass MR imaging series provided myocardial perfusion images that improve the objective assessment of myocardial perfusion in patients with CAD.