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Abstract Background Microarray analyses allow the identification and assessment of molecular signatures in whole tissues undergoing pathological processes. To better understand cerebral malaria pathogenesis, we investigated intra-cerebral gene-expression profiles in well-defined genetically cerebral malaria-resistant (CM-R) and CM-susceptible (CM-S) mice, upon infection by Plasmodium berghei ANKA (PbA). We investigated mouse transcriptional responses at early and late stages of infection by use of cDNA microarrays. Results Through a rigorous statistical approach with multiple testing corrections, we showed that PbA significantly altered brain gene expression in CM-R (BALB/c), and in CM-S (CBA/J and C57BL/6) mice, and that 327 genes discriminated between early and late infection stages, between mouse strains, and between CM-R and CM-S mice. We further identified 104, 56, 84 genes with significant differential expression between CM-R and CM-S mice on days 2, 5, and 7 respectively. The analysis of their functional annotation indicates that genes involved in metabolic energy pathways, the inflammatory response, and the neuroprotection/neurotoxicity balance play a major role in cerebral malaria pathogenesis. In addition, our data suggest that cerebral malaria and Alzheimer's disease may share some common mechanisms of pathogenesis, as illustrated by the accumulation of β-amyloid proteins in brains of CM-S mice, but not of CM-R mice. Conclusion Our microarray analysis highlighted marked changes in several molecular pathways in CM-S compared to CM-R mice, particularly at early stages of infection. This study revealed some promising areas for exploration that may both provide new insight into the knowledge of CM pathogenesis and the development of novel therapeutic strategies.

111In-AMA scintigraphy coupled with rest 201Tl imaging may be useful for the positive diagnosis of subacute myocardial necrosis in patients with angina, aortic stenosis, and normal coronary arteries. The present observation suggests that diffuse myocyte necrosis, histologically confirmed in this case, can be identified with 111In-AMA and may be a cause of cardiac complications in such patients. [ABSTRACT FROM AUTHOR]

DNA barcoding has been succesfully used for bio-surveillance of forest and agricultural pests in temperate areas, but has few applications in the tropics and particulary in Africa. Cacosceles newmannii (Coleoptera: Cerambycidae) is a Prioninae species that is locally causing extensive damage in commercially-grown sugarcane in the KwaZulu-Natal Province in South Africa. Due to the risk of spread of this species to the rest of southern Africa and to other sugarcane growing regions, clear and easy identification of this pest is critical for monitoring and for phytosanitary services. The genus Cacosceles Newman, 1838 includes four species, most being very similar in morphology. The damaging stage of the species is the larva, which is inherently difficult to distinguish morphologically from other Cerambycidae species. A tool for rapid and reliable identification of this species was needed by plant protection and quarantine agencies to monitor its potential abundance and spread. Here, we provide newly-generated barcodes for C. newmannii that can be used to reliably identify any life stage, even by non-trained taxonomists. In addition, we compiled a curated DNA barcoding reference library for 70 specimens of 20 named species of Afrotropical Prioninae to evaluate DNA barcoding as a valid tool to identify them. We also assessed the level of deeply conspecific mitochondrial lineages. Sequences were assigned to 42 different Barcode Index Numbers (BINs), 28 of which were new to BOLD. Out of the 20 named species barcoded, 11 (52.4%) had their own unique Barcode Index Number (BIN). Eight species (38.1%) showed multiple BINs with no morphological differentiation. Amongst them, C. newmannii showed two highly divergent genetic clusters which co-occur sympatrically, but further investigation is required to test whether they could represent new cryptic species., (Marion Javal, John S Terblanche, Desmond E Conlong, Norbert Delahaye, Elizabeth Grobbelaar, Laure Benoit, Carlos Lopez-Vaamonde, Julien M Haran.)

Background: BRAF and NRAS mutation detection is crucial for advanced melanoma treatment. Our aim was to evaluate how different characteristics from formalin-fixed paraffin-embedded (FFPE) samples, age of the block or DNA concentration could influence the success of BRAF and NRAS mutational screening., Methods: DNA was obtained from 144 FFPE samples (62 primary melanoma, 43 sentinel lymph nodes [SLN] and 39 metastasis). BRAF and NRAS were sequenced by Sanger sequencing., Results: Complete sequencing results were obtained from 75% (108/144) of the samples, and at least one gene was sequenced in 89% (128/144) of them. BRAF was mutated in 55% (29/53) and NRAS in 11% (5/45) of the primary melanomas sequenced. DNA concentration correlated with the tumor area used for DNA extraction (mm2) (adj p-value<0.01, r=0.73). The age of the block did not affect sequencing success. In 60% of samples kept for more than 10 years, both BRAF and NRAS were successfully sequenced., Conclusions: Preserving sufficient tumor area in FFPE blocks is important. It is necessary to keep the FFPE blocks, no matter their age, as they are necessary to decide the best treatment for the melanoma patient.

The success of anticancer chemotherapy relies at least in part on the induction of an immune response against tumor cells. Thus, tumors growing on mice that lack the pattern recognition receptor TLR4 or the purinergic receptor P2RX7 fail to respond to chemotherapy with anthracyclins or oxaliplatin in conditions in which the same neoplasms growing on immunocompetent mice would do so. Similarly, the therapeutic efficacy (measured as progression-free survival) of adjuvant chemotherapy with anthracyclins is reduced in breast cancer patients bearing loss-of-function alleles of TLR4 or P2RX7. TLR4 loss-of-function alleles also have a negative impact on the therapeutic outcome of oxaliplatin in colorectal cancer patients. Here, we report that loss-of-function TLR4 and P2RX7 alleles do not affect overall survival in non-small cell lung cancer (NSCLC) patients, irrespective of the administration and type of chemotherapy. The intrinsic characteristics of NSCLC (which near-to-always is chemoresistant and associated with poor prognosis) and/or the type of therapy that is employed to treat this malignancy (which near-to-always is based on cisplatin) may explain why two genes that affect the immune response to dying cells fail to influence the clinical progression of NSCLC patients.

Immunosuppressive cytokines subvert innate and adaptive immune responses during cancer progression. The inflammatory cytokine interleukin-18 (IL-18) is known to accumulate in cancer patients, but its pathophysiological role remains unclear. In this study, we show that low levels of circulating IL-18, either exogenous or tumor derived, act to suppress the NK cell arm of tumor immunosurveillance. IL-18 produced by tumor cells promotes the development of NK-controlled metastases in a PD-1-dependent manner. Accordingly, PD-1 is expressed by activated mature NK cells in lymphoid organs of tumor bearers and is upregulated by IL-18. RNAi-mediated knockdown of IL-18 in tumors, or its systemic depletion by IL-18-binding protein, are sufficient to stimulate NK cell-dependent immunosurveillance in various tumor models. Together, these results define IL-18 as an immunosuppressive cytokine in cancer. Our findings suggest novel clinical implementations of anti-PD-1 antibodies in human malignancies that produce IL-18.

In response to stress, cells start transcriptional and transcription-independent programs that can lead to adaptation or death. Here, we show that multiple inducers of autophagy, including nutrient depletion, trigger the activation of the IKK (IkappaB kinase) complex that is best known for its essential role in the activation of the transcription factor NF-kappaB by stress. Constitutively active IKK subunits stimulated autophagy and transduced multiple signals that operate in starvation-induced autophagy, including the phosphorylation of AMPK and JNK1. Genetic inhibition of the nuclear translocation of NF-kappaB or ablation of the p65/RelA NF-kappaB subunit failed to suppress IKK-induced autophagy, indicating that IKK can promote the autophagic pathway in an NF-kappaB-independent manner. In murine and human cells, knockout and/or knockdown of IKK subunits (but not that of p65) prevented the induction of autophagy in response to multiple stimuli. Moreover, the knockout of IKK-beta suppressed the activation of autophagy by food deprivation or rapamycin injections in vivo, in mice. Altogether, these results indicate that IKK has a cardinal role in the stimulation of autophagy by physiological and pharmacological stimuli.

Cells respond to stress by activating cytoplasmic mechanisms as well as transcriptional programs that can lead to adaptation or death. Autophagy represents an important cytoprotective response that is regulated by both transcriptional and transcription-independent pathways. NFkappaB is perhaps the transcription factor most frequently activated by stress and has been ascribed with either pro- or anti-autophagic functions, depending on the cellular context. Our results demonstrate that activation of the IKK (IkappaB kinase) complex, which is critical for the stress-elicited activation of NFkappaB, is sufficient to promote autophagy independent of NFkappaB, and that IKK is required for the optimal induction of autophagy by both physiological and pharmacological autophagic triggers.

Background: In patients with coronary artery disease (CAD), the characteristics of those with discordant exercise thallium 201 single photon emission computed tomography (SPECT) lung uptake (lung-to-heart [L/H] ratio) and left ventricular (LV) transient ischemic dilation (LVTID) are not well defined., Methods and Results: The population included 310 patients having exercise Tl-201 SPECT and coronary angiography. The population was subclassified into 4 subgroups: increased L/H ratio only, increased LVTID only, both, and neither. The L/H ratio was weakly correlated to LVTID (r = 0.18). The L/H ratio was correlated to the summed difference score (r = 0.26), summed rest score (r = 0.31), summed stress score (r = 0.5), and rest and stress LV volume (r = 0.5 and r = 0.54, respectively). LVTID was only correlated to the summed difference score (r = 0.32) and stress LV volume (r = 0.17). Increased LVTID only was associated with more frequent ischemia and patients with it tended to be more extensively ischemic, as compared with patients with increased L/H ratio only, but had a similar angiographic extent of CAD. These results were independent of prior myocardial infarction variable., Conclusions: As compared with patients with increased L/H ratio alone, patients with increased LVTID alone are more frequently ischemic but have a similar angiographic extent of CAD. Increased L/H ratio was correlated to both rest and postexercise LV volume, whereas increased LVTID was correlated only to postexercise LV volume.

Iterative reconstruction algorithms, such as the ordered subsets expectation maximisation (OS-EM), are a promising alternative to filtered backprojection (FBP). The aims of this study were first to optimise the OS-EM algorithm in terms of iteration number and to study the usefulness of post-filtering, and second to compare OS-EM and FBP for image reconstruction on a fluorine-18 fluorodeoxyglucose ((18)F-FDG) dual-head camera (DHC). These two goals were addressed using phantom acquisitions. The performances of these algorithms were also studied in patient acquisitions performed on a DHC and a PET on the same day. Phantom experiments were performed on a DHC using a Jaszczak phantom containing six spheres filled with (18)F-FDG, two background levels (0.95, 6.80 kBq/ml) and three object contrasts (5.9, 3.7, 2.7). The reconstruction algorithms were FBP with a Gaussian filter (FWHM 0.5-2 pixel width) and OS-EM using 8-128 equivalent iterations (equivalent to the ML-EM algorithm) with and without Gaussian post-filtering [OS-EM (iterations, pixel width)]. Contrast recovery coefficient (CRC) and noise characteristics were assessed. Twenty-two patients (21 male, one female; age 55+/-15 years) with lung cancer underwent, on the same day, PET (1 h post injection of 37 MBq/kg (18)F-FDG) and DHC acquisitions (3 h post injection). DHC data were reconstructed using six methods: FBP (1), OS-EM (16), (40), (40,1), (64) and (64,1). These sets were evaluated by two observers and compared to PET reconstructed with OS-EM (16). The number of detected lesions and the visual quality were assessed. A marked improvement in CRC was observed with OS-EM as compared with FBP when more than 24 iterations were used. The CRC increased markedly from 8 to 40 iterations and then reached a plateau. The noise was stable until 40 iterations and then increased. The best compromise was obtained for OS-EM (32) and OS-EM (40,1). For the patient study, OS-EM provided images of better visual quality, but with no significant difference in detection sensitivity. OS-EM was superior to FBP in terms of contrast recovery and noise level. The optimal compromise between contrast recovery and noise was obtained for OS-EM (32) and (40,1) on the phantom study. The clinical study showed that OS-EM yielded images of better visual quality but with no improvement in terms of detection of lung cancer.

Unlabelled: Ciprofloxacin labeled with (99m)Tc specifically binds to various bacteria. Thus, it potentially constitutes a specific marker allowing discrimination between septic arthritis/osteomyelitis and aseptic osteoarticular diseases. The aim of this prospective study was to evaluate such properties in patients with skeletal diseases., Methods: We prospectively investigated 2 groups of patients: patients with suspected osteoarticular infections (G1, n = 16) and a control group of patients with a presentation of osteoarticular diseases and no sign suggestive of infection (G2, n = 11). All had clinical, biologic, and radiologic evaluations and had 1-, 4-, and 24-h images from (99m)Tc-ciprofloxacin scintigraphy (370 MBq) before planned biopsy or surgery. For 23 patients, the scintigraphic results were compared with histologic and bacteriologic analyses of biopsy tissue samples; for 4 patients, the scintigraphic results were compared with the findings from 23 +/- 5 mo of follow-up., Results: In G1, (99m)Tc-ciprofloxacin findings were true-positive in all 11 infected sites, true-negative in 2 cases, and false-positive in 3. In G2, (99m)Tc-ciprofloxacin was true-negative in 4 cases and false-positive in 7. Neither the location of (99m)Tc-ciprofloxacin activity nor its intensity or kinetics between 1, 4, and 24 h allowed discrimination between infection and aseptic diseases (sterile loosened joint replacement, pseudoarthrosis, or arthrosis). Sensitivity, specificity, and accuracy were 100%, 37.5%, and 63%., Conclusion: (99m)Tc-Ciprofloxacin scintigraphy showed good sensitivity and a high negative predictive value for the detection of bone and joint infection, but it did not discriminate between infected and aseptic osteoarticular diseases in symptomatic patients referred for surgery.

Background: The ability of the size of a total myocardial perfusion defect (MPD) to detect extensive coronary artery disease (CAD) is currently suboptimal with exercise thallium 201 single photon emission computed tomography (SPECT). To improve its performance, exercise electrocardiography and indirect scintigraphic markers of extensive CAD were proposed (increased right ventricular Tl-201 uptake, lung-to-heart [L/H] ratio, and left ventricular transient ischemic dilation ratio). We aimed to determine the additive value of these criteria for the detection of extensive CAD., Methods and Results: The population included 338 patients who underwent exercise Tl-201 SPECT and coronary angiography. Patients were classified as having extensive CAD (left main, multivessel, or 1-vessel proximal left anterior descending CAD) or limited CAD (1-vessel disease other than proximal left anterior descending CAD or no CAD). First, Tl-201 SPECT provided higher diagnostic value than exercise electrocardiography. Second, age, percent target heart rate achieved, total MPD, and L/H ratio were independent predictors of extensive CAD. Third, visually estimated abnormal right ventricular Tl-201 uptake did not present additional information. Fourth, L/H ratio presented a higher diagnostic accuracy than left ventricular transient ischemic dilation ratio., Conclusions: With exercise Tl-201 SPECT, age, percent target heart rate achieved, total MPD, and L/H ratio were independent predictors of extensive CAD.

Unlabelled: A lack of specificity for myocardial perfusion imaging has been widely reported, mostly related to false-positive defects on the inferior wall. The application of depth-dependent resolution recovery (RR), attenuation correction (AC) using external source devices, and scatter correction has been proposed to resolve this pitfall., Methods: We studied the clinical benefit of depth-dependent RR, nonuniform AC using a scanning line source, and scatter correction (photon energy recovery [PER]) compared with filtered backprojection alone. Eighty-two patients were included: 40 healthy volunteers with a low likelihood of coronary artery disease (control group) and 42 patients with proven right or circumflex coronary artery disease but without involvement of the left anterior descending artery. Among these 82 patients, the images of 33 were also processed with PER., Results: RR did not alter the performance of filtered backprojection alone. AC + RR greatly improved specificity and the rate of normal (201)Tl SPECT findings in the control population (from 56% to 95% and from 53% to 100%, respectively) but significantly decreased sensitivity (from 92% to 54%). AC + RR generated a false anteroapical defect in 21% of patients and reverse redistribution of the apex in 23%. AC + RR significantly decreased the extent of the stress defect (from 4.09 to 3.21 segments, P < 0.003) and increased the perfusion score of the stress defect (from 0.78 +/- 0.72 to 1.47 +/- 1.11, P < 0.00061). Moreover, AC + RR generated overcorrection on the inferior wall, leading to false estimation of viability for 11 of 15 patients with an old inferior myocardial scar without evidence of residual viability. PER decreased overcorrection on the inferior wall, but without improving sensitivity. PER did not significantly reduce the number of anteroapical false-positives or the number of apical reverse distribution cases., Conclusion: AC + RR improved the specificity and normalcy rate of (201)Tl SPECT myocardial perfusion imaging but generated overcorrection on the inferior wall, leading to low sensitivity and to false evaluation of myocardial viability in 73% of the patients with inferior infarction. AC + RR also generated anteroapical artifacts. The addition of scatter correction did not significantly reduce these drawbacks.

Unlabelled: Exercise lung 201 TI uptake calculated with planar imaging has an important diagnostic and prognostic value in patients with coronary artery disease (CAD). However, its value with SPECT imaging raises methodological concerns and is controversial. We studied its value for the discrimination between extensive (E) and limited (L) angiographic CAD with exercise SPECT., Methods: Four methods of lung-to-heart ratio quantification were calculated in patients with a low likelihood (< 5%) of CAD (n = 62). Their dependent variables were defined, and corresponding correction equations were derived. Receiver operating characteristic (ROC) analysis was performed in a pilot group (L-CAD, n = 49; E-CAD, n = 126) to define the optimal method of calculation of the lung-to-heart ratio. Its best threshold providing the best sensitivity for a specificity of 90% was defined. After correction for dependent variables, the 4 methods were also compared by ROC analysis and the optimal corrected method was compared with the optimal uncorrected method using ROC analysis and the best threshold. The consistency of these results in the validation group (L-CAD, n = 41; E-CAD, n = 122) and of the results of visual analysis of lung 201TI uptake were then verified., Results: On ROC analysis in the pilot group, the optimal method of calculation of the lung-to-heart ratio was the mean activity in a region of interest drawn at the base of the lungs to the mean activity over the heart (Lb/H). For the best threshold, Lb/H presented a sensitivity of 34%. Corrected Lb/H still remained the best method of calculation on ROC analysis compared with the other corrected methods. On ROC analysis, there was no difference between corrected and uncorrected Lb/H. For the best threshold, corrected Lb/H presented a similar sensitivity of 37% compared with uncorrected Lb/H. When applied to the validation group (L-CAD, n = 41; E-CAD, n = 122), the best-defined threshold in the pilot group for corrected Lb/H presented a diagnostic value similar to that in the pilot group (sensitivity, 41%; specificity, 90%), but uncorrected Lb/H presented a higher sensitivity (47%; P < 0.04) and a slightly lower specificity (80%). Results of lung 201TI uptake visual analysis were inconsistent between pilot and validation groups (42% versus 58% sensitivity, P = 0.012; 86% versus 66% specificity, P = 0.023)., Conclusions: For evaluation of E-CAD versus L-CAD, quantification of the exercise lung-to-heart 201TI uptake ratio with SPECT is feasible, reproducible, more discriminate than simple visual analysis, and best calculated as Lb/H. It presents an intrinsic diagnostic value even after correction for other clinically valuable dependent variables.

Unlabelled: Scintigraphy with somatostatin analogs is a sensitive method for the staging and therapeutic management of patients with endocrine gastroenteropancreatic (GEP) tumors. The aim of this study was to compare prospectively somatostatin receptor scintigraphy (SRS) using 111n-pentetreotide with bone scintigraphy using 99mTc-hydroxymethylene diphosphonate for the detection of bone metastases., Methods: One-hundred-forty-five patients with proven endocrine GEP tumors were investigated. Patients were classified according to the presence of bone metastases as indicated by CT, MRI or histologic data. Group I included 19 patients with confirmed bone metastases, and group II included 126 patients without bone metastases., Results: In group I, SRS was positive in all 19 patients with bone metastases, and bone scintigraphy was positive in 17 patients. Bone metastases were found to occur predominantly in patients with liver metastases. In group 11, 5 patients had recent bone surgery for fracture or arthritis. SRS showed bone uptake in 4 of these patients, and bone scanning showed abnormal uptake in 5. In 7 of the remaining 121 group II patients, SRS was negative and bone scanning showed abnormal bone uptake suggesting bone metastases. The detection of bone metastases was of major prognostic value, because 42% of group 1 patients died during a 2-y follow-up., Conclusion: In patients with GEP tumors, the accuracy of SRS appears to be similar to that of bone scintigraphy for the detection of bone metastases.

Familial amyloid polyneuropathy (FAP) is a rare and severe hereditary form of amyloidosis, due to nervous deposits of a genetic variant transthyretin produced by the liver and characterized by both sensorimotor and autonomic neuropathy. Left ventricular systolic dysfunction is rare, but conduction disturbances and sudden deaths can occur. The neurological status of the heart has not been elucidated, and an alteration of the sympathetic nerves may be involved. We studied 17 patients (42+/-12 years) before liver transplantation by iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy, heart rate variability analysis, coronary angiography, radionuclide ventriculography, rest thallium single-photon emission tomography (SPET) and echocardiography. Coronary arteries, left ventricular systolic function and rest thallium SPET were normal in all patients. Only mild evidence of amyloid infiltration was found at echocardiographic examination. Cardiac MIBG uptake was dramatically decreased in patients compared with age-matched control subjects (heart-to-mediastinum activity ratio at 4 h: 1.36+/-0.26 versus 1.98+/-0.35, P<0.001), while there was no difference in MIBG washout rate. Heart rate variability analysis showed a considerable scatter of values, with high values in four patients despite cardiac sympathetic denervation as assessed by MIBG imaging. The clinical severity of the polyneuropathy correlated with MIBG uptake at 4 h but not with the heart rate variability indices. Cardiac MIBG uptake and the heart rate variability indices did not differ according to the presence or absence of conduction disturbances. Patients with FAP have sympathetic cardiac denervation as assessed by MIBG imaging despite a preserved left ventricular systolic function and cardiac perfusion, without correlation with conduction disturbances. Results of the heart rate variability analysis were more variable and this technique does not seem to be the best way to evaluate the extent of cardiac sympathetic denervation in FAP patients.

Unlabelled: Norepinephrine (NE) reuptake function is impaired in heart failure and this may participate in myocyte hyperstimulation by the neurotransmitter. This alteration can be assessed by 123I-metaiodobenzylguanidine (MIBG) scintigraphy., Methods: To determine whether the impairment of neuronal NE reuptake was reversible after metoprolol therapy, we studied 18 patients (43+/-7 y) with idiopathic dilated cardiomyopathy who were stabilized at least for 3 mo with captopril and diuretics. Patients underwent, before and after 6 mo of therapy with metoprolol, measurements of radionuclide left ventricular ejection fraction (LVEF), maximal oxygen consumption and plasma NE concentration. The cardiac adrenergic innervation function was scintigraphically assessed with MIBG uptake and release measurements on the planar images obtained 20 min and 4 h after tracer injection. To evaluate whether metoprolol had a direct interaction with cardiac MIBG uptake and release, six normal subjects were studied before and after a 1-mo metoprolol intake., Results: In controls, neither cardiac MIBG uptake and release nor circulating NE concentration changed after the 1-mo metoprolol intake. Conversely, after a 6-mo therapy with metoprolol, patients showed increased cardiac MIBG uptake (129%+/-10% versus 138%+/-17%; P = 0.009), unchanged cardiac MIBG release and decreased plasma NE concentration (0.930+/-412 versus 0.721+/-0.370 ng/mL; P = 0.02). In parallel, patients showed improved New York Heart Association class (2.44+/-0.51 versus 2.05+/-0.23; P = 0.004) and increased LVEF (20%+/-8% versus 27%+/-8%; P = 0.0005), whereas maximal oxygen uptake remained unchanged., Conclusion: Thus, a parallel improvement of myocardial NE reuptake and of hemodynamics was observed after a 6-mo metoprolol therapy, suggesting that such agents may be beneficial in heart failure by directly protecting the myocardium against excessive NE stimulation.

We assessed the ventricular-arterial coupling at peak exercise in 20 patients with dilated cardiomyopathy (ejection fraction, 27+/-12%) and 7 normal subjects by radionuclide ventriculography during exercise, coupled with respiratory gas analysis. The end-systolic pressure-volume ratio, taken as an index of contractility, and the effective arterial elastance were calculated at rest and at peak exercise. The end-systolic pressure/volume ratio increased from 3.7+/-2.7 to 6.9+/-4.0 mm Hg/mL at peak exercise in the normal subjects, but did not change significantly (from 0.9+/-0.5 to 1.0+/-0.6 mm Hg/mL) in the patients. Arterial elastance did not change significantly in the patients (+17+/-32%, not significant [NS] vs rest) or in the normal subjects (+22+/-28%, NS vs rest). The change in ejection fraction during exercise correlated both with the end-systolic pressure/volume ratio and with effective arterial elastance changes (r=0.60 and 0.68, respectively). We conclude that ventricular arterial coupling is further altered at peak exercise in these patients because of the lack of increase in contractility and not of altered effective arterial elastance response.

Background: Congestive heart failure is associated with decreased stimulated myocardial adenylate cyclase activity, increased Gi-binding protein, attenuated parasympathetic tone, and increased modulation of beta-adrenergic inotropic left ventricular stimulation by parasympathetic agonists. Despite these abnormalities, changes in the density or affinity of ventricular muscarinic receptors have not been demonstrated in patients., Methods and Results: The density and affinity constants of myocardial muscarinic receptors were evaluated noninvasively by means of positron emission tomography with 11C-MQNB (methylquinuclidinyl benzilate), a specific hydrophilic antagonist, in 20 patients with congestive heart failure due to idiopathic dilated cardiomyopathy (mean left ventricular ejection fraction, 22+/-9%) and compared with values in 12 normal subjects. The mean receptor concentration was significantly higher in patients than in control subjects (B'max, 34.5+/-8.9 versus 25+/-7.7 pmol/mL, P<.005), with no changes in affinity constants. The change in heart rate after injection of 0.6 mg of cold MQNB was lower in patients than in control subjects (34+/-20% versus 55+/-36%, P<.05), and receptor density correlated negatively with maximal heart rate in the patients (r=.45, P<.05)., Conclusions: Congestive heart failure is associated with an upregulation of myocardial muscarinic receptors. This may be an adaptive mechanism to beta-agonist stimulation and should increase the number of potential targets for pharmacological intervention.

Submaximal exercise tests have been advocated to assess exercise capacity in chronic heart failure, but hemodynamic responses have not been characterized. To determine left ventricular (LV) responses during submaximal exercise, the LV ejection fraction (EF) and volumes were evaluated by using an ambulatory radionuclide detector in 13 patients with idiopathic dilated cardiomyopathy during upright maximal graded bicycle exercise, stair climbing and a 6-minute walk test. The 3 tests elicited different responses in volumes and, to a lesser degree, in LVEF. The maximal bicycle exercise led to a decrease in LVEF from 22 +/- 9% to 17 +/- 8% (p <0.05), with marked increases in both end-diastolic volume (EDV) (+15 +/- 10%, p <0.001) and end-systolic volume (ESV) (+23 +/- 18%, p <0.001). Stair climbing tended to reduce LVEF (from 24 +/- 11% to 21 +/- 10%, p = 0.05), with a lesser increase in volumes, which was more marked for ESV (+8 +/- 9%, p <0.01) than for EDV (+4 +/- 4%, p <0.01). The 6-minute walk test did not significantly change LVEF (23 +/- 10% vs 22 +/- 10%), but increased both EDV (+10 +/- 6%, p <0.001) and ESV (+8 +/- 8%, p <0.01) moderately and proportionally. Exercise capacity indexes (peak oxygen consumption, maximal bicycle work rate, stair climbing time, and the distance covered during the 6-minute walk test) correlated significantly with one another. There was no correlation between submaximal exercise tolerance indexes and resting or exercise LVEF. This study shows that (1) LVEF changes are inadequate to report on LV volume changes during exercise; (2) the 3 tests induce different LV volume changes; (3) the 6-minute walk test induces significant changes in LV volumes but no change in LVEF.