Myocardial blood flow and oxygen consumption in patients with Friedreich's ataxia prior to the onset of cardiomyopathy

OBJECTIVES: We tested the hypothesis, in patients with Friedreich's ataxia and no overt structural heart disease, that impairment of cardiac oxidative metabolism may be compensated for either by increased rest myocardial blood flow or more efficient oxygen consumption in performance of external work. BACKGROUND: Friedreich's ataxia is characterized by a mutant frataxin gene, which causes mitochondrial iron overload and impaired energy production. Further, it is frequently associated with cardiomyopathy. Studies using magnetic resonance spectroscopy, however, suggest impaired cardiac energetics even in the absence of structural heart disease. METHODS: Positron emission tomography measured rest myocardial blood flow (N-13-ammonia method) and myocardial oxygen consumption (11-C-acetate, Kmono) in Friedreich's ataxia patients (n=8; 31+/-5 years, mean+/-SD, four women) and healthy controls (n=8; 30+/-7 years, five women) matched for stroke work index and age. Stroke work index and power were determined by electrocardiogram gated positron emission tomography N-13-ammonia using modified Simpson's rule to compute left ventricular volumes. RESULTS: Neither stroke work index nor rest myocardial blood flow differed significantly between the groups. Although myocardial oxygen consumption was lower in Friedreich's ataxia (P<0.001), Kmono/rest myocardial blood flow, an index of myocardial oxygen extraction, did not differ between the groups. Power/Kmono, an index of the efficiency of myocardial oxygen consumption, was greater in Friedreich's ataxia (P<0.04). Rest myocardial blood flow normalized to rate pressure product was lower in Friedreich's ataxia (P<0.05). CONCLUSIONS: Prior to the onset of cardiomyopathy, selected patients with Friedreich's ataxia may compensate for impaired cardiac energetics through more efficient oxygen consumption rather than increased rest myocardial blood flow. The data illustrate a more general mechanism pertaining to metabolic regulation of myocardial blood flow and myocardial oxygen consumption.     

Multicenter intercomparison assessment of consistency of left ventricular function from a gated cardiac SPECT phantom.

BACKGROUND: A multicenter intercomparison assessment was made of the variation in left ventricular (LV) volumes and ejection fractions (EFs) obtained from gated myocardial perfusion single photon emission computed tomography (SPECT) of the 3-dimensional AGATE (Amsterdam gated) cardiac phantom. METHODS AND RESULTS: The phantom was configured to produce 3 different standard end-systolic volume and end-diastolic volume combinations (50 mL and 120 mL, 90 mL and 160 mL, and 120 mL and 190 mL) with corresponding EF (58%, 44%, and 37%). Quantitative gated myocardial perfusion SPECT was performed with 39 SPECT systems in 35 departments. In the multicenter study, for all 3 filling conditions, a wide range of results was obtained. The EF was overestimated (by 1% to 15%), and both the end-systolic volume and end-diastolic volume were underestimated (by 1 to 65 mL). The extent of overestimation of EF was related to the extent of underestimation of the volumes and was independent of filling condition. The trend in error per center was comparable for all 3 filling conditions. Acquisition time per projection was the only independent predictor of the difference between measured and expected EF (P = .0001). CONCLUSIONS: Care should be taken before extrapolation of published and accepted cutoff values for LV EF and volumes in clinical decision making. Results should be validated in each center and monitored for accuracy and consistency over time.     

Coping with recurrent breast cancer: predictors of distressing symptoms and health-related quality of life

Little is known about how postmenopausal women with recurrent breast cancer cope with distressing symptoms and which factors predict health-related quality of life (HRQOL). In the present study, 56 consecutively enrolled patients completed questionnaires measuring symptom occurrence, coping capacity, coping efforts, and HRQOL at the time of recurrence. Results from this study illustrate that women with recurrent breast cancer suffer from multiple, concurrent, and interrelated symptoms of illness, anxiety, depression, and fatigue. Highly prevalent symptoms are lack of energy, difficulty sleeping, pain, worrying, problems with sexual interest, feeling sad, and dry mouth. The most frequently occurring symptom is problem with sexual interest, and the most severe symptom is worrying. The most distressing symptom experienced is pain. The majority of the women report 10-23 symptoms. Women who experience multiple symptoms also report higher levels of symptom distress. The experience of distressing symptoms is predicted by coping capacity, and the coping efforts experienced predict HRQOL. Patients with lower coping capacity report higher prevalence of symptoms, experience higher levels of distress, and experience worse perceived health, which in turn may decrease their HRQOL. To help women manage recurrent breast cancer, it is important to use multidimensional measurement to identify, evaluate, and treat distressing symptoms, and not assess single symptoms only. Care must be based upon the awareness of critical factors that exacerbate vulnerability to distress, as well as the ability to adapt to a recurrent breast cancer disease.     

Discordant atrial natriuretic peptide and brain natriuretic peptide levels in lone atrial fibrillation

OBJECTIVES: We sought to characterize natriuretic peptide levels in a cohort of rigorously characterized subjects with lone atrial fibrillation (AF). BACKGROUND: Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are sensitive biomarkers of cardiac contractile dysfunction. Both peptides have been reported to be elevated in cohorts with AF, but previous studies have included subjects with underlying structural heart disease. We studied these hormones in 150 subjects with lone AF. METHODS: Study subjects had electrocardiographic evidence of at least one episode of AF and a structurally normal heart on echocardiography. Subjects were excluded if they had a history of a myocardial infarction, rheumatic heart disease, cardiomyopathy, significant valvular disease, hyperthyroidism, or hypertension that preceded the onset of AF. Control subjects were obtained from a healthy outpatient primary care population. Plasma pro-ANP and N-terminal pro-BNP (nt-pro-BNP) levels were determined using commercially available immunoassays. RESULTS: A total of 150 serial subjects with lone AF were enrolled and studied, the majority during normal sinus rhythm. Median levels of nt-pro-BNP were significantly elevated in subjects with lone AF as compared with control subjects (166 vs. 133 fmol/ml, p=0.0003). There was no significant difference in pro-ANP levels between subjects with lone AF and control subjects (1,730 vs. 1,625 fmol/ml, p=0.90). CONCLUSIONS: Discordant natriuretic peptide levels were observed in this homogeneous population of subjects with lone AF. This biomarker pattern, which is present even in sinus rhythm, may represent an underlying subclinical predisposition to this common arrhythmia.     

Changes in health-related quality of life may predict recurrent breast cancer

BackgroundPatient-reported outcomes incorporated in cancer clinical trials, are increasingly hypothesized to be predictors of disease-free survival. Previous research supports health-related quality of life (HRQoL) as an independent predictor of survival in patients with advanced or metastatic breast cancer. In contrast, recent studies provide evidence that baseline HRQoL scores are not associated with increased risk of relapse or survival in women with early-stage breast cancer. One plausible assumption might be that baseline HRQoL scores are limited as predictors of a recurrence of breast cancer several years after the initial diagnosis. In this explorative study, we examined whether changes in HRQoL over time may predict breast cancer recurrence. As a supplement, we investigated whether baseline HRQoL predicted recurrence.MethodsThe study sample consisted of 141 participants in the International Breast Cancer Study Group adjuvant Trial 12-93 and Trial 14-93, from the Western region of Sweden. HRQoL was assessed, during a 5-year follow up. Poisson regression analysis was used to estimate the hazard function of recurrence depending on time since primary diagnosis and on HRQoL variables.ResultsAccording to the Poisson multivariable regression analysis changes in physical well-being (β = 0.00439, p-value = 0.0470), and nausea/vomiting (β = ?0.00612, p-value = 0.0136) significantly predicted recurrence. Baseline HRQoL outcomes were not predictors of recurrence.ConclusionsChanges of HRQoL during adjuvant therapy may be associated with recurrence. This explorative finding needs prospective investigation.     

Sputum eosinophils and the response of exercise-induced bronchoconstriction to corticosteroid in asthma

BACKGROUND: The relationship between eosinophilic airway inflammation and exercise-induced bronchoconstriction (EIB), and the response to inhaled corticosteroid (ICS) therapy was examined. METHODS: Twenty-six steroid-na?ve asthmatic patients with EIB were randomized to two parallel, double-blind, crossover study arms (13 subjects in each arm). Each arm compared two dose levels of inhaled ciclesonide that were administered for 3 weeks with a washout period of 3 to 8 weeks, as follows: (1) 40 vs 160 microg daily; and (2) 80 vs 320 microg daily. Baseline and weekly assessments with exercise challenge and sputum analysis were performed. RESULTS: Data were pooled and demonstrated that 10 subjects had baseline sputum eosinophilia >or= 5%. Only high-dose ICS therapy (ie, 160 and 320 microg) significantly attenuated the sputum eosinophil percentage. Sputum eosinophil percentage significantly correlated with EIB severity, and predicted the magnitude and temporal response of EIB to high-dose therapy, but not to low-dose therapy (ie, 40 and 80 microg). Low-dose ICS therapy provided a significant reduction in EIB at 1 week, with little additional improvement thereafter, irrespective of baseline sputum eosinophil counts. In contrast, high-dose ICS therapy provided a significantly greater improvement in EIB in subjects with sputum eosinophilia compared to those with an eosinophil count of < 5%. The difference between the eosinophilic groups in the magnitude of improvement in EIB was evident after the first week of high-dose ICS therapy and increased with time. CONCLUSIONS: These results suggest that eosinophilic airway inflammation may be important in modifying the severity of EIB and the response to ICS therapy. Measurements of sputum eosinophil percentage may, therefore, be useful in predicting the magnitude and temporal response of EIB to different dose levels of ICSs. Trial registration: clinicaltrial.gov; Identifier: NCT00525772.     

ApoE(-/-)/lysozyme M(EGFP/EGFP) mice as a versatile model to study monocyte and neutrophil trafficking in atherosclerosis

ObjectivesIntravital microscopy is a useful tool for studying leukocyte trafficking in atherosclerosis. However, distinction between various subclasses of leukocytes using this technology is lacking. Therefore, we generated ApoE^?/?/Lysozyme M^EGFP/EGFP mice and investigated whether targeted cell types could be visualized by in vivo microscopy and whether absence of lysozyme M will influence atherosclerosis.MethodsWe crossed male ApoE^?/? mice with mice homozygous for a knock-in mutation of enhanced green fluorescent protein (EGFP) in the lysozyme M locus (Lys^EGFP/EGFP) creating ApoE^?/?/Lys^EGFP/EGFP mice. Mice were sacrificed at the age of 26 weeks. Blood was collected for serum lipid analysis, differential white blood cell count and flow cytometry. Lesion area was determined on en face mounted aortas and sections from aortic roots were stained for immunohistochemistry. Atherosclerotic lesions were also studied by confocal- and intravital microscopy.ResultsBasic parameters, such as white blood cell count, cholesterol profile, lesion area and plaque composition was unaltered in ApoE^?/?/Lys^EGFP/EGFP mice compared to ApoE^?/? mice. Fluorescent neutrophils and monocytes were clearly visualized by intravital fluorescence and confocal microscopy. Fluorescent cells were distributed primarily in the periphery of atherosclerotic lesions indicating a preference for recruitment in these areas.ConclusionsApoE^?/?/Lys^EGFP/EGFP mice will serve as a useful model to study leukocyte trafficking in atherosclerosis and how different subsets of leukocytes influence atherogenesis.     

DC-SIGN, C1q, and gC1qR form a trimolecular receptor complex on the surface of monocyte-derived immature dendritic cells

C1q modulates the differentiation and function of cells committed to the monocyte-derived dendritic cell (DC) lineage. Because the 2 C1q receptors found on the DC surface-gC1qR and cC1qR-lack a direct conduit into intracellular elements, we postulated that the receptors must form complexes with transmembrane partners. In the present study, we show that DC-SIGN, a C-type lectin expressed on DCs, binds directly to C1q, as assessed by ELISA, flow cytometry, and immunoprecipitation experiments. Surface plasmon resonance analysis revealed that the interaction was specific, and both intact C1q and the globular portion of C1q bound to DC-SIGN. Whereas IgG reduced this binding significantly, the Arg residues (162-163) of the C1q-A chain, which are thought to contribute to the C1q-IgG interaction, were not required for C1q binding to DC-SIGN. Binding was reduced significantly in the absence of Ca(2+) and by preincubation of DC-SIGN with mannan, suggesting that C1q binds to DC-SIGN at its principal Ca(2+)-binding pocket, which has increased affinity for mannose residues. Antigen-capture ELISA and immunofluorescence microscopy revealed that C1q and gC1qR associate with DC-SIGN on blood DC precursors and immature DCs. The results of the present study suggest that C1q/gC1qR may regulate DC differentiation and function through the DC-SIGN-mediated induction of cell-signaling pathways.     

Factors affecting error in integration of electroanatomic mapping with CT and MR imaging during catheter ablation of atrial fibrillation

Objective Integration of 3-D electroanatomic mapping with Computed Tomographic (CT) and Magnetic Resonance (MR) imaging is gaining acceptance to facilitate catheter ablation of atrial fibrillation. This is critically dependent on accurate integration of electroanatomic maps with CT or MR images. We sought to examine the effect of patient- and technique-related factors on integration accuracy of electroanatomic mapping with CT and MR imaging of the left atrium. Materials and methods Sixty-one patients undergoing catheter-based atrial fibrillation (AF) ablation procedures were included. All patients underwent cardiac CT (n = 11) or MR (n = 50) imaging, and image integration with real-time electroanatomic mapping of the aorta and left atrium (LA). CARTO-Merge software (Biosense-Webster) was used to calculate the overall average accuracy of integration of electroanatomic points with the CT and MR-derived reconstructions of the LA and aorta. Results There was a significant correlation between LA size assessed by electroanatomic mapping (112 ± 31 ml) and average integration error (1.9 ± 0.6 mm) (r = 0.46, p = 0.0003). There was also greater integration error for patients with LA volume ≥ 110 ml (n = 31) versus < 110 ml (n = 30) (p = 0.004). In contrast, there was no significant association between average integration error and paroxysmal versus persistent AF, left ventricular ejection fraction, days from imaging to electroanatomic mapping, or images derived from CT versus MR. Conclusions Patients with larger LA volume may be prone to greater error during integration of electroanatomic mapping with CT and MR imaging. Strategies to reduce integration error may therefore be especially useful in patients with large LA volume.     

Biodistribution and dosimetry of iodine-123-labelled Z -MIVE: an oestrogen receptor radioligand for breast cancer imaging

This study reports on the distribution and radiation dosimetry of iodine-123-labelled cis-11β-methoxy-17α-iodovinyloestradiol (Z-[¹²³I]MIVE), a promising radioligand for imaging of oestrogen receptors (ERs) in human breast cancer. Whole-body scans were performed up to 24 h after intravenous injection of 138–193 MBq Z-[¹²³I]MIVE in five healthy female volunteers, four with and one without thyroid blockade. Blood samples were taken at various times up to 24 h after injection. Urine was collected up to 24 h after injection in order to calculate renal clearance and to aid in the interpretation of whole-body clearance, including faecal excretion. Time-activity curves were generated for the thyroid, heart, brain, breasts and liver, by fitting the organ-specific geometric mean counts, obtained from regions of interest, to a multicompartmental model. The MIRD formulation, using 11 source organs, was applied to calculate the absorbed radiation doses for various organs upon administration of Z-[¹²³I]MIVE. The images showed rapid hepatobiliary excretion which resulted in good imaging conditions for the thoracic region. Imaging of the abdominal region was impeded due to extensive bowel activity. Diffuse uptake and retention of activity was seen in breast tissue, the breast-to-non-specific uptake ratio increasing over time. Z-[¹²³I]MIVE was cleared by both the kidneys and the gastrointestinal tract. At 50 h p.i. the mean excretion in urine was predicted to be 58%±14% (SD) and that in faeces 31%±19%. If the thyroid was not blocked, it was the most critical organ (0.33 mGy/MBq). In general, the excretory organs received the highest absorbed doses, i.e. the lower and upper large intestinal walls (0.11 and 0.098 mGy/MBq, respectively), the urinary bladder wall (0.090 mGy/MBq), the gallbladder wall (0.087 mGy/MBq) and the small intestine (0.043 mGy/MBq). The average effective dose equivalent of Z-[¹²³I]MIVE was estimated to be 0.033 mSv/MBq. The amount of Z-[¹²³I]MIVE required for adequate breast cancer ER imaging results in an acceptable effective dose equivalent to the patient. Received 28 June and in revised form 26 September 1997