P62-positive aggregates are homogenously distributed in the myocardium and associated with the type of mutation in genetic cardiomyopathy.

Genetic cardiomyopathy is caused by mutations in various genes. The accumulation of potentially proteotoxic mutant protein aggregates due to insufficient autophagy is a possible mechanism of disease development. The objective of this study was to investigate the distribution in the myocardium of such aggregates in relation to specific pathogenic genetic mutations in cardiomyopathy hearts. Hearts from 32 genetic cardiomyopathy patients, 4 non-genetic cardiomyopathy patients and 5 controls were studied. Microscopic slices from an entire midventricular heart slice were stained for p62 (sequestosome-1, marker for aggregated proteins destined for autophagy). The percentage of cardiomyocytes with p62 accumulation was higher in cardiomyopathy hearts (median 3.3%) than in healthy controls (0.3%; P < .0001). p62 accumulation was highest in the desmin (15.6%) and phospholamban (7.2%) groups. P62 accumulation was homogeneously distributed in the myocardium. Fibrosis was not associated with p62 accumulation in subgroup analysis of phospholamban hearts. In conclusion, accumulation of p62-positive protein aggregates is homogeneously distributed in the myocardium independently of fibrosis distribution and associated with desmin and phospholamban cardiomyopathy. Proteotoxic protein accumulation is a diffuse process in the myocardium while a more localized second hit, such as local strain during exercise, might determine whether this leads to regional myocyte decay.

Distinct fibrosis pattern in desmosomal and phospholamban mutation carriers in hereditary cardiomyopathies.

BACKGROUND: Desmosomal and phospholamban (PLN) mutations are associated with arrhythmogenic cardiomyopathy. Ultimately, most cardiomyopathic hearts develop significant cardiac fibrosis. OBJECTIVE: To compare the fibrosis patterns of desmosomal and p. Arg14del PLN-associated cardiomyopathies with the pattern in hearts with other hereditary cardiomyopathies. METHODS: A midventricular transversal slice was obtained from hearts of 30 patients with a cardiomyopathy with a known underlying mutation and from 8 controls. Fibrosis and fatty changes were quantitatively analyzed using digital microscopy. RESULTS: Hearts from patients with desmosomal mutations (n = 6) showed fibrosis and fibrofatty replacement in the left ventricular (LV) outer myocardium, mainly in the posterolateral wall, and in the right ventricle. A similar phenotype, but with significantly more severe fibrotic changes in the LV, was found in the PLN mutation group (n = 8). Cardiomyopathies associated with lamin A/C (n = 5), sarcomeric (n = 8), and desmin (n = 3) mutations all showed a different pattern from that of the desmosomal and PLN mutation carriers. The posterolateral LV wall appeared to be the most discriminative area with fibrosis and fatty changes predominantly at the outer compact myocardium in 13 of 14 hearts with desmosomal and PLN mutations (93%), in 0 of 13 hearts with lamin A/C and sarcomeric mutations (0%), and in 1 of 3 desminopathic hearts (33%) (P < .001). CONCLUSION: Desmosomal- and PLN-associated cardiomyopathies have a fibrosis pattern distinct from the patterns in other hereditary cardiomyopathies. The posterolateral LV wall appeared to be the most discriminative region between mutation groups. These results may provide a roadmap for cardiac imaging interpretation and may help in further unraveling disease mechanisms.

Seven-tesla magnetic resonance imaging of atherosclerotic plaque in the significantly stenosed carotid artery: a feasibility study.

OBJECTIVES: The objective of this study was to assess the feasibility of carotid vessel wall imaging at 7.0 for T magnetic resonance imaging (MRI) in a series of patients with a symptomatic greater than 70% stenosis of the internal carotid artery. MATERIALS AND METHODS: First, a series of 6 healthy volunteers were scanned at 3.0 T and 7.0 T MRI to perform a signal-to-noise ratio comparison between these 2 field strengths. Second, in patients with a greater than 70% stenosed carotid artery, a 7.0 T MRI protocol, consisting of a dual-echo turbo spin echo sequence (echo times of 45 and 150 milliseconds) and a T1-weighted turbo spin echo sequence, was obtained. Lumen and vessel wall were delineated for interobserver and intraobserver reproducibility, and signal intensity distribution in the most severely stenosed part of the internal carotid artery was correlated with different plaque components on histopathologic findings. RESULTS: The mean (SD) signal-to-noise ratio in the vessel wall was 42 (12) at 7.0 T and 24 (4) at 3.0 T. Nineteen patients were included, but technical issues yielded carotid MRI data of 14 patients available for the final analysis. Of these patients, 4 were diagnosed with stroke, 7 were diagnosed with a transient ischemic attack, and 3 were diagnosed with amaurosis fugax. Intraclass correlation coefficient of the agreements of lumen and vessel wall determination between 2 observers and between the repeated measures of 1 observer were above 0.80 in both 3.0 T and 7.0 T data sets of the healthy volunteers and also in the 7.0 T data set of the patients. Signal hyperintensity in the 7.0 T magnetic resonance images was inversely proportional to calcification. Other correlations between plaque components and signal intensity could not be confirmed. CONCLUSIONS: This first series of patients with carotid atherosclerotic plaque who were scanned at 7.0 T MRI shows that 7.0 T MRI enables to adequately determine lumen and vessel wall areas. Signal hyperintensity in these 7.0 T magnetic resonance images was inversely proportional to calcification. However, at this stage, no other correlations between histologic findings and vessel wall contrast were found. Implementation of in vivo high-resolution 7.0 T MRI of plaque components for risk stratification remains challenging. Future development of hardware and software is still needed to attain a more robust setup and to enable complete plaque characterization, similar to what is currently possible with multiple MRI sequences at 1.5 T and 3.0 T MRI.

Involvement of the opportunistic pathogen Aspergillus tubingensis in osteomyelitis of the maxillary bone: a case report.

BACKGROUND: Aspergillus tubingensis is a black Aspergillus belonging to the Aspergillus section Nigri, which includes species that morphologically resemble Aspergillus niger. Recent developments in species determination have resulted in clinical isolates presumed to be Aspergillus niger being reclassified as Aspergillus tubingensis by sequencing. We present a report of a patient with an osteomyelitis of the maxillary bone with a probable invasive Aspergillus tubingensis infection. CASE PRESENTATION: We describe an immune compromised patient suffering from osteomyelitis of the maxillary bone after tooth extraction. The osteomyelitis probably resulted in dentogenic pansinusitis presenting as an acute ethmoiditis. Histologic examination of biopsy samples showed osteomyelitis, and inflammation of the surrounding connective tissue. Cultures of the alveolar wound grew Aspergillus tubingensis. The patient was treated with liposomal amphoterocin B, which was changed to oral treatment with voriconazole based on susceptibility testing (MIC for voriconazole was 1 µg/ml). CONCLUSION: This case shows that Aspergillus tubingensis may have the potential to cause severe invasive infections in immunocompromised hosts. A larger proportion of Aspergillus tubingensis isolates are less susceptible to azoles compared to Aspergillus niger. Therefore, correct species identification and susceptibility testing is crucial for the choice of anti-fungal treatment, screening of azole resistance, and characterization of the pathogenic potential of the various species within Aspergillus section Nigri.

Cardiac output measured by a new arterial pressure waveform analysis method without calibration compared with thermodilution after cardiac surgery.

OBJECTIVES: To investigate whether measuring cardiac output and its course after cardiac surgery by a new analysis technique of radial artery pressure waves, without need for calibration (FloTrac/Vigileo [FV]; Edwards Lifesciences, Irvine, CA), conforms to the standard bolus thermodilution method via a pulmonary artery catheter (PAC). DESIGN: Prospective study. SETTING: Intensive care unit of university hospital. PARTICIPANTS: Twenty patients for up to 24 hours after cardiac surgery. INTERVENTIONS: Simultaneous and triplicate PAC thermodilution and FV cardiac output measurements at 1 and 3 hours after surgery and the following morning. MEASUREMENTS AND MAIN RESULTS: Fifty-six simultaneous measurement sets were obtained. Mean cardiac output (PAC) ranged between 2.8 and 10.3 L/min and for the FV method between 3.3 and 8.8 L/min. The coefficient of variation for pooled measurements was 7.3% for the PAC and 3.0% for the FV method. For pooled data, the r2 was 0.55 (p < 0.001), with a bias of -0.14, precision of 1.00 L/min, and 95% limits of agreement between -2.14 and 1.87 L/min in a Bland-Altman plot. Also, the FV method tended to overestimate cardiac output when <7 L/min and increased with time, whereas mean arterial pressure increased and PAC cardiac output did not change. Changes in cardiac output correlated (r2 = 0.52, p < 0.001). CONCLUSIONS: The FV arterial pressure waveform analysis method is a clinically applicable method for cardiac output assessment without calibration, after cardiac surgery. It performs well at low cardiac outputs but remains sensitive to changes in vascular tone.