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Objective: The aim of this study was to identify the main CT features that may help in distinguishing a progression of interstitial lung disease (ILD) secondary to SSc from COVID-19 pneumonia., Methods: This multicentric study included 22 international readers grouped into a radiologist group (RADs) and a non-radiologist group (nRADs). A total of 99 patients, 52 with COVID-19 and 47 with SSc-ILD, were included in the study., Results: Fibrosis inside focal ground-glass opacities (GGOs) in the upper lobes; fibrosis in the lower lobe GGOs; reticulations in lower lobes (especially if bilateral and symmetrical or associated with signs of fibrosis) were the CT features most frequently associated with SSc-ILD. The CT features most frequently associated with COVID- 19 pneumonia were: consolidation (CONS) in the lower lobes, CONS with peripheral (both central/peripheral or patchy distributions), anterior and posterior CONS and rounded-shaped GGOs in the lower lobes. After multivariate analysis, the presence of CONs in the lower lobes (P < 0.0001) and signs of fibrosis in GGOs in the lower lobes (P < 0.0001) remained independently associated with COVID-19 pneumonia and SSc-ILD, respectively. A predictive score was created that was positively associated with COVID-19 diagnosis (96.1% sensitivity and 83.3% specificity)., Conclusion: CT diagnosis differentiating between COVID-19 pneumonia and SSc-ILD is possible through a combination of the proposed score and radiologic expertise. The presence of consolidation in the lower lobes may suggest COVID-19 pneumonia, while the presence of fibrosis inside GGOs may indicate SSc-ILD., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The T 1 Mapping and Extracellular volume (ECV) Standardization (T1MES) program explored T 1 mapping quality assurance using a purpose-developed phantom with Food and Drug Administration (FDA) and Conformité Européenne (CE) regulatory clearance. We report T 1 measurement repeatability across centers describing sequence, magnet, and vendor performance., Methods: Phantoms batch-manufactured in August 2015 underwent 2 years of structural imaging, B 0 and B 1 , and "reference" slow T 1 testing. Temperature dependency was evaluated by the United States National Institute of Standards and Technology and by the German Physikalisch-Technische Bundesanstalt. Center-specific T 1 mapping repeatability (maximum one scan per week to minimum one per quarter year) was assessed over mean 358 (maximum 1161) days on 34 1.5 T and 22 3 T magnets using multiple T 1 mapping sequences. Image and temperature data were analyzed semi-automatically. Repeatability of serial T 1 was evaluated in terms of coefficient of variation (CoV), and linear mixed models were constructed to study the interplay of some of the known sources of T 1 variation., Results: Over 2 years, phantom gel integrity remained intact (no rips/tears), B 0 and B 1 homogenous, and "reference" T 1 stable compared to baseline (% change at 1.5 T, 1.95 ± 1.39%; 3 T, 2.22 ± 1.44%). Per degrees Celsius, 1.5 T, T 1 (MOLLI 5s(3s)3s) increased by 11.4 ms in long native blood tubes and decreased by 1.2 ms in short post-contrast myocardium tubes. Agreement of estimated T 1 times with "reference" T 1 was similar across Siemens and Philips CMR systems at both field strengths (adjusted R 2 ranges for both field strengths, 0.99-1.00). Over 1 year, many 1.5 T and 3 T sequences/magnets were repeatable with mean CoVs < 1 and 2% respectively. Repeatability was narrower for 1.5 T over 3 T. Within T1MES repeatability for native T 1 was narrow for several sequences, for example, at 1.5 T, Siemens MOLLI 5s(3s)3s prototype number 448B (mean CoV = 0.27%) and Philips modified Look-Locker inversion recovery (MOLLI) 3s(3s)5s (CoV 0.54%), and at 3 T, Philips MOLLI 3b(3s)5b (CoV 0.33%) and Siemens shortened MOLLI (ShMOLLI) prototype 780C (CoV 0.69%). After adjusting for temperature and field strength, it was found that the T 1 mapping sequence and scanner software version (both P < 0.001 at 1.5 T and 3 T), and to a lesser extent the scanner model (P = 0.011, 1.5 T only), had the greatest influence on T 1 across multiple centers., Conclusion: The T1MES CE/FDA approved phantom is a robust quality assurance device. In a multi-center setting, T 1 mapping had performance differences between field strengths, sequences, scanner software versions, and manufacturers. However, several specific combinations of field strength, sequence, and scanner are highly repeatable, and thus, have potential to provide standardized assessment of T 1 times for clinical use, although temperature correction is required for native T 1 tubes at least.

Early detection of myocardial dysfunction in Fabry disease (FD) cardiomyopathy suggests the contribution of myofilament structural alterations. Six males with untreated FD cardiomyopathy submitted to cardiac studies, including tissue Doppler imaging and left ventricular endomyocardial biopsy. Active and resting tensions before and after treatment with protein kinase A (PKA) were determined in isolated Triton-permeabilized cardiomyocytes. Cardiomyocyte cross-sectional area, glycosphingolipid vacuole area, myofibrillolysis, and extent of fibrosis were also determined. Biopsies of mitral stenosis in patients with normal left ventricles served as controls. Active tension was four times lower in FD cardiomyocytes and correlated with extent of myofibrillolysis. Resting tension was six times higher in FD cardiomyocytes than in controls. PKA treatment decreased resting tension but did not affect active force. Protein analysis revealed troponin I and desmin degradation products. FD cardiomyocytes were significantly larger and filled with glycosphingolipids. Fibrosis was mildly increased compared with controls. Tissue Doppler imaging lengthening and shortening velocities were reduced in FD cardiomyocytes compared with controls, correlating with resting and active tensions, respectively, but not with cardiomyocyte area, percentage of glycosphingolipids, or extent of fibrosis. In conclusion, myofilament degradation and dysfunction contribute to FD cardiomyopathy. Partial reversal of high resting tension after pharmacological PKA treatment of cardiomyocytes suggests potential benefits from enzyme replacement therapy and/or energy-releasing agents.

Purpose: Prospective evaluation of diagnostic accuracy of single field-of-view contrast-enhanced MR Angiography (ceMRA) with 1.0M gadobutrol compared to intraarterial DSA in body arteries., Materials and Methods: In an European multicenter study 179 patients underwent ceMRA and DSA. For each indication five prospectively defined vessel segments were evaluated by local investigators onsite and by three site-independent blinded readers (BR) independently., Results: The agreement between ceMRA and DSA diagnosis was statistically significant in the onsite (96.6%) and blinded reader (86.6-90.2%) evaluation. Sensitivity, specificity, accuracy, positive (PPV) and negative predictive values (NPV) for detection of relevant stenosis (>50%) were calculated for the right and left internal carotid arteries, and common and external iliac arteries: Sensitivity was 95-98% (onsite) and 76-96% (BR), specificity 94-96% (onsite) and 86-94% (BR), accuracy 96% (onsite) and 87-93% (BR), NPV 98-99% (onsite) and 84-98% (BR), and PPV 79-93% (onsite) and 44-91% (BR), respectively., Conclusion: CeMRA of body arteries using 1.0M gadobutrol provides diagnostic information comparable to intraarterial DSA.

Fabry disease (FD) is an X-linked lysosomal storage disorder which leads to the accumulation of globotriaosylceramide (Gb3) in various organs, including the heart. FD can be subdivided into classic disease resulting from negligible residual enzyme activity and a milder, atypical phenotype with later onset and less severe clinical presentation. The use of multimodality cardiac imaging including echocardiography, cardiac magnetic resonance and nuclear imaging is important for the diagnostic and prognostic evaluation in these patients. There are gaps in the literature regarding the comprehensive description of cardiac findings of FD and its evaluation by multimodality imaging. In this review, we describe the contemporary practices and roles of multimodality cardiac imaging in individuals affected with Fabry disease. [ABSTRACT FROM AUTHOR]

The sarcomere is the fundamental contractile unit in skeletal muscle, and the regularity of its structure is critical for function. Emerging data demonstrates that nanoscale changes to the regularity of sarcomere structure can affect the overall function of the protein dense ~2μm sarcomere. Further, sarcomere structure is implicated in many clinical conditions of muscle weakness. However, our understanding of how sarcomere structure changes in disease, especially at the nanoscale, has been limited in part due to the inability to robustly detect and measure at sub-sarcomere resolution. We optimized several methodological steps and developed a robust pipeline to analyze sarcomere structure using structured illumination super-resolution microscopy in conjunction with commercially-available and fluorescently-conjugated Variable Heavy-Chain only fragment secondary antibodies (nanobodies), and achieved a significant increase in resolution of z-disc width (353nm vs. 62nm) compared to confocal microscopy. The combination of these methods provides a unique approach to probe sarcomere protein localization at the nanoscale and may prove advantageous for analysis of other cellular structures. [ABSTRACT FROM AUTHOR]

As a slowly progressive form of hypertrophic cardiomyopathy (HCM), Anderson-Fabry disease (FD) resembles the phenotype of the most common sarcomeric forms, although significant differences in presentation and long-term progression may help determine the correct diagnosis. A variety of electrocardiographic and imaging features of FD cardiomyopathy have been described at different times in the course of the disease, and considerable discrepancies remain regarding the assessment of disease severity by individual physicians. Therefore, we here propose a practical staging of FD cardiomyopathy, in hopes it may represent the standard for cardiac evaluation and facilitate communication between specialized FD centres and primary care physicians. We identified 4 main stages of FD cardiomyopathy of increasing severity, based on available evidence from clinical and imaging studies: non-hypertrophic, hypertrophic — pre-fibrotic, hypertrophic — fibrotic, and overt dysfunction. Each stage is described and discussed in detail, following the principle that speaking a common language is critical when managing such complex patients in a multi-disciplinary and sometimes multi-centre setting. [ABSTRACT FROM AUTHOR]

In patients with Fabry disease (FD), cardiovascular involvement is the main cause of death and reduction of quality of life. Left ventricular hypertrophy mimicking hypertrophic cardiomyopathy is the main feature of FD cardiac involvement although glycolipid storage occurs in all cardiac cellular types. Accumulation of lysosomal globotriasylceramide represents the main mechanism of cardiac damage in early stages, but secondary pathways of cellular and tissue damage, triggered by lysosomal storage, and including altered energy production, inflammation and cell death, contribute to cardiac damage and disease progression. These mechanisms appear prominent in more advanced stages, hampering and reducing the efficacy of FD-specific treatments. Therefore, additional cardiovascular therapies are important to manage cardiovascular symptoms and reduce cardiovascular events. Although new therapies targeting lysosomal storage are in development, a better definition and comprehension of the complex pathophysiology of cardiac damage in FD, may lead to identify new therapeutic targets beyond storage and new therapeutic strategies. [ABSTRACT FROM AUTHOR]

The extension of a partial pancreatectomy up to total pancreatectomy because of positive neck margin examined at intraoperative frozen section (IFS) analysis is an accepted procedure in modern pancreatic surgery with good accuracy. The goal of this practice is to improve the rate of radical (R0) resection in malignant tumors, mainly pancreatic ductal adenocarcinoma (PDAC), and to completely resect pre-invasive neoplasms such as intraductal papillary mucinous neoplasms (IPMNs). In the setting of IPMNs there is a consensus for pancreatic re-resection when high-grade dysplasia and invasive cancer are present at the neck margin. The presence of denudation is another indication for further resection in IPMNs. The role of IFS analysis in the management of pancreatic cancer is more debated. The presence of a positive intraoperative transection margin can be considered the surrogate of a biologically aggressive disease associated with a poorer prognosis. There are conflicting data regarding possible advantages of pancreatic re-resection up to total pancreatectomy, and the lack of randomized trials comparing different strategies does not offer a definitive answer. The goal of this review is to provide an up-to-date overview of the role IFS analysis of pancreatic margin and of pancreatic re-resection up to total pancreatectomy considering different pancreatic tumors. [ABSTRACT FROM AUTHOR]

Background Troponin elevation is common in hospitalized COVID-19 patients, but underlying aetiologies are ill-defined. We used multi-parametric cardiovascular magnetic resonance (CMR) to assess myocardial injury in recovered COVID-19 patients. Methods and results One hundred and forty-eight patients (64 ± 12 years, 70% male) with severe COVID-19 infection [all requiring hospital admission, 48 (32%) requiring ventilatory support] and troponin elevation discharged from six hospitals underwent convalescent CMR (including adenosine stress perfusion if indicated) at median 68 days. Left ventricular (LV) function was normal in 89% (ejection fraction 67% ± 11%). Late gadolinium enhancement and/or ischaemia was found in 54% (80/148). This comprised myocarditis-like scar in 26% (39/148), infarction and/or ischaemia in 22% (32/148) and dual pathology in 6% (9/148). Myocarditis-like injury was limited to three or less myocardial segments in 88% (35/40) of cases with no associated LV dysfunction; of these, 30% had active myocarditis. Myocardial infarction was found in 19% (28/148) and inducible ischaemia in 26% (20/76) of those undergoing stress perfusion (including 7 with both infarction and ischaemia). Of patients with ischaemic injury pattern, 66% (27/41) had no past history of coronary disease. There was no evidence of diffuse fibrosis or oedema in the remote myocardium (T1: COVID-19 patients 1033 ± 41 ms vs. matched controls 1028 ± 35 ms; T2: COVID-19 46 ± 3 ms vs. matched controls 47 ± 3 ms). Conclusions During convalescence after severe COVID-19 infection with troponin elevation, myocarditis-like injury can be encountered, with limited extent and minimal functional consequence. In a proportion of patients, there is evidence of possible ongoing localized inflammation. A quarter of patients had ischaemic heart disease, of which two-thirds had no previous history. Whether these observed findings represent pre-existing clinically silent disease or de novo COVID-19-related changes remain undetermined. Diffuse oedema or fibrosis was not detected. [ABSTRACT FROM AUTHOR]

Cardiac magnetic resonance (CMR) has emerged as new mainstream technique for the evaluation of patients with cardiac diseases, providing unique information to support clinical decision-making. This document has been developed by a joined group of experts of the Italian Society of Cardiology and Italian society of Radiology and aims to produce an updated consensus statement about the current state of technology and clinical applications of CMR. The writing committee consisted of members and experts of both societies who worked jointly to develop a more integrated approach in the field of cardiac radiology. Part 1 of the document will cover ischemic heart disease, congenital heart disease, cardio-oncology, cardiac masses and heart transplant. [ABSTRACT FROM AUTHOR]

In the past few years, the use of specific cell types derived from induced pluripotent stem cells (iPSCs) has developed into a powerful approach to investigate the cellular pathophysiology of numerous diseases. Despite advances in therapy, heart disease continues to be one of the leading causes of death in the developed world. A major difficulty in unravelling the underlying cellular processes of heart disease is the extremely limited availability of viable human cardiac cells reflecting the pathological phenotype of the disease at various stages. Thus, the development of methods for directed differentiation of iPSCs to cardiomyocytes (iPSC-CMs) has provided an intriguing option for the generation of patient-specific cardiac cells. In this review, a comprehensive overview of the currently published iPSC-CM models for hereditary heart disease is compiled and analysed. Besides the major findings of individual studies, detailed methodological information on iPSC generation, iPSC-CM differentiation, characterization, and maturation is included. Both, current advances in the field and challenges yet to overcome emphasize the potential of using patient-derived cell models to mimic genetic cardiac diseases. [ABSTRACT FROM AUTHOR]

Despite its considerable morbidity and mortality, paroxysmal nocturnal haemoglobinuria (PNH) is still underdiagnosed. Patients with PNH can suffer from cardiovascular, gastrointestinal, neurological or haematological symptoms and refer to several specialists. The aim of this paper is to review the diagnosis and the management of PNH patients, with the primary focus on identifying high‐risk groups. Additionally, the implementation and prognostic value of the defined high‐risk groups will be commented on and the management of PNH patients is discussed from a Belgian perspective. Finally, based on the available data, recommendations are provided. Eculizumab is a potent C5 complement inhibitor and reduces intravascular haemolysis and thrombosis in PNH patients and improves their quality of life. As thrombosis is the main cause of death in PNH patients, identifying high‐risk PNH patients in need of therapy is essential. Currently, novel complement inhibitors are in development and the first data seem promising. Another challenge in PNH is to identify new markers to assess the thrombotic risk to achieve a better risk‐based prophylactic anti‐thrombotic management. Finally, because of the low prevalence of the disease, PNH patients should be included in the prospective PNH registry, which will offer new insights on the natural course of the disease and the impact of treatment of PNH. [ABSTRACT FROM AUTHOR]

Purpose: To examine the association between CT measures of visceral obesity and short-term postoperative outcomes in renal clear cell carcinoma (RCCC) patients.Methods: In this retrospective study, 76 patients treated with unilateral laparoscopic radical nephrectomy for stage I-III renal cancer were classified as obese or non-obese by preoperative CT-based measures of adiposity [obese: visceral fat area (VFA) > 100 cm2, BMI ≥ 28 kg/m2]. Clinical variables, Fuhrman grade, operation time, estimated blood loss (EBL), postoperative complications, postoperative stay, drainage time and hospitalization expenses were compared between the two groups.Results: Viscerally obese patients significantly had higher Fuhrman grade than the non-obese (p = 0.018). The operation time of obese patients by VFA or BMI was more than the non-obese (171.6 ± 68.9 vs. 140.8 ± 35.5 min, p = 0.012 and 197.2 ± 67.2 vs. 153.2 ± 57.7 min, p = 0.013, respectively). And obese patients by VFA or BMI tended to have more EBL than non-obese (132.0 ± 120.7 vs. 83.8 ± 53.4 ml, p = 0.018 and 215.3 ± 165.0 vs. 92.5 ± 68.8 ml, p = 0.013, respectively). Viscerally obese patients by VFA (not BMI) were more likely to develop postoperative complications as compared to patients classified as non-obese: VFA (26.9 vs. 4.2%, p = 0.045) and BMI (33.3 vs. 16.4%, p =0.265). Furthermore, obese patients by VFA (not BMI) were more likely to have longer postoperative stay: VFA (8.7 ± 2.5 vs. 7.5 ± 1.4 dollars, p = 0.013) and BMI (9.1 ± 2.9 vs. 8.1 ± 2.1 dollars, p = 0.209). Obese patients expensed more than non-obese: VFA (7570.9 ± 2674.3 vs. 6368.8 ± 1289.8 dollars, p = 0.040) and BMI (8390.8 ± 2929.7 vs. 6896.3 ± 2159.1 dollars, p = 0.029).Conclusions: Elevated visceral obesity by VFA is associated with increased surgical complexity, postoperative morbidity, postoperative stay and hospitalization expenses for RCCC patients and may be superior to BMI for renal cancer outcome assessment. VFA may be a useful index for the evaluation and calculation of RCCC aggressiveness. [ABSTRACT FROM AUTHOR]

Fabry disease resulting from a deficiency of α-galactosidase A leads to the accumulation of globotriaosylceramide in various organs. Because the disease is an X-linked recessive disorder, males tend to develop more symptoms and more severe symptoms than females. There are also some variants of Fabry disease, and cardiac variant (cardiac Fabry disease) has the dysfunctions only in heart. Cardiac manifestations in Fabry disease are initially symmetrical and concentric left ventricular hypertrophy, and later progressive cardiac dysfunction with localized thinning of the basal posterior wall. In recent years, enzyme replacement therapy has been performed as a treatment for Fabry disease, and the initiation of this therapy is expected before the cardiac fibrosis develops. Therefore, early diagnosis of Fabry disease is essential, and echocardiography is an indispensable tool for clinical practice of this disease. Then, it is necessary to remember this disease as a differential diagnosis when encountering unexplained left ventricular hypertrophy. [ABSTRACT FROM AUTHOR]

Background: Sustained ventricular tachycardia (VT) in patients with nonischemic cardiomyopathy (NICM) often involves midmyocardial and epicardial structures. Delayed-enhancement magnetic resonance imaging (DE-MRI) of scar and fibrosis is the method of choice to define the substrate of monomorphic VT. Objective: The aim of the study was to compare the outcome of endocardial vs. epicardial VT ablation in patients with epicardial DE-MRI substrates in NICM. Results: Among 44 patients with NICM referred for VT ablation who underwent DE-MRI, 12 patients had an epicardial-only ( n = 4) or predominantly epicardial DE-MRI substrate ( n = 8). 9 of the 12 patients had a prior myocarditis. Endocardial-only VT ablation was successful in two patients with epicardial DE-MRI substrate. A pericardial access for epicardial mapping and ablation was attempted in 8 patients and could be accomplished in seven. Epicardial low voltage (<1.5 mV) and very low voltage (<0.5 mV) areas were in good qualitative correlation to the epicardial DE-MRI substrates. Epicardial abnormal electrograms in combination with a good pace map QRS match were found in epicardial very low voltage areas in five patients and in low voltage areas in two patients. 2 patients with endocardial-only ablation, five patients with endo-epicardial ablation and two patients with primary epicardial ablation had a favorable post-ablation outcome (follow-up 32 ± 26 months) but one patient had to undergo heart transplantation for heart failure deterioration. Conclusions: Endo-epicardial ablation or primary epicardial ablation should early be considered in patients after myocarditis or with other forms of nonischemic cardiomyopathy with epicardial DE-MRI substrates. [ABSTRACT FROM AUTHOR]

Objective: To compare prospectively image quality and diagnostic confidence of flow-sensitive 3D turbo spin echo (TSE)-based non-contrast-enhanced MR angiography (NE-MRA) at 3.0 T using dual-source radiofrequency (RF) transmission with contrast-enhanced MRA (CE-MRA) in patients with peripheral arterial occlusive disease (PAOD).Methods: After consent was obtained, 35 patients (mean age 69.1 ± 10.6 years) with PAOD stage II-IV underwent NE-MRA followed by CE-MRA. Signal-to-noise ratio and contrast-to-noise ratio were calculated. Subjective image quality was independently assessed by two radiologists and stenosis scoring was performed in 875 arterial segments. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for stenosis classification were calculated using CE-MRA as a reference method. Diagnostic agreement with CE-MRA was evaluated with Cohen's kappa statistics.Results: NE-MRA provided high objective and subjective image quality at all levels of the arterial tree. Sensitivity and specificity for the detection of relevant stenosis was 91 % and 89 %, respectively; the NPV was 96 % and the PPV 78 %. There was good concordance between CE-MRA and NE-MRA in stenosis scoring.Conclusions: 3D electrocardiography (ECG)-gated TSE NE-MRA with patient-adaptive dual-source RF transmission at 3.0 T is a promising alternative for PAOD patients with contraindications for gadolinium-based contrast agents. It offers high sensitivity and NPV values in the detection of clinically relevant arterial stenosis.Key Points: • Flow-sensitive TSE NE-MRA is a promising technique for PAOD evaluation. • Diagnostic accuracy is comparable to contrast-enhanced MRA. • NE-MRA eliminates the risk of NSF in patients with renal insufficiency. • Costs arising from the use of contrast agents can be avoided. [ABSTRACT FROM AUTHOR]

Purpose: Whether cardiac sympathetic nervous function abnormalities may be present in patients with Anderson-Fabry disease (AFD) remains unexplored. We investigated the relationship between left ventricular (LV) function and cardiac sympathetic nervous function in patients with AFD. Methods: Twenty-five patients (12 men, mean age 43 ± 13 years) with genetically proved AFD and preserved LV ejection fraction and ten age and gender-matched control subjects underwent speckle tracking echocardiography and I-meta-iodobenzylguanidine (MIBG) imaging from which early and late heart to mediastinum (H/M) ratios and myocardial washout rate values were calculated. Results: In AFD patients, a significant correlation between late H/M ratio and LV mass index ( r = −61, p = 0.001), left atrial volume ( r = −0.72, p < 0.001), systolic pulmonary artery pressure ( r = −0.75, p < 0.001), and early diastolic untwisting rate ( r = −0.66, p < 0.001) was found. Ten AFD patients exhibited a late H/M ratio below two fold standard deviation of control subjects (≤1.75). Patients showing late H/M ratio ≤ 1.75 had significantly higher LV mass index, relative wall thickness, left atrial volume and systolic pulmonary artery pressure, lower systolic longitudinal strain and an early diastolic untwisting rate compared to patients with late H/M ratio > 1.75. At multivariable linear regression analysis, early diastolic untwisting rate was the only independent predictor of late H/M ratio ≤ 1.75 (odds ratio 1.15, 95 % confidence interval 1.07-1.31, p < 0.05). Conclusion: The present findings provide the first demonstration of a cardiac sympathetic derangement in AFD patients with preserved LV ejection fraction, which is mostly related to LV diastolic dysfunction. [ABSTRACT FROM AUTHOR]

Background: Abnormalities of cardiac sympathetic innervation have been demonstrated in Anderson-Fabry disease (AFD). We aimed to investigate the relationship between regional left ventricular (LV) denervation and regional function abnormalities., Methods: Twenty-four AFD patients (43.7 ± 12.8 years) were studied by 123 I-metaiodobenzylguanidine (MIBG) cardiac imaging and speckle-tracking echocardiography. Segmental tracer uptake was estimated according to 0 to 4 score, and total defect score (TDS) was calculated for each patient., Results: Segmental longitudinal strain worsened as MIBG uptake score increased (P < 0.001). By ROC analysis, a segmental longitudinal strain > - 16.2% predicted a segmental MIBG uptake score ≥1, with 79.7% sensitivity and 65.3% specificity. Segmental MIBG uptake defects were found in 13 out 24 AFD patients. LV mass index (60.8 ± 10.1 vs. 41.4 ± 9.8 g/h 2.7 ), relative wall thickness (0.51 ± 0.06 vs. 0.40 ± 0.06), systolic pulmonary artery pressure (35.2 ± 6.7 vs. 27.2 ± 4.2 mmHg), and longitudinal strain (- 14.3 ± 2.7 vs. -19.4 ± 1.8%) were significantly higher in patients with segmental defect (all P < 0.01). At multivariate linear regression analysis, global longitudinal strain was independently associated with TDS (B = 3.007, 95% confidence interval 1.384 to 4.630, P = 0.001)., Conclusions: Reduced cardiac MIBG uptake reflects the severity of cardiac involvement in AFD patients. LV longitudinal function impairment seems to be an earlier disease feature than regional myocardial denervation.

Background In Taiwan, DNA-based newborn screening showed a surprisingly high incidence of a cardiac Fabry mutation (IVS4 + 919G > A). The prevalence of this mutation is too high to be believed that it is a real pathogenic mutation. The purpose of this study is to identify the cardiac pathologic characteristics in patients with left ventricular hypertrophy and this mutation. Methods and results Endomyocardial biopsies were obtained in 22 patients (Median age: 61, males: 17; females: 5) with left ventricular hypertrophy and the IVS4 + 919G > A mutation; five patients had not received enzyme replacement therapy (ERT) before biopsy, while the other 17 patients had received ERT from 8 months to 51 months. Except for three patients who had received ERT for more than 3 years, all other patients showed significant pathological change and globotriaosylceramide (Gb3) accumulation in their cardiomyocytes. In contrast to classical Fabry patients, no Gb3 accumulation was found in the capillary endothelial cells of any of our patients. Fourteen patients (63.6%) were found to have myofibrillolysis. Conclusions All of the untreated and most of the treated IVS4 + 919G > A patients showed typical pathological changes of Fabry disease in their cardiomyocytes. No endothelial accumulation of Gb3 was found, which is similar to the findings of several previous reports regarding lateronset Fabry disease. This result highly suggests that the IVS4 + 919G > A is a real pathogenic later-onset Fabry mutation. [ABSTRACT FROM AUTHOR]

Diabet. Med. 29, 359-365 (2012) Abstract Aims To observe the effects of pioglitazone on coronary plaque area, plaque burden, serum high-sensitivity C-reactive protein, adiponectin and plasma endothelin-1 levels in patients with impaired glucose tolerance and coronary borderline lesions. Methods Thirty patients were randomly divided into two groups: a pioglitazone group and a control group. The latter was administered placebo in addition to standard therapy; the former pioglitazone 15 mg/d in addition to standard therapy. Before treatment and 6 months later, left ventricular ejection fraction, serum lipid profile, high-sensitivity C-reactive protein, adiponectin and plasma endothelin-1 levels were detected. Coronary plaque area and plaque burden were examined using intravascular ultrasound. Results No significant differences were found in left ventricular ejection fraction and serum lipid levels pre- and post-trial. Compared with the control group, 6 months' treatment with pioglitazone significantly decreased coronary plaque burden (50.7 ± 11.1 vs. 64.1 ± 10.3%, P < 0.05), plaque area (6.22 ± 2.03 vs. 8.31 ± 4.29, P < 0.05), thin-cap fibroatheroma prevalence (11 vs. 22%, P < 0.05) and percentage of necrotic core area (16 ± 8 vs. 31 ± 7%, P < 0.05). Compared with the control group, serum high-sensitivity C-reactive protein and plasma endothelin-1 levels were significantly lower and adiponectin level significantly higher in patients in the pioglitazone group. Serum adiponectin level was negatively correlated with plasma endothelin-1 level and coronary plaque area ( r = 0.739 and -0.431, respectively, both P < 0.05). Conclusions Pioglitazone may induce regression and stabilization of coronary atherosclerotic plaques. The mechanisms might involve inhibition of inflammation, increase in adiponectin level and improvement in endothelial function. [ABSTRACT FROM AUTHOR]

Objective: To assess the diagnostic value of 3D CEMRA in TA compared with DSA.Methods: Twenty-two patients with clinically suspected TA based on 1990 ACR criteria for the classification of TA, were included in this study. There were 16 female and 6 male patients with ages ranging from 11 to 50 years (mean age 25 years). CEMRA and DSA were performed in all patients within 4 weeks of each other, for detection of stenosis, occlusion and aneurysm in the arch vessels, renal arteries and aortic segments.Results: (1) TA was confirmed by CEMRA in all patients. (2) 147 arteries did not reveal any steno-occlusive lesion on CEMRA compared with 158 on DSA. (3) 75 stenoses, (excluding occlusions) were detected on CEMRA compared with DSA, which revealed 65 stenotic lesions, with sensitivity, specificity, PPV, NPV and DA for detection of a significant (>50%) stenotic lesion being 98.33%, 97.25%, 92.18%, 99.43% and 97.52% respectively. (4) Aneurysmal dilatation was detected in 13 arteries on CEMRA compared with 16 on DSA.Conclusions: Diagnostic value of CEMRA is comparable to that of DSA with a very strong and statistically significant correlation between DSA and CEMRA in detection and grading of characteristic steno-occlusive lesions of TA. [ABSTRACT FROM AUTHOR]

Objective: To prove that 1.0 M gadobutrol provides superior contrast enhancement in suspicion of osteomyelitis of the feet compared with 0.5 M gadoterate.Methods: MRI of feet was performed on 2 separate occasions. Independent injections of 1.0 M gadobutrol and 0.5 M gadoterate at doses of 0.1 mmol Gd/kg body weight were administered per patient. The interval between the two MR examinations was between 24 h and 7 days. Evaluation was performed in an off-site blinded read.Results: 41 patients were eligible for efficacy analysis. Results of secondary efficacy variables did not show statistically significant differences. For the primary efficacy variable, a trend in favour of gadobutrol was seen in the full analysis set (ITT) population resulting in at least non-inferiority. In the per protocol (PP) analysis set gadobutrol had better contrast than gadoterate (Wilcoxon signed rank test, p = 0.0466).Conclusion: Imaging of the distal lower limb in this special patient population requires a large number of patients to obtain enough comparative images where non-contrast-agent-dependent factors do not disturb contrast agent efficacy. The ITT analysis showed at least non-inferiority of gadobutrol in comparison to gadoterate. The avoidance of imaging artefacts demonstrates a better outcome for gadobutrol. [ABSTRACT FROM AUTHOR]

Objective: To determine the diagnostic value of non-contrast-enhanced, 3D-high-resolution, ECG-gated, multi-step MR angiography (non-ceMRA) of the lower extremities using a modified turbo-spin-echo technique in comparison to 1.0-molar contrast-enhanced MR angiography (ceMRA) in patients with suspected peripheral vascular disease (PVD).Methods: Fifty consecutive patients underwent non-ceMRA before ceMRA within the same session. We assessed examination time, image quality, localisation and severity of stenosis.Results: Examination time was shorter for ceMRA (12 ± 4 min) compared with non-ceMRA (28 ± 6 min, p < 0.001). The image quality of the aorta-iliac, femoral and combined popliteal and lower leg arteries was inferior for non-ceMRA (2.8 ± 0.8/3.3 ± 0.8/3.3 ± 0.9) versus ceMRA (4.7 ± 0.8/4.8 ± 0.6/4.8 ± 0.7) on a 5-point scale with 5 for maximum quality (p < 0.01). CeMRA offered more assessable data sets than non-ceMRA (98% vs. 90%). For detecting stenosis >50% or occlusions of pelvic and femoral arteries using non-ceMRA the sensitivity, specificity, positive and negative predictive values were 94%, 86%, 67% and 98% and for popliteal and lower leg arteries 93%, 87%, 69% and 98%, respectively.Conclusion: We demonstrated that 3D non-ceMRA represents a very promising technique in patients with lower extremities PVD and could be used as an alternative if gadolinium-based contrast agents cannot be administered. [ABSTRACT FROM AUTHOR]

Background: Contrast-enhanced magnetic resonance (MR) imaging with gadolinium-based contrast agents is widely used for the detection of cerebral metastases with standard contrast agents. Newer developments in MR contrast agents have led to a higher relaxivity and/or concentration for these agents. Purpose: To assess the effectiveness of a standard dose of 1.0 M gadobutrol compared with a standard dose of gadopentetate dimeglumine for the MR detection of brain metastases. Material and Methods: 27 patients with at least one cerebral metastasis were examined twice with contrast-enhanced MR imaging, using gadobutrol at 0.1 ml/kg and gadopentetate dimeglumine at 0.2 ml/kg (i.e., identical gadolinium dosage of 0.1 mmol/kg bodyweight). The interval between examinations was 18 hours, and the order of injection was fully randomized. Images were acquired using a three-dimensional (3D) fast gradient echo sequence, and evaluated in blinded fashion by two experienced neuroradiologists in consensus in terms of the total number of lesions detected at each examination in each patient and qualitatively in terms of the lesion conspicuity observed. Results: A total of 67 lesions were detected after gadobutrol compared with 65 lesions detected after gadopentetate dimeglumine. In two patients, a lesion was seen only after gadobutrol. Qualitative comparison of images revealed improved lesion conspicuity after gadobutrol in 10/27 cases compared with 0/27 cases after gadopentetate dimeglumine, and equivalent conspicuity in 17/27 cases (P=0.002, gadobutrol vs. gadopentetate dimeglumine). Conclusion:At equal gadolinium dosage, gadobutrol appears to offer significant advantages over gadopentetate dimeglumine for the visualization of brain metastases, with particular benefit for improving the conspicuity of detected lesions. [ABSTRACT FROM AUTHOR]

Retinol binding protein 4 (RBP4) has recently been suggested as a good biomarker for insulin resistance and the metabolic syndrome. With this study, we wanted to investigate the effect of pioglitazone (PIO) and simvastatin (SIMVA) on insulin resistance and RBP4 plasma concentrations in nondiabetic patients with metabolic syndrome and increased risk for cardiovascular complications. The prospective, parallel, randomized, double-blind clinical trial was performed with 125 nondiabetic patients with increased cardiovascular risk (78 females, 47 males, age (mean?STD): 58.6?7.8 years, BMI: 30.8?4.2?kg/m 2). They were randomized to either receive PIO (45?mg)+placebo, SIMVA (40?mg)+placebo, or PIO+SIMVA for 3 months. Key outcome measures were the HOMA IR-Score, an oral glucose tolerance test, adiponectin, hsCRP, and RBP4 at baseline and endpoint. No correlation could be detected between the HOMA IRvalues or the impaired fasting glucose tolerance status and RBP-4. Treatment with PIO alone or in combination with SIMVA resulted in a significant improvement of the HOMA IR-Score and the adiponectin values, while no change in HOMA IRand a decrease in adiponectin (p<0.05) were observed with SIMVA monotherapy. Reductions of hsCRP were seen in all three treatment arms (p<0.001). No changes of the plasma RBP4 concentrations were observed in any of the treatment groups (PIO: 35.6?7.2/36.3?8.7?ng/ml, PIO+SIMVA: 36.5?10.8/36.5?8?ng/ml, SIMVA: 36.1?8.1/36.6?11.1?ng/ml, all n.s. vs. baseline). Despite a partial or comprehensive improvement in insulin resistance and/or cardiovascular risk indicators in all treatment arms, no change in RBP4-levels could be observed. The regulation of RBP4 expression and secretion occurs through biochemical pathways independent from those influenced by pioglitazone or simvastatin. [ABSTRACT FROM AUTHOR]

Adenoviral gene transfer of sarco(endo)plasmic reticulum Ca2~-ATPase (SERCA)2a to the hyper- trophic heart in vivo has been consistently reported to lead to en- hanced myocardial contractility. It is unknown if the faster skeletal muscle isoform, SERCA1, expressed in the whole heart in early failure, leads to similar improvements and whether metabolic requirements are maintained during an adrenergic challenge. In this study, Ad.cmv.SERCA1 was delivered in vivo to aortic banded and sham- operated Sprague-Dawley rat hearts. The total SERCA content increased 34%. At 48-72 h posttransfer, echocardiograms were acquired, hearts were excised and retrograded perfused, and he- modynamics were measured parallel to NMR measures of the phosphocreatine (PCr)-to-ATP ratio (PCr/ATP) and energy substrate selection at basal and high workloads (isoproterenol). In the Lange- ndorff mode, the rate-pressure product was enhanced 27% with SERCAI in hypertrophic hearts and 10% in shams. The adrenergic response to isoproterenol was significantly potentiated in both groups with SERCA1. 31P NMR analysis of PCr/ATP revealed that the ratio remained low in the hypertrophic group with SERCA1 overexpression and was not further compromised with adrenergic challenge. `3C NMR analysis revealed fat and carbohydrate oxidation were unaffected at basal with SERCA1 expression; however, there was a shift from fats to carbohydrates at higher workloads with SERCA 1 in both groups. Transport of NADH-reducing equivalents into the mitochon- dna via the cx-ketoglutamate-malate transporter was not affected by either SERCA1 overexpression or adrenergic challenge in both groups. Echocardiograms revealed an important distinction between in vivo versus ex vivo data. In contrast to previous SERCA2a studies, the echocardiogram data revealed that SERCA1 expression compromised function (fractional shortening) in the hypertrophic group. Shams were unaffected. While our ex vivo findings support much of the earlier cardiomyocyte and transgenic data, the in vivo data challenge previous reports of improved cardiac function in heart failure models after SERCA intervention. [ABSTRACT FROM AUTHOR]

The purpose of this phase III clinical trial was to compare two different extracellular contrast agents, 1.0 M gadobutrol and 0.5 M gadopentate dimeglumine, for magnetic resonance imaging (MRI) in patients with known or suspected focal renal lesions. Using a multicenter, single-blind, interindividual, randomized study design, both contrast agents were compared in a total of 471 patients regarding their diagnostic accuracy, sensitivity, and specificity to correctly classify focal lesions of the kidney. To test for noninferiority the diagnostic accuracy rates for both contrast agents were compared with CT results based on a blinded reading. The average diagnostic accuracy across the three blinded readers ('average reader') was 83.7% for gadobutrol and 87.3% for gadopentate dimeglumine. The increase in accuracy from precontrast to combined precontrast and postcontrast MRI was 8.0% for gadobutrol and 6.9% for gadopentate dimeglumine. Sensitivity of the average reader was 85.2% for gadobutrol and 88.7% for gadopentate dimeglumine. Specificity of the average reader was 82.1% for gadobutrol and 86.1% for gadopentate dimeglumine. In conclusion, this study documents evidence for the noninferiority of a single i.v. bolus injection of 1.0 M gadobutrol compared with 0.5 M gadopentate dimeglumine in the diagnostic assessment of renal lesions with CE-MRI. [ABSTRACT FROM AUTHOR]

One of the most exciting cell biology fields of study concerns the physiology and pathology of fat. The basic assumptions once held concerning the function of adipose tissue have been shown to be oversimplified or sometimes completely wrong. Fat does more than store excess energy; it is actually the largest endocrine organ in the body, and it may be one of the most active. Adipocytes release hormones and other molecules that act on nearby tissues and travel through the vasculature to distant sites, such as the brain, skeletal muscle, and liver. Under conditions of normal weight, those signals help the body to suppress hunger, utilize glucose, and decrease the risk of cardiovascular disease. However, under conditions of obesity, the hormones (or the proteins that bind the hormones) become abnormal and can result in states of chronic inflammation leading to diabetes and heart disease. In addition, excessive fat can lead to the accumulation of lipid droplets in nonfat cells, including skeletal and cardiac muscle, Although some lipid droplets are used as an immediate source of energy for cells, large numbers of stored droplets can cause cellular damage and cell death. The purposes of this article are to review the normal and deviant signals released by fat cells, to draw a link between those signals and chronic diseases such as diabetes, and to discuss the role of exercise in reversing some of the deviant signaling perpetrated by excess fat. [ABSTRACT FROM AUTHOR]

Insulin resistance is a characteristic feature of type 2 diabetes and obesity. Insulin-resistant individuals manifest multiple disturbances in free fatty acid (FFA) metabolism and have excessive lipid accumulation in insulin target tissues. Although much evidence supports a causal role for altered FFA metabolism in the development of insulin resistance, i.e., "lipotoxicity", the intracellular mechanisms by which elevated plasma FFA levels cause insulin resistance have yet to be completely elucidated. Recent studies have implicated a possible role for mitochondrial dysfunction in the pathogenesis of insulin resistance in skeletal muscle. We examined the effect of FFA metabolites [palmitoyl carnitine (PC), palmitoyl-coenzyme A (CoA), and oleoyl-CoA] on ATP synthesis in mitochondria isolated from mouse and human skeletal muscle. At concentrations ranging from 0.5 to 2 μM, these FFA metabolites stimulated ATP synthesis; however, above 5 μM, there was a dose-response inhibition of ATP synthesis. Furthermore, 10 μM PC inhibits ATP synthesis from pyruvate. Elevated PC concentrations (≥10 μM) inhibit electron transport chain activity and decrease the mitochondrial inner membrane potential. These acquired mitochondrial defects, caused by a physiological increase in the concentration of FFA metabolites, provide a mechanistic link between lipotoxicity, mitochondrial dysfunction, and muscle insulin resistance. [ABSTRACT FROM AUTHOR]

Background The metabolic syndrome is a disorder that includes dyslipidemia, insulin resistance, and hypertension and is associated with an increased risk of diabetes and cardiovascular disease. We determined whether patterns of regional fat deposition are associated with metabolic syndrome in older adults. Methods A cross-sectional study was performed that included a random, population-based, volunteer sample of Medicare-eligible adults within the general communities of Pittsburgh, Pa, and Memphis, Tenn. The subjects consisted of 3035 men and women aged 70 to 79 years, of whom 41.7% were black. Metabolic syndrome was defined by Adult Treatment Panel III criteria, including serum triglyceride level, high-density lipoprotein cholesterol level, glucose level, blood pressure, and waist circumference. Visceral, subcutaneous abdominal, intermuscular, and subcutaneous thigh adipose tissue was measured by computed tomography. Results Visceral adipose tissue was associated with the metabolic syndrome in men who were of normal weight (odds ratio, 95% confidence interval: 2.1, 1.6-2.9), overweight (1.8, 1.5-2.1), and obese (1.2, 1.0-1.5), and in women who were of normal weight (3.3, 2.4-4.6), overweight (2.4, 2.0-3.0), and obese (1.7, 1.4-2.1), adjusting for race. Subcutaneous abdominal adipose tissue was associated with the metabolic syndrome only in normal-weight men (1.3, 1.1-1.7). Intermuscular adipose tissue was associated with the metabolic syndrome in normal-weight (2.3, 1.6-3.5) and overweight (1.2, 1.1-1.4) men. In contrast, subcutaneous thigh adipose tissue was inversely associated with the metabolic syndrome in obese men (0.9, 0.8-1.0) and women (0.9, 0.9-1.0). Conclusion In addition to general obesity, the distribution of body fat is independently associated with the metabolic syndrome in older men and women, particularly among those of normal body weight. [ABSTRACT FROM AUTHOR]

Goodpaster BH, Wolf D. Skeletal muscle lipid accumulation in obesity, insulin resistance, and type 2 diabetes.In addition to obesity, many factors, including the distribution of body fat, contribute to the development of insulin resistance and type 2 diabetes mellitus (T2DM). Lipid contained within skeletal muscle as triglyceride is a parameter of regional fat accumulation thought to be an important link among obesity, insulin resistance, and type 2 diabetes, even in the pediatric population. Intramuscular triglycerides can also be a fuel source for healthy muscle during periods of physical activity. Thus, the balance between storage and efficient utilization of muscle triglycerides is likely a key to a better understanding of the interaction between dysregulated fat and glucose metabolism by muscle in both adults and children. This review examines the evidence that muscle lipid accumulation is linked with insulin resistance and type 2 diabetes of both adults and children. In addition, we explore the potential mechanisms for muscle lipid accumulation as well as the effects of weight loss and physical activity on muscle lipid. Further defining the links between muscle lipid accumulation and insulin action should help develop more effective strategies to prevent or treat type 2 diabetes and other obesity-associated disorders. [ABSTRACT FROM AUTHOR]

Muscle contains the largest reservoir of glycogen (Glyc), a depot that is closely regulated and with influence on insulin sensitivity. The currant study examines muscle Glyc in type 2 diabetes mellitus (T2DM) and obesity and with respect to muscle fiber type, intramyocellular lipid content (IMCL), and mitochondrial function (oxidative enzyme activity; OX-Enz). There is increasing interest in the relation of IMCL and mitochondrial dysfunction with insulin resistance (IR), yet the association with muscle Glyc has not been examined with regard to these parameters. Using a quantitative histological approach specific to muscle fiber types, we assessed muscle Glyc, IMCL, and OX-Enz in vastus lateralis obtained by percutaneous biopsy in lean nondiabetic (L; n = 16), obese nondiabetic (Ob; n = 15), and T2DM volunteers (n = 14). Insulin sensitivity was estimated using homeostasis model assessment (HOMA)-IR. Muscle Glyc was reduced in T2DM, a deficit evident for type IIa fibers, yet minor in types I and IIb fibers. Low Glyc in T2DM correlated with fasting hyperglycemia. Also, in T2DM and Ob, there was significantly higher IMCL and lower OX-Enz in all fiber types. The IMCL-to-OX-Enz ratio, especially for type I fibers, correlated strongly with IR. Similarly, a Glyc-to-OX-Enz ratio correlated with IR, particularly for type IIb fibers. This ratio tended to be higher in Ob and T2DM. In summary, there is decreased muscle Glyc in T2DM yet a disproportional Glyc-to-OX-Enz relationship that is related to IR, although not as robustly as the IMCL-to-OX-Enz ratio. [ABSTRACT FROM AUTHOR]

Numerous cross-sectional studies find association between intramyocellular lipid (IMCL) content and insulin resistance (IR). However, less is known concerning the effects of interventions on this association. For instance, the effects on IMCL content by interventions of weight loss and physical activity, classically known to improve IR, have only recently begun to be examined. In a recent study, content of IMCL following bariatric surgery was found to decrease dramatically. The decrease in IMCL content was related to the improvement in IR that occurred following bariatric surgery. Conversely, several studies find that with physical activity, IMCL content typically remains unchanged or increases, even though IR improves. Potential explanations for this difference between weight loss and physical activity are discussed in this article. [ABSTRACT FROM AUTHOR]