Francesco De Cobelli

Increased mediastinal fat and impaired left ventricular energy metabolism in young men with newly found fatty liver.

Fatty liver is characterized by metabolic abnormalities at the liver, but also at skeletal muscle and adipose tissue sites. It is hypothesized that the heart may be suffering metabolic alterations, and this study was undertaken to ascertain whether individuals with fatty liver have left ventricular (LV) alterations of energy metabolism, structure, and function and abnormal amounts of epicardial fat as a specific marker of visceral fat accumulation. To this end we studied young, nondiabetic men matched for anthropometric features with (n = 21) or without (n = 21) fatty liver by means of (1) cardiac magnetic resonance imaging (MRI); (2) cardiac 31P‐MR spectroscopy (MRS); and (3) hepatic 1H‐MRS to assess quantitatively the intrahepatic fat (IHF) content. Insulin sensitivity was determined by the updated HOMA‐2 computer model. Individuals with fatty liver showed reduced insulin sensitivity, increased serum free fatty acid (FFA), and E‐selectin, abnormal adipokine concentrations, and higher blood pressure. LV morphology and systolic and diastolic functions were not different; however, in the scanned intrathoracic region, the intrapericardial (7.8 ± 3.1 versus 5.9 ± 2.5 cm2; P < 0.05) and extrapericardial (11.7 ± 6.1 versus 7.8 ± 3.2 cm2; P < 0.03) fat was increased in men with fatty liver compared with those without fatty liver. The phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio, a recognized in vivo marker of myocardial energy metabolism, was reduced in men with fatty liver in comparison with normals (1.85 ± 0.35 versus 2.11 ± 0.31; P < 0.016). In conclusion, in newly found individuals with fatty liver, fat was accumulated in the epicardial area and despite normal LV morphological features and systolic and diastolic functions, they had abnormal LV energy metabolism. (HEPATOLOGY 2008.)

In Vivo Quantification of Helical Blood Flow in Human Aorta by Time-Resolved Three-Dimensional Cine Phase Contrast Magnetic Resonance Imaging

The mechanics of blood flow in arteries plays a key role in the health of individuals. In this framework, the role played by the presence of helical flow in the human aorta is still not clear in its relation to physiology and pathology. We report here a method for quantifying helical flow in vivo employing time-resolved cine phase contrast magnetic resonance imaging to obtain the complete spatio-temporal description of the three-dimensional pulsatile blood flow patterns in aorta. The method is applied to data of one healthy volunteer. Particle traces were calculated from velocity data: to them we applied a Lagrangian-based method for helical flow quantification, the Helical Flow Index, which has been developed and evaluated in silico in order to reveal global organization of blood flow. Our results: (i) put in evidence that the systolic hemodynamics in aorta is characterized by an evolving helical flow (we quantified a 24% difference in terms of the content of helicity in the streaming blood, between mid and early systole); (ii) indicate that in the first part of the systole helicity is ascrivable mainly to the asymmetry of blood flow in the left ventricle, joined with the laterality of the aorta. In conclusion, this study shows that the quantification of helical blood flow in vivo is feasible, and it might allow detection of anomalies in the expected physiological development of helical flow in aorta and accordingly, could be used in a diagnostic/prognostic index for clinical practice.

Maturing Dendritic Cells Depend on RAGE for In Vivo Homing to Lymph Nodes

The mobilization of dendritic cells (DCs) from peripheral tissues is critical for the establishment of T cell-dependent immune responses or tolerance, because the physical interaction of DCs with naive T cells takes place in the T cell areas of lymph nodes. The autocrine/paracrine release of the high mobility group box 1 (HMGB1) nuclear protein by DCs controls the outcome of the DC–T cell interaction, influencing the priming/Th1 polarization of naive T cells. We herein present evidence that the receptor for advanced glycation end products (RAGE), a multiligand member of the Ig superfamily of cell-surface molecules that acts as a receptor for HMGB1, plays a nonredundant role in DC homing to lymph nodes. We used noninvasive imaging by magnetic resonance and immunohistochemistry to track DCs after s.c. injection in the footpad of wild-type+/+ or RAGE−/− mice. Maturing DCs expressing RAGE effectively migrated in both conditions. In contrast, RAGE−/− DCs failed to reach the draining popliteal lymph nodes of +/+ and −/− mice, indicating that the integrity of RAGE is required for DC mobilization. Thus the HMGB1-RAGE pathway is a checkpoint in DC maturation and function and a candidate for targeted therapies.

Delayed-enhanced cardiac MRI for differentiation of Fabry's disease from symmetric hypertrophic cardiomyopathy.

OBJECTIVE Fabrys disease may be difficult to differentiate from symmetric hypertrophic cardiomyopathy. Our aim was to compare the myocardial location and distribution patterns of delayed enhancement between patients with Fabrys disease who are affected by symmetric myocardial hypertrophy and patients with symmetric hypertrophic cardiomyopathy in order to identify a specific sign to best differentiate the two diseases. CONCLUSION Patients with Fabrys disease-related hypertrophy showed left ventricular (LV) delayed enhancement with a typical and consistently found pattern characterized by the involvement of the inferolateral basal or mid basal segments and a mesocardial distribution that spared the subendocardium. This pattern seems to be specific to Fabrys disease; in fact, patients with symmetric hypertrophic cardiomyopathy had variable locations and distributions of delayed enhancement. These observations may contribute to identifying Fabrys disease as a specific cause of symmetric hypertrophy.

Two Different Mechanisms of Myocardial Ischemia Involving 2 Separate Myocardial Segments in a Patient With Normal Coronary Angiography

A 53-year-old woman with no risk factors was admitted to our hospital in December 2006 because of worsening angina and positive exercise stress test. Two months earlier, she had been admitted to another hospital because of prolonged epigastrial pain without radiation, which had subsided just before she reached the hospital, that was associated with diagnostic elevation of troponin; she reported 3 episodes of the same pain lasting ≈5 minutes in the early morning hours over the preceding 3 weeks. A few hours after admission, she had a recurrence of pain with ST elevation on the inferior electrocardiogram (ECG) leads that responded to intravenous nitrates. Subsequent angiography failed to show lumen stenosis, irregularities, and thrombus deposition, but ventriculography showed akinesia of the basal inferior wall. The discharge diagnosis was inferior ST-elevation myocardial infarction (creatine kinase-MB peak, 112 U/L; troponin I peak, 9.74 ng/mL) with normal coronary arteries, and she was prescribed aspirin, calcium, antagonists, and β-blockers. She remained symptom free for about a month. Then, during a very stressful period of her life, she began to present with anginal pain during effort, sometimes on emotion. She insisted …

Hemorrhage from a Right Hepatic Artery Pseudoaneurysm: Endovascular Treatment with a Coronary Stent-Graft

PURPOSE To report a novel case demonstrating the successful endovascular treatment of a right hepatic artery pseudoaneurysm using a balloon-expandable coronary stent-graft. CASE REPORT A 60-year-old woman underwent surgical treatment for a Klatskin tumor, but her postoperative course was complicated by serious blood loss. An emergent celiac angiogram through a right transfemoral approach demonstrated a small iatrogenic pseudoaneurysm in the proximal right hepatic artery. A 7-F guiding catheter was positioned at the origin of the celiac trunk, and a Jostent coronary stent-graft mounted on a 2.7-F, 4-mm x 30-mm balloon catheter was successfully placed across the aneurysm neck. The final angiogram demonstrated total exclusion of the pseudoaneurysm with preservation of the arterial lumen. The hemodynamic condition of the patient became stable. At 12-month follow-up, duplex scanning confirmed regular right hepatic artery patency and absence of thrombotic tissue or signs of infection around the stent-graft. CONCLUSION For hepatic artery pseudoaneurysms, endovascular repair using small covered stents may be a viable alternative to transcatheter embolization. The use of coronary instruments facilitates treatment of vascular lesions in small caliber visceral vessels.

Italian multicenter, prospective study to evaluate the negative predictive value of 16- and 64-slice mdct imaging in patients scheduled for coronary angiography (nimiscad-non invasive multicenter italian study for coronary artery disease)

This was a prospective, multicenter study designed to evaluate the utility of MDCT in the diagnosis of coronary artery disease (CAD) in patients scheduled for elective coronary angiography (CA) using different MDCT systems from different manufacturers. Twenty national sites prospectively enrolled 367 patients between July 2004 and June 2006. Computed tomography (CT) was performed using a standardized/optimized scan protocol for each type of MDCT system (≥16 slices) and compared with quantitative CA performed within 2 weeks of MDCT. A total of 284 patients (81%) were studied by 16-slice MDCT systems, while 66 patients (19%) by 64-slice MDCT scanners. The primary analysis was on-site/off-site evaluation of the negative predictive value (NPV) on a per-patient basis. Secondary analyses included on-site evaluation on a per-artery and per-segment basis. On-site evaluation included 327 patients (CAD prevalence 58%). NPV, positive predictive value (PPV), sensitivity, specificity, and diagnostic accuracy (DA) were 0.91 (95% CI 0.85–0.95), 0.91 (95% CI 0.86–0.95), 0.94 (95% CI 0.89–0.97), 0.88 (95% CI 0.81–0.93), and 0.91 (95% CI 0.88–0.94), respectively. Off-site analysis included 295 patients (CAD prevalence 56%). NPV, PPV, sensitivity, specificity, and DA were 0.73 (95% CI 0.65–0.79), 0.93 (95% CI 0.87–0.97), 0.73 (95% CI 0.65–0.79), 0.93 (95% CI 0.87–0.97), and 0.82 (95% CI 0.77–0.86), respectively. The results of this study demonstrate the utility of MDCT in excluding significant CAD even when conducted by centers with varying degrees of expertise and using different MDCT machines.

Defining the optimal biological dose of NGR-hTNF, a selective vascular targeting agent, in advanced solid tumours.

BACKGROUND NGR-hTNF consists of human tumour necrosis factor-alpha (hTNF-alpha) fused to the tumour-homing peptide NGR, a ligand of an aminopeptidase N/CD13 isoform, which is overexpressed on endothelial cells of newly formed tumour blood vessels. NGR-TNF showed a biphasic dose-response curve in preclinical models. This study exploring the low-dose range aimed to define safety and optimal biological dose of NGR-hTNF. PATIENTS AND METHODS Pharmacokinetics, plasma biomarkers and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were evaluated at baseline and after each cycle in 16 patients enrolled at four doubling-dose levels (0.2-0.4-0.8-1.6 microg/m(2)). NGR-hTNF was given intravenously as 1-h infusion every 3 weeks (q3w). Tumour response was assessed q6w. RESULTS Eighty-three cycles (median, 2; range, 1-29) were administered. Most frequent treatment-related toxicity was grade 1-2 chills (69%), occurring during the first infusions. Only one patient treated at 1.6 microg/m(2) had a grade 3 drug-related toxicity (chills and dyspnoea). Both C(max) and AUC increased proportionally with dose. No shedding of soluble TNF-alpha receptors was observed up to 0.8 microg/m(2). Seventy-five percent of DCE-MRI assessed patients showed a decrease over time of K(trans), which was more pronounced at 0.8 microg/m(2). Seven patients (44%) had stable disease for a median time of 5.9 months, including a colon cancer patient who experienced an 18-month progression-free time. CONCLUSION Based on tolerability, soluble TNF-receptors kinetics, anti-vascular effect and disease control, NGR-hTNF 0.8 microg/m(2) will be further developed either as single-agent or with standard chemotherapy.

Dynamic Gadolinium-Enhanced Magnetic Resonance Imaging in Staging of Superficial Bladder Cancer

PURPOSE We evaluated the usefulness of dynamic enhanced magnetic resonance imaging (MRI) in the staging of superficial tumors following a bolus administration of gadopentetate dimeglumine. MATERIALS AND METHODS In 48 patients with proved bladder tummors the results of preoperative plain spin echo T1 (repetition time/echo time 500/20 msec.) and T2 (repetition time/echo time 2,000/40 to 100 msec.)-weighted MRI, dynamic gadolinium-enhanced MRI (repetition time/echo time 200/15 msec.) and late gadolinium-enhanced MRI (repetition time/echo time 500/20 msec.) were compared and correlated with the histopathological findings. RESULTS Unenhanced spin echo T1 and T2-weighted MRI sequences were able to stage correctly 14 (56%) and 17 (68%) of 25 superficial bladder cancers, respectively. Muscular infiltration (stages pT2 and pT3a) was correctly depicted in 3 (27%) and 6 (54%) of 11 cases respectively, with over staging being the most frequent error. On the basis of the dynamic gadolinium-enhanced T1-weighted MRI appearance, superficial involvement of the bladder wall was correctly assessed in 21 of 25 cases (84%) and muscular infiltration (stages pT2 to pT3a) in 7 of 11 (63%). Delayed enhanced T1-weighted sequences showed a low accuracy rate in staging superficial tumors (44%). The overall accuracy of T1 and T2-weighted, dynamic T1-weighted and delayed T1-weighted MRI in staging bladder cancer was 58, 71, 81 and 56% respectively. CONCLUSIONS The use of gadolinium improved the accuracy of dynamic enhanced MRI in staging superficial bladder cancer. On the contrary, delayed enhanced MRI was not useful for staging superficial bladder cancer. The degree of bladder distension was a determinant factor in staging superficial tumors.

Takayasu Arteritis: Intravascular Contrast Medium for MR Angiography in the Evaluation of Disease Activity

OBJECTIVE Takayasu arteritis is difficult to diagnose, and the evaluation of disease activity is even more challenging. Laboratory, clinical, and radiologic criteria are limited indicators of disease activity. Gadofosveset trisodium is a recently introduced intravascular contrast agent. In this study we sought to investigate a correlation between clinical activity and enhancement of vascular wall thickening in patients with Takayasu arteritis who underwent MR angiography with gadofosveset. SUBJECTS AND METHODS Twenty-three consecutively registered patients (21 women, two men) with Takayasu arteritis underwent MR angiography of the supraaortic trunks, aorta, and visceral vessels. Intravascular contrast medium was used to correlate thickened vessel wall enhancement with clinical criteria of disease activity. ECG-triggered black-blood first-pass high-resolution steady-state imaging was performed for all patients. RESULTS Before MR angiography, 14 patients were considered to have active disease. Heterogeneous structural involvement of the vascular tree was found. Twenty of 23 patients (87.0%) had supraaortic trunk involvement, including 12 of the 14 patients (85.7%) with active disease. Seventeen of the 23 patients (73.9%) had aortic and visceral vessel involvement, including 12 of the 14 patients (85.7%) with active disease. On steady state images in the active disease group, the mean signal-to-noise-ratio increased from 17.4 to 35.3 after gadofosveset injection (p > 0.0001), while in the nonactive disease group it increased from 52.8 to 69.6 (p = 0.08). A cutoff of 40% was best for differentiating active from inactive disease (sensitivity, 100%; specificity, 89%; positive predictive value, 92%; negative predictive value, 100%). CONCLUSION Use of intravascular contrast medium significantly increases the effectiveness of MR angiography in differentiating active and inactive disease.