Late gadolinium enhancement by cardiovascular magnetic resonance is complementary to left ventricle ejection fraction in predicting prognosis of patients with stable coronary artery disease

Background

Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) predicts adverse prognosis in patients with stable coronary artery disease (CAD). However, the interaction with conventional risk factors remains uncertain. Our aim was to assess whether the extent of LGE is an independent predictor of adverse cardiac outcome beyond conventional risk factors, including left ventricle ejection fraction (LVEF).

Methods

We enrolled 376 patients (88% males, 64 ± 11 years) with stable CAD, who underwent LGE assessment and a detailed conventional evaluation (clinical and pharmacological history, risk factors, ECG, Echocardiography). During a follow-up of 38 ± 21 months, 56 events occurred (32 deaths, 24 hospitalizations for heart failure).

Results

LGE and LVEF showed the strongest univariate associations with end-points (HR: 13.61 [95%C.I.: 7.32-25.31] for LGE ≥ 45% of LV mass; and 12.34 [6.80-22.38] for LVEF ≤ 30%; p < 0.0001). Multivariate analysis identified baseline LVEF, loop diuretic therapy, moderate-severe mitral regurgitation and pulmonary hypertension as significant predictors among conventional risk factors. According to a step-wise approach, LGE showed strong association with prognosis as well (5.25 [2.64-10.43]; p < 0.0001). LGE significantly improved the model predictability (chi-square 239 vs 221, F-test p < 0.0001) with an additive effect on the prognostic power of LVEF, which however retained its prognostic power (4.89 [2.50-09.56]; p < 0.0001). Patients with LGE ≥ 45% and/or LVEF ≤ 30% had much worse prognosis compared to patients without risk factors (annual event rates of 43% vs 3%; p < 0.0001). Interestingly LGE was a significant predictor when all cause mortality was analyzed as the only endpoint.

Conclusions

This study demonstrates that LGE assessed by CMR is a robust independent non-invasive marker of prognosis in stable CAD patients. LGE can integrate the available metrics to substantially improve risk stratification.     

Improved quantification of left ventricular volumes and mass based on endocardial and epicardial surface detection from cardiac MR images using level set models.

PURPOSE: The reproducibility of left ventricular (LV) volume and mass measurements based on subjective slice-by-slice tracing of LV borders is affected by image quality, and volume estimates are biased by geometric modeling. The authors developed a technique for volumetric surface detection (VoSD) and quantification of LV volumes and mass without tracing and geometric approximations. The authors hypothesized that this technique is accurate and more reproducible than the conventional methodology. METHODS: Images were obtained in 24 patients in 6 to 10 slices from LV base to apex (GE 1.5 T, FIESTA). Volumetric data were reconstructed, and endocardial and epicardial surfaces were detected using the level set approach. LV volumes were obtained from voxel counts and used to compute ejection fraction (EF) and mass. Conventional measurements (MASS Analysis) were used as a reference to test the accuracy of VoSD technique (linear regression, Bland-Altman). For both techniques, measurements were repeated to compute inter- and intra-observer variability. RESULTS: VoSD values resulted in high correlation with the reference values (EDV: r = 0.98; ESV: r = 0.99; EF: r = 0.91; mass: r = 0.98), with no significant biases (8 ml, 5 ml, 0.2% and -9 g) and narrow limits of agreement (SD: 13 ml, 10 ml, 6% and 9 g). Inter-observer variability of the VoSD technique was lower (range 3 to 5%) than that of the reference technique (5 to 11%; p < 0.05). Intra-observer variability was also lower (1 to 3% vs. 7 to 10%; p < 0.05). CONCLUSION: VoSD technique allows accurate measurements of LV volumes, EF, and mass, which are more reproducible than the conventional methodology.     

Multiplex ligation-dependent probe amplification and fluorescence in situ hybridization to detect chromosomal abnormalities in chronic lymphocytic leukemia: a comparative study

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease characterized by recurrent chromosomal aberrations of prognostic significance. We aimed to evaluate the potential of the multiplex ligation-dependent probe amplification (MLPA) assay to detect genomic alterations in CLL. Highly purified (>90%) peripheral mononuclear CD19+ cell populations from 100 untreated CLL patients (pts) in early stage disease (Binet stage A) were included in this study. All samples were investigated by fluorescence in situ hybridization (FISH) for the presence of trisomy 12 and 17p13.1, 11q22.3, and 13q14.3 deletions. For MPLA analysis, DNA was amplified by means of two commercially available probes sets allowing the simultaneous screening of 56 genomic sequences. Overall, a high degree of concordance (95%) between MPLA and FISH results was found, if the abnormal clone was present in more than 30% of the leukemic cell population. The use of multiple MPLA probes allowed the fine-mapping of the 13q14 deletion and the identification of intragenic or small alterations undetected by FISH. Moreover, additional alterations in 2p24 (MYCN) (3 pts), 8q24 (MYC) (1 pt), 9p21 (CDKN2A2B) (1 pt), 1q21 (LMNA) (1 pt), and 6q25-26 (1 pt) regions not covered by a standard FISH assay were detected and all confirmed by FISH. Our data extend previously limited evidence that MLPA may represent a useful technique for the characterization of well-known lesions as well as the investigation of additional genomic changes in CLL.     

Simultaneous bilateral tubal pregnancies and intrauterine pregnancy with five fetuses

A 28-year-old woman with severe right lower abdominal pain and vaginal bleeding at 7 weeks' (+/- 2 days') gestation was seen in the emergency room of our institution. The pregnancy was the result of natural conception after ovarian stimulation with gonadotropins. Transvaginal sonography revealed five intrauterine gestational sacs containing five live embryos. A positive fetal heartbeat was detected in the fallopian tube on the right. Laparoscopic findings disclosed the enlarged uterus with the unruptured right ectopic pregnancy in the ampullary region and an extrauterine pregnancy in the left tube as well. A linear salpingotomy was performed on the right tubal pregnancy. We decided to perform salpingectomy on the left tube because it was impossible to preserve the tube, and exploration of it showed the existence of another gestational sac. It is necessary to decry inappropriate and injudicious use of assisted reproductive technologies, especially by individuals with little or no training in monitoring the agents and treatments prescribed. In 2003, still waiting for official legislation from the Italian Parliament on assisted reproductive technology, we have to face dramatic situations, such as this very unique case of heterotopic pregnancy.     

State of lucid delirium after orthotopic liver transplantation. Clinical case

Neuropsychiatric complications after liver transplantation are common and have an incidence ranging from 0.5% to 47% in several international reports. They are due to different causes (coagulation, haemodynamic or electrolyte disorders, infections, immunosuppressive drugs). In patients receiving cyclosporin and tacrolimus, headache, tremors, dysarthria, seizures and delirium are the most common disorders and are not always related to toxic drug concentrations or overdosage. We report the case of a liver transplant patient receiving cyclosporin who presented a state of lucid delirium with a mystic persecutory content. in the first few postoperative days. Cyclosporin was withdrawn and the patient switched to tacrolimus, initially combined with chlorpromazine and later with clotiapine. She rapidly improved and recovered completely within a few days. At follow-up the patient is doing well and can remember the episode of delirium perfectly well. Psychiatric evaluation preoperatively and during follow-up is important to recognize and treat these complications, which can prevent the full recovery of transplanted patients and also increase the cost of this procedure.     

Relationship Between Interferon-γ, Interleukin-10, and Interleukin-12 Production in Chronic Hepatitis C and In Vitro Effects of Interferon-α

In the current study, increased interferon (IFN)-, interleukin (IL)-10, and IL-12 p40 serum levels were observed in patients with chronic hepatitis C (CHC) compared to controls. Patients also displayed an increased spontaneous IFN- release but a deficient peripheral blood mononuclear cells (PBMC) IFN- production following stimulation with Staphylococcus aureus Cowan I strain (SAC). No difference was found with reference to spontaneous or phytohaemagglutinin (PHA)-induced IL-10 release between patients and controls, whereas a higher IL-12 p70 and IL-12 p40 secretion triggered by SAC was observed in patients. Moreover, IL-12 p40/p70 ratio following SAC stimulation was higher in patients compared to controls and a negative correlation was found between this ratio and IFN- amounts. Recombinant IL-12 (rIL-12) as well as neutralizing anti-IL-10 monoclonal antibodies (mAbs) were able to restore the compromised IFN- production. Of note, anti-IL-10 supplementation induced a lower IL-12 p40/p70 ratio in HCV subjects as compared to controls. Finally, IFN- upregulated in vitro IFN-, IL-10, and IL-12 p70 release but not IL-12 p40 secretion, this giving rise to a normalization of IL-12 p40/p70 ratio. The data suggest the occurrence of an enhanced responsiveness to IL-10 modulating effects, likely mediated by an imbalance of IL-12 p40/p70 ratio, in chronic HCV infection. Cytokine balance restoration might thus contribute to achieve therapeutical results in chronic hepatitis C.     

Office hysteroscopic metroplasty: three "diagnostic criteria" to differentiate between septate and bicornuate uteri

Study objectiveTo evaluate the benefits of adopting 3 simple “diagnostic criteria” in the differential diagnosis between septate and bicornuate uteri, and the relative treatment by hysteroscopy in an office setting.DesignProspective clinical study (Canadian Task Force classification III).SettingUniversity-affiliated hospital.PatientsTwo hundred-sixty patients with a hysteroscopic diagnosis of a double uterine cavity were enrolled.InterventionsOffice hysteroscopic metroplasty was performed without analgesia or anesthesia using 5F scissors.Measurements and Main ResultsThe presence of vascularized tissue, sensitive innervation, and the appearance of the tissue at the incision of a supposed septum during an office hysteroscopic procedure were the criteria used to differentiate a septate from a bicornuate uterus. In 93.1% of the cases, office hysteroscopic metroplasty was successfully performed during the same diagnostic procedure. In 15 of 18 patients scheduled for laparoscopic control of the uterine anatomy, the suspicion of a bicornuate uterus was confirmed. Hysteroscopic follow-up at 3 months showed a regular uterine cavity with a fundal notch less than 1 cm.ConclusionThe study demonstrates the possibility of obtaining complete, safe removal of uterine septae in most cases by office hysteroscopy confirmation, using mechanical instruments, in an office setting. This was achieved by relating the diagnosis and treatment to simple anatomic and physiologic diagnostic criteria.     

Mast cells and angiogenesis in pancreatic ductal adenocarcinoma

Mast cells are recognized as critical components of the tumor stromal microenvironment in several solid and hematological malignancies, promoting angiogenesis and tumor growth. A correlation between mast cells infiltration, angiogenesis and tumor progression has been reported for pancreatic ductal adenocarcinoma as well. Mast cells contribute to the aggressiveness of the pancreatic ductal carcinoma enhancing the expression of several pro-angiogenic factors such as vascular endothelial growth factor, fibroblast growth factor-2, platelet-derived growth factor and angiopoietin-1 as well as stimulating the pancreatic cancer cells proliferation by IL-13 and tryptase. The disruption of this pro-angiogenic and proliferative stimulation by inhibiting the mast cells migration and degranulation is under investigation as a potential therapeutic approach in pancreatic ductal adenocarcinoma patients. This review will summarize the literature concerning the mast cells infiltration in the pancreatic ductal adenocarcinoma analyzing its role in angiogenesis and tumor progression.     

Evolutionary descent of a human chromosome 6 neocentromere: A jump back to 17 million years ago

Molecular cytogenetics provides a visual, pictorial record of the tree of life, and in this respect the fusion origin of human chromosome 2 is a well-known paradigmatic example. Here we report on a variant chromosome 6 in which the centromere jumped to 6p22.1. ChIP-chip experiments with antibodies against the centromeric proteins CENP-A and CENP-C exactly defined the neocentromere as lying at chr6:26,407–26,491 kb. We investigated in detail the evolutionary history of chromosome 6 in primates and found that the primate ancestor had a homologous chromosome with the same marker order, but with the centromere located at 6p22.1. Sometime between 17 and 23 million years ago (Mya), in the common ancestor of humans and apes, the centromere of chromosome 6 moved from 6p22.1 to its current location. The neocentromere we discovered, consequently, has jumped back to the ancestral position, where a latent centromere-forming potentiality persisted for at least 17 Myr. Because all living organisms form a tree of life, as first conceived by Darwin, evolutionary perspectives can provide compelling underlying explicative grounds for contemporary genomic phenomena.One of the major tenets of Darwin''s theory of evolution is that all forms of life are connected by descent from common ancestors. Extant species represent the endpoint of branches on the tree of life. Paleontology, comparative anatomy, embryology, and more recently comparative genomics, drew trees in which, as in a million-pieces puzzle, each species was placed into a particular position. Bioinformatic sequence comparisons, which can evaluate billions of characters, are robust in scientific terms, but not very accessible to the general public. The molecular cytogenetic approach to the tree of life is more adapt for public viewing because it provides images “that speak.” The most renowned example in this respect is the fusion of two hominid ancestral chromosomes that generated human chromosome 2 and reduced the total number of human chromosomes from 48 found in great apes to 46 (Yunis and Prakash 1982).Between 17 and 23 million yeas ago (Mya) the centromere of chromosome 6 repositioned to its current location in a common ancestor of the Hominoids (lesser apes [gibbon and siamang], great apes [orangutan, gorilla, and chimpanzee], and humans). Its original position corresponded to human 6p22.1, which (we show here) is the ancestral centromere location for primates. In this report we demonstrate that a human variant chromosome 6, segregating in a three-generational family of normal individuals, has a centromere that repositioned back to the ancestral primate location. Knowledge of the evolutionary past provides compelling underlying explicative grounds for contemporary genomic phenomena.     

Contrast-enhanced magnetic resonance imaging assessment of scar size in patients with chronic myocardial infarction.

BACKGROUND: In the assessment of myocardial infarction (MI) mass, contrast-enhanced magnetic resonance imaging (CE-MRI) is comparable to single-photon emission computed tomography (SPECT). The aim of the present study was to determine whether the MI area, as assessed at CE-MRI and SPECT, is comparable to mass evaluation. We also compared CE-MRI and SPECT estimates of the MI area with functional evaluations made at echocardiography and kinetic MRI (cine-MRI). METHODS: We used a 1.0 Tesla MRI scanner and an inversion-recovery turboFLASH sequence, a tomographic gamma-camera and second-harmonic ultrasound systems. Two blinded operators assessed the extent of scarring, expressed as a percentage of the whole left ventricle (LV), using a 16-segment model. We studied 55 consecutive patients with a clinically stable healed MI (50 Q wave, 5 non-Q wave). RESULTS: The scar mass was 19+/-23% of the LV at CE-MRI and 21+/-25% at SPECT; the scar area was 29+/-23% of the LV at CE-MRI, 41+/-28% at SPECT, 29+/-31% at cine-MRI, and 32+/-29% at echocardiography. The Bland-Altman bias between CE-MRI and SPECT mass estimations was -2% of the LV with a+/-23% limit of agreement (LOA), while the bias between the area assessments was -12% with a+/-42% LOA. Bias between CE-MRI and functional evaluation by cine-MRI and echocardiography was 0% with a+/-39% LOA and -3% with a+/-36% LOA respectively. Comparing SPECT with cine-MRI and echocardiography the bias was 12% with a+/-52% LOA and 9% with a+/-56% LOA respectively. CONCLUSIONS: CE-MRI has proved to be comparable to SPECT in the assessment of the healed MI mass. Conversely, a high systematic error (high bias and LOA) renders CE-MRI and SPECT assessments of the MI area incomparable. Similarly (high bias and/or LOA) CE-MRI and SPECT estimations of the MI area cannot be compared with functional evaluation by echocardiography or cine-MRI.