Prognostic Role of the Progression of Late Gadolinium Enhancement in Hypertrophic Cardiomyopathy.

In hypertrophic cardiomyopathy (HCM), late gadolinium enhancement (LGE) extent ≥15% of left ventricular mass is considered a prognostic risk factor. LGE extent increases over time and the clinical role of the progression of LGE over time (LGE rate) was not prospectively evaluated. We sought to evaluate the prognostic role of the LGE rate in HCM. We enrolled 105 patients with HCM who underwent cardiac magnetic resonance (CMR) at baseline (CMR-I) and after ≥2 years of follow-up (CMR-II). LGE rate was defined as the ratio between the increase of LGE extent (grams) and the time interval (months) between examinations. A combined end point of sudden cardiac death, resuscitated cardiac arrest, appropriate Implanted Cardioverter Defibrillator (ICD) intervention, and sustained ventricular tachycardia was used (hard events). The percentage of patients with LGE extent ≥15% increased from 9% to 20% from CMR-I to CMR-II (p = 0.03). During a median follow-up of 52 months, 25 hard events were recorded. The presence of LGE ≥15% at CMR-II allowed a significant reclassification of the risk of patients than at LGE ≥15% at CMR-I (net reclassification improvement 0.21, p = 0.046). On the MaxStat analysis, the optimal prognostic cut point for LGE rate was >0.07 g/month. On the Kaplan-Meier curve, patients with LGE rate >0.07 had worse prognosis than those without (p <0.0001). LGE rate >0.07 allowed a significant reclassification of the risk compared with LGE ≥15% at CMR-I and at CMR-II (net reclassification improvement 0.49, p = 0.003). In the multivariable models, LGE rate >0.07 was the best independent predictor of hard events. In conclusion, CMR should be repeated after 2 years to reclassify the risk for sudden death of those patients. A high LGE rate may be considered a novel prognostic factor in HCM.

Diagnostic Role of Native T1 Mapping Compared to Conventional Magnetic Resonance Techniques in Cardiac Disease in a Real-Life Cohort.

We sought to compare native T1 mapping to conventional late gadolinium enhancement (LGE) and T2-STIR techniques in a cohort of consecutive patients undergoing cardiac MRI (CMR). CMR was performed in 323 patients, 206 males (64%), mean age 54 ± 8 years, and in 27 age- and sex- matched healthy controls. In T2-STIR images, myocardial hyperintensity suggesting edema was found in 41 patients (27%). LGE images were positive in 206 patients (64%). T1 mapping was abnormal in 171 (49%). In 206 patients (64%), a matching between LGE and native T1 was found. T1 was abnormal in 32 out of 41 (78%) with edema in T2-STIR images. Overall, LGE and/or T2-STIR were abnormal in 209 patients, whereas native T1 was abnormal in 154 (52%). Conventional techniques and T1 mapping were concordant in 208 patients (64%). In 39 patients, T1 mapping was positive despite negative conventional techniques (12%). T1 mapping was able in conditions with diffuse myocardial damage such as cardiac amyloidosis, scleroderma, and Fabry disease (additive role in 42%). In contrast, T1 mapping was less effective in cardiac disease with regional distribution of myocardial damage such as myocardial infarction, HCM, and myocarditis. In conclusion, conventional LGE/T2-STIR and T1 mapping are complementary techniques and should be used together in every CMR examination.

Diagnostic and prognostic role of late gadolinium enhancement in cardiomyopathies.

Late gadolinium enhancement (LGE) is the most relevant tool of cardiac magnetic resonance for tissue characterization, and it plays a pivotal role for diagnostic and prognostic assessment of cardiomyopathies. The pattern of presentation of LGE allows differential diagnosis between ischaemic and non-ischaemic heart disease with high diagnostic accuracy, and among different cardiomyopathies, specific presentation of LGE may help to make a diagnosis. Late gadolinium enhancement may be caused by conditions that significantly increase the interstitial space or, less frequently, that slow down Gd exit, like myocardial fibrosis. In chronic myocardial infarction, hypertrophic cardiomyopathies (HCM), dilated cardiomyopathy, Fabry disease, and other conditions, LGE is a marker of myocardial fibrosis, but also in patients with acute myocarditis where LGE may be also explained by the increase of interstitial space caused by interstitial oedema or by tissue infiltration of inflammatory cells. In cardiac amyloidosis, LGE represents myocardial fibrosis but the interstitial overload of amyloid proteins should also be considered as a potential cause of LGE. The identification of the pattern of presentation of LGE is also very important. In the ischaemic pattern, LGE always involves the subendocardial layer with more or less transmural extent, it is confluent, and every single scar should be located in the territory of one coronary artery. In the non-ischaemic pattern, LGE does not fulfil the previous criteria, being midwall, subepicardial, or mixed, not necessarily confluent or confined to a territory of one coronary artery. For cardiomyopathies, the exact pattern of non-ischaemic LGE is important. Quantitative analysis of LGE is required in some specific conditions as in HCM. Magnetic resonance imaging with LGE technique should be performed in every patient with suspect of cardiomyopathy. The lack of standardization of pulse sequence and mostly of quantification methods is the main limitation of LGE technique.

Cardiac Magnetic Resonance in Fabry Disease: Morphological, Functional, and Tissue Features.

Fabry disease (FD) is an X-linked inheritable storage disease caused by a deficiency of alpha-galactosidase causing lysosomal overload of sphingolipids. FD cardiomyopathy is characterized by left ventricular (LV) hypertrophy and should be considered in differential diagnosis with all the other causes of LV hypertrophy. An early diagnosis of FD is very important because the enzyme replacement therapy (ERT) may change the fate of patients by blocking both cardiac and systemic involvement and improving prognosis. Diagnosis may be relatively easy in young patients with the typical signs and symptoms of FD, but in male patients with late onset of disease and in females, diagnosis may be very challenging. Morphological and functional aspects are not specific to FD, which cannot be diagnosed or excluded by echocardiography. Cardiac magnetic resonance (CMR) with tissue characterization capability is an accurate technique for the differential diagnosis of LV hypertrophy. The finding of decreased myocardial T1 value in LV hypertrophy is specific to FD. Late gadolinium enhancement (LGE) is found in the late stage of the disease, but it is useful to predict the cardiac response to ERT and to stratify the prognosis.

Survival in acute heart failure in intensive cardiac care unit: a prospective study.

The aim of this study is to identify the best predictors of mortality among clinical, biochemical and advanced echocardiographic parameters in acute heart failure (AHF) patients admitted to coronary care unit (CCU). AHF is a clinical condition characterized by high mortality and morbidity. Several studies have investigated the potential prognostic factors that could help the risk assessment of cardiovascular events in HF patients, but at the moment it has not been found a complete prognostic score (including clinical, laboratory and echocardiographic parameters), univocally used for AHF patients. Patients (n = 118) admitted to CCU due to AHF de novo or to an exacerbation of chronic heart failure were enrolled. For each patient, clinical and biochemical parameters were reported as well as the echocardiographic data, including speckle tracking echocardiography analysis. These indexes were then related to intra- and extrahospital mortality. At the end of the follow-up period, the study population was divided into two groups, defined as 'survivors' and 'non-survivors'. From statistical analysis, C-reactive protein (CRP) (AUC = 0.75), haemoglobin (AUC = 0.71), creatinine clearance (AUC = 0.74), left atrial strain (AUC = 0.73) and freewall right ventricular strain (AUC = 0.76) showed the strongest association with shortterm mortality and they represented the items of the proposed risk score, whose cut-off of 3 points is able to discriminate patients at higher risk of mortality. AHF represents one of the major challenges in CCU. The use of a combined biochemical and advanced echocardiographic score, assessed at admission, could help to better predict mortality risk, in addition to commonly used indexes.

High-resolution, handheld camera use for occult breast lesion localization plus sentinel node biopsy (SNOLL): a single-institution experience with 186 patients.

BACKGROUND: Sentinel node and occult lesion localization (SNOLL) calls for a combination of two specific procedures: intraoperative detection of sentinel lymph node (SLN) via gamma probe and radioguided occult lesion localization (ROLL). This applies to nonpalpable invasive breast cancer or high-grade in situ carcinoma. As opposed to standard techniques, today's handheld gamma cameras enable intraoperative scintigraphic images. METHODS: A cohort (N = 186) of consecutive patients with breast cancer was subjected to radioguided conservative surgery (quadrantectomy and SLN biopsy), using a standard gamma probe and a high-resolution handheld camera. Intraoperative SLN frozen section was also performed. RESULTS: Neoplastic lesions were removed in 99.4% of all patients, and SLN biopsy was achieved in 99%. Of the 137 patients with invasive cancer, SLN metastasis was confirmed in 21. In 12% of patients, a second operation was required for close or tumor-positive surgical margins. DISCUSSION: This combination of procedures represents an improvement in the surgical management of occult breast carcinomas and is the method of choice for accurate tumor localization and SLN biopsy. Handheld cameras have the potential to become highly useful intraoperative aids.

Nitrite as Direct S-Nitrosylating Agent of Kir2.1 Channels.

Nitrite, a physiological nitric oxide (NO) storage form and an alternative way for NO generation, affects numerous biological processes through NO-dependent and independent pathways, including the S-nitrosylation of thiol-containing proteins. Mechanisms underlying these phenomena are not fully understood. The purpose of this study was to analyse in the rat heart (as prototype of mammalian heart) whether nitrite affects S-nitrosylation of cardiac proteins and the potential targets for S-nitrosylation. Rat hearts, perfused according to Langendorff, were exposed to nitrite. By Biotin Switch Method, we showed that nitrite treatment increased the degree of S-nitrosylation of a broad range of membrane proteins. Further analysis, conducted on subfractioned proteins, allowed us to identify a high level of nitrosylation in a small range of plasmalemmal proteins characterized by using an anti-Kir2.1 rabbit polyclonal antibody. We also verified that this effect of nitrite is preserved in the presence of the NO scavenger PTIO (2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide). Our results suggest, for the first time, that nitrite represents a direct S-nitrosylating agent in cardiac tissues and that inward-rectifier potassium ion channels (Kir2.1) are one of the targets. These observations are of relevance since they support the growing evidence that nitrite is not only a NO reserve but also a direct modulator of important functional cardiac proteins.

Glycyrrhizin and glycyrrhetinic acid directly modulate rat cardiac performance.

Root extract of liquorice is traditionally used to treat several diseases. Liquorice-derived constituents present several biological actions. In particular, glycyrrhizin and its aglycone, glycyrrhetinic acid, exhibit well-known cardiovascular properties. The aim of this research was to explore the direct cardiac activity of glycyrrhizin and glycyrrhetinic acid. The effects of synthetic glycyrrhizin and glycyrrhetinic acid were evaluated on the isolated and Langendorff perfused rat heart. The intracellular signaling involved in the effects of the two substances was analyzed on isolated and perfused heart and by Western blotting on cardiac extracts. Under basal conditions, both glycyrrhizin and glycyrrhetinic acid influenced cardiac contractility and relaxation. Glycyrrhizin induced significant positive inotropic and lusitropic effects starting from very low concentrations, while both inotropism and lusitropism were negatively affected by glycyrrhetinic acid. Both substances significantly increased heart rate. Analysis of the signal transduction mechanisms suggested that glycyrrhizin acts through the endothelin receptor type A/phospholipase C axis while glycyrrhetinic acid acts through endothelin receptor type B/Akt/nitric oxide synthase/nitric oxide axis. To our knowledge, these data reveal, for the first time, that both glycyrrhizin and glycyrrhetinic acid directly affect cardiac performance. Additional information on the physiological significance of these substances and their cardiac molecular targets may provide indication on their biomedical application.

Post-ischemic early acidosis in cardiac postconditioning modifies the activity of antioxidant enzymes, reduces nitration, and favors protein S-nitrosylation.

Postconditioning (PostC) modifies the early post-ischemic pH, redox environment, and activity of enzymes. We hypothesized that early acidosis in PostC may affect superoxide dismutase (SOD) and catalase (CAT) activities, may reduce 3-nitrotyrosine (3-NT) protein levels, and may increase S-nitrosylated (SNO) protein levels, thus deploying its protective effects. To verify this hypothesis, we studied the early (7(th) min) and late (120(th) min) phases of reperfusion (a) endogenous SOD and CAT activities and (b) 3-NT protein levels and SNO protein levels. Isolated rat hearts underwent 30-min ischemia/120-min reperfusion (I/R) or PostC (5 cycles of 10-s I/R at the beginning of 120-min reperfusion) either with or without exogenous CAT or SOD infused during the initial 3 min of reperfusion. The effects of early reperfusion with acid buffer (AB, pH 6.8) on endogenous antioxidant enzymes were also tested. Pressure, infarct size, and lactate dehydrogenase release were also measured. At the 7(th) min, PostC induced a significant decrease in SOD activity with no major change both in Mn and Cu/Zn SOD levels and in CAT activity and level. PostC also reduced 3-NT and increased SNO levels. Exogenous SOD, but not CAT, abolished PostC cardioprotection. In late reperfusion (120-min), I/R increased SOD activity but decreased CAT activity and Cu/Zn SOD levels; these effects were reversed by PostC; 3-NT was not affected, but SNO was increased by PostC. AB reproduced PostC effects on antioxidant enzymes. The conclusions are as follows: PostC downregulates endogenous SOD and preserves CAT activity, thus increasing SNO and reducing 3-NT levels. These effects are triggered by early post-ischemic acidosis. Yet acidosis-induced SOD downregulation may limit denitrosylation, thus contributing to PostC triggering. Hence, exogenous SOD, but not CAT, interferes with PostC triggering. Prolonged SOD downregulation and SNO increase may contribute to PostC and AB beneficial effects.

Nitrite as a physiological source of nitric oxide and a signalling molecule in the regulation of the cardiovascular system in both mammalian and non-mammalian vertebrates.

The circulating anion nitrite (NO(2)(-)) has long been considered an inert oxidative metabolite of nitric oxide (NO). Over the last decade several studies have identified inorganic nitrite as a key player in many biological processes because it acts both as a principal storage source of NO and as a signalling molecule distinct from its link with NO. This new field of research involves the exploration of the molecular, biochemical, and physiological activities of nitrite under a variety of physiological and pathophysiological states. As a signalling molecule, nitrite is involved in various biological responses, including hypoxic vasodilation, inhibition of mitochondrial respiration, cytoprotection following ischemia/reperfusion and regulation of protein and gene expression. As a stored form of NO, since the cardiovascular system is under an important NO-mediated autocrine-paracrine control, intensive investigations involve nitrite effects on vessel and heart regulation. Recently, some authors have reported that nitrite, through both direct and indirect pathways, plays a fundamental role in vascular homeostasis and cardiac function not only in mammals but also in non-mammalian species (fish, amphibians). This review highlights some patents and the importance of the signalling properties of nitrite anion in a comparative vertebrate context for providing significant insights on "ancestral" functions of the nitrite-NO system, which may facilitate its potential use as a therapeutic agent of cardiovascular disease.

Thyroid cancer imaging in vivo by targeting the anti-apoptotic molecule galectin-3.

BACKGROUND: The prevalence of thyroid nodules increases with age, average 4-7% for the U.S.A. adult population, but it is much higher (19-67%) when sub-clinical nodules are considered. About 90% of these lesions are benign and a reliable approach to their preoperative characterization is necessary. Unfortunately conventional thyroid scintigraphy does not allow the distinction among benign and malignant thyroid proliferations but it provides only functional information (cold or hot nodules). The expression of the anti-apoptotic molecule galectin-3 is restricted to cancer cells and this feature has potential diagnostic and therapeutic implications. We show here the possibility to obtain thyroid cancer imaging in vivo by targeting galectin-3. METHODS: The galectin-3 based thyroid immuno-scintigraphy uses as radiotracer a specific (99m)Tc-radiolabeled mAb. A position-sensitive high-resolution mini-gamma camera was used as imaging capture device. Human galectin-3 positive thyroid cancer xenografts (ARO) and galectin-3 knockout tumors were used as targets in different experiments in vivo. 38 mice with tumor mass of about 1 gm were injected in the tail vein with 100 microCi of (99m)Tc-labeled mAb to galectin-3 (30 microg protein/in 100 microl saline solution). Tumor images were acquired at 1 hr, 3 hrs, 6 hrs, 9 hrs and 24 hrs post injection by using the mini-gamma camera. FINDINGS: Results from different consecutive experiments show an optimal visualization of thyroid cancer xenografts between 6 and 9 hours from injection of the radiotracer. Galectin-3 negative tumors were not detected at all. At 6 hrs post-injection galectin-3 expressing tumors were correctly visualized, while the whole-body activity had essentially cleared. CONCLUSIONS: These results demonstrate the possibility to distinguish preoperatively benign from malignant thyroid nodules by using a specific galectin-3 radio-immunotargeting. In vivo imaging of thyroid cancer may allow a better selection of patients referred to surgery. The possibility to apply this method for imaging and treatment of other galectin-3 expressing tumors is also discussed.

Somatostatin receptor scintigraphy using 99mTc-EDDA/HYNIC-TOC in patients with medullary thyroid carcinoma.

PURPOSE: Several new somatostatin analogues have been developed for the diagnosis and therapy of different tumours. Since somatostatin receptors are often over-expressed in medullary thyroid carcinoma (MTC), the aim of our study was to evaluate the utility of scintigraphy with the somatostatin analogue (99m)Tc-EDDA/HYNIC-TOC in MTC in comparison with other diagnostic techniques. METHODS: Forty-five patients with MTC, aged 14-83 years, were investigated. Scintigraphy using (99m)Tc-EDDA/HYNIC-TOC (Tektrotyd) was performed 2 and 4 h post injection of 740 MBq (20 mCi) of the tracer. Other imaging techniques were also applied and analysed in individual cases (ultrasonography, computed tomography, (99m)Tc(V)-DMSA, (131)I-MIBG, (99m)Tc-MDP, (111)In-DTPA-octreotide and (18)F-FDG-PET) and compared with (99m)Tc-EDDA/HYNIC-TOC. RESULTS: In group 1 (eight patients before thyroidectomy), uptake of the tracer was found in the primary tumours. In group 2 (six patients with remission), a false positive result was found in one patient; in the remaining five patients, no pathological foci were visualised. In group 3 (31 patients with post-surgical hypercalcitoninaemia), scintigraphy was true positive in 23 patients (74.2%): uptake in the thyroid bed was found in five patients, in the lymph nodes in 18 and in bone metastases in four. Using (99m)Tc-EDDA/HYNIC-TOC scintigraphy, the overall sensitivity was 79.5%, specificity 83.3%, accuracy 80.0%, positive predictive value 96.9% and negative predictive value 38.5%. CONCLUSION: (99m)Tc-EDDA/HYNIC-TOC is clinically useful for scintigraphy in the follow-up of patients with MTC. It can be used in clinical practice for preoperative evaluation, for localisation of local recurrence or distant metastases and particularly for therapy decision making.

Nuclear medicine imaging of bone infections.

The inflammation and infection of bone include a wide range of processes that can result in a reduction of function or in the complete inability of patients. Apart from the inflammation, infection is sustained by pyogenic microorganisms and results mostly in massive destruction of bones and joints. The treatment of osteomyelitis requires long and expensive medical therapies and, sometimes, surgical resection for debridement of necrotic bone or to consolidate or substitute the compromised bones and joints. Radiographs and bone cultures are the mainstays for the diagnosis but often are useless in the diagnosis of activity or relapse of infection in the lengthy management of these patients. Imaging with radiopharmaceuticals, computed tomography and magnetic resonance are also used to study secondary and chronic infections and their diffusion to soft or deep tissues. The diagnosis is quite easy in acute osteomyelitis of long bones when the structure of bone is still intact. But most cases of osteomyelitis are subacute or chronic at the onset or become chronic during their evolution because of the frequent resistance to antibiotics. In chronic osteomyelitis the structure of bones is altered by fractures, surgical interventions and as a result of bone reabsorption produced by the infection. Metallic implants and prostheses produce artefacts both in computed tomography and magnetic resonance images, and radionuclide studies should be essential in these cases. Vertebral osteomyelitis is a specific entity that can be correctly diagnosed by computed tomography or magnetic resonance imaging at the onset of symptoms but only with radionuclide imaging is it possible to assess the activity of the disease after surgical stabilization or medical therapy. The lack of comparative studies showing the accuracy of each radiopharmaceutical for the study of bone infection does not allow the best nuclear medicine techniques to be chosen in an evidence-based manner. To this end we performed a meta-analysis of peer reviewed articles published between 1984 and 2004 describing the use of nuclear medicine imaging for the study of the most frequent causes of bone infections, including prosthetic joint, peripheric post-traumatic bone infections, vertebral and sternal infections. Guidelines for the choice of the optimal radiopharmaceuticals to be used in each clinical condition and for different aims is provided.

99mTc-EDDA/HYNIC-TOC in the management of medullary thyroid carcinoma.

An early diagnosis of distant metastases or local recurrences of medullary thyroid carcinoma (MTC) can be achieved by several conventional radiological modalities (e.g., ultrasonography, computed tomography [CT], and magnetic resonance imaging [MRI] as well as by radioisotopic procedures, such as positron emission tomography (PET), scintigraphy with different types of radiopharmaceuticals, and radiolabeled receptor-ligands in particular. The aim of this study was to evaluate the clinical utility of 99mTc-EDDA/HYNIC-TOC, a new octreotide derivative, to detect recurrences of disease or distant metastases in MTC. Images obtained of 5 patients with high levels of serum calcitonin were compared to findings obtained with other diagnostic procedures: 111In-octreotide, 99mTc-DMSA-V, 18F-flouro-D-deoxyglucose-PET, and CT/MRI. 99mTc-EDDA/HYNIC-TOC was positive in all patients and showed 15 areas of pathological uptake in the cervical and mediastinal regions. 111In-octreotide was positive in 3 of 3 patients and showed 4 areas, compared to 8 of 99mTc-EDDA/HYNIC-TOC. 99mTc-V-DMSA was positive in 3 of 4 patients but showed 6 pathological areas, compared to 13 of 99mTc-EDDA/HYNIC-TOC. 18F-FDG-PET was positive in 5 of 5 patients but showed only 11 areas, compared to 15 of 99mTc-EDDA/HYNIC-TOC. The CT scan was positive in only 2 patients. In conclusion, 99mTc-EDDA/HYNIC-TOC detected more sites of pathological uptake than other modalities, showed better imaging properties than 111In-octreotide, and might be the radiopharmaceutical of choice for providing a rationale for radioisotopic therapy.