Brain gliomas and growth factors: immunohistochemical, immunofluorescence, flow cytometry and RT-PCR profile in pediatric age.

Gliomas represent over 50% of tumors occurring in children. Evidence suggests that glioma stem cells (GSCs), maintained by the transforming growth factor-beta (TGF-ß1) pathway, and vascularization substantially contribute to tumor aggressiveness. The identification of important angiogenic factors such as vascular endothelial growth factor (VEGF) may represent a crucial step in the therapeutic approach against tumor growth and metastatic diffusion. The aim of this study was to identify the expression of TGF-ß1, VEGF and VEGF-receptors in brain gliomas. Specimens of 16 gliomas and 4 controls from children aged 0.2-14 years were used in the study. Immunohistochemical analysis and gene expression study from specimens was performed. Flow cytometry analysis on GSCs was performed to ascertain the expression of VEGF and VEGF-R2 in the tumor stem cell compartment. Newly diagnosed gliomas mainly showed moderate to strong VEGF immunostaining and increased expression of pro-inflammatory molecules in glioma cells. The proportion of TGF-ß1 positive endothelial cells was markedly lower in normal brain vessels compared to tumor vessels. These findings demonstrate that the glioma mass is constituted by a phenotypically immature anoxic central area with a proliferating hypoxic layer; the peripheral area is characterized by cell types with a higher degree of differentiation expressing pro-angiogenic factors. Our data have proven that GSCs play a central role in promoting glioma neovascularization. These findings are useful to understand glioma vascularization, have relevant implications in the therapeutic options and may favor new insights into stem cells biology and suggest therapeutic opportunities for the anti-vascular treatment strategy.

PAPILLARY THYROID CANCER IS CHARACTERIZED BY ALTERED EXPRESSION OF GENES INVOLVED IN THE SUMOYLATION PROCESS.

Small Ubiquitin–like MOdifier (SUMO) proteins are small protein modifiers capable of regulating cellular localization and function of target proteins. Over the last few years, a relevant role has been demonstrated for sumoylation in the modulation of important cellular processes, including gene transcription, DNA repair, cell-cycle regulation and apoptosis. Components of the sumoylation machinery have been found deregulated in different human cancers, and are thought to significantly affect cancer cell progression. In the present study we sought to analyze the expression of all the components of the sumoylation machinery in a case study comprising 77 papillary thyroid cancers (PTC) and normal matched tissues. In particular, we evaluated the expression of the SENP1 to SENP8 (SENtrin-specific proteases), SAE1 (SUMO1 activating enzyme subunit 1), UBA2 (UBiquitin-like modifier activating enzyme 2), UBC9 (UBiquitin conjugating enzyme 9), RanBP2 (RAN binding protein 2), MSMCE2 (Non- SMC element 2), CBX4 (ChromoBoX homolog 4), PIAS1 to PIAS4 (protein inhibitor of activated STAT), ZMIZ1 (zinc finger, MIZ-type containing 1) and ZMIZ2 (Zinc finger, MIZ-type containing 2) by means of quantitative RT-PCR. In most of the PTC examined we observed a significant alteration in the mRNAs of SENP8, ZMIZ1, SAE1, PIAS1 and PIAS2. These tended to be reduced in about 50 to 66% of cases, and unchanged or increased in the remaining ones. Univariate and Kaplan-Mayer analyses documented the lack of association between the expression of the above 5 genes and clinicopathological parameters. Only SAE1 was significantly higher in female PTC tissues, in respect to male PTC tissues (p=0.021), and SENP8 was significantly lower in TNM stages III-V, with respect to stages I-II (p=0.047). In conclusion, we demonstrated that the expression of SENP8, SAE1, PIAS1, PIAS2 and ZMIZ1 is deregulated in the majority of PTC tissues, likely contributing to the PTC phenotype. However, differently from other human cancers, their mRNA level does not represent a prognostic biomarker in PTC patients.

Reduced expression of THRß in papillary thyroid carcinomas: relationship with BRAF mutation, aggressiveness and miR expression.

PURPOSE: Down-regulation of thyroid hormone receptor beta (THRß) gene has been described in several human malignancies, including thyroid cancer. In this study, we analyzed THRß mRNA expression in surgical specimens from a series of human papillary thyroid carcinomas (PTCs), characterized by their genotypic and clinical-biological features. METHODS: Thirty-six PTCs were divided into two groups according to the 2009 American Thyroid Association risk classification (17 low, 19 intermediate), and each group was divided into subgroups based on the presence or absence of the BRAFV600E mutation (21 BRAF mutated, 15 BRAF wild type). Gene expression was analyzed using fluidic cards containing probes and primers specific for the THRß gene, as well as for genes of thyroperoxidase (TPO), sodium/iodide symporter (NIS), thyroglobulin (Tg) and thyroid stimulating hormone receptor (TSH-R) and for some miRNAs involved in thyroid neoplasia and targeting THRß. The mRNA levels of each tumor tissue were compared with their correspondent normal counterpart. RESULTS: THRß transcript was down-regulated in all PTCs examined. No significant differences were found between intermediate- vs low-risk PTCs patients, and BRAF-mutated vs BRAF wild-type groups. THRß expression was directly correlated with NIS, TPO, Tg and TSH-R, and inversely correlated to miR-21, -146a, -181a and -221 expression. CONCLUSIONS: Our results demonstrate that down-regulation of THRß is a common feature of PTCs. While it is not associated with a more aggressive phenotype of PTC, it correlates with the reduction of all the markers of differentiation and is associated with overexpression of some miRNAs supposed to play a role in thyroid tumorigenesis.

Renal antifibrotic effect of N-acetyl-seryl-aspartyl-lysyl-proline in diabetic rats.

BACKGROUND AND AIM: Diabetic nephropathy is the main cause of end-stage renal disease. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), a physiological tetrapeptide hydrolyzed by the angiotensin-converting enzyme (ACE), has antifibrotic effects in the cardiovascular system and in the kidney in experimental models of hypertension, heart failure and renal disease. The aim of the study was to evaluate the effect of Ac-SDKP in diabetic nephropathy and the potential additive effect of Ac-SDKP, when compared to ACE inhibitors alone, on the development of renal fibrosis. METHOD: Diabetes was induced in 28 Sprague-Dawley rats by a single intraperitoneal injection of streptozotocin. Control rats (n = 10) received only buffer solution. An ACE inhibitor (ramipril, 3 mg/kg/day) was administered to 11 diabetic rats. After 2 months, Ac-SDKP (1 mg/kg/day) was administered by osmotic minipumps for 8 weeks to 7 diabetic rats and to 6 diabetic rats treated with ramipril. Osmotic minipumps delivered saline solution in the corresponding sham-treated rats (diabetic rats, n = 10, and ramipril-treated diabetic rats, n = 5). RESULTS: Diabetic rats showed a significant increase in blood glucose level, urinary albumin excretion and renal fibrosis, and a reduction of glomerular nephrin expression with respect to control rats. Ac-SDKP administration significantly reduced renal fibrosis in diabetic rats, without significantly reducing urinary albumin excretion. Ramipril treatment caused a significant decrease in albuminuria and renal fibrosis and restored glomerular nephrin expression. Administration of Ac-SDKP, in addition to ramipril, further reduced renal fibrosis with respect to ramipril alone, while it did not improve the antiproteinuric effect of ramipril. CONCLUSION: Ac-SDKP administration reduces renal fibrosis in diabetic nephropathy. Addition of Ac-SDKP to ACE inhibition therapy improves the reduction of renal fibrosis with respect to ACE inhibition alone, suggesting a beneficial effect of this pharmacological association in diabetic nephropathy.

Porcine coronary arteries: immunohistochemical profile of TNF-alpha, IL-1beta, TGF-beta1 and ICAM-1.

BACKGROUND: In our study we used immunohistochemical technique to demonstrate the presence of the cytokines tumour necrosis factor alpha (TNF-α), interleukin 1beta (IL-1ß), transforming growth factor beta1 (TGF-ß1) and intercellular adhesion molecule-1 (ICAM-1) in porcine coronaries even in physiological conditions. MATERIALS AND METHODS: Inflammatory cytokines are polypeptide mediators which act as a communication signal between immune system cells and other types of cellsin different organs and tissues, both in human and pig coronary circulation. RESULTS: Our results show that pro-inflammatory cytokines TNF-α, IL-1ß, TGF-ß1 and ICAM-1 are also present in the medium tunica of the coronary arteries under physiological conditions. These results may be compared with those found in coronary atherosclerosis, where the increase in TNF-α has a dramatic effect on the function of the left ventricle, and the high value of IL-1 correlates directly with the extent of myocardial necrosis. In our study we observe the damage and activation of endothelial cells; this induces endothelial dysfunction by accumulation and oxidation of low density lipoproteins (LDL). The formation of oxidized LDL could play a central role in the amplification of the inflammatory response causing an increased expression of pro-inflammatory cytokines which promotes leukocyte recruitment in the intimal layer. These leukocytes, after the adhesion to the endothelium, penetrate the intimate tunic. CONCLUSIONS: Therefore inflammatory processes promote the onset and evolution of atheroma and the development of thrombotic complications.

Epicardial adipose tissue adiponectin expression is related to intracoronary adiponectin levels.

The role of adiponectin and epicardial adipose tissue in coronary artery disease (CAD) is a subject of debate. Whether plasma adiponectin concentration in the coronary circulation is locally modulated by the epicardial fat is still unexplored. We evaluated the hypothesis whether intracoronary plasma adiponectin levels are related to adiponectin expression in epicardial adipose tissue in vivo in patients with CAD and without CAD (non-CAD). We examined 12 patients with CAD who required CABG and 10 patients with non-CAD who underwent cardiac surgery for valve replacement. Plasma levels of adiponectin were measured in peripheral vein circulation and in left coronary artery (LCA) during coronary angiography. Epicardial adipose tissue biopsy for adiponectin protein extraction was performed during cardiac surgery in both CAD and non-CAD subjects. Adiponectin protein expression in epicardial adipose tissue was lower in patients with CAD than in those with non-CAD (0.45+/-0.4 vs. 1.1+/-1.0, p<0.05). LCA plasma adiponectin levels significantly correlated with epicardial adipose tissue adiponectin protein expression (r=0.68, p=0.02) in all subjects. Peripheral adiponectin levels and epicardial fat adiponectin protein expression were the best correlates of LCA adiponectin, r (2)=0.49, p<0.01, p<0.05, respectively). Our study showed that intracoronary adiponectin levels reflect systemic adiponectin levels. Epicardial adipose tissue could partially contribute to adiponectin levels in the coronary circulation.

Epicardial adipose tissue and intracoronary adrenomedullin levels in coronary artery disease.

The aim of the study was to test 1) whether chronic and stable coronary artery disease (CAD) could downregulate epicardial fat adrenomedullin synthesis and secretion, and decrease intracoronary plasma adrenomedullin levels, and 2) whether intracoronary plasma adrenomedullin levels could be related to epicardial adipose tissue adrenomedullin gene and protein expression in subjects with CAD. We examined 12 patients with CAD who required coronary artery bypass graft (CABG) and 10 patients with non-CAD who underwent cardiac surgery for valve replacement. Plasma levels of adrenomedullin were measured in peripheral vein circulation, in left coronary artery (LCA) and coronary sinus (CS) during coronary angiography. Epicardial adipose tissue biopsy for Reverse Transcription and Real-Time PCR (RT-PCR) adrenomedullin mRNA analysis and Western Blotting (WB) protein expression was performed during cardiac surgery in all subjects. Peripheral, LCA, and CS plasma adrenomedullin levels were significantly lower in CAD patients than in those with non-CAD (3.0+/-0.9 vs. 4.4+/-0.9 pg/ml p<0.01; 2.9+/-1 vs. 4.05+/-0.8 pg/ml, p<0.01, 3.1+/-0.9 vs. 3.98+/-0.9 pg/ml p=0.04, respectively). However, CS adrenomedullin levels were not statistically different than those in LCA suggesting that adrenomedullin was not secreted from epicardial fat into the coronary artery lumen. Epicardial fat adrenomedullin mRNA levels and protein expression were lower in patients with CAD than in those with non-CAD (p<0.01 for both). We conclude that 1) epicardial fat adrenomedullin gene and protein expression can be downregulated in CAD subjects, and 2) intracoronary adrenomedullin levels are lower in CAD. No evidence that epicardial adipose tissue really contributes intracoronary adrenomedullin can be provided at this time.

Dilated cardiomyopathy due to thrombotic microangiopathy as the only manifestation of antiphospholipid syndrome: a case report.

Dilated cardiomyopathy due to thrombotic microangiopathy has been rarely reported as a clinical manifestation of antiphospholipid syndrome (APS). We describe the case of a 39-year-old woman affected by systemic lupus erythematosus (SLE) and positive antiphospholipid antibodies (aPL) who presented with orthopnea and peripheral oedema. Diagnosis of dilated cardiomyopathy due to myocardial thrombotic microangiopathy was made and treatment with anticoagulants prevented the worsening of the clinical condition. Interestingly, at variance with other cases, our patient showed no extracardiac signs of APS. The review of the current literature has confirmed that dilated cardiomyopathy due to thrombotic microangiopathy is a rare manifestation of APS.

Multiparametric ultrasound evaluation with CEUS and shear wave elastography for carotid plaque risk stratification.

PURPOSE: To assess the diagnostic effectiveness of Multiparametric ultrasound (MPUS), which includes color Doppler ultrasound (CDUS), CEUS and Shear wave elastography (SWE), for evaluating carotid plaque as compared with CT-angiography (CTA) and histology. MATERIALS AND METHODS: Forty-three consecutive patients scheduled to undergo carotid endarterectomy underwent MPUS. Then, after periods ranging from 2 days to 2 weeks, all underwent CTA. Each plaque was classified by means of dedicated scores for CEUS and SWE as compared with CTA features. At surgery, each plaque was removed in a single fragment to facilitate histological analysis, which evaluated 4 features: extension of the lipid core, thickness of the fibrous cap, inflammatory infiltrate (CD68 + and CD3 + markers) and the presence of intraplaque microvessels. For the CEUS, SWE and CTA, the following values for identifying plaque vulnerability were evaluated: sensitivity, specificity, accuracy, negative predictive value (NPV), positive predictive value (PPV) and Area under the curve (AUC). Cohen's kappa was used to evaluate the concordance between measurements in the different imaging methods. A p < 0.05 was considered statistically significant. RESULTS: At histology, 31 out of 43 plaques were identified as vulnerable because of the presence of at least one of the following criteria: fibrous cap < 200 µm, lipid core, intraplaque hemorrhage, inflammatory infiltrate or intraplaque neovascularization. CTA showed a sensitivity of 87.1%, a specificity of 100%, a PPV of 100%, an NPV of 75% and an AUC of 93.5%. SWE showed a sensitivity of 87.1%, a specificity of 66.7%, a PPV of 87.1%, an NPV of 66.7% and an AUC of 76.9%. CEUS showed a sensitivity of 87.1%, a specificity of 58.3%, a PPV of 84.4%, an NPV of 63.6% and an AUC of 72.7%. CONCLUSIONS: Multiparametric ultrasound is an effective modality to obtain comprehensive information on carotid plaques. Further studies are needed to determine whether it can be considered a diagnostic standard.

Atrial electroanatomic remodeling after circumferential radiofrequency pulmonary vein ablation: efficacy of an anatomic approach in a large cohort of patients with atrial fibrillation.

BACKGROUND: Circumferential radiofrequency ablation around pulmonary vein (PV) ostia has recently been described as a new anatomic approach for atrial fibrillation (AF). METHODS AND RESULTS: We treated 251 consecutive patients with paroxysmal (n=179) or permanent (n=72) AF. Circular PV lesions were deployed transseptally during sinus rhythm (n=124) or AF (n=127) using 3D electroanatomic guidance. Procedures lasted 148+/-26 minutes. Among 980 lesions surrounding individual PVs (n=956) or 2 ipsilateral veins with close openings or common ostium (n=24), 75% were defined as complete by a bipolar electrogram amplitude <0.1 mV inside the lesion and a delay >30 ms across the line. The amount of low-voltage encircled area was 3594+/-449 mm(2), which accounted for 23+/-9% of the total left atrial (LA) map surface. Major complications (cardiac tamponade) occurred in 2 patients (0.8%). No PV stenoses were detected by transesophageal echocardiography. After 10.4+/-4.5 months, 152 patients with paroxysmal AF (85%) and 49 with permanent AF (68%) were AF-free. Patients with and without AF recurrence did not differ in age, AF duration, prevalence of heart disease, or ejection fraction, but the LA diameter was significantly higher (P<0.001) in permanent AF patients with recurrence. The proportion of PVs with complete lesions was similar between patients with and without recurrence, but the latter had larger low-voltage encircled areas after radiofrequency (expressed as percent of LA surface area; P<0.001). CONCLUSIONS: Circumferential PV ablation is a safe and effective treatment for AF. Its success is likely due to both PV trigger isolation and electroanatomic remodeling of the area encompassing the PV ostia.

Increased expression of thyroid hormone receptor isoforms in end-stage human congestive heart failure.

Thyroid hormone plays an important role on myocardial development and function. The local effects of thyroid hormone are mediated by the receptor isoforms ultimately driving the expression of cardiac-specific genes. Although overt and subclinical thyroid dysfunction causes well-known changes in the cardiovascular system, little is known about local thyroid hormone action in normal and failing human myocardium. With a newly developed multiplex competitive RT-PCR method, we evaluated the expression of thyroid hormone receptor (TR) isoforms alpha-1, alpha-2, and beta-1 in normal human hearts and in end-stage congestive heart failure. A statistically significant difference in the expression of all three TR isoforms was observed among samples from normal subjects, ischemic heart disease (IHD), and dilated cardiomyopathy (DCM). In DCM, compared with normal, the studied TR isoforms were significantly increased. In IHD, the increased expression was found significant only for alpha-1 and alpha-2 isoforms. No differences were observed between the pathologic groups. In conclusion, a coordinated increment in the expression of the TR isoforms was observed in both DCM and IHD by multiplex competitive RT-PCR. The observed changes could represent a compensatory mechanism to myocardial failure or to locally altered thyroid hormone action.

Angiotensin II modulates calponin gene expression in rat vascular smooth muscle cells in vivo.

OBJECTIVES: It has been shown that angiotensin II (Ang II) induces the expression of calponin, a 34 kD actin-binding protein, in vascular smooth muscle cells in vitro. The aim of this study was to investigate whether Ang II can modulate calponin gene expression in rat aorta in vivo. DESIGN: Aortic calponin gene expression was studied after chronic exogenous Ang II administration and in Goldblatt hypertension. METHODS: To investigate the effect of Ang II administration, Sprague Dawley rats were treated for 6 days with a continuous infusion of Ang II (200 ng/kg per min) or saline by osmotic minipumps. The effect of endogenous Ang II on aortic calponin mRNA expression was studied in Goldblatt hypertensive rats with (2K1C model), or without (1K1C model) activation of the renin-angiotensin system. In particular, calponin gene expression in 2K1C rats was studied both at 1 week (2K1C-HR, high renin) and 4 weeks after the onset of hypertension, when plasma renin activity (PRA) was returned to normal values (2K1C-NR, normal renin). Systolic blood pressure (SBP) was measured twice a week. At the end of the experimental period, PRA was measured by radioimmunoassay, and aortic calponin gene expression was measured by Northern hybridization. RESULTS: SBP was significantly higher (P < 0.01), whereas PRA was suppressed (P < 0.01), in Ang II versus saline-treated rats. Northern hybridization showed that the aortic calponin gene expression significantly increased (2.5-fold) in Ang II-treated rats (P = 0.01). In Goldblatt hypertensive rats, SBP was significantly higher in 2K1C-HR (P < 0.01), 2K1C-NR (P < 0.01) and 1K1C (P < 0.01) rats compared with the corresponding sham-treated rats. Activation of the renin-angiotensin system was present only in 2K1C-HR rats (P < 0.01), and Northern analysis showed that aortic calponin mRNA expression was significantly increased (2.2-fold) in this group of rats only (P < 0.01). CONCLUSIONS: Our data demonstrate that both exogenous and endogenous Ang II increase calponin gene expression in aortic smooth muscle cells, independently of the hemodynamic effect of Ang II.

Arrhythmogenic right ventricular cardiomyopathy: clinicopathologic correlation based on a revised definition of pathologic patterns.

Different morphologic features of arrhythmogenic right ventricular cardiomyopathy (ARVC) have been described. However, it is still unclear whether they correspond to distinct forms of the same disease. A pathologic study was performed on a series of ARVC (15 from heart transplant and 12 from autopsy) from 2 Italian referral university hospitals. Based on both myocellular features and the nature of myocardial replacement, hearts were divided into 2 groups: infiltrative, with a lacelike pattern of transmural fatty infiltration and strands of normal residual cardiomyocytes (n = 11); and cardiomyopathic, with massive myocardial replacement by fibro fatty tissue and cardiomyopathic changes (such as hypertrophy and myofibril loss) of residual cardiomyocytes (n = 16). Hearts from the infiltrative group were mostly obtained at autopsy of patients who died suddenly. Fatty substitution was limited almost exclusively to the right ventricle. Mitral valve dysplasia (prolapse or cleft) was frequently present. Hearts from the cardiomyopathic group came mainly from heart transplants for congestive heart failure. Fibro fatty replacement was more extensive, usually biventricular. Active myocarditis and features suggestive of myocardial transdifferentiation were also observed. Despite these differences in clinical outcome and morphologic features, patients from the 2 groups showed similar mean age, sex distribution, occurrence of threatening ventricular arrhythmias, and prevalence of family history of sudden death, arrhythmias, or cardiomyopathy. Infiltrative and cardiomyopathic patterns represent different clinical and pathologic subsets of ARVC. Myocellular features are an important clue in the distinction between the two entities. The differentiation between the 2 patterns is feasible on endomyocardial biopsy and could give important prognostic information.

Does cyclosporin A have any effect on accelerated atherosclerosis in absence of graft rejection? Pathologic and morphometric evaluation in an experimental model.

BACKGROUND: The effects of cyclosporin A on accelerated atherosclerosis were studied in an experimental model of aortic isotransplantation. METHODS: Seventy-six Lewis rats were studied. Forty-one abdominal aortic isografts were performed and divided into five groups: 2-day isografts and 15- and 100-day isografts with and without cyclosporin treatment. The remaining rats were divided into seven groups: 15- and 100-day sham-operated, with and without cyclosporin administration; 15- and 100-day animals with cyclosporin treatment only; and normal controls. Cyclosporin was injected subcutaneously in doses of 10 mg/kg daily for the first 15 days and afterward every other day. Longitudinal sections of the proximal anastomosis and cross sections of the midgraft region were measured with a semiautomatic image-analyzer. RESULTS: Histologic analysis showed that accelerated atherosclerosis was not observed either in NT2 rats or in nontransplanted animals. In the 15-day isografts, accelerated atherosclerosis was present in the perianastomotic tract of the recipient aorta in nine of nine NT15 rats, whereas it was found only in three of nine T15 animals (p < 0.02). Histomorphometric analysis showed that accelerated atherosclerosis was less pronounced in the T100 isografts than in the NT100 ones, this difference being significant at the recipient anastomotic side only (p < 0.0005). CONCLUSIONS: The present results support the hypothesis that cyclosporin, at immunosuppressant and nontoxic doses, can delay the onset and progression of accelerated atherosclerosis and that its effects are more significant at the recipient side of the anastomosis where accelerated atherosclerosis begins to develop.

Causes of late failure after heart transplantation: a ten-year survey.

BACKGROUND: Little is known about the causes of death of heart transplant recipients who survive long-term. METHODS: The pathologic and clinical records of 97 patients who underwent heart transplantation in Italy from 1985 to 1995 and died (85 of 97) or underwent retransplantation (12 of 97) at least 2 years after transplantation were surveyed. Graft failures were classified as late (occurring between 2 and 5 years after transplantation) and belated (more than 5 years). RESULTS: Graft vasculopathy was the single most common cause of death (40.0%) and the only cause of late retransplantation. Tumors ranked second (23.5% of deaths), but the expected non-Hodgkin's lymphomas and Kaposi's sarcoma were accompanied by a high number of lung cancers (especially metastasizing adenocarcinomas). They were followed by the emergence or recurrence of pretransplantation diseases (9.4%), fatal infections (exclusively bacterial) (4.7%), the development of transmissible diseases (viral hepatitis and acquired immunodeficiency syndrome, 4.7%), and late acute rejection (2.3%). The distribution of failures differed in the late and belated periods: death and organ loss proportions for graft vasculopathy, respectively, fell and rose from the late to the belated period; some types of malignancy and fatal acute rejection were never observed in the belated period, whereas the emergence of pretransplantation diseases prevailed in the belated period. Graft vasculopathy was more frequent and tumors were less frequent among patients undergoing transplantation for ischemic heart disease. CONCLUSIONS: The reasons why heart transplant recipients die or undergo retransplantation, respectively, in the late and belated periods slightly differ from one another and are widely different than in short-term survivors.

Long-term histologic features of synthetic chordal replacement for mitral valve repair: a case report.

Expanded polytetrafluoroethylene (e-PTFE) sutures have been used with increasing frequency to replace chordae tendineae in mitral valves prolapsing because of myxoid change. A case is reported where fibrosis and calcification of the endocardial overgrowth covering the synthetic chordae led to severe mitral regurgitation 7 years after plastic repair and required mechanical prosthetic valve implantation.

Eosinophilic infiltration immediately following transplantation: recurrent hypersensitivity reaction?

Hypersensitivity myocarditis is a well-known complication of pharmaceutical therapy, often requiring heart transplantation. We report the unusual case of pre-transplant hypersensitivity myocarditis with eosinophilic myocardial infiltration in the donor heart, demonstrated by needle biopsy at the time of transplant ('time-zero' biopsy). At first the myocarditic process was temptatively attributed to a pre-transplant pathology in the donor heart, but the close similarity between the pre-transplant and the post-transplant infiltrate and the clinical data of an eosinophilic peak of the recipient during the transplant procedure brought to the diagnosis of early recurrent hypersensitivity myocarditis.

Pathology of atrioventricular valve dysplasia.

The congenital heart disease series of the Pathological Museum at La Sapienza University of Rome was revised in order to detect specimens featuring atrioventricular valve dysplasia (AVVD) in fetuses and infants. Selected for study were 67 specimens from a collection of 667 hearts: there were 36 cases of isolated tricuspid valve dysplasia (TVD), 11 cases of isolated mitral valve dysplasia (MVD), and 20 cases of combined atrioventricular valve dysplasia. All the valves were graded according to Becker's criteria, which were morphometrically validated. There is an increasing degree of dysplasia in terms of differentiation and detachment of the valve from the ventricular wall. The concept of AVVD is supported by a substantial morphologic and morphometric analogy between TVD and MVD, in spite of some peculiarities of each grade and of side-specific anomalies ("mitral arcade" on the left side and grade III dysplasia on the right one), probably attributable to differences in the embryonic development of the two valves. AVVD is sometimes associated with dysplasia of the semilunar valves, in the setting of a polyvalvular disease of possible genetic origin. More often it is combined with other defects that cause ventricular overload. In such cases, AVVD usually occurs within the overloaded cardiac section, as if it were a result of mechanical stress.

Peculiarities of prevalence and morphology of congenital heart disease detected in utero.

Intrauterine echocardiography is changing our knowledge of congenital heart disease; cardiac defects diagnosed in utero have distinctive features of both prevalence and morphology when compared with those observed just after birth. We reviewed a series of 171 fetal heart conditions: 148 were diagnosed at intrauterine echocardiography, the diagnosis being verified at autopsy in 41, and 23 were observed at the postmortem only. Peculiarities of prevalence consisted in an excess of various defects, such as hypoplastic left heart syndrome, atrial isomerism, pulmonary atresia, and atrioventricular and atrial septal defects, and in a reduced number of completely different conditions, such as transposition of great arteries and aortic coarctation. Differences in prevalence have been attributed to difficulties in diagnosing some particular anomalies in utero, to the selection of pregnancies undergoing screening, and to the special intrauterine evidence of some heart defects. Peculiarities in morphology result from the coexistence with extracardiac malformations, from the changes in shape conditioned by fetal hemodynamics, and from the intrauterine evolution of the morphology of some malformations. We concluded that the knowledge of these characteristic traits was helpful to cardiac pathologists, pediatric cardiologists, and obstetricians, and allowed the re-evaluation of the role of hemodynamic factors in remodeling the malformed cardiovascular appara-tus.

Immediate causes of death in short-term surviving heart transplant recipients.

From 1985 to 1992, 1068 cardiac transplants have been performed in the Italian units. The immediate causes of death of 142 of the 148 orthotopic cardiac transplantation recipients who died within the first 6 postoperative months were surveyed. Deaths were grouped into three periods: perioperative (⩽1 month, 68.3%), early (>1 ⩽3 months, 23.2%), and advanced (>3 ⩽6 months, 8.5%). Acute graft failure (arising from the ischemic damage to the donor heart, from surgical problems, from severe pulmonary hypertension, or from multiorgan failure) accounted for 49% of perioperative deaths and, along with noncardiac emergencies (23% of perioperative deaths), was significantly more frequent in this period than in the subsequent ones. The dissection of thoracic arteries was responsible for 4% of postoperative deaths, occurring exclusively among patients transplanted for ischemic or valvular heart disease. In the early and advanced periods, untreatable acute rejection (13%) and fatal infections (38%), mostly saprophytic, were significantly more frequent. Ischemic heart damage secondary to graft vasculopathy already caused 26% of deaths between the fourth and sixth months after transplantation. Some diseases, such as acute rejection, had the same frequency as both underlying disease and immediate cause of death. On the contrary, graft failure is more common as primary disease, leading to death also through noncardiac complications and saprophytic infections. Bacterial infections have the same frequency as both prime and immediate cause of death, viral infections are more common as primary disease, and the opposite is true for saprophytic infections.