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American Journal of Transplantation 02/2013; · 6.39 Impact Factor
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M Fedrigo,
F Poli,
G Esposito,
G Feltrin,
G Toscano,
C d'Agostino,
B Schiavon,
G Gerosa,
A Amadori,
M Valente,
G Thiene, A Angelini
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ABSTRACT: We report the case of a 68-year-old woman who underwent heart transplantation for hypertrophic cardiomyopathy. Two months after the transplant she developed mild fever and dyspnea with a marked drop in left ventricle ejection fraction of 31%. Coronary angiography was negative for cardiac allograft vasculopathy. Endomyocardial biopsy revealed ischemic damage with no evidence of acute cellular rejection, antibody-mediated rejection or viral myocarditis. A neoplastic process was suspected even though full-body computerized tomography was negative for malignancy. The patient died 4 months after transplantation. The autopsy showed acute antero-septal myocardial infarction due to a nodular epicardial EBV-related posttransplant lymphoproliferative disorder (PTLD) infiltrating the left anterior descending coronary artery with occlusive neoplastic thrombosis. We highlight two major aspects of this case: (1) the unusual occurrence of early PTLD involving the cardiac allograft and causing a fatal outcome, (2) the application of an immunological technique for HLA-DRB1 typing to posttransplant paraffin-embedded autopsy material to identify the recipient origin of this early malignancy, thus excluding a possible donor-transmitted neoplasm.
American Journal of Transplantation 01/2013; · 6.39 Impact Factor
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American Journal of Transplantation 11/2011; 12(1):262; author reply 263-4. · 6.39 Impact Factor
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A L P Caforio,
A Brucato,
A Doria,
G Brambilla, A Angelini,
A Ghirardello,
S Bottaro,
F Tona,
C Betterle,
L Daliento,
G Thiene,
S Iliceto
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ABSTRACT: Idiopathic recurrent acute pericarditis (IRAP) is a rare disease of suspected, yet unproved, immune-mediated origin. The finding of serum heart-specific autoantibodies in IRAP would strengthen the autoimmune hypothesis and provide aetiology-specific non-invasive biomarkers. Objective To assess frequency of serum anti-heart (AHA), anti-intercalated-disk (AIDA) and non-cardiac-specific autoantibodies and their clinical and instrumental correlates in patients with IRAP. Patients 40 consecutive patients with IRAP, 25 male, aged 37+/-16 years, representing a large single-centre cohort collected at a referral centre over a long time period (median 5 years, range 1-22 years). Control groups included patients with non-inflammatory cardiac disease (NICD) (n=160), ischaemic heart failure (n=141) and normal subjects (n=270).
AHA (organ-specific, cross-reactive 1 and 2 types) and AIDA were detected in serum samples from patients, at last follow-up, and control subjects by indirect immunofluorescence (IIF) on human myocardium and skeletal muscle. Non-cardiac-specific autoantibodies were detected by IIF, and anti-Ro/SSA, anti-La/SSB by ELISA.
The frequencies of cross-reactive 1 AHA and of AIDA were higher (50%; 25%) in IRAP than in NICD (4%; 4%), ischaemic (1%; 2%) or normal subjects (3%; 0%) (p=0.0001). AHA and/or AIDA were found in 67.5% patients with IRAP. Of the non-cardiac-specific antibodies, only antinuclear autoantibodies at titre > or =1/160 were more common in IRAP (5%) versus normal (0.5%, p<0.04). AIDA in IRAP were associated with a higher number of recurrences (p=0.01) and hospitalisations (p=0.0001), high titre (1/80 or higher) AHA with a higher number of recurrences (p=0.02).
The detection of AHA and of AIDA supports the involvement of autoimmunity in the majority of patients with IRAP.
Heart (British Cardiac Society) 05/2010; 96(10):779-84. · 4.22 Impact Factor
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Circulation 01/2008; 116(25):e569-72. · 14.74 Impact Factor
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ABSTRACT: Background: Anderson–Fabry disease (AFD) is an X-linked inborn error of glycosphingolipid metabolism due to a deficiency of the lysosomal hydrolase α-galactosidase A associated with multisystemic involvement subsequent to deposition of neutral glycosphingolipid in many organs. Over time, microvascular disease of the kidneys, heart and brain progresses leading to premature death.Aim: To evaluate cardiac involvement in patients with AFD using gadolinium-enhanced cardiovascular magnetic resonance imaging (MRI).Methods: We studied five patients (age range, 23–53 years two males and three females belonging to two different families) with a diagnosis of AFD made by low plasma α-galactosidase activity and molecular analysis of mutations. Four of them had been treated with recombinant human α-galactosidase A replacement therapy for at least 14 months. Clinical manifestations were assessed and an electrocardiogram and echocardiography (ECG) were performed in all patients for a preliminary evaluation of the cardiac involvement before initiating therapy. Coronary angiography and endomyocardial biopsy were performed in one patient. All patients finally underwent cine and late-phase gadolinium-enhanced cardiovascular MRI.Results: ECG and echocardiogram showed left ventricular hypertrophy in two patients and mitral insufficiency in three. Cine-MRI confirmed these findings. Angiography showed the coronary artery to be free from lesions and histology revealed hypertrophic myocytes and the presence of fibrosis. Gadolinium-enhanced MRI revealed hyperenhancement, mainly in the basal inferolateral wall, both in the subendocardial and mid-wall layer, in the three older patients.Conclusion: These observations suggest that myocardial fibrosis occurs in Anderson–Fabry disease and may contribute to the hypertrophy and the natural history of the disease. The characteristic patterns of hyperenhancement differ from those seen in other myocardial pathologies (myocardial infarction, hypertrophic cardiomyopathy) and this may help in the differential diagnosis of the late-onset forms (cardiac variant). Mitral valve insufficiency was also present in three patients, and this could be due to dysfunction of the inferolateral wall.
Acta Paediatrica 01/2007; 95(S451):129 - 132. · 2.07 Impact Factor
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ABSTRACT: The North Italy Transplant program (NITp) is one of the three organ exchange organizations in Italy together with AIRT and OCST, supervised by the Centro Nazionale Trapianti. It started its activity on June 18, 1972 and serves an area of about 18 million inhabitants in northern Italy. From June 18, 1972 to December 31, 2004, 5761 cadaveric donors have been used and 18,390 transplants performed in the NITp. At December 31, 2004, the NITp waiting list included 3407 patients (2261 kidney, 425 heart, 387 liver, 153 pancreas, 181 lung). From January 1 to August 31, 2005, 13 donors with cancer were used, namely, 4.2% of the overall number of procured donors. The yearly projection of this figure is more than twofold above that in the previous year. Pathologists play a crucial role in NITp activity, by assessing donor suitability and organ quality, by performing the autopsy control of donors, and by participating in transplant follow-up. In addition the pathologist responsible for the Veneto-centralized pathology unit plays the role of expert for second opinion for the NITp area. Pathologists are involved in expanding the pool of donors by analyzing organ biopsies in specific programs. Eight HBV(+) and/or HCV(+) liver biopsies have been evaluated during 2003 and 18 during 2004 and 12 livers, according to the protocol, were suitable for transplantation, and 14 double kidney transplantations were performed in 2003 and 35 in 2004.
Transplantation Proceedings 06/2006; 38(4):983-5. · 1.00 Impact Factor
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ABSTRACT: Physicians caring for heart and lung transplantation patients utilize routine follow-up biopsies on a prearranged schedule unrelated to the suspicion of a clinical diagnosis of rejection. Of course biopsies are also performed outside the prearranged scheme at any time the clinician is puzzled by clinical suspicion of rejection or infections. Technical considerations are important in handling the biopsies; pathologists who are aware of bias produced by tissue processing are forced to serially section the samples to increase the sensitivity for detection of the pathological processes. During the 20 years since the first Italian cardiac transplantation was performed in our center, 600 patients have been transplanted and monitored with 12,386 endomyocardial biopsies. The overall 5-year mortality was 24.5% and 18.4% in pediatric populations; at 10 years, 34%, and at 19 years, 55%. There was a progressive decrease in mortality from 36.8% in 1985 to 1990 to 12% in the 1996 to 2000. During a decade of experience in lung transplantation from May 1995 to May 2005 (n = 129), all patients underwent surveillance bronchoscopy including transbronchial biopsy (n = 722) and bronchoalveolar lavage (n = 629). The ancillary techniques of immunohistochemistry and molecular analysis have allowed the pathologists to play a pivotal role in the pre- and posttransplant management of patients requiring thoracic organ transplantation.
Transplantation Proceedings 06/2006; 38(4):1163-6. · 1.00 Impact Factor
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The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 05/2006; 25(4):492-4. · 3.54 Impact Factor
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ABSTRACT: Noninvasive tests have proven unsatisfactory in cardiac allograft vasculopathy (CAV) diagnosis. We assessed coronary flow reserve (CFR) by contrast-enhanced transthoracic echocardiography (CE-TTE) in heart transplantation (HT). CFR was assessed in the left anterior descending coronary artery in 73 HT recipients (59 male, aged 50+/-12 years at HT), at 8+/-4.5 years post-HT. CFR measurements were taken blindly from coronary angiographies. CFR cut points were the standard value of <or=2 and those defined by receiver operating characteristics (ROC) curve analysis. CFR was lower in patients with CAV (2.3+/-0.7 vs. 3.2+/-0.5, p<0.0001). The <or=2 cut point was 100% specific and 38% sensitive. The <or=2.7 cut point, optimal by ROC analysis, was 87% specific and 82% sensitive. Accuracy rose from 71% with the standard<or=2 cut point to 85% with the optimal cut point of <or=2.7. CFR by CE-TTE may offer promise as a novel, easily repeatable and accurate noninvasive tool in CAV detection. However, further longitudinal studies in larger patient cohorts are warranted before widespread adoption can be advocated.
American Journal of Transplantation 05/2006; 6(5 Pt 1):998-1003. · 6.39 Impact Factor
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ABSTRACT: Myocarditis is a non-ischemic inflammatory disease of the myocardium associated with cardiac dysfunction. It most often results from infectious agents, hypersensitivity responses, or immune-related injury. In spite of the development of various diagnostic modalities, early and definite diagnosis of myocarditis still depends on the detection of inflammatory infiltrates in endomyocardial biopsy specimens according to Dallas criteria. Routine application of immunohistochemistry (for characterization of inflammatory cell infiltration) and Polymerase Chain Reaction PCR analysis (for identification of infective agents) has become an essential part of the diagnostic armamentarium for a more precise biopsy report. A new morphological classification is advanced to overcome the limits of Dallas criteria. A semiquantitative assessment of myocyte damage/inflammation (grading) as well as of fibrosis (staging) is indicated, thus providing histopathological diagnosis useful to the clinician for more appropriate patient risk stratification and for the application of new therapies. Consequently, the final diagnosis of myocarditis should be mainly based on three features: etiology, grade, and stage of the disease.
Ernst Schering Research Foundation workshop 02/2006;
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Pathologica 09/2005; 97(4):195-6.
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ABSTRACT: We report a female patient suffering from Takayasu arteritis (TA) who underwent surgical revascularization.
By studying specimens obtained at surgery, we evaluated the cell composition of the arterial wall, along with the maturation pattern of vascular smooth muscle cells (VSMC) during the active phase of TA. Using TUNEL, we detected apoptotic cells within the tunica media.
The highest percentage of apoptotic cells was found in areas where inflammatory infiltrate was present and the medial structure was more or less damaged. Apoptotic cells were also found in structurally preserved areas, where VSMC but not inflammatory cells were present.
Apoptosis involved not only inflammatory cells but also VSMC, particularly those of the immature type. We hypothesize a role for VSMC apoptosis in the development of TA.
Rheumatology 05/2005; 44(4):484-7. · 4.06 Impact Factor
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ABSTRACT: Criteria of organ-specific autoimmunity are fulfilled in a subset of patients with myocarditis/dilated cardiomyopathy (DCM). In particular, circulating heart-reactive autoantibodies are found in patients and symptom-free relatives. These autoantibodies are directed against multiple antigens, some of which are expressed in the heart (organ-specific), others in heart and some skeletal muscle fibres (partially-heart specific) or in heart and skeletal muscle (muscle-specific). Distinct autoantibodies have different frequency in disease and normal controls. Different techniques detect one or more antibodies, thus they cannot be used interchangeably for screening. It is unknown whether the same patients produce more antibodies or different patient groups develop autoimmunity to distinct antigens. IgG antibodies, shown to be cardiac and disease-specific for myocarditis/DCM, can be used as autoimmune markers for identifying patients in whom immunosuppression may be beneficial and relatives at risk. Some autoantibodies may also have a functional role, but further work is needed.
Lupus 02/2005; 14(9):652-5. · 2.34 Impact Factor
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ABSTRACT: This report details a recent experience with a 56-year-old man affected by an incompetent mitral valve due to Barlow's disease. The patient underwent a mitral valve repair and extracorporeal membrane oxygenator (ECMO) assistance due to postcardiotomy cardiogenic shock. During the ECMO assistance he experienced a left atrial thrombosis. A few days later, being unaware of the pulmonary vein thrombosis, we transplanted the patient, who ultimately died due to multiorgan failure and coagulopathy. This article highlights both the vain experience with ECMO and the uselessness of heart transplant, to avoid in the future an irresponsible waste of donor organs, as occurred in the current case.
Transplantation Proceedings 07/2004; 36(5):1551-3. · 1.00 Impact Factor
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ABSTRACT: To compare active (AM) with borderline (BM) myocarditis to verify whether the pathological distinction between the two forms may help to identify patients with different clinical and haemodynamic characteristics and to aid prognosis.
Myocarditis was diagnosed in 56 patients on endomyocardial biopsy (EMB) within one year from clinical onset of the disease between 1991 and 1998. Fourteen patients were excluded because of a lack of adequate and complete information. EMBs and clinical records of the 42 remaining patients were reviewed. Immunohistochemistry on bioptic samples was regularly performed. Polymerase chain reaction (PCR) for a panel of viruses was performed in 23 patients (55%). Clinicopathological correlations were calculated.
The histological diagnosis was AM in 26 patients (62%) and BM in 16 (38%). Significant differences were found in the following parameters: presence of left bundle branch block on ECG (AM 2 (8%) v BM 5 (31%), p = 0.05); left ventricular volume on echocardiogram (mean (SD) AM 90 (42) ml/m(2) v BM 128 (50) ml/m(2), p = 0.002); mass to volume ratio (AM 1.0 (0) v BM 0.8 (0.1), p = 0.03); time interval between clinical onset of the disease and EMB (AM 40 (55) v BM 90 (93) days, p = 0.04); and degree of inflammatory infiltrates, scored on a scale of 0 to 3 (AM 1.65 (0.8) v BM 0.85 (0.3), p = 0.004). In 6 of 15 patients (40%) with AM and in 2 of 8 (25%) with BM, a viral genome was detected by PCR (NS). At follow up, no differences in death or heart transplantation were detected between the two forms (AM 4 patients (15%) v BM 2 patients (12.5%)). Three of eight PCR positive patients (37.5%) and 1 of 15 virus negative patients (7%) died or underwent heart transplantation.
BM seems to encompass inflammatory forms with a less aggressive inflammatory infiltrate evolving towards left ventricular dilatation. The term "chronic myocarditis" seems to be more appropriate. The absence of myocyte necrosis does not predict a more favourable prognosis, whereas the absence of a viral genome seems to predict it.
Heart (British Cardiac Society) 04/2002; 87(3):210-5. · 4.22 Impact Factor
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ABSTRACT: Skeletal muscle in congestive heart failure (CHF) is responsible for increased fatigability, decreased endurance and exercise capacity. A specific myopathy with increased expression of fast myosin heavy chains (MHCs), myocyte atrophy, secondary to myocyte apoptosis, that is triggered by high levels of circulating tumor necrosis factor (TNF-alpha) has been described. However, a direct effect of TNF-alpha on skeletal muscle has not been described yet. In this paper we put forward the hypothesis that TNF-alpha plays an indirect effect on skeletal myocytes. In an animal model of CHF, the monocrotaline-treated rat, we have observed a significant (P<0.001) increase of circulating TNF-alpha that is paralleled by increased serum levels of the endogenous second messenger, sphingosine (SPH), (from 0.71+/-0.15 to 1.32+/-0.39 nmoles/ml, P<0.01). In the tibialis anterior (TA) muscle we found a marked increase of myocyte apoptosis (from 1.4+/-2.4 to 40.1+/-39.5 nuclei/mm(3), P<0.04). We correlated plasma levels of TNF-alpha with those of SPH and in turn with the magnitude of apoptosis. Linear regression showed a significant correlation between TNF-alpha, SPH, and apoptosis (r(2)=0.74, P=0.004 and r(2)=0.87, P=0.001 respectively). Analysis of covariance showed that TNF-alpha and SPH were independently correlated with the number of apoptotic nuclei (P=0.0001). In parallel in vitro experiments, where increasing concentrations of SPH were applied to skeletal muscle cells in culture, we observed a dose-dependent increase in apoptosis. These results suggest that TNF-alpha-induced SPH production may be responsible for skeletal muscle apoptosis. The link between TNF-alpha and skeletal muscle apoptosis could be represented by the second messenger SPH, which can directly induce apoptosis in these cells.
Journal of Molecular and Cellular Cardiology 10/2001; 33(10):1871-8. · 5.17 Impact Factor
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ABSTRACT: In congestive heart failure (CHF), skeletal muscle shows increased expression of fast myosin heavy chains (MHC) and fibers, muscle atrophy, increased fatigability, and decreased endurance. Atrophy is secondary to myocyte apoptosis, which is probably triggered by tumor necrosis factor-alpha (TNFalpha). Angiotensin II receptors are thought to play a role in controlling apoptosis. We tested the hypothesis that angiotensin II receptor blockade could prevent skeletal muscle apoptosis in rats with CHF.
CHF was induced by injecting 36 rats with 30 mg/kg monocrotaline. Ten additional animals were injected with saline and acted as controls. After 2 weeks, 18 of the 36 rats with CHF were treated with 7 mg. kg(-1). d(-1) irbesartan through osmotic minipumps, and 10 of the 36 rats were treated with 2 mg. kg(-1). d(-1) nifedipine in drinking water. After 2 additional weeks, rats were killed. Tibialis anterior cross-sectional area, MHC composition, myocyte apoptosis, Bcl-2, pro-caspase 3, and activated caspases 3 and 9 were determined, as were plasma levels of TNFalpha and angiotensin II. Myocyte apoptosis and muscle atrophy were significantly decreased with irbesartan compared with untreated CHF rats. Irbesartan-treated rats had fewer cells labeled positively with terminal deoxynucleotidal transferase-mediated dUTP nick-end labeling and fewer caspases; however, they also had increased Bcl-2 levels and muscle fiber cross-sectional areas. The MHC pattern in irbesartan-treated animals was similar to that in controls. Nifedipine animals behaved like the untreated CHF animals. Angiotensin II was increased 3- to 4-fold in all CHF rats (treated and untreated). TNFalpha levels were decreased in irbesartan-treated rats but not in nifedipine-treated rats.
Angiotensin II receptor blockade can protect from the development of apoptosis-dependent atrophy and from changes in MHCS: The reduction of TNFalpha may play a role in this process.
Circulation 06/2001; 103(17):2195-200. · 14.74 Impact Factor
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ABSTRACT: Management of cyclosporine (CsA)-associated hyperuricemia in heart transplantation (HT) is difficult. Because of the myelotoxicity of combined allopurinol and azathioprine, we tested sulfinpyrazone.
We studied 120 HT recipients (109 men; mean age at HT, 52+/-10 years). All had received allopurinol for at least 6 months, which was stopped for 1 month before initiation of sulfinpyrazone. Mean follow-up from HT to onset of sulfinpyrazone (200 mg/day) was 59+/-41 months. We stopped the drug after 6+/-2 months. We compared CsA level and daily dose, serum creatinine, blood urea, and uric acid at onset and before interruption of sulfinpyrazone and, as control, in the last 6 months of allopurinol.
Mean uricemia decreased with allopurinol (0.58+/-0.12 vs. 0.41+/-0.07 mmol/liter, p = 0.0001) as well as with sulfinpyrazone (0.51+/-0.13 vs. 0.40+/-0.12 mmol/liter, p = 0.0001). Mean creatinine increased (171+/-42 and 164+/-35 micromol/liter, p = 0.01) with allopurinol, whereas it tended to decrease with sulfinpyrazone (160+/-35 and 154+/-48 micromol/liter, p = NS). Mean urea did not change with allopurinol (14+/-5 vs. 15+/-7 mmol/liter, p = NS), but fell with sulfinpyrazone (14.01+/-5 vs. 12.60 +/-5 mmol/liter, p = 0.0004). Mean CsA levels were constant with allopurinol (193+/-73 vs. 188+/-65 ng/ml, p = NS), although CsA dose was slightly reduced (2.7+/-0.8 vs. 2.6+/-0.8 mg/kg/day, p = 0.007). Conversely, CsA levels dropped with sulfinpyrazone (183+/-89 vs. 121 +/-63 ng/ml, p = 0.0001) despite an increase in CsA daily dose (2.6 +/-0.9 vs. 2.8+/-0.9 mg/kg/day, p = 0.0001). Two subjects were treated for acute rejection. We observed no other side effects. In HT recipients sulfinpyrazone, as an alternative to allopurinol, is effective in achieving metabolic control of hyperuricemia. However, this drug reduced CsA levels, thus the risk of rejection is present.
The Journal of Heart and Lung Transplantation 01/2001; 19(12):1205-8. · 4.33 Impact Factor
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ABSTRACT: To test the hypothesis, using endomyocardial biopsies, that unexplained cases of apparent acute myocardial infarction were caused by myocarditis.
Between 1992 and 1998, 12 patients were admitted to the coronary care unit with severe chest pain, ST segment elevation, increased serum creatine kinase and MB isoenzyme, and with wall motion abnormalities on echocardiogram highly suggestive of acute myocardial infarction. These patients were further investigated by endomyocardial biopsy, as their coronary angiograms were normal. A diagnosis of myocarditis was made according to the Dallas criteria. A panel of antibodies was used for immunohistochemical characterisation of inflammatory cell infiltrate. Polymerase chain reaction (PCR) was used to detect viral genomes in seven cases.
Haematoxylin and eosin staining of the endomyocardial biopsy showed active myocarditis in six patients and borderline myocarditis in one. Immunohistochemistry was positive for inflammatory cell infiltrates in 11 patients, including all the seven who were positive on haematoxylin and eosin staining according to the Dallas criteria. Only one patient had no evidence of inflammation. PCR was positive in two patients, both for Epstein-Barr virus. Follow up showed complete resolution of echocardiographic abnormalities in all patients except one.
Myocarditis can mimic acute myocardial infarction in patients with angiographically normal coronary arteries, leading to errors of treatment. In patients with apparent myocardial infarction and a normal coronary angiogram, endomyocardial biopsy may help in the diagnosis of myocarditis. The sensitivity of endomyocardial biopsy was enhanced by using immunohistochemical and molecular biological techniques.
Heart (British Cardiac Society) 10/2000; 84(3):245-50. · 4.22 Impact Factor
