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Objectives: Endomyocardial biopsies are the criterion standard in diagnosing acute cardiac transplant rejection. This study sought to analyze mRNA expression profiles of various immuneresponse-related genes in endomyocardial biopsies of heart transplant patients and to correlate the results with histologic findings., Materials and Methods: Forty-three biopsies obtained from 6 heart transplant recipients experiencing acute rejection were analyzed for granzyme B, CTLA4, IL-6, TGF-beta, and TNFa expression using real-time polymerase chain reaction. The results were compared with the histologic findings. Biopsies obtained before, during, and after acute rejection episodes were grouped according to the International Society of Heart and Lung Transplantation standard biopsy grading from 1990. Group 1 consisted of biopsies with International Society of Heart and Lung Transplantation grade 0 (n=12), group 2 of International Society of Heart and Lung Transplantation grade 1A (n=14), and group 3 of International Society of Heart and Lung Transplantation grades 1B, 2, 3A, and 4 (n=17)., Results: A strong correlation was seen between histologic groups and gene expression of granzyme B, which showed the highest overall transcript levels. CTLA4 was elevated in group 2, but no further increase in the rejecting group 3 was seen. For IL-6, TGF-beta, and TNFa gene expression was strongly elevated in group 3 compared with groups 1 and 2. On analysis of biopsies with International Society of Heart and Lung Transplantation, grade 0 and 1A, relative to the time point of rejection, we found a substantial increase in mRNA expression of all analyzed immune response-related genes before a rejection episode. The strongest up-regulation was seen for granzyme B, TNFa, and TGF-beta., Conclusions: Our data suggest that analyses of gene expression provides valuable information in diagnosing heart transplant rejection. Furthermore, analyses of granzyme B, TGF-beta, and TNFa might not only confirm an ongoing rejection episode, but also may have a positive predictive value.

Background: Cytochrome P450 (CYP) enzyme 2J2, an epoxygenase predominantly expressed in the heart, metabolizes arachidonic acid to biologically active eicosanoids. One of the CYP2J2 products, 11, 12-epoxyeicosatrienoic acid, has several vasoprotective effects. The CYP2J2-G-50T-promotor polymorphism decreases gene expression and is associated with coronary artery disease. This association supports the vascular protective role of CYP-derived eicosanoids in cardiovascular disease. In the present study, we investigated the influence of this polymorphism on survived myocardial infarction in two study groups of patients with on average high cardiovascular risk profile., Methods: The CYP2J2 polymorphism was genotyped in two groups of patients that were collected with the same method of clinical data collection. Data from 512 patients with sleep apnoea (group: OSA) and on average high cardiovascular risk profile and from another 488 patients who were admitted for coronary angiography (CAR-group) were evaluated for a potential correlation of the CYP2J2 polymorphism G-50T and a history of myocardial infarction. The G-50T polymorphism of the CYP2J2 gene was genotyped by allele specific restriction and light cycler analysis., Results: The T-allele of the polymorphism was found in 111 (11.1%; CAR-group: N = 65, 13.3%; OSA: N = 46, 9.0%). 146 patients had a history of myocardial infarction (CAR: N = 120, 24.6%; OSA: N = 26, 5.1%). Cardiovascular risk factors were equally distributed between the different genotypes of the CYP2J2 G-50T polymorphism. In the total group of 1000 individuals, carriers of the T-allele had significantly more myocardial infarctions compared to carriers of the wild type (T/T or G/T: 21.6%; G/G: 13.7%; p = 0.026, odds ratio 1.73, 95%-CI [1.06-2.83]). In the multivariate logistic regression analysis the odds ratio for a history of myocardial infarction in carriers of the T-allele was 1.611, 95%-CI [0.957-2.731] but this trend was not significant (p = 0.073)., Conclusion: In presence of other risk factors, the CYP2J2 G-50T failed to show a significant role in the development of myocardial infarction. However, since our result is close to the border of significance, this question should be clarified in larger, prospective studies in the future.

We describe a 15-year-old boy and his 19-year-old sister with progressive dilated cardiomyopathy and mild non-progressive proximal lower limb myopathy, secondary to the accumulation of amylopectin-like fibrillar glycogen, (polyglucosan) bodies, in heart and skeletal muscle. Evidence of idiopathic amylopectinosis or polysaccharidosis was demonstrated in heart and skeletal muscle tissue by histology, electron microscopy, biochemical, and genetic analysis. In both siblings the heart muscle stored PAS-positive, proteinase-k resistant and partly diastase resistant granulo-filamentous material, simulating polyglucosan bodies. Glycogen branching enzyme activity, and phosphofructokinase enzyme activity, measured in skeletal muscle tissue and explanted heart tissue were all within the normal limits, however glycogen content was elevated. Furthermore, GBE1, PRKAG2, desmin, alphabeta-crystallin, ZASP, myotilin, and LAMP-2 gene sequencing revealed no mutation, excluding e.g. glycogen storage disease type 4 and desmin-related myofibrillar cardiomyopathies. In both patients the diagnosis of an idiopathic polysaccharidosis with progressive dilated cardiomyopathy was made, requiring heart transplantation at age 13 and 14, respectively. Both patients belong to an autosomal recessive group of biochemically and genetically unclassified severe vacuolar glycogen storage disease of the heart and skeletal muscle. Up to now unidentified glycogen synthesis or glycogen degradation pathways are supposed to contribute to this idiopathic glycogen storage disease.