Pheochromocytoma and paraganglioma (PPGL) are rare tumours and at least 30% are part of hereditary syndromes. Approximately 20% of hereditary PPGL are caused by pathogenic germ line variants in genes of the succinate dehydrogenase complex (SDHx), TMEM127 or MAX. Herein we present guidelines regarding genetic testing of family members and their surveillance based on a thorough literature review. All cases of PPGL are recommended genetic testing for germ line variants regardless of patient and family characteristics. At minimum, FH, NF1, RET, SDHB, SDHD and VHL should be tested. In addition, testing of MEN1, SDHA, SDHAF2, SDHC, TMEM127 and MAX is recommended. Healthy first‐degree relatives (and second‐degree relatives in the case of SDHD and SDHAF2 which are maternally imprinted) should be offered carrier testing. Carriers of pathogenic variants should be offered surveillance with annual biochemical measurements of methoxy‐catecholamines and bi‐annual rapid whole‐body magnetic resonance imaging and clinical examination. Surveillance should start 5 years before the earliest age of onset in the family and thus only children eligible for surveillance should be offered pre‐symptomatic genetic testing. The surveillance of children younger than 15 years needs to be individually designed. Our guidelines will provide a framework for patient management with the possibility to follow outcome via national registries and/or follow‐up studies. Together with improved insights into the disease, this may enable optimisation of the surveillance scheme in order to minimise both anxiety and medical complications while ensuring early disease detection.

Although numerous reports support the existence of stem cells in the adult heart, few studies have been conducted using human cardiac tissue. Therefore, cells from human cardiac atrial biopsies were analyzed regarding progenitor properties. Expression of stem cell markers was analyzed using fluorescence-activated cell sorting. This identified a small population of C-kit+ cells, which could be further subdivided based on expression of CD45. The C-kit+ CD45+ population was determined to be of mast cell identity, while the C-kit+ CD45- population expressed mRNA of the endothelial lineage. Since the number of cells obtainable from biopsies was limited, a comparison between directly isolated and monolayer and explant cultured cells, respectively, was carried out. While both cultures retained a small population of mast cells, only monolayer culture produced a stable and relatively high percentage of C-kit+ CD45- cells. This population was found to co-express endothelial progenitor cell markers such as CD31, CD34, CXCR4, and FLK-1. The mRNA expression profile was similar to the one from directly isolated cells. When sorted cells were cultured in endothelial differentiation medium, the C-kit+ CD45- population retained its expression of endothelial markers to a large extent, but downregulated progenitor markers, indicating further differentiation into endothelial cells. We have confirmed that the human cardiac atrium contains a small C-kit+ CD45- population expressing markers commonly found on endothelial progenitor cells. The existence of an endothelial progenitor population within the heart might have future implications for developing methods of inducing neovascularization after myocardial infarction.

Cardiac "side population" (SP) cells have previously been found to differentiate into both endothelial cells and cardiomyocytes in mice and rats, but there are no data on SP cells in the human adult heart. Therefore, human cardiac atrial biopsies were dissociated, stained for SP cells and analyzed with FACS. Identified cell populations were analyzed for gene expression by quantitative real-time PCR and subjected to in vitro differentiation. Only biopsies from the left atrium contained a clearly distinguishable population of SP cells (0.22 ± 0.08%). The SP population was reduced by co-incubation with MDR1 inhibitor Verapamil, while the ABCG2 inhibitor FTC failed to decrease the number of SP cells. When the gene expression was analyzed, SP cells were found to express significantly more MDR1 than non-SP cells. For ABCG2, there was no detectable difference. SP cells also expressed more of the stem cell-associated markers C-KIT and OCT-4 than non-SP cells. On the other hand, no significant difference in the expression of endothelial and cardiac genes could be detected. SP cells were further subdivided based on CD45 expression. The CD45-SP population showed evidence of endothelial commitment at gene expression level. In conclusion, the results show that a SP population of cells is present also in the human adult heart.

Ischemic heart disease is a major cause of death and morbidity and the search for novel therapeutic targets is still required. We have previously shown that the enzyme arachidonate 15 lipoxygenase (ALOX15), which catalyzes the conversion of arachidonic acid to 15-hydroxy eicosatetraenoic acid (15-HETE), is highly expressed in ischemic heart tissue, but its role in the pathogenesis of ischemic heart disease is unclear. Here we showed that expression of ALOX15, but not ALOX12 or ALOX15B, was increased in ischemic versus non-ischemic human heart biopsy samples. A similar ALOX expression pattern was found in hypoxic human cardiomyocytes and cardiac endothelial cells. We also showed that levels of 15-HETE were significantly higher in ischemic versus non-ischemic human heart biopsy samples and showed a tendency to increase in serum from the patients with ischemic heart disease. Moreover, hypoxia increased the production of 15-HETE levels from human cardiomyocytes and cardiac endothelial cells. The hypoxia-induced increase in 15-HETE levels from human cardiomyocytes was inhibited by the ALOX15 inhibitor baicalein. Finally, by using intrinsic rotational thromboelastometry, we showed that human whole blood clotted faster in the presence of 15-HETE. In summary, we propose that increased ALOX15 expression in heart tissue under ischemic conditions may lead to increased production of 15-HETE, potentially contributing to thrombosis.