Immunohistochemical study of remodeling of myocardial lymphatic and blood microvascular structures in terminal heart failure: differences between ischemic and dilated cardiomyopathy

This study investigated (cardiac) remodeling of the myocardial microvasculature in patients with terminal heart failure due to ischemic (ICM) and dilative (DCM) cardiomyopathy. Seventeen transmural left-ventricular (LV) biopsies (9 ICM and 8 DCM), taken from heart transplant recipients at transplantation (n=4) or during ventricular assist device implantation (n=13) were investigated by immunohistostaining for VEGFR-1 and VEGFR-2 as capillary markers and VEGFR-3, D2-40, PROX-1 and LYVE-1 as lymphatic markers. Results were compared to LV biopsies from 7 donor hearts (control). Compared to control, DCM hearts showed a significantly higher density of LYVE-1 positive lymphatics (p < 0.05), whereas no difference was seen for other markers. ICM hearts showed a significantly higher density of D2-40 positive lymphatics (p < 0.01) and a lower density of VEGFR-2 capillaries compared to control (p < 0.05). In comparison to normal donor hearts, ICM and DCM hearts showed a significantly different pattern of microvascular receptor expression. As distinct patterns were seen in ICM and DCM, the effect of microvascular remodeling may be substantially different between two clinically important causes of cardiomyopathy. Further research should be aimed at defining the impact of extracellular matrix composition and VEGF-related angiogenesis on the myocardial microvasculature at various stages of heart failure.     

Cardiac surgery in Germany during 2009. A report on behalf of the German Society for Thoracic and Cardiovascular Surgery

All cardiac surgical procedures performed in 80 German cardiac surgical units throughout the year 2009 are presented in this report, based on a voluntary registry which is organized by the German Society for Thoracic and Cardiovascular Surgery. In 2009 a total of 96?129 cardiac surgical procedures (excluding ICD and pacemaker procedures) were collected in this registry. More than 11.8?% of the patients were older than 80 years compared to 10.3?% in 2008. Hospital mortality in 45?171 isolated CABG procedures (13.1?% off-pump) was 2.8?%. In 23?556 isolated valve procedures (including 2216 catheter-based procedures) a mortality of 4.7?% was observed. This voluntary registry of the German Society for Thoracic and Cardiovascular Surgery continues to be an important tool for quality control and illustrates the development of cardiac surgery in Germany.     

Inactivating calcium‐sensing receptor mutations in patients with primary hyperparathyroidism

Objective Primary hyperparathyroidism (HPT) is characterised by autonomous secretion of PTH from enlarged parathyroid glands leading, in most patients, to asymptomatic hypercalcaemia. Familial hypocalciuric hypercalcaemia (FHH) is an autosomal dominant disorder caused by inactivating mutations in the calcium‐sensing receptor (CaSR) gene; it is characterised by lifelong and usually asymptomatic hypercalcaemia. Establishing the correct diagnosis is important because surgery can be curative in HPT, but ineffective in FHH. There is overlap in the diagnostic criteria for the two disorders and some patients carrying inactivating mutations in the CaSR gene, which is suggestive of FHH, also have HPT with hyperplastic parathyroid glands or adenomas. Design and patients CaSR gene mutations were analysed and clinical and biochemical parameters evaluated in 139 consecutive outpatients presenting with hypercalcaemia and suspected of having HPT. Results Six different mutations of the CaSR gene were found in eight patients. In four patients, classical FHH was suspected based on clinical and biochemical results and was confirmed by the CaSR mutations. In the other four patients, HPT was diagnosed based on the biochemical profile or symptoms; in these four patients, the parathyroids were operated on and single adenomas were histologically confirmed. In all four patients, serum calcium decreased postoperatively; and in three patients, serum calcium normalised postoperatively. The CaSR mutations in these patients were R25X, E250K and Q926R. Conclusion The coexistence of HPT and FHH in four of 139 patients suggests a pathogenetic role of CaSR mutations in HPT. Despite also having a CaSR mutation, these patients benefited from parathyroid surgery.     

KANK deficiency leads to podocyte dysfunction and nephrotic syndrome

Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of progressive renal function decline and affects millions of people. In a recent study, 30% of SRNS cases evaluated were the result of monogenic mutations in 1 of 27 different genes. Here, using homozygosity mapping and whole-exome sequencing, we identified recessive mutations in kidney ankyrin repeat-containing protein 1 (KANK1), KANK2, and KANK4 in individuals with nephrotic syndrome. In an independent functional genetic screen of Drosophila cardiac nephrocytes, which are equivalents of mammalian podocytes, we determined that the Drosophila KANK homolog (dKank) is essential for nephrocyte function. RNAi-mediated knockdown of dKank in nephrocytes disrupted slit diaphragm filtration structures and lacuna channel structures. In rats, KANK1, KANK2, and KANK4 all localized to podocytes in glomeruli, and KANK1 partially colocalized with synaptopodin. Knockdown of kank2 in zebrafish recapitulated a nephrotic syndrome phenotype, resulting in proteinuria and podocyte foot process effacement. In rat glomeruli and cultured human podocytes, KANK2 interacted with ARHGDIA, a known regulator of RHO GTPases in podocytes that is dysfunctional in some types of nephrotic syndrome. Knockdown of KANK2 in cultured podocytes increased active GTP-bound RHOA and decreased migration. Together, these data suggest that KANK family genes play evolutionarily conserved roles in podocyte function, likely through regulating RHO GTPase signaling.     

Surgery in patients with coronary artery disease—silent ischaemia during transurethral resection of tumors of prostate or bladder

Background: Asymptomatic episodes of myocardial ischemia in clinically stable patients seem to occur frequently and may hint at a worse prognosis. Hypothesis: This study was undertaken to determine whether surgical patients with coronary artery disease (CAD) have a higher risk of cardiac ischemia during the perioperative period compared with the late postoperative period and compared with patients without CAD. Methods: In all, 14 patients with and 14 patients without CAD were examined by Holter monitoring during the perioperative and three days later during the postoperative periods for the presence of ST-segment depression as a marker of silent myocardial ischemia. Results: While patients without CAD did not show ST-segment depression, patients with CAD were found to have had 143 episodes of ST-segment depression, 49% in the perioperative and 51% in postoperative recordings. Conclusion: Though patients were asymptomatic with antianginal therapy, there were episodes of ST-segment depression indicating silent myocardial ischemia in patients with CAD. Surgical interventions such as transurethral resection of tumors of prostate or bladder did not produce an increase of ischemic burden registered by Holter monitoring.     

Experimental approach to improve endothelial barrier function in myocardium

Recently, we showed that activated factor XIII (FXIIIa) has a direct influence on permeability (P) of cultured endothelial monolayer. Clinical investigation on children operated on for congenital heart disease has demonstrated a distinct correlation between decrease of endothelial barrier function (edema formation) and reduced FXIII activity. Our experiments investigated whether significant effects of FXIII could also be shown in a full-organ model. The effect of FXIII on endothelial barrier function was studied by determining the passage of trypan blue-labeled albumin in a model of cultured monolayers of porcine aortic endothelial cells and changes in myocardial water content of saline-perfused rat hearts in a Langendorff-circuit. The plasma FXIIIa (1 U/ml) reduced albumin permeability of aortic endothelial monolayers within 20 minutes from a basal value of 5.9±0.4×10^–6 cm/second by 30±7% whereas the nonactivated plasma FXIII had no effect on permeability. Reduction of permeability to the same extent (by 34±9%) could also be obtained with a thrombin-activated recombinant factor XIII A subunit (rhu FXIII; 1 U/ml) in this culture model. The effect of factor XIII A* on permeability was dose dependent with maximum effect at 5 U/ml (52±11% reduction of permeability compared with control), and existed even if cells had hyperpermeability stress (KCN/2-DG). Activated rhuFXIII prevented the increase in myocardial water content in anoxic-reperfused rat hearts (448±24 vs 517±29 ml/100g dry weight). The data of the present study show that FXIII has a stabilizing effect at the site of endothelial cells not only in cultured monolayers but also in a model of the anoxic perfused rat heart.Presented in part at the 40th Annual World Congress, International College of Angiology, Lisbon, Portugal, June 1998.     

Low frequency of germline mutations in the RET proto-oncogene in patients with apparently sporadic medullary thyroid carcinoma

BACKGROUND AND OBJECTIVES Medullary thyroid carcinoma (MTC) occurs both sporadically and In the autosomal domlnantly inherited multiple endocrine neoplasia (MEN) type 2 syndromes. The distinction between true sporadic MTC and a new mutation familial case is important for future clinical managment of both the patient and family. The susceptibility gene for MEN 2 is theRET proto-oncogene. Systematic analysis for germ-line mutations of theRET proto-oncogene was performed in a series of 67 patients with apparently sporadic MTC to determine whether they were true sporadic cases or unsuspected de novo MEN 2 cases. DESIGN AND PATIENTS Sixty-seven unselected patients with sporadic MTC were randomly ascertained from clinic patients from four centres. The diagnosis of MTC was confirmed by hlstopathology. Germline DNA was extracted from peripheral blood leucocytes or from paraffin-embedded tissue and subsequently used for polymerase chain reaction amplification. MEASUREMENTS Polymerase chain reaction basedRET mutation analysis was performed by direct double-stranded cycle sequencing of axons 10, 11, 13 and 16, within which the majority ofMEN2 mutations have been shown to occur. RESULTS In this series, there was one proven case of germline mutation InRET codon 620, which previously has been shown to be responsible for MEN 2, thus Indicating heritable disease. No germline mutation in codon 918, typical of MEN 2B, was found. CONCLUSIONS A figure of 1.5% germline mutations In 67 apparently sporadic MTC Is lower than the incidence of familial disease reported in previous series Involving clinical and biochemical screening. The presence of a germline mutation in theRET proto-oncogene in a patient with MTC indicates heritable disease. The absence of germlineRET exon 10,11,13 or 16 mutation appears to rule out MEN 2A to a high probability, although the presence of a familial form of MTC other than classical MEN 2A cannot be excluded conclusively.     

A truncating NRIP1 variant in an Arabic family with congenital anomalies of the kidneys and urinary tract

Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the most common cause of early-onset chronic kidney disease. In a previous study, we identified a heterozygous truncating variant in nuclear receptor-interacting protein 1 (NRIP1) as CAKUT causing via dysregulation of retinoic acid signaling. This large family remains the only family with NRIP1 variant reported so far. Here, we describe one additional CAKUT family with a truncating variant in NRIP1. By whole-exome sequencing, we identified one heterozygous frameshift variant (p.Asn676Lysfs*27) in an isolated CAKUT patient with bilateral hydroureteronephrosis and right grade V vesicoureteral reflux (VUR) and in the affected father with left renal hypoplasia. The variant is present twice in a heterozygous state in the gnomAD database of 125,000 control individuals. We report the second CAKUT family with a truncating variant in NRIP1, confirming that loss-of-function mutations in NRIP1 are a novel monogenic cause of human autosomal dominant CAKUT.