[Renal manifestations of light chain associated diseases - epidemiology and prognosis]. / Renale Manifestationen von Leichtkettenerkrankungen - Epidemiologie und Prognose.

BACKGROUND: An impaired renal function in light chain associated disorders may be caused by myeloma cast nephropathy (MCN) but also by AL-amyloidosis (AL-A) and monoclonal immundeposition disease (MIDD). PATIENTS AND METHODS: In a monocentric, retrospective analysis, patients suffering from multiple myeloma (MM) (n = 392) requiring medical therapy, AL-A (n = 53) or MIDD (n = 12) diagnosed between 1996 and 2008 were evaluated for renal insufficiency. The different patient cohorts were compared in terms of their clinical course and outcome. RESULTS: Renal insufficiency in MM-, AL-A- or MIDD-patients at the time of diagnosis was found in 45,5 % of the patients. MCN, AL-A and MIDD were found in 68, 25 and 6 %, respectively. Dialysis dependency was seen in 17 % of MCN, in 8 % of AL-A and in 50 % of MIDD patients. Signs of hypervolemia were the leading symptoms in MIDD/AL-A. The time between the occurence of first symptoms and diagnosis was as long as 52 weeks in patients with AL-A. Patients with renal involvement showed a reduced median survival of 17 compared with 77 months in patients with a normal renal function. Median survival was only 12 months in AL-A compared to 21 months in MCN. Stabilization of renal function after chemotherapy occurred only in MCN. Multivariate Cox regression analysis showed impaired renal function as independent risk factor (Hazard-Ratio 2,88 [2,06-4,0]. In terms of survival and kidney function, autologous stem cell transplantation (ASCT) was beneficial for patients with renal involvement. CONCLUSION: Renal insufficiency is an independent risk factor in MM, AL-A and MIDD. Specific therapy, especially ASCT may improve prognosis in patients with renal insufficiency and could stabilize renal function in MCN-patients.

[Unusual cause of Staphylococcus aureus septicemia in a 79-year-old male patient]. / Ungewöhnliche Ursache einer Staphylococcus-aureus-Septikämie bei einem 79-jährigen Patienten.

High grade fever in the context of Staphylococcus aureus bacteremia led to hospital admission of a 79 year old male patient. A covered perforation of the ascending aorta resulted in the formation of a pseudoaneurysm which was complicated by superinfection caused by hematogenic spread of Staphylococcus aureus. The infected pseudoaneurysm found per continuitatem contact to the pericardium and resulted in bacterial pericarditis. Antibiotic pretreatment was followed by operation with a complex procedure including resection of pseudoaneurysm and suture closure of the perforation site.

Apoptosis in patients with dilated cardiomyopathy and diabetes: a feature of diabetic cardiomyopathy?

BACKGROUND: Dilated cardiomyopathy (DCM) has been suggested to be a consequence of a prior viral infection leading to a chronic inflammatory and immunological reaction that leads to a structural and functional deterioration of the heart. Nevertheless, the results of present studies are conflicting, regarding the natural course of heart diseases associated with detection of viral genome and inflammation. On the other hand, diabetes mellitus (DM) is the leading endocrine disorder worldwide and sufficient to induce a cardiomyopathy. It is not known whether DM contributes to the clinical picture of cardiomyopathy associated with the presence of viral genome or inflammatory cells in the myocardium. Therefore, the present study was undertaken to compare histological, immunohistochemical, biochemical, and functional data as well as the outcome of patients presenting with DCM and positive for DM with patients negative for DM to evaluate for a diabetic contribution in the course of the disease. METHODS: A total of 216 patients were biopsied between January 1998 and April 2003. From 197 patients diagnosed as having DCM, we were able to complete data set regarding the presence of DM in 108 patients, 20 patients with and 88 patients without DM. RESULTS: There was no significant difference regarding age, gender, body mass index, presence of viral genome and inflammatory cells in the myocardium, left ventricular function and diameter, and the degree of heart insufficiency. There was a significant difference of apoptotic cells in the myocardium of patients with DCM and DM compared to patients with DCM alone (1.7+/-1.9 vs. 0.2+/-0.4, p=0.028). During the follow-up of 16 months, left ventricular function improved in both groups significantly, but not between the groups. Death or transplantation-free survival was not significantly different. CONCLUSION: The different findings regarding the presence of apoptotic cells suggest a contribution of pathobiological pathways in the patients with DM to the underlying heart disease.

Chemotactic activity of serum obtained from patients with idiopathic dilated cardiomyopathy.

Elevated circulating levels of alpha- and beta-chemokines in heart failure have been reported. The objective of this study was to investigate the interrelation of chemotactic activity of serum and circulating chemokine levels in patients suffering from idiopathic dilated cardiomyopathy (IDCM). Chemokine serum levels (MCP-1, MIP1-alpha, RANTES, IL-8 and TNF-alpha) were determined in patients with IDCM (n = 10), patients with coronary artery disease with normal (CAD-1; n = 10) or depressed (CAD-2; n = 10) left ventricular function and healthy controls (n = 10). The chemotactic effect of sera obtained from these groups was measured using an in vitro chemotaxis assay. Sera obtained from IDCM (5475 +/- 681 cells) showed the highest chemotactic activity when compared to controls (1850 +/- 215 cells), CAD-1 (3325 +/- 275 cells) and CAD-2 (2800 +/- 275 cells, P < 0.05) associated with significantly higher circulating MCP-1 levels. Sera obtained from IDCM patients show a high chemotactic activity associated with significantly elevated circulating MCP-1.

Expression of androgen-binding protein (ABP) in human cardiac myocytes.

Cardiomyocytes are known to be androgen targets. Changing systemic steroid levels are thought to be linked to various cardiac ailments, including dilated cardiomyopathy (DCM). The mode of action of gonadal steroid hormones on the human heart is unknown to date. In the present study, we used high-resolution immunocytochemistry on semithin sections (1 microm thick), IN SITU hybridization, and mass spectrometry to investigate the expression of androgen-binding protein (ABP) in human myocardial biopsies taken from male patients with DCM. We observed distinct cytoplasmic ABP immunoreactivity in a fraction of the myocytes. IN SITU hybridization with synthetic oligonucleotide probes revealed specific hybridization signals in these cells. A portion of the ABP-positive cells contained immunostaining for androgen receptor. With SELDI TOF mass spectrometry of affinity purified tissue extracts of human myocardium, we confirmed the presence of a 50 kDa protein similar to ABP. Our observations provide evidence of an intrinsic expression of ABP in human heart. ABP may be secreted from myocytes in a paracrine manner perhaps to influence the bioavailabity of gonadal steroids in myocardium.

[Diplopia and cardiogenic shock]. / Doppelbilder und kardiogener Schock. Eine okuläre Myositis assoziiert mit einer Riesenzellmyokarditis.

Idiopathic giant cell myocarditis is a rare and frequently fatal inflammatory heart disease which leads to congestive heart failure or ventricular arrhythmias. It is often associated with other autoimmune disorders. We report a 39-year-old woman who first presented with diplopia and painful eye movements, the typical clinical picture of orbital myositis. Shortly afterwards, she developed rapidly progressive congestive heart failure due to giant cell myocarditis, which took a fatal course within some weeks. Autopsy confirmed both disorders. This case report underlines the importance of early and repeated monitoring of cardiac function, if orbital myositis is suspected, in order to consider cardiac transplantation, the only efficacious treatment of giant cell myocarditis, in time.

Immunohistochemical differentiation of eosinophilic heart diseases using antibodies against eosinophil activation markers.

AIMS: Eosinophilic heart syndromes are rare in Western countries and include endocarditis parietalis fibroplastica (EPF) and hypersensitivity myocarditis (HM). There are striking differences in natural history and morphological findings. Since diagnosis can be difficult when analysing small myocardial biopsies lacking the characteristic histological features, we studied a set of immunohistochemical markers in order to characterize the activation status of the infiltrating eosinophils to distinguish between these two entities. METHODS AND RESULTS: This study is based on the investigation of seven explanted hearts and one left ventricular specimen collected during implantation of a left ventricular assist device from a total of seven patients with HM. Also investigated were three right and three left ventricular specimens from five patients with EPF. We used antibodies (Ab) against EG1, and EG2, CD44, and CD69 which have been described as markers to distinguish between resting and activated eosinophils. The EG1 to EG2 ratio of eosinophils and the immunoreactivity against CD44 showed no differences between the two entities. However, eosinophils in the EPF were completely negative for CD69, whereas eosinophils reacted positively within the HM group. CONCLUSION: The immunohistochemical investigation of eosinophilic heart diseases using antibodies against CD69 can be a useful tool to distinguish between hypersensitivity myocarditis and endocarditis parietalis fibroplastica.

Cardiac remodelling in end stage heart failure: upregulation of matrix metalloproteinase (MMP) irrespective of the underlying disease, and evidence for a direct inhibitory effect of ACE inhibitors on MMP.

OBJECTIVE: To investigate matrix metalloproteinases (MMP-2 and MMP-9) in heart failure caused by ischaemic and idiopathic dilated cardiomyopathy, and the impact of angiotensin converting enzyme (ACE) inhibition on MMP. DESIGN AND MAIN OUTCOME MEASURES: MMP were extracted from myocardium of patients with heart failure (coronary artery disease, n = 13; idiopathic dilated cardiomyopathy (IDCM), n = 16) and from controls (n = 6). The active form of MMP-2 and MMP-9 was measured by enzyme linked immunosorbent assay; activity of MMPs by zymography; mRNA expression of MMPs by reverse transcriptase polymerase chain reaction. RESULTS: Active MMP-9 was significantly increased in coronary artery disease (mean (SD) 1.6 (0.35) ng/ml) and IDCM (2.11 (0.54) ng/ml) in comparison with controls (0.53 (0.15) ng/ml). Increased MMP-2 was only found in IDCM (3.68 (0.41) ng/ml). There were corresponding increases in MMP activity but no upregulation of mRNA expression was found. The ACE inhibitors captopril and ramiprilate inhibited MMP-2 and MMP-9 activity in vitro (inhibitory capacity (IC50), in mmol/l: MMP-2: captopril 2.0 (0.16), ramiprilate 2.1 (0.3); MMP-9: captopril 1.65 (0.18), ramiprilate 2.0 (0.3)). Lisinopril inhibited MMP-9 significantly but did not inhibit MMP-2 in vitro (IC50 MMP-2: 7.4 (0.88); MMP-9: 7.86 (2.23)). Inhibition of MMP activity by ACE inhibitors was blunted by zinc excess. CONCLUSIONS: Upregulation of MMP-9 activity is common in the failing myocardium, independent of the underlying disease. Missing upregulation of transcription suggests that activation of latent forms of MMP is the source of increased MMP activity, rather than increased de novo synthesis. Some ACE inhibitors may influence MMP activity by a direct effect.

Damaged myocytes as detected by the colocalization of DNA fragmentation and tissue transglutaminase and their prognostic significance in enterovirus-associated dilated cardiomyopathy.

BACKGROUND: Apoptotic cardiac myocytes have been described in chronic heart failure, but no data exist on the relationship between these 'damaged' myocytes and myocardial detection of enterovirus RNA often associated with dilated cardiomyopathy (DCM). DESIGN: In patients with idiopathic DCM, endomyocardial biopsy samples were studied for enteroviral RNA by one step reverse transcription-polymerase chain reaction (PCR) and a subsequent hybridization of the PCR product using a Southern blot technique. The endomyocardial biopsies were further investigated for markers of cell damage and apoptosis: DNA fragmentation and expression of tissue-transglutaminase (TTG) in the myocytes using the in-situ endlabelling method or an anti-TTG-staining, respectively. To assess the prognostic significance of these two markers the correlation between the percentage of myocytes positive both for DNA fragmentation and TTG (the index of damaged myocytes) and the hemodynamic course of the patients during a mean follow-up period of 15.9 +/- 6.2 months was investigated prospectively by echocardiography. RESULTS: In 14 (45%) of the 31 patients with idiopathic DCM, enteroviral RNA was found in the endomyocardial biopsy samples, while 17 patients (55%) were enterovirus-negative. In enterovirus-positive patients, the index of 'damaged' myocytes was significantly lower (10.7 +/- 4.9% vs. 19.2 +/- 8.8%, P = 0.002) and the left ventricular ejection fraction (LVEF) improved significantly (P = 0.00017 vs. P = 0.13) during long-term follow-up. In addition, a weak negative correlation was seen between the index of damaged myocytes and the changes in LVEF in all patients during long-term follow-up (r = - 0.48, P = 0.004). CONCLUSION: Our results favour the view that enterovirus-positive patients with DCM have less damaged myocytes and a better haemodynamic course than enterovirus-negative patients.

Tumour necrosis factor-alpha expression in idiopathic dilated cardiomyopathy: correlation to myocardial inflammatory activity.

High numbers of inflammatory cells are found in a subgroup of patients with idiopathic dilated cardiomyopathy (IDCM). We hypothesized that the extent of inflammation is linked to myocardial TNF-alpha expression in human IDCM. Fourteen patients who consecutively underwent endomyocardial biopsy (EMB) were stratified into two groups-a group with low and a group with high myocardial inflammatory index (MII)-based on immunohistochemical analysis of cellular infiltration and HLA I and II expression. Myocardial TNF-alpha messenger RNA (mRNA) expression was determined by reverse transcriptase polymerase chain reaction, TNF-alpha protein was localized by immunohistochemistry and TNF-alpha serum levels were measured by EIA. IDCM patients with a high MII (n=6) showed a 1. 9-fold higher TNF-alpha mRNA expression when compared to IDCM patients with low MII (n=8, P=0.020). TNF-alpha protein was detected at perinuclear regions of cardiac myocytes and the endothelium. TNF-alpha serum levels were 3.0 (0.55) pg/ml in patients with high MII compared to 1.35 (0.20) pg/ml in patients with low MII (P=0.017). According to immunolocalization cardiac myocytes and the endothelium seem to be the major source of TNF-alpha production. Whether the elevated systemic level of TNF-alpha found in patients with high MII are elaborated by the myocardium or are produced by other tissues representing a general immune activation is not clear.

Lack of association between 27-bp repeat polymorphism in intron 4 of the endothelial nitric oxide synthase gene and the risk of coronary artery disease.

The gene encoding endothelial nitric oxide synthase (ecNOS) is a candidate gene for the mediation of initial endothelial cell damage seen in arteriosclerosis. Although the association of ecNOS polymorphisms with hypertension has been studied extensively, there is little information regarding its association with coronary artery disease (CAD). We decided to study a 27 base-pair tandem repeat polymorphism in intron 4 of the ecNOS gene in 1043 individuals (413 controls, 630 patients with CAD) who consecutively underwent coronary angiography at our institution. The frequencies of the genotypes drawn from 1038 individuals were 0.69, 0.28 and 0.03 in the controls and 0.73, 0.25 and 0.02 in individulas with CAD for the ecNOS4b/b, ecNOS4b/a and ecNOS4a/a genotypes, respectively (p = n.s). There was no shift of the genotype frequencies from the expected distribution based on the Hardy-Weinberg equilibrium. Neither the rare ecNOS4a allele nor the ecNOS4a/a genotype conferred an independent risk factor for CAD in subgroups, e.g. smokers, diabetic individuals, hypertensive individuals and individuals with a low conventional risk for CAD. In five individuals we identified an additional 27-bp repeat in the ecNOS gene (ecNOS4c), which occurred heterozygous with the ecNOS4b allele (ecNOS4b/c genotype). In conclusion, the ecNOS4a allele as well as the ecNOS4a/a genotype did not show a general association with CAD in the studied European population. Even in high-risk subgroups the ecNOS4a/4a genotype did not represent an independent risk factor for CAD. In addition, the severity of CAD was not associated with the ecNOS4a allele/ecNOS4a/a genotype.

A common variant of the angiotensinogen gene and the risk of coronary artery disease in a German population.

The thymidine to cytosine transition at position 704 in exon 2 of the angiotensinogen gene leads to the amino acid substitution of threonine for methionine (T235 variant) and is responsible for elevated plasma levels of angiotensinogen. To examine the influence of T235 on the risk of coronary artery disease (CAD) we genotyped 184 CAD patients, 77 controls in whom CAD was excluded angiographically, and 155 healthy controls without signs of CAD by polymerase chain amplification and restriction enzyme digestion. Allele frequencies for A (wildtype) and a (mutant allele) in the total study population were 0.538 and 0.462, 0.536 and 0.464 in the healthy controls, and 0.481 and 0.519 in patients with excluded CAD, respectively. The allele frequencies and the genotype distribution in these groups did not show a significant difference. In conclusion, we did not observe an association between the T235 variant of the angiotensinogen gene and the risk of CAD.

Monocyte chemoattractant protein 1 (MCP-1) gene expression in dilated cardiomyopathy.

The cytotoxic action of leukocytes may be a most probable cause of cardiac myocyte damage seen in chronic myocarditis and dilated cardiomyopathy (DCM). The migration and tissue infiltration of leukocytes is regulated by chemotactic cytokines. Recently, the presence of monocyte chemoattractant protein 1 (MCP-1) messenger RNA has been demonstrated in endomyocardial biopsy tissue obtained from patients with DCM. This chemokine could contribute to enhanced leukocyte recruitment and activation resulting in chronic damage of cardiomyocytes. Accordingly, we sought to determine whether the severity of left ventricular dysfunction in DCM is associated with quantitative alterations of MCP-1 messenger RNA and MCP-1 protein in endomyocardial biopsy tissue. A group of DCM patients with low to moderate impairment of left ventricular function (ejection fraction 45.3+/-2.3%, n=7) was compared to patients with severe left ventricular dysfunction (ejection fraction 25.5+/-3.1%, n=7). MCP-1 messenger RNA expression was determined by quantitative polymerase chain reaction. MCP-1 protein and the presence of infiltrating inflammatory cells were detected by immunohistochemistry. DCM patients with severe left ventricular dysfunction showed a 2.35 fold higher MCP-1 messenger RNA expression when compared to DCM patients with less severe dysfunction (P=0.0229). Positive immunohistochemical staining for MCP-1 was found in all seven patients with severe left ventricular dysfunction and was particularly distinct within the cardiac interstitum. In five of seven patients with less severe systolic dysfunction, MCP-1 protein was found, but was less pronounced and distributed in patchy interstitial areas, close to intramyocardial vessels. Furthermore, there was a consistent trend toward a higher infiltration of inflammatory cells in DCM patients with lower ejection fraction. In conclusion, MCP-1 is dynamically regulated in DCM related deterioration of left ventricular function. This mechanism might contribute to myocyte damage via infiltrated and activated monocytes.

[Clinical picture and differential diagnosis of cardiomyopathy and myocarditis]. / Klinisches Bild und Differentialdiagnose von Kardiomyopathie und Myokarditis.

The main feature of idiopathic dilated cardiomyopathy is the dilation and impaired contractility of the left ventricle or both ventricles. The clinical picture with forward and backward failure is based on the pump impairment of the left ventricle. However, the clinical presentation of patients with dilated cardiomyopathy is indistinguishable from any other secondary form of heart failure. The symptoms of myocarditis are also often determined by the degree of left ventricular dysfunction and--apart from perimyocarditis-associated precordial discomfort--therefore also often indistinguishable from dilated cardiomyopathy. The differentiation of dilated cardiomyopathy from other myocardial diseases by noninvasive methods is insufficient. Without invasive tests about 1/3 of the patients will be diagnosed incorrectly. Therefore, invasive diagnostics including coronary angiography are necessary to differentiate dilated cardiomyopathy from other diseases, especially coronary artery disease. Standard laboratory findings and cytokine serum concentrations (e.g. TNF-alpha) are not suitable to differentiate dilated cardiomyopathy and myocarditis and endomyocardial biopsy is indicated. Endomyocardial biopsies have to undergo evaluation by standard histology and immunohistology, and should be tested for the persistence of infectious agents. According to cardiac catheterization and evaluation of the endomyocardial biopsy idiopathic left ventricular dysfunction can be further stratified using the criterion of a myocardial virus persistence and the presence/absence of inflammatory infiltrates. Idiopathic dilated cardiomyopathy (approximately 70 to 75%), virus-associated dilated cardiomyopathy (approximately 20 to 25%), myocarditis (approximately 7%) and autoimmune myocarditis (approximately 3%) are the 4 possible resulting forms of idiopathic left ventricular dysfunction. Beside conventional medical therapy there are new therapeutic concepts e.g. using interferon for enterovirus-positive patients and immunosuppression for autoimmune, virus-negative patients with a cellular infiltrate.

Absence of association between a common mutation in the methylenetetrahydrofolate reductase gene and the risk of coronary artery disease.

BACKGROUND: Elevated total plasma homocysteine levels are associated with an increased risk of coronary artery disease. Plasma homocysteine levels are influenced by nutritional and hereditary factors. A point mutation (cytosin to thymidine substitution; C677-->T) in the gene encoding methylenetetrahydrofolate reductase (MTHFR), has been reported to render the enzyme thermolabile and has been associated with elevations in homocysteine levels in homozygous carriers (TT genotype). METHODS: To examine the hypothesis that the T allele (coding for the thermolabile defect of MTHFR) influences the risk of coronary artery disease, we genotyped 340 patients with coronary artery disease and 105 control subjects in whom coronary artery disease was excluded by coronary angiography. Furthermore, we studied the genotype frequency in 104 age- and sex-matched healthy persons as a control group without signs of atherosclerotic disease. RESULTS: Allele frequencies for C (wild-type allele) and T allele (mutant allele) were 0.68 and 0.32 respectively in the healthy control subjects, 0.66 and 0.34 respectively in patients with angiographically excluded coronary artery disease and 0.69 and 0.31 respectively in coronary artery disease patients (P = NS). The allele frequencies of the total study population were 0.68 and 0.32. CONCLUSION: Our data show that homozygosity for the C677-->T mutation in this European population is not associated with increased risk of coronary artery disease. This finding suggests that the C677-->T mutation of the MTHFR gene does not represent a marker for increased cardiovascular risk.