Distinct Microbial Communities in Dilated Cardiomyopathy Explanted Hearts Are Associated With Different Myocardial Rejection Outcomes

BackgroundIdiopathic dilated cardiomyopathy (IDCM) myocardial inflammation may be associated with external triggering factors such as infectious agents. Here, we searched if moderate/severe heart transplantation rejection is related to the presence of myocardial inflammation in IDCM explanted hearts, associated with microbial communities.MethodReceptor myocardial samples from 18 explanted hearts were separated into groups according to post-transplant outcome: persistent moderate rejection (PMR; n = 6), moderate rejection (MR; n = 7) that regressed after pulse therapy, and no rejection (NR; n = 5)/light intensity rejection. Inflammation was quantified through immunohistochemistry (IHC), and infectious agents were evaluated by IHC, molecular biology, in situ hybridization technique, and transmission electron microscopy (TEM).ResultsNR presented lower numbers of macrophages, as well as B cells (p = 0.0001), and higher HLA class II expression (p ≤ 0.0001). PMR and MR showed higher levels of Mycoplasma pneumoniae (p = 0.003) and hepatitis B core (p = 0.0009) antigens. NR presented higher levels of parvovirus B19 (PVB19) and human herpes virus 6 (HHV6) and a positive correlation between Borrelia burgdorferi (Bb) and enterovirus genes. Molecular biology demonstrated the presence of M. pneumoniae, Bb, HHV6, and PVB19 genes in all studied groups. TEM revealed structures compatible with the cited microorganisms.ConclusionsThis initial study investigating on infectious agents and inflammation in the IDCM explanted hearts showed that the association between M. pneumoniae and hepatitis B core was associated with a worse outcome after HT, represented by MR and PMR, suggesting that different IDCM microbial communities may be contributing to post-transplant myocardial rejection.

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Differences in Virus Prevalence and Load in the Hearts of Patients with Idiopathic Dilated Cardiomyopathy with and without Immune-Mediated Inflammatory Diseases

Clinical and Vaccine Immunology ◽

10.1128/cvi.00281-12 ◽

2012 ◽

Vol 19 (8) ◽

pp. 1182-1187 ◽

Cited By ~ 16

Author(s):

Robert Dennert ◽

Pieter van Paassen ◽

Petra Wolffs ◽

Catrien Bruggeman ◽

Sebastiaan Velthuis ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Inflammatory Diseases ◽

Dominant Role ◽

Parvovirus B19 ◽

Idiopathic Dilated Cardiomyopathy ◽

Control Group ◽

Myocardial Inflammation ◽

Tissue Samples ◽

Copy Numbers ◽

Immune Mediated

ABSTRACTInfections with cardiotrophic viruses and immune-mediated responses against the heart have been suggested to play a dominant role in the pathogenesis of idiopathic dilated cardiomyopathy (DCM). Furthermore, immune-mediated inflammatory diseases (IMIDs) may result in DCM. It has not previously been assessed whether DCM patients with and without an IMID have different prevalences and quantities of cardiotrophic viruses in the heart. Therefore, we compared the profiles of cardiotrophic viruses in heart tissue of DCM patients with and without an IMID. Serum and myocardial tissue samples were obtained from 159 consecutive patients with DCM and 20 controls. Patients were subdivided into three groups, the first two based on the presence (n= 34) or absence (n= 125) of an IMID and the third being a control group. The parvovirus B19 virus genome was detected in equal quantities in the non-IMID DCM patients (100/125) and the control group (15/20) but in lower quantities in the IMID patients (21/34,P= 0.02). Both the non-IMID and IMID DCM patients demonstrated increased myocardial inflammation compared to controls: 12.5 ± 1.8 and 14.0 ± 3.2 CD45-positive inflammatory cells, respectively, versus 5.1 ± 0.7 for the controls (P< 0.05 for both). Importantly, significantly higher parvovirus B19 copy numbers could be amplified in non-IMID than in IMID patients (561 ± 97 versus 191 ± 92 copies/μg DNA,P< 0.001) and control subjects (103 ± 47 copies/μg DNA,P< 0.001). The present study shows decreased parvovirus B19 prevalence and copy numbers in hearts of DCM patients with an IMID compared to those without an IMID. These findings may suggest that DCM patients with an IMID have a different pathophysiologic mechanism from that which is present in the virus-induced form of DCM.

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Frequent detection of parvovirus B19 genome in the myocardium of adult patients with idiopathic dilated cardiomyopathy

Medical Microbiology and Immunology ◽

10.1007/s00430-003-0211-0 ◽

2004 ◽

Vol 193 (2-3) ◽

pp. 75-82 ◽

Cited By ~ 24

Author(s):

Ulrich Lotze ◽

Renate Egerer ◽

Christiane Tresselt ◽

Brigitte Gl�ck ◽

Gudrun Dannberg ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Parvovirus B19 ◽

Adult Patients ◽

Idiopathic Dilated Cardiomyopathy

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Abstract 2316: Myocardial PAI-1 Over-expression Mediates Graft Sclerosis in Cardiac Transplant Recipients with Idiopathic Dilated Cardiomyopathy

Circulation ◽

10.1161/circ.116.suppl_16.ii_506-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Seyedhossein Aharinejad ◽

Katharina Krenn ◽

Romana Schäfer ◽

Andreas Zuckermann ◽

Patrick Paulus ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Plasminogen Activator ◽

Cardiac Transplantation ◽

Left Ventricular ◽

Idiopathic Dilated Cardiomyopathy ◽

Vascular Endothelial ◽

Collagen Deposition ◽

Post Transplant ◽

Pai 1

Idiopathic dilated cardiomyopathy (DCM) is associated with reduced myocardial vascular density and increased collagen deposition with subsequent myocardial fibrosis and heart failure. The urokinase plasminogen activator (uPA)/plasminogen activator inhibitor (PAI) system plays an important role in extracellular matrix homeostasis as well as in preserving the integrity of the vascular endothelial cell (EC) intimal layer and EC regeneration, proliferation and motility. However, the involvement of the uPA/PAI system in DCM and graft remodeling following cardiac transplantation remains unclear. Gene expression of uPA, the uPA receptor uPAR and PAI-1 was examined in left ventricular (LV) biopsies of explanted hearts in 24 ischemic cardiomyopathy (ICM) and 60 DCM patients and 12 controls by real time RT-PCR and Western blotting. Vascular endothelial growth factor (VEGF) and uPA/PAI interplay was examined in stimulated DCM and ICM myocardium in vitro. Expression of uPA and PAI-1 mRNA was evaluated in endomyocardial biopsies (EMB) at 1, 2, 3, 4, 7, 12, 24 and 52 weeks post-transplant. The mRNA levels of uPA and uPAR were unchanged in both ICM and DCM patients compared to controls. PAI-1 mRNA and protein were up-regulated in DCM compared to ICM and controls (p<0.01). Active and inactive uPA protein was down-regulated in DCM and ICM compared to controls (p<0.05). VEGF stimulation in vitro did not affect uPA, uPAR or PAI-1 expression. Following transplantation, PAI-1 expression returned to baseline control levels in EMB from both patient groups, although PAI-1 expression increased at 24 and 52 weeks post-transplant in DCM patients (p<0.01 compared to post-transplant weeks 6 and 12). These data indicate a significant PAI-1 up-regulation associated with uPA down-regulation in DCM, independent of VEGF, which was temporarily corrected by cardiac transplantation. However, recurring up-regulation of myocardial PAI-1 levels at 6 and 12 months post-transplant suggest a persistent PAI-1-related molecular pathology in DCM. We have previously shown increased endothelin-1 expression and collagen deposition in grafts of DCM patients at 1 year post-transplant. The present data point to a previously unknown role of PAI-1 in mediating graft sclerosis.

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