An unequivocal diagnosis of myocarditis and cardiac virus persistence is based on histological, immunohistological, and molecular biological analyses of endomyocardial biopsies (EMBs). Biopsy-based ...diagnosis of myocarditis has become increasingly important because recent studies have demonstrated the beneficial effects of biopsy-based causal treatment strategies (immunosuppressive or antiviral). Because the risks of major complications caused by EMB procedures have not yet been well defined, we evaluated the incidence of major and minor complications of right ventricular EMB procedures in this retrospective and prospective single-center study.
With the use of a modified Cordis bioptome, 1919 patients underwent 2505 EMB procedures retrospectively over a 9-year period (January 1995 to December 2003), and 496 patients underwent 543 EMB procedures prospectively between January 2004 and December 2005. A total of 2415 patients had 3048 EMB procedures via the right femoral vein approach under biplane fluoroscopic control to evaluate unexplained left ventricular dysfunction (retrospective left ventricular ejection fraction, 49.8+/-18.8%; prospective, 48.8+/-19.7%) after exclusion of secondary causes. During each EMB procedure, an average of 8.2+/-0.8 EMBs were obtained retrospectively and 10.1+/-0.6 specimens prospectively for a total of 26 025 specimens. No patient died or required emergency cardiac surgery. Other major complications like cardiac tamponade requiring pericardiocentesis or complete atrioventricular block requiring permanent pacing were very rare: 0.12% in the retrospective study and 0% in the prospective study. Minor complications such as pericardial effusion, conduction abnormalities, or arrhythmias occurred in 0.20% of the EMB procedures in the retrospective study and 5.5% in the prospective study.
The EMB procedure via the femoral vein approach under fluoroscopic guidance has a very low complication rate when performed by experienced operators.
Giant cell myocarditis (GCM) is a rare disorder in which survival beyond 1 year without heart transplantation is uncommon. Long-term follow-up data on those with such survival are lacking. Twenty-six ...patients with biopsy-proved GCM who survived for >1 year without heart transplantation were identified from a multicenter GCM registry. The incidence of death, transplantation, ventricular assist device placement, and histologically proved disease recurrence was ascertained retrospectively. The rates of recurrent heart failure, ventricular arrhythmias, renal failure, and infectious complications were calculated. The mean age of the cohort was 54.6 ± 13.9 years (65% women). The mean follow-up duration was 5.5 years starting 1 year after diagnosis. There were 3 deaths (12%), 5 heart transplantations (19%), and 1 ventricular assist device placement (4%). Three histologically confirmed recurrences of GCM (12%) occurred between 1.5 and 8 years after diagnosis. Thirteen of 26 patients experienced a total of 30 heart failure episodes ≥1 year after initial diagnosis. There were 23 episodes of elevated creatinine in 12 patients, 41 infectious events in 13 patients, and 19 episodes of ventricular arrhythmias in 6 patients with a total of 144 years of follow-up. Starting 1 year after GCM diagnosis, the combined rate of death, transplantation, ventricular assist device placement, and GCM recurrence was 47% at 5 years. In conclusion, the risk for GCM recurrence continues to ≥8 years after diagnosis.
Aim
To analyze the long-term outcome after immunosuppressive treatment of patients with virus-negative chronic myocarditis or inflammatory cardiomyopathy (CMi).
Methods and results
We investigated ...114 patients with endomyocardial biopsy (EMB)-proven virus-negative chronic myocarditis or CMi, who were treated with prednisone and azathioprine for 6 months. Myocardial inflammation was assessed by quantitative immunohistology. We examined hemodynamic measurements after 6 months and long-term follow-up periods of up to 10 years {median 10.5 months 95 % confidence interval (CI) 11.69–59.16}. At follow-up, the patients showed a significant improvement of left ventricular ejection fraction (LVEF) compared to baseline after 6-month period (LVEF rising from 44.6 ± 17.3 to 51.8 ± 15.5 %,
p
= 0.006) and in the long-term follow-up (LVEF 52.1 ± 15.6 %,
p
= 0.006). Simultaneously, EMB-analysis revealed significant reduction of quantified inflammatory infiltrates (CD3
+
cells 16.03 ± 29.09–8.2 ± 9.0/mm
2
,
p
= 0.002; CD2
+
cells 12.62 ± 20.01 to 6.61 ± 8.47/mm
2
,
p
= 0.001; perforin
+
cells 3.94 ± 4.65–1.03 ± 1.47/mm
2
,
p
= 0.0001), and cell-adhesion molecule HLA-1 9.91 ± 5.55–6.65 ± 2.81/area fraction (AF),
p
= 0.0001. In a subgroup analysis, patients with initial LVEF ≤45 % (
n
= 53) significantly increased with LVEF at follow-up (29.3 ± 8.8–41.7 ± 13.2–42.1 ± 13.1 %,
p
< 0.0001, Group I), defined as CMi. Patients with initial LVEF >45–60 % (
n
= 25) significantly improved further or recovered completely, regarding LVEF (53.0 ± 3.6–59.0 ± 9.4–59.8 ± 10.0 %,
p
= 0.03, Group II). Patients with initial LVEF >60 % (
n
= 36) remained stable and did not deteriorate over long-term follow-up (68.8 ± 6.7–67.5 ± 10.9–68.8 ± 10.7 %,
p
= 0.5, Group III). Groups II and III were defined as chronic myocarditis.
Conclusions
In patients with virus-negative chronic myocarditis or CMi, we could show the effectiveness and beneficial effects of immunosuppressive treatment. Based on the normalization of the inflammatory process LVEF improvement is lasting for a long-term period of time.
To retrospectively compare the diagnostic accuracy of three cardiac magnetic resonance (MR) imaging approaches for the detection of histologic and immunohistologic criteria (reference standard) ...proved myocardial inflammation in patients clinically suspected of having chronic myocarditis (CMC).
Cardiac MR imaging was performed in 83 consecutive patients (55 male, 28 female; mean age, 44.8 years +/- 17.7 standard deviation) clinically suspected of having CMC, after written informed consent was obtained according to guidelines of the local ethics committee, which approved the study. T2-weighted triple-inversion-recovery imaging to calculate the edema ratio (ER), T1-weighted imaging before and after contrast agent administration to calculate the myocardial global relative enhancement (gRE), and inversion-recovery gradient-echo imaging to evaluate areas of late gadolinium enhancement (LE) were performed. The MR results were correlated with the endomyocardial biopsy (EMB) findings to detect intramyocardial inflammation and cardiotropic viral genomes analyzed at polymerase chain reaction assay. For statistical analyses, receiver operating characteristic analysis and the Wilcoxon test for unpaired data were used because the Kolomogorov-Smirnov test revealed a distribution of data that was different from normality.
Intramyocardial inflammation and cardiotropic viral persistence were confirmed at immunohistologic analysis in 48 and 49 of the 83 patients, respectively. The sensitivity, specificity, and diagnostic accuracy of the MR parameters, as compared with the immunohistologic detection of inflammation, were, respectively, 62%, 86%, and 72% for gRE; 67%, 69%, and 68% for ER; and 27%, 80%, and 49% for LE. Cardiac MR-derived gRE, ER, and LE were not associated with polymerase chain reaction proof of viral genomes.
In patients clinically suspected of having CMC, increased gRE and ER indicating inflammation were common findings that could be confirmed at immunohistologic analysis, whereas LE had low sensitivity and accuracy. Cardiac MR imaging may be helpful in detecting intramyocardial inflammation noninvasively, but it fails to depict viral persistence.
Aim
The acute phase of a coxsackievirus 3 (CVB3)‐induced myocarditis involves direct toxic cardiac effects and the systemic activation of the immune system, including the cardiosplenic axis. ...Consequently, the nucleotide‐binding oligomerization domain‐like receptor pyrin domain‐containing‐3 (NLRP3) inflammasome pathway is activated, which plays a role in disease pathogenesis and progression. The anti‐inflammatory drug colchicine exerts its effects, in part, via reducing NLRP3 activity, and has been shown to improve several cardiac diseases, including acute coronary syndrome and pericarditis. The aim of the present study was to evaluate the potential of colchicine to improve experimental CVB3‐induced myocarditis.
Methods and results
C57BL6/j mice were intraperitoneally injected with 1 × 105 plaque forming units of CVB3. After 24 h, mice were treated with colchicine (5 μmol/kg body weight) or phosphate‐buffered saline (PBS) via oral gavage (p.o.). Seven days post infection, cardiac function was haemodynamically characterized via conductance catheter measurements. Blood, the left ventricle (LV) and spleen were harvested for subsequent analyses. In vitro experiments on LV‐derived fibroblasts (FB) and HL‐1 cells were performed to further evaluate the anti‐(fibro)inflammatory and anti‐apoptotic effects of colchicine via gene expression analysis, Sirius Red assay, and flow cytometry. CVB3 + colchicine mice displayed improved LV function compared with CVB3 + PBS mice, paralleled by a 4.7‐fold (P < 0.01) and 1.7‐fold (P < 0.001) reduction in LV CVB3 gene expression and cardiac troponin‐I levels in the serum, respectively. Evaluation of components of the NLRP3 inflammasome revealed an increased percentage of apoptosis‐associated speck‐like protein containing a CARD domain (ASC)‐expressing, caspase‐1‐expressing, and interleukin‐1β‐expressing cells in the myocardium and in the spleen of CVB3 + PBS vs. control mice, which was reduced in CVB3 + colchicine compared with CVB3 + PBS mice. This was accompanied by 1.4‐fold (P < 0.0001), 1.7‐fold (P < 0.0001), and 1.7‐fold (P < 0.0001) lower numbers of cardiac dendritic cells, natural killer cells, and macrophages, respectively, in CVB3 + colchicine compared with CVB3 + PBS mice. A 1.9‐fold (P < 0.05) and 4.6‐fold (P < 0.001) reduced cardiac gene expression of the fibrotic markers, Col1a1 and lysyl oxidase, respectively, was detected in CVB3 + colchicine mice compared with CVB3 + PBS animals, and reflected by a 2.2‐fold (P < 0.05) decreased Collagen I/III protein ratio. Colchicine further reduced Col3a1 mRNA and collagen protein expression in CVB3‐infected FB and lowered apoptosis and viral progeny release in CVB3‐infected HL‐1 cells. In both CVB3 FB and HL‐1 cells, colchicine down‐regulated the NLRP3 inflammasome‐related components ASC, caspase‐1, and IL‐1β.
Conclusions
Colchicine improves LV function in CVB3‐induced myocarditis, involving a decrease in cardiac and splenic NLRP3 inflammasome activity, without exacerbation of CVB3 load.
Human herpesvirus-6A and B (HHV-6A, HHV-6B) have recently defined endogenous genomes, resulting from integration into the germline: chromosomally-integrated "CiHHV-6A/B". These affect approximately ...1.0% of human populations, giving potential for virus gene expression in every cell. We previously showed that CiHHV-6A was more divergent than CiHHV-6B by examining four genes in 44 European CiHHV-6A/B cardiac/haematology patients. There was evidence for gene expression/reactivation, implying functional non-defective genomes. To further define the relationship between HHV-6A and CiHHV-6A we used next-generation sequencing to characterize genomes from three CiHHV-6A cardiac patients. Comparisons to known exogenous HHV-6A showed CiHHV-6A genomes formed a separate clade; including all 85 non-interrupted genes and necessary cis-acting signals for reactivation as infectious virus. Greater single nucleotide polymorphism (SNP) density was defined in 16 genes and the direct repeats (DR) terminal regions. Using these SNPs, deep sequencing analyses demonstrated superinfection with exogenous HHV-6A in two of the CiHHV-6A patients with recurrent cardiac disease. Characterisation of the integration sites in twelve patients identified the human chromosome 17p subtelomere as a prevalent site, which had specific repeat structures and phylogenetically related CiHHV-6A coding sequences indicating common ancestral origins. Overall CiHHV-6A genomes were similar, but distinct from known exogenous HHV-6A virus, and have the capacity to reactivate as emerging virus infections.
Human parvovirus B19 (B19V) infection is responsible for apoptosis of angiogenic cells and dysfunctional endogenous vascular repair with secondary end-organ damage. We here show that B19V deranges ...the CXCR4/SDF-1α axis, leading to impaired cardiac regeneration in symptomatic chronic B19V cardiomyopathy.
Abstract
Background
Human parvovirus B19 (B19V) infection and damage of circulating angiogenic cells (CAC) results in dysfunctional endogenous vascular repair (DEVR) with secondary end-organ damage. Trafficking of CAC is regulated by SDF-1α and the respective receptor CXCR4. We thus tested the hypothesis of a deregulated CXCR4/SDF-1α axis in symptomatic B19V-cardiomyopathy.
Methods
CAC were infected in vitro with B19V and transfected with B19V-components. Read-out were: CXCR4-expression and migratory capacity at increasing doses of SDF-1α. In 31 patients with chronic B19V-cardiomyopathy compared to 20 controls read-outs were from blood: migratory capacity, CXCR4 expression on CAC, serum SDF-1α; from cardiac biopsies: SDF-1α mRNA, HIF-1α mRNA, microvascular density, resident cardiac stem cells (CSC), transcardiac gradients of CAC.
Results
In vitro B19V-infected CAC showed up-regulation of surface CXCR4 with increased migratory capacity further enhanced by elevated SDF-1α concentrations. Overexpression of the B19V capsid protein VP2 was associated with this effect. Chronic B19V-cardiomyopathy patients showed increased numbers of ischaemia mobilised CAC but DEVR as well as diminished numbers of CAC after transcardiac passage. Cardiac microvascular density and CSC were significantly reduced in B19V-cardiomyopathy.
Conclusions
We thus conclude that B19V infection has a direct VP2-mediated negative impact on trafficking of CAC in the presence of impaired cardiac regeneration.
Background. The diagnosis of acute myocarditis (AMC) and inflammatory cardiomyopathy (DCMi) can be difficult. Speckle tracking echocardiography with accurate assessments of regional contractility ...could have an outstanding importance for the diagnosis. Methods and Results. N=25 patients with clinically diagnosed AMC who underwent endomyocardial biopsies (EMBs) were studied prospectively. Speckle tracking imaging was examined at the beginning and during a mean follow-up period of 6.2 months. In the acute phase patients had markedly decreased left ventricular (LV) systolic function (mean LV ejection fraction (LVEF) 40.4±10.3%). At follow-up in n=8 patients, inflammation persists, correlating with a significantly reduced fractional shortening (FS, 21.5±6.0%) in contrast to those without inflammation in EMB (FS 32.1±7.1%, P<0.05). All AMC patients showed a reduction in global systolic longitudinal strain (LS, −8.36±−3.47%) and strain rate (LSR, 0.53±0.29 1/s). At follow-up, LS and LRS were significantly lower in patients with inflammation, in contrast to patients without inflammation (−9.4±1.4 versus −16.8±2.0%, P<0.0001; 0.78±0.4 versus 1.3±0.3 1/s). LSR and LS correlate significantly with lymphocytic infiltrates (for CD3 r=0.7, P<0.0001, and LFA-1 r=0.8, P<0.0001). Conclusion. Speckle tracking echocardiography is a useful adjunctive assisting tool for evaluation over the course of intramyocardial inflammation in patients with AMC and DCMi.
Myocarditis is an inflammatory disease of the cardiac muscle caused by myocardial infiltration of immunocompetent cells following any kind of cardiac injury. Classic myocarditis mainly occurs as a ...result of the host's immune response against organisms that cause common infectious illnesses, as a manifestation of hypersensitivity or as a toxic reaction to drug therapy. Chronic inflammatory events may survive successful clearance of initial cardiotoxic agents, be triggered or amplified by autoimmunological processes, or develop in the context of systemic diseases. If the underlying infectious or immune-mediated causes of the disease are carefully defined by clinical and biopsy-based tools, specific immunosuppressive and antiviral treatment options may improve the prognosis of patients with acute and chronic disease.
Abstract
Background
The aetiology of dilated cardiomyopathy (DCM) is highly heterogeneous including genetic and/or acquired (infective, toxic, immune, endocrine, and nutritional) factors. The major ...part of acquired DCM in developed countries is caused by either viral or autoimmune myocarditis. It is believed that the activation of the T-lymphocyte cell system is the major pathomechanism underlying autoimmune myocarditis and inflammatory DCM (DCMi). However, in the hearts of a subset of patients, a significant number of CD20+ B-lymphocytes can be detected too. Limited information exists on the role of B-cell-dependent mechanisms in the progression of DCMi. Particularly CD20+ B-lymphocytes, which can be targeted by anti-CD20+ B-lymphocytes antibodies or inhibitors, might contribute to the pathogenesis of myocardial damage beyond antibody production.
Case summary
Here, we present a case series of six patients with subacute and chronic endomyocardial biopsy-proven CD20+ B-lymphocyte-associated DCMi, where symptomatic heart failure therapy, with or without combined immunosuppressive therapy with steroid-based treatment regime, was insufficient to improve cardiac function. Five patients improved clinically several weeks after a standard infusion protocol with rituximab, a chimeric monoclonal antibody against the pan-B-cell surface molecule CD20.
Discussion
Our case series shows that CD20+ B-lymphocyte persistence can play a pathophysiologic role in a subset of DCMi patients and highlights the potential of targeting CD20+ B cells in patients with prominent CD20+ B-lymphocyte persistence.
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