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1.
J Proteomics ; : 103508, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31476444

RESUMO

To identify potential biomarkers supporting better phenotyping and to improve understanding of the pathophysiology of dilated cardiomyopathy (DCM), this study comparatively analyzed plasma protein profiles of DCM patients and individuals with low normal and normal left ventricular ejection fraction (LVEF) by mass spectrometry. After plasma depletion using a MARS Hu-6 column, global proteome profiling was performed using an LTQ-Orbitrap Velos mass spectrometer. To compare and confirm results, two different discovery sets of samples were investigated. Differentially abundant proteins are involved in lipid metabolism, coagulation, and acute phase response. Serum paraoxonase 1 (PON1), cystatin C, lysozyme C, apolipoprotein A-II, and apolipoprotein M were validated by targeted protein analysis in a third independent patient cohort. Additionally, PON1 levels were also determined by an ELISA. These data highlight PON1 as a potential marker for differentiating DCM patients not only from patients with normal LVEF, but also from heart failure patients with preserved ejection fraction. The results highlight lipid metabolism and inflammation as the major pathways being altered in DCM patients in comparison to patients presenting with suspicious myocarditis to the hospital. SIGNIFICANCE: Several studies focused on the identification of heart failure (HF) associated protein signatures in blood plasma, but only few that are largely based on only small sample series considered specific HF pathologies. Therefore, we performed a comparative global blood plasma protein profiling of a larger sample of individuals with reduced left ventricular ejection fraction (LVEF) classified as dilated cardiomyopathy patients and individuals with normal LVEF but presenting with suspicious myocarditis. DCM patients displayed altered levels of proteins involved in lipid metabolism, coagulation, and acute phase response. The most reliable candidates, such as serum paraoxonase 1 (PON1), cystatin C, lysozyme C, apolipoprotein A-II, and apolipoprotein M were validated by targeted protein analysis in an independent patient cohort. PON1 levels were also determined by an ELISA. These data highlight PON1 as a potential marker for differentiating DCM patients not only from patients with normal LVEF, but also from heart failure patients with preserved ejection fraction.

2.
Clin Res Cardiol ; 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31401672

RESUMO

AIMS: In the placebo-controlled, double-blind BOne marrOw transfer to enhance ST-elevation infarct regeneration (BOOST) 2 trial, intracoronary autologous bone marrow cell (BMC) transfer did not improve recovery of left ventricular ejection fraction (LVEF) at 6 months in patients with ST-elevation myocardial infarction (STEMI) and moderately reduced LVEF. Regional myocardial perfusion as determined by adenosine stress perfusion cardiac magnetic resonance imaging (S-CMR) may be more sensitive than global LVEF in detecting BMC treatment effects. Here, we sought to evaluate (i) the changes of myocardial perfusion in the infarct area over time (ii) the effects of BMC therapy on infarct perfusion, and (iii) the relation of infarct perfusion to LVEF recovery at 6 months. METHODS AND RESULTS: In 51 patients from BOOST-2 (placebo, n = 10; BMC, n = 41), S-CMR was performed 5.1 ± 2.9 days after PCI (before placebo/BMC treatment) and after 6 months. Infarct perfusion improved from baseline to 6 months in the overall patient cohort as reflected by the semi-quantitative parameters, perfusion defect-infarct size ratio (change from 0.54 ± 0.20 to 0.43 ± 0.22; P = 0.006) and perfusion defect-upslope ratio (0.54 ± 0.23 to 0.68 ± 0.22; P < 0.001), irrespective of randomised treatment. Perfusion defect-upslope ratio at baseline correlated with LVEF recovery (r = 0.62; P < 0.001) after 6 months, with a threshold of 0.54 providing the best sensitivity (79%) and specificity (74%) (area under the curve, 0.79; 95% confidence interval, 0.67-0.92). CONCLUSION: Infarct perfusion improves from baseline to 6 months and predicts LVEF recovery in STEMI patients undergoing early PCI. Intracoronary BMC therapy did not enhance infarct perfusion in the BOOST-2 trial.

3.
Eur J Med Res ; 24(1): 23, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31331388

RESUMO

BACKGROUND: Data concerning the effect of chronic right ventricular pacing in patients with normal left ventricular ejection fraction (LVEF%) are contradictory. The aim of this study is to evaluate the prevalence of pacing-induced cardiomyopathy (PICM) at midterm follow-up after permanent pacemaker implantation (PPM). METHODS: A series of 170 patients were submitted to PPM within our facility. Inclusion criteria were the absence of structural heart disease and a preserved LVEF% (> 45%) at the time of PPM. A midterm clinical and echocardiographic follow-up was performed, and data were collected and analyzed retrospectively. PICM was defined as follow-up LVEF ≤ 45%, dyskinesia during RV pacing, and the absence of other known causes of cardiomyopathy. RESULTS: At a median echocardiographic follow-up of 24.5 months (IQR 10.0-43.0 months), the overall mean LVEF% decreased from a preimplantation value of 66.7% (± 8.6%) to 63.2% (± 10.6%) (p < 0.0001). PICM occurred in 11 patients (6.5%). Patients developing PICM had a significantly lower preimplantation LVEF% (58.4 ± 8.0% vs. 67.3 ± 8.4%; p = 0.005), a trend for higher right ventricular pacing time rate (0.7 ± 0.3 vs. 0.5 ± 0.4; p = 0.1), a significantly lower rate of PPM indication for sick sinus syndrome (SSS) (18.2% vs. 61.0%; p = 0.009), and significantly higher rate of second-grade cardiac conduction block (36.4% vs. 11.3%; p = 0.03). At multivariate logistic regression, only preimplantation LVEF% (OR = 0.88; CI 0.80-0.96; p = 0.006) and the presence of SSS (OR = 0.1; CI 0.03-0.9; p = 0.04) were independently related (inverse relationship) to follow-up PICM. CONCLUSIONS: In this selected PPM patient cohort with preserved LVEF%, the rate of PICM at midterm follow-up is relatively low, but its occurrence seems to be related to baseline LVEF% and PPM indication category.

4.
Nat Rev Dis Primers ; 5(1): 32, 2019 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-31073128

RESUMO

Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction that is not explained by abnormal loading conditions (for example, hypertension and valvular heart disease) or coronary artery disease. Mutations in several genes can cause DCM, including genes encoding structural components of the sarcomere and desmosome. Nongenetic forms of DCM can result from different aetiologies, including inflammation of the myocardium due to an infection (mostly viral); exposure to drugs, toxins or allergens; and systemic endocrine or autoimmune diseases. The heterogeneous aetiology and clinical presentation of DCM make a correct and timely diagnosis challenging. Echocardiography and other imaging techniques are required to assess ventricular dysfunction and adverse myocardial remodelling, and immunological and histological analyses of an endomyocardial biopsy sample are indicated when inflammation or infection is suspected. As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM. Cardiac resynchronization therapy and implantable cardioverter-defibrillators may be required to prevent life-threatening arrhythmias. In addition, identifying the probable cause of DCM helps tailor specific therapies to improve prognosis. An improved aetiology-driven personalized approach to clinical care will benefit patients with DCM, as will new diagnostic tools, such as serum biomarkers, that enable early diagnosis and treatment.

5.
Viruses ; 11(3)2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30845701

RESUMO

Aims: Human parvovirus B19 (B19V) infection directly induces apoptosis and modulates CXCR4 expression of infected marrow-derived circulating angiogenic cells (CACs). This leads to dysfunctional endogenous vascular repair. Treatment for B19V-associated disease is restricted to symptomatic treatment. Telbivudine, a thymidine analogue, established in antiviral treatment for chronic hepatitis B, modulates pathways that might influence induction of apoptosis. Therefore, we tested the hypothesis of whether telbivudine influences B19V-induced apoptosis of CAC. Methods and Results: Pretreatment of two CAC-lines, early outgrowth endothelial progenitor cells (eo-EPC) and endothelial colony-forming cells (ECFC) with telbivudine before in vitro infection with B19V significantly reduced active caspase-3 protein expression (-39% and -40%, both p < 0.005). Expression of Baculoviral Inhibitor of apoptosis Repeat-Containing protein 3 (BIRC3) was significantly downregulated by in vitro B19V infection in ECFC measured by qRT-PCR. BIRC3 downregulation was abrogated with telbivudine pretreatment (p < 0.001). This was confirmed by single gene PCR (p = 0.017) and Western blot analysis. In contrast, the missing effect of B19V on angiogenic gene expression postulates a post-transcriptional modulation of CXCR4. Conclusions: We for the first time show a treatment approach to reduce B19V-induced apoptosis. Telbivudine reverses B19V-induced dysregulation of BIRC3, thus, intervening in the apoptosis pathway and protecting susceptible cells from cell death. This approach could lead to an effective B19V treatment to reduce B19V-related disease.

6.
Exp Mol Med ; 51(2): 16, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30765687

RESUMO

The lifetime risk of developing heart failure is approximately 20%, and survival rates remain poor. Myocardial mitochondrial function has been suggested to play a pivotal role in heart failure pathophysiology. Human studies on ex vivo mitochondrial function have mostly been limited to atrial tissue obtained during open heart surgery and have provided contradictory results. This study aimed at measuring myocardial mitochondrial function in transcatheter ventricular endomyocardial biopsies and assessing the relationship between oxidative capacity and heart function. We enrolled 40 heart failure patients undergoing ventricular assist device surgery or heart transplantation (34 males, age 57 ± 11 years, body mass index 26.6 ± 4.8 kg/m2) and 29 heart transplant recipients of comparable age and body mass index with normal left ventricular function undergoing surveillance biopsies (23 males, 57 ± 12 years, body mass index 26.2 ± 4.1 kg/m2). High-resolution respirometry was established in the myocardium to measure oxidative capacity ex vivo. The mitochondrial oxidative capacity was 90% higher in ventricular compared to atrial tissues (n = 11, p < 0.01) of explanted hearts. Respiration rates were comparable in ventricular samples of heart failure patients obtained during open heart surgery by standard tissue preparation or ex vivo endomyocardial biopsy (r = 0.9988, p < 0.0001, n = 8), and the mitochondrial oxidative capacity in samples from these patients remained stable for 8 h when stored in either of two common preservation buffers. The oxidative capacity was 44% lower in heart failure than in transplant recipients (67 ± 3 vs. 97 ± 5 pmol/[s mg], p < 0.0001) and correlated positively with heart function (r = 0.49, p < 0.01). High-resolution respirometry of ventricular tissue is feasible in transcatheter biopsies, facilitating clinical studies on myocardial mitochondrial function in patients not undergoing heart surgery.


Assuntos
Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Ventrículos do Coração/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo , Idoso , Biomarcadores , Biópsia , Respiração Celular , Comorbidade , Expressão Gênica , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Peróxido de Hidrogênio/metabolismo , Pessoa de Meia-Idade , Mitocôndrias Cardíacas/metabolismo , Miocárdio/patologia , Oxirredução
7.
J Am Heart Assoc ; 8(2): e008968, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30638108

RESUMO

Background Myocarditis is an important cause of acute and chronic heart failure. Men with myocarditis have worse recovery and an increased need for transplantation compared with women, but the reason for the sex difference remains unclear. Elevated sera soluble (s) ST2 predicts mortality from acute and chronic heart failure, but has not been studied in myocarditis patients. Methods and Results Adults with a diagnosis of clinically suspected myocarditis (n=303, 78% male) were identified according to the 2013 European Society of Cardiology position statement. Sera sST2 levels were examined by ELISA in humans and mice and correlated with heart function according to sex and age. Sera sST2 levels were higher in healthy men ( P=8×10-6) and men with myocarditis ( P=0.004) compared with women. sST2 levels were elevated in patients with myocarditis and New York Heart Association class III - IV heart failure ( P=0.002), predominantly in men ( P=0.0003). Sera sST2 levels were associated with New York Heart Association class in men with myocarditis who were ≤50 years old ( r=0.231, P=0.0006), but not in women ( r=0.172, P=0.57). Sera sST2 levels were also significantly higher in male mice with myocarditis ( P=0.005) where levels were associated with cardiac inflammation. Gonadectomy with hormone replacement showed that testosterone ( P<0.001), but not estradiol ( P=0.32), increased sera sST2 levels in male mice with myocarditis. Conclusions We show in a well-characterized subset of heart failure patients with clinically suspected and biopsy-confirmed myocarditis that elevated sera sST2 is associated with an increased risk of heart failure based on New York Heart Association class in men ≤50 years old.

8.
J Transl Med ; 16(1): 249, 2018 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-30180856

RESUMO

BACKGROUND: Enteroviral cardiomyopathy is a life-threatening disease, and detection of enterovirus (EV) RNA in the initial endomyocardial biopsy is associated with adverse prognosis and increased mortality. Some patients with EV infection may spontaneously eliminate the virus and recover, whereas those with virus persistence deteriorate and progress to heart failure. Interferon-beta (IFN-ß) therapy eliminates the virus, resulting in increased survival of treated patients. CCR5 is expressed on antigen-presenting cells (both macrophages and dendritic cells) and immune effector cells (T-lymphocytes with memory/effector phenotype and natural killer cells). Its 32-bp deletion (CCR5del32) is the most frequent human coding sequence mutation. This study addresses the correlation of CCR5 polymorphism to the clinical course of EV infection and the necessity for IFN-ß treatment. METHODS: We examined 97 consecutive patients with chronic/inflammatory cardiomyopathy and biopsy-proven EV infection and reliable information on clinical outcomes by CCr5 genotyping. These data were evaluated in relation to virus persistence in follow-up biopsies and survival rates over a 15-year period. RESULTS: Genotyping revealed a strong correlation between the CCR5del32 genotype and spontaneous virus clearance with improved outcomes. All patients with CCR5del32 eliminated EV spontaneously and none of them died within the observed period. In the group of untreated CCR5 wildtype patients, 33% died (Kaplan-Meier log-rank p = 0.010). However, CCR5 wildtype individuals treated with IFN-ß are more likely to survive than without therapy (Kaplan-Meier log-rank p = 0.004) in identical proportions to individuals with the CCR5del32 genotype. CONCLUSIONS: These data suggest that CCR5 genotyping is a novel predictive genetic marker for the clinical course of human EV cardiomyopathies. Hereby clinicians can identify those EV positive individuals who will eliminate the virus spontaneously based on CCR5 phenotype and those patients with CCR5 wildtype genotype who would be eligible for immediate antiviral IFN-ß treatment to minimize irreversible cardiac damage.

9.
ESC Heart Fail ; 5(4): 630-641, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29745463

RESUMO

BACKGROUND: Aetiology of heart failure (HF) often remains obscure. We therefore evaluated the usefulness of a combined diagnostic approach including cardiac magnetic resonance imaging (CMRI) and endomyocardial biopsy (EMB) to assess the cause of unexplained cardiomyopathy underlying HF. METHODS AND RESULTS: We retrospectively investigated 100 consecutive patients (36% women, mean age 53.6 ± 18.8 years) presenting with unexplained cardiomyopathy (HF with reduced ejection fraction or left ventricular hypertrophy; excluding ischaemic and valvular heart disease; left ventricular ejection fraction 31.6 ± 13.9%, Left ventricular end-diastolic pressure 18.2 ± 9.3 mmHg, heart rate 89 ± 26.6 b.p.m.; mean ± SEM) at the University Medical Center Mainz. We performed electrocardiography, echocardiography, CMRI, and cardiac catheterization with EMB analysed at a Food and Drug Administration-approved reference centre in 100%, 94%, 69%, and 100% of patients, respectively. On the basis of CMRI findings, electrocardiography, echocardiography, and medical history, the exact cause of cardiomyopathy remained uncertain in 37 of 69 cases (53.6%). In EMB, 25% of patients had viral replication, 23% had inflammation defined as lymphocytic infiltrations without active virus replication, 1% had giant cell myocarditis, and 1% had eosinophilic myocarditis. After diagnostic workup including EMB findings, the cause of cardiomyopathy remained unidentified in 14% of the cases, classified as idiopathic dilated cardiomyopathy or hypertrophic cardiomyopathy in 10% or 4%, respectively. EMB helped to discuss a causal treatment strategy of HF involving immunosuppression or antiviral treatment in 53% of patients, which was opted for in 12% of the patients. CONCLUSIONS: A comprehensive workup including imaging and EMB in an all-comer population of patients with HF may help physicians to improve diagnostics of unexplained cardiomyopathy in the majority of cases.

10.
J Infect Dis ; 217(3): 456-465, 2018 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-28961998

RESUMO

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.

11.
Heart Vessels ; 33(2): 205-211, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28808788

RESUMO

Prediction of follow-up shock is crucial to stratify patients with dilated cardiomyopathy (DCM) requiring implantable cardioverter defibrillator (ICD). The objective of the article is to assess the predictive value of endo-myocardial biopsy (EMB) towards ICD shock and follow-up mortality. A series of patients with DCM scheduled for ICD implantation underwent EMB to further determine the genesis of DCM. Presence of fibrosis and inflammation was documented and related to outcomes. A total of 240 patients were referred for ICD as primary (56%) and secondary (44%) prophylaxis. EMB showed myocardial fibrosis in 55.4%, inflammation in 55.7%, and viral genomic material in 60%. Median follow-up was 39 months (1-209). Appropriate and inappropriate shocks occurred in 29.2 and 20.4%. At logistic regression, determinants of appropriate shock were ICD indication for secondary prophylaxis (direct relationship: p = 0.009, OR 3.4, CI 1.3-8.8) and presence of inflammation at EMB (inverse relationship: p = 0.04, OR 0.4, CI 0.1-0.9). Moreover, the sole determinant of inappropriate shock was age at implant (inverse relationship: p = 0.003, OR = 0.9, CI 0.90-0.98). Overall mean estimated survival was 168 months and 5-year survival was 83%. Degree of improvement in LVEF% was the sole determinant of follow-up mortality (inverse relationship p = 0.02; HR = 0.9; CI 0.88-0.99). Present selection criteria for ICDs implant rely mainly on LVEF% that lacks sensitivity and specificity. EMB can identify the substrate of increased or reduced life-threatening arrhythmias. Presence of inflammation is a positive prognostic factor for reduced arrhythmogenic risk, independently by the ICD implantation indication.


Assuntos
Biópsia/métodos , Cardiomiopatia Dilatada/terapia , Desfibriladores Implantáveis , Miocárdio/patologia , Choque Cardiogênico/etiologia , Cardiomiopatia Dilatada/diagnóstico , Ecocardiografia , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Choque Cardiogênico/diagnóstico , Choque Cardiogênico/epidemiologia , Taxa de Sobrevida/tendências
12.
Eur Heart J ; 39(10): 876-887, 2018 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-29136142

RESUMO

Aims: Foxo3 is a transcription factor involved in cell metabolism, survival, and inflammatory disease. However, mechanistic insight in Foxo3 effects is still limited. Here, we investigated the role of Foxo3 on natural killer (NK) cell responses and its effects in viral myocarditis. Methods and results: Effects of Foxo3 on viral load and immune responses were investigated in a model of coxsackie virus B3 myocarditis in wild-type (WT) and Foxo3 deficient mice. Reduced immune cell infiltration, viral titres, and pro-inflammatory cytokines in cardiac tissue were observed in Foxo3-/- mice 7 days post-infection (p.i.). Viral titres were also attenuated in hearts of Foxo3-/- mice at Day 3 while interferon-γ (IFNγ) and NKp46 expression were up-regulated suggesting early viral control by enhanced NK cell activity. CD69 expression of NK cells, frequencies of CD11b+CD27+ effector NK cells and cytotoxicity of Foxo3-/- mice was enhanced compared to WT littermates. Moreover, microRNA-155 expression, essential in NK cell activation, was elevated in Foxo3-/- NK cells while its inhibition led to diminished IFNγ production. Healthy humans carrying the longevity-associated FOXO3 single nucleotide polymorphism (SNP) rs12212067 exhibited reduced IFNγ and cytotoxic degranulation of NK cells. Viral inflammatory cardiomyopathy (viral CMI) patients with this SNP showed a poorer outcome due to less efficient virus control. Conclusion: Our results implicate Foxo3 in regulating NK cell function and suggest Foxo3 playing an important role in the antiviral innate immunity. Thus, enhanced FOXO3 activity such as in the polymorphism rs12212067 may be protective in chronic inflammation such as cancer and cardiovascular disease but disadvantageous to control acute viral infection.

13.
Eur J Heart Fail ; 20(4): 751-757, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29067795

RESUMO

AIMS: To evaluate the influence of endomyocardial biopsy (EMB)-proven intramyocardial inflammation on mortality in patients with cardiac transthyretin amyloid (ATTR) or amyloid light-chain (AL) amyloidosis. METHODS AND RESULTS: We included 54 consecutive patients (mean age 68.83 ± 9.59 years; 45 men) with EMB-proven cardiac amyloidosis. We followed up patients from first diagnostic biopsy to as long as 36 months (mean 11.5 ± 12 months) and compared their outcome with information on all-cause mortality with or without proof of inflammation on EMB. Intramyocardial inflammation was assessed by quantitative immunohistology. Patients suffering from amyloidosis revealed a significant poor prognosis with proof of intramyocardial inflammation in contrast to those without inflammation (log-rank P = 0.019). Re-grouping of patients indicated AL amyloidosis to have a significant impact on all-cause mortality (log-rank P = 0.012). The detailed subgroup analysis showed that patients suffering from AL amyloidosis with intramyocardial inflammation have a significantly worse prognosis compared with AL amyloidosis without inflammation and ATTR with or without inflammation, respectively (log-rank P = 0.014, contingency Fisher's exact test, P = 0.008). CONCLUSION: Our study reports for the first time a high incidence (48.1%) of intramyocardial inflammation in a series of patients with EMB-proven cardiac amyloidosis and could show that in patients with AL amyloidosis, intramyocardial inflammation correlated significantly with increased mortality. Our data have a direct clinical impact because one can hypothesize that additional immunomodulating/anti-inflammatory treatment regimens in patients with biopsy-proven inflammation of heart muscle tissue could be beneficial for patients suffering from cardiac AL amyloidosis.

14.
Physiol Rep ; 5(24)2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29263115

RESUMO

Adiponectin (APN) is a multifunctional adipocytokine that inhibits myocardial fibrosis, dilatation, and left ventricular (LV) dysfunction after myocardial infarction (MI). Coxsackievirus B3 (CVB3) myocarditis is associated with intense extracellular matrix (ECM) remodeling which might progress to dilated cardiomyopathy. Here, we investigated in experimental CVB3 myocarditis whether APN inhibits adverse ECM remodeling following cardiac injury by affecting matrix metalloproteinase (MMP) expression. Cardiac injury was induced by CVB3 infection in APN knockout (APN-KO) and wild-type (WT) mice. Expression and activity of MMPs was quantified by qRT-PCR and zymography, respectively. Activation of protein kinases was assessed by immunoblot. In cardiac myocytes and fibroblasts APN up-regulates MMP-9 expression via activation of 5' adenosine monophosphate-activated protein kinase (AMPK) and extracellular signal-regulated kinase (ERK)1/2 which function as master regulators of inflammation-induced MMP-9 expression. Correspondingly, APN further increased up-regulation of MMP-9 expression triggered by tumor necrosis factor (TNF)α, lipopolysaccharide (LPS) and R-848 in cardiac fibroblasts. In vivo, compared to WT mice cardiac MMP-9 activity and serum levels of carboxy-terminal telopeptide of type I collagen (ICTP) were attenuated in APN-KO mice in subacute (day 7 p.i.) CVB3 myocarditis. Moreover, on day 3 and day 7 post CVB3 infection splenic MMP-9 expression was diminished in APN-KO mice correlating with attenuated myocardial immune cell infiltration in subacute CVB3 myocarditis. These results indicate that APN attenuates adverse cardiac remodeling following cardiac injury by up-regulating MMP-9 expression in cardiac and immune cells. Thus, APN mediates intensified collagen cleavage that might explain inhibition of LV fibrosis and dysfunction.


Assuntos
Adiponectina/metabolismo , Matriz Extracelular/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Miocardite/metabolismo , Animais , Células Cultivadas , Colágeno Tipo I/metabolismo , Matriz Extracelular/patologia , Feminino , Fibrose , Masculino , Metaloproteinase 9 da Matriz/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Miocardite/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteínas Quinases/metabolismo , Regulação para Cima
15.
J Am Heart Assoc ; 6(8)2017 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-28862949

RESUMO

BACKGROUND: The authors analyzed the effects of perforin-dependent infiltration on long-term mortality in patients with inflammatory cardiomyopathy (CMi). We previously demonstrated that left ventricular function deteriorates and progresses to substantial cardiac dysfunction in patients with perforin-positive cardiac cell infiltration. METHODS AND RESULTS: Between 2003 and 2013, 2389 consecutive patients with clinically suspected CMi who underwent endomyocardial biopsies were enrolled. Endomyocardial biopsies were performed at first admission after exclusion of ischemic or valvular heart disease, and CMi was confirmed in 1717 patients. Follow-up was up to 10.1 years (median 0.47 years; interquartile range, 0.03-2.56 years) and information on vital status was obtained from official resident data files. Multivariable statistical analysis was conducted for all patients with CMi regarding significant predictors of all-cause mortality or need for heart transplantation. Multiple Cox regression analysis revealed perforin above the calculated cutoff point of 2.9 cells/mm² as a strong predictor of impaired survival with a hazard ratio of 1.881 (95% confidence interval, 1.177-3.008; P=0.008), independent of left ventricular function and other myocardial inflammation markers (CD3, macrophage-1 antigen, leukocyte function-associated antigen-1, human leukocyte antigen-1, and intercellular cell adhesion molecule-1). Unexpectedly, male sex emerged as another strong adverse predictor of survival in CMi (hazard ratio, 1.863; confidence interval, 1.096-3.168 [P=0.022]). Whereas left ventricular ejection fraction course is adversely affected by myocardial perforin, multivariate analysis indicates that left ventricular ejection fraction explains only part of the observed overall mortality. CONCLUSIONS: High perforin-positive cardiac cell infiltration and male sex are independent adverse predictors of long-term mortality in CMi. Furthermore, exact quantification of immunohistochemically detected infiltrates is necessary to assess the prognosis.


Assuntos
Cardiomiopatias/mortalidade , Quimiotaxia de Leucócito , Miocardite/mortalidade , Miocárdio/química , Perforina/análise , Adulto , Idoso , Biomarcadores/análise , Biópsia , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Miocardite/metabolismo , Miocardite/patologia , Miocardite/fisiopatologia , Miocárdio/imunologia , Miocárdio/patologia , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores Sexuais , Volume Sistólico , Fatores de Tempo , Regulação para Cima , Função Ventricular Esquerda
16.
Circ Heart Fail ; 10(9)2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28912259

RESUMO

BACKGROUND: The cytoplasmatic pattern recognition receptor, NOD2 (nucleotide-binding oligomerization domain 2), belongs to the innate immune system and is among others responsible for the recognition of single-stranded RNA. With Coxsackievirus B3 (CVB3) being a single-stranded RNA virus, and the recent evidence that the NOD2 target, NLRP3 (NOD-like receptor family, pyrin domain containing 3) is of importance in the pathogenesis of CVB3-induced myocarditis, we aimed to unravel the role of NOD2 in CVB3-induced myocarditis. METHODS AND RESULTS: Endomyocardial biopsy NOD2 mRNA expression was higher in CVB3-positive patients compared with patients with myocarditis but without evidence of persistent CVB3 infection. Left ventricular NOD2 mRNA expression was also induced in CVB3-induced myocarditis versus healthy control mice. NOD2 knockdown(-/-) mice were rescued from the detrimental CVB3-mediated effects as shown by a reduced cardiac inflammation (less cardiac infiltrates and suppression of proinflammatory cytokines), cardiac fibrosis, apoptosis, lower CAR (Coxsackievirus and adenovirus receptor) expression and CVB3 copy number, and an improved left ventricular function in NOD2-/- CVB3 mice compared with wild-type CVB3 mice. In agreement, NOD2-/- decreased the CVB3-induced inflammatory response, CVB3 copy number, and apoptosis in vitro. NOD2-/- was further associated with a reduction in CVB3-induced NLRP3 expression and activity as evidenced by lower ASC (apoptosis-associated speck-like protein containing a CARD) expression, caspase 1 activity, or IL-1ß (interleukin-1ß) protein expression under in vivo and in vitro CVB3 conditions. CONCLUSIONS: NOD2 is an important mediator in the viral uptake and inflammatory response during the pathogenesis of CVB3 myocarditis.


Assuntos
Infecções por Coxsackievirus/metabolismo , Enterovirus Humano B/metabolismo , Miocardite/metabolismo , Miocárdio/metabolismo , Proteína Adaptadora de Sinalização NOD2/metabolismo , Animais , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Adaptadoras de Sinalização CARD , Estudos de Casos e Controles , Caspase 1/metabolismo , Linhagem Celular , Infecções por Coxsackievirus/imunologia , Infecções por Coxsackievirus/prevenção & controle , Infecções por Coxsackievirus/virologia , Modelos Animais de Doenças , Enterovirus Humano B/genética , Enterovirus Humano B/imunologia , Predisposição Genética para Doença , Interações Hospedeiro-Patógeno , Humanos , Interleucina-1beta/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocardite/imunologia , Miocardite/prevenção & controle , Miocardite/virologia , Miocárdio/imunologia , Miocárdio/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína Adaptadora de Sinalização NOD2/deficiência , Proteína Adaptadora de Sinalização NOD2/genética , Fenótipo , Interferência de RNA , Transdução de Sinais , Transfecção , Regulação para Cima
17.
Int J Cardiol ; 243: 374-378, 2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28536004

RESUMO

BACKGROUND: Up to one third of patients with chronic myocarditis (MC) have preserved left ventricular (LV) ejection fraction (MCpEF). The purpose of this study was to evaluate the role of adding 2D speckle-tracking echocardiography (STE) to cardiac magnetic resonance imaging (cMRI) in the diagnosis of patients with MCpEF. METHODS AND RESULTS: We analyzed 67 patients with suspected MCpEF who underwent endomyocardial biopsy (EMB). Thirty-two patients with confirmed chronic myocardial inflammation by EMB served as study group (MCpEF) and the remaining patients (n=35) served as control group. In all patients, 2D STE and cMRI were performed within 48h before EMB. Patients with MCpEF had significantly lower LV global longitudinal systolic strain (GLS) than controls (GLS: -17.01±2.42% vs. -19.39±3.81%, p<0.001; respectively). In line, an abnormal GLS had adequate diagnostic performance to detect MCpEF (sensitivity, specificity, and accuracy of 82%, 70%, and 76%, respectively), which was superior to cMRI based on the Lake-Louise criteria (sensitivity, specificity, and accuracy 54%, 71%, and 67%, respectively). In addition, adding GLS to the Lake-Louise criteria improved significantly the diagnostic performance of cMRI to detect MCpEF (sensitivity, specificity, and accuracy 96%, 55%, and 75%, respectively). CONCLUSION: The findings of this study suggest that GLS using 2D STE could play an important role in the diagnostic evaluation of patients with suspected chronic myocarditis with preserved LV ejection fraction (MCpEF).


Assuntos
Ecocardiografia/métodos , Imagem Multimodal/métodos , Miocardite/diagnóstico por imagem , Miocardite/fisiopatologia , Volume Sistólico/fisiologia , Função Ventricular Esquerda/fisiologia , Adulto , Doença Crônica , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
Eur Heart J ; 38(39): 2936-2943, 2017 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-28431003

RESUMO

Aims: Intracoronary infusion of autologous nucleated bone marrow cells (BMCs) enhanced the recovery of left ventricular ejection fraction (LVEF) after ST-segment elevation myocardial infarction (STEMI) in the randomised-controlled, open-label BOOST trial. We reassessed the therapeutic potential of nucleated BMCs in the randomised placebo-controlled, double-blind BOOST-2 trial conducted in 10 centres in Germany and Norway. Methods and results: Using a multiple arm design, we investigated the dose-response relationship and explored whether γ-irradiation which eliminates the clonogenic potential of stem and progenitor cells has an impact on BMC efficacy. Between 9 March 2006 and 16 July 2013, 153 patients with large STEMI were randomly assigned to receive a single intracoronary infusion of placebo (control group), high-dose (hi)BMCs, low-dose (lo)BMCs, irradiated hiBMCs, or irradiated loBMCs 8.1 ± 2.6 days after percutaneous coronary intervention (PCI) in addition to guideline-recommended medical treatment. Change in LVEF from baseline (before cell infusion) to 6 months as determined by MRI was the primary endpoint. The trial is registered at Current Controlled Trials (ISRCTN17457407). Baseline LVEF was 45.0 ± 8.5% in the overall population. At 6 months, LVEF had increased by 3.3 percentage points in the control group and 4.3 percentage points in the hiBMC group. The estimated treatment effect was 1.0 percentage points (95% confidence interval, -2.6 to 4.7; P = 0.57). The treatment effect of loBMCs was 0.5 percentage points (-3.0 to 4.1; P = 0.76). Likewise, irradiated BMCs did not have significant treatment effects. BMC transfer was safe and not associated with adverse clinical events. Conclusion: The BOOST-2 trial does not support the use of nucleated BMCs in patients with STEMI and moderately reduced LVEF treated according to current standards of early PCI and drug therapy.


Assuntos
Transplante de Medula Óssea/métodos , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Células da Medula Óssea/efeitos da radiação , Método Duplo-Cego , Feminino , Raios gama , Humanos , Infusões Intralesionais , Angiografia por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea , Transplante de Células-Tronco/métodos , Células-Tronco/efeitos da radiação , Transplante Autólogo , Resultado do Tratamento , Função Ventricular Esquerda/fisiologia
19.
ESC Heart Fail ; 4(2): 190-192, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28451456

RESUMO

A healthy woman with acute onset of pulmonary oedema and severely depressed left ventricular function underwent endomyocardial biopsy under the clinical suspicion of fulminant myocarditis. While awaiting the results of biopsy, the situation deteriorated to Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) and extracorporeal membrane oxygenation was implanted. Finally, immunohistochemistry in biopsy specimen corresponded to fulminant lymphocytic myocarditis, although active myocarditis was excluded. Furthermore, gene expression profiling identified giant cell myocarditis although multinuclear cells were absent. This prompted the start of immunosuppression with cortisone and cyclosporine. The patient fully recovered.

20.
Int J Cardiol ; 241: 322-325, 2017 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-28343767

RESUMO

Chronic intramyocardial inflammation (inflammatory cardiomyopathy/DCMi) is linked to the pathogenesis of dilated cardiomyopathy (DCM). Neural cell adhesion molecule (NCAM) is involved in orchestrating cardiac muscle morphogenesis, but is down-regulated after embryogenesis. We investigated NCAM expression in adult DCM hearts, its possible association with DCMi-parameters, and with cardiomyocyte hypertrophy (CMH). Endomyocardial biopsies (EMBs) from DCM patients (n=85; n=37 females; age: 48±19years; LVEF <40%) and controls from non-cardiac deaths were immunostained for DCMi markers and for NCAM expression, and quantified by digital image analysis (DIA). NCAM expression on the intercalated discs and the sarcolemma was confirmed in n=46 (54%) of the DCM-EMBs. In the 17 controls, NCAM expression was confined to scattered intramyocardial nerves, but was absent on cardiomyocytes. DIA-quantified area fraction (AF) of NCAM was significantly (p=0.0001) higher in the DCM hearts (0.0044±0.017) compared with the controls (0.0006±0.0004). Multivariate analysis of DIA-quantified NCAM-AF revealed significant associations with infiltrates (CD18+, CD11a/LFA-1+, CD11b/Mac-1+, TNFα+, CD3+) and with endothelial cell adhesion molecules (CAM; CD54/ICAM-1 and CD29; p<0.05). The mean cardiomyocyte diameter (MCD) correlated highly significantly (p<0.01) with NCAM-AF, ICAM-1-AF, CD29-AF, CD18+ and TNFa+ infiltrates, and was associated less significantly (p<0.05) with CD3+, CD11a/LFA-1+, and CD11b/Mac-1+ infiltrates. In conclusion, NCAM-expression in ca. 50% of adult DCM hearts is associated with CMH, and may be induced by inflammatory pathways.


Assuntos
Cardiomiopatia Dilatada/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Moléculas de Adesão de Célula Nervosa/biossíntese , Adulto , Idoso , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/patologia , Feminino , Expressão Gênica , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Miócitos Cardíacos/patologia , Moléculas de Adesão de Célula Nervosa/genética
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