RESUMEN
AIMS: Human herpesvirus 6 (HHV-6) A and B are two betaherpesviruses that are associated with many conditions including roseola, drug-induced hypersensitivity syndrome, limbic encephalitis, and myocarditis. HHV-6 is integrated in the germline [chromosomically integrated HHV-6 (ciHHV-6)] in â¼0.8% of the human population. To date, the prevalence, species distribution, and treatment responses of ciHHV-6 are unknown for cardiac patients. METHODS AND RESULTS: We determined the prevalence of HHV-6 and ciHHV-6 genotypes in 1656 endomyocardial biopsies of patients with persisting unexplained symptoms of heart failure. Infection of cardiac tissue was identified by nested PCR, electron microscopy, and immunohistochemistry. Virus load and mRNA levels were followed in ciHHV-6 patients treated with ganciclovir. HHV-6 was detected in 273 of 1656 cardiac tissues (16.5%; HHV-6B, 98.2%, HHV-6A, 1.8%) by PCR. Nineteen of the 1656 patients (1.1%) presented with persistently high HHV-6 copy numbers indicative of ciHHV-6. Sequencing confirmed ciHHV-6A in seven patients (36.8%) which was considerably higher than detected in non-ciHHV-6 patients. Inheritance was demonstrated in three selected families, confirming ciHHV-6 chromosomal integration by PCR and fluorescence in situ hybridization. HHV-6 reactivation and chromosomal integration were confirmed in peripheral blood mononuclear cells and heart tissue. Virus particles were identified in degenerating myocytes and interstitial cells. Antiviral treatment abolished viral mRNA and ameliorated cardiac symptoms. CONCLUSION: Virus replication in cardiac tissue of ciHHV-6 heart failure patients suggests that ciHHV-6 reactivation causes persistence of unexplained heart failure symptoms. We demonstrated that antiviral treatment, effective in decreasing viral transcripts and clinical complaints of cardiomyopathies, is a new therapeutic option for ciHHV-6-associated diseases.
Asunto(s)
ADN Viral/genética , Insuficiencia Cardíaca/epidemiología , Corazón/virología , Herpesvirus Humano 6/genética , Miocardio/metabolismo , Infecciones por Roseolovirus/epidemiología , Integración Viral , Adulto , Antivirales/uso terapéutico , Cardiomiopatía Dilatada/epidemiología , Cardiomiopatía Dilatada/virología , Estudios de Cohortes , Femenino , Ganciclovir/uso terapéutico , Alemania/epidemiología , Insuficiencia Cardíaca/virología , Humanos , Masculino , Microscopía Electrónica , Persona de Mediana Edad , Miocarditis/epidemiología , Miocarditis/virología , Miocardio/ultraestructura , Prevalencia , Estudios Prospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Infecciones por Roseolovirus/tratamiento farmacológico , Resultado del Tratamiento , Carga ViralRESUMEN
BACKGROUND: Cardiotropic viral infections have been suspected as one possible cause of myocarditis and dilated cardiomyopathy. Although adverse outcomes in dilated cardiomyopathy patients have been documented, the natural course of heart diseases caused by cardiotropic viruses is unknown. METHODS AND RESULTS: Consecutive patients (n=172) with biopsy-proven viral infection in endomyocardial biopsies (EMBs) were followed up by reanalysis of EMBs and hemodynamic measurements after a median period of 6.8 months (range, 5.4 to 11.9). Nested polymerase chain reaction (PCR) and reverse transcription-PCR were performed to analyze the genomic sequences. Myocardial inflammation was assessed by histology and immunohistology. At baseline, 32.6% of EMBs in the study group contained enteroviral (EV) RNA, 8.1% adenovirus (ADV) DNA, 36.6% parvovirus B19 (PVB19) DNA, and 10.5% human herpesvirus type 6 (HHV6) DNA. In 12.2% of the samples, dual infection with PVB19 and HHV6 was present. Follow-up analysis of EMBs by PCR documented spontaneous clearance of viral genomes in 36.2% (55/151) of all patients with single infections. Virus-specific clearance rates were 50% for EV, 35.7% for ADV, 22.2% for PVB19, and 44.4% for HHV6. In patients with dual infection with PVB19+ and HHV6(+)-, HHV6 was cleared in 42.8% (9/21), whereas PVB19 persisted in all 21 patients. Clearance of viral genomes was associated with a significant improvement in left ventricular ejection fraction (LVEF), improving from 50.2+/-19.1% to 58.1+/-15.9% (P<0.001). In contrast, LV function decreased in patients with persisting viral genomes (LVEF, 54.3+/-16.1% versus 51.4+/-16.1%, P<0.01). CONCLUSIONS: In this first biopsy-based analysis of the course of viral heart disease, we show that EV, ADV, PVB19, and HHV6 persistence detected in the myocardium of patients with LV dysfunction was associated with a progressive impairment of LVEF, whereas spontaneous viral elimination was associated with a significant improvement in LV function.
Asunto(s)
Volumen Sistólico , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Izquierda/virología , Virosis/complicaciones , Adenoviridae/aislamiento & purificación , Adulto , Enterovirus/aislamiento & purificación , Femenino , Estudios de Seguimiento , Corazón/virología , Hemodinámica , Herpesvirus Humano 6/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Parvovirus B19 Humano/aislamiento & purificación , Factores de Tiempo , Disfunción Ventricular Izquierda/patologíaRESUMEN
BACKGROUND: Viral cardiomyopathy resulting from myocardial virus persistence can be associated with inflammatory immune responses that involve the myocardium and coronary blood vessels. The aim of this study was to investigate the differential impact of myocardial virus persistence and inflammation on endothelial function of the coronary microcirculation. METHODS AND RESULTS: In 71 patients with nonischemic cardiomyopathy, myocardial biopsies were examined for virus persistence (by polymerase chain reaction) and inflammation (by immunohistology). Endothelial function of the coronary microcirculation was examined during heart catheterization by measuring diameter (by quantitative coronary angiography) and velocity changes (by intracoronary Doppler) of the left anterior descending artery in response to acetylcholine. Coronary blood flow (CBF) was calculated. Endothelium-independent vasoreactivity to adenosine was assessed. Mean age of the patients (37 men, 34 women) was 43+/-13 years; mean ejection fraction was 64+/-11%. In 43 patients, adenovirus, enterovirus, parvovirus, or HHV-6 was detected; 28 had no virus. Endothelial function of the coronary microcirculation was significantly impaired in patients with myocardial virus persistence (V) compared with patients without virus (Co) (DeltaCBF-V, 22+/-86%; DeltaCBF-Co, 110+/-113%; P=0.001), which was confirmed in 51 patients with myocardial inflammation (MC) (32 with virus, 19 with no virus) (DeltaCBF-MC-V, 12+/-89%; DeltaCBF-MC-Co, 81+/-109%; P=0.034) and in 20 patients with normal immunohistology of the myocardial biopsies (Co) (11 with virus, 9 with no virus) (DeltaCBF-Co-V, 51+/-72%; DeltaCBF-Co-Co, 175+/-97%; P=0.006). Endothelial function of the coronary microcirculation was also significantly impaired in patients with myocardial inflammation/endothelial activation compared with patients without inflammatory immune response. Endothelium-independent vasodilation was not influenced significantly. CONCLUSIONS: Myocardial virus persistence and myocardial inflammation/endothelial activation are associated with endothelial dysfunction of the coronary microcirculation. Endothelial dysfunction in patients with myocardial virus persistence can occur independently of myocardial inflammation/endothelial activation but is more pronounced in patients with concurrent inflammation.
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Cardiomiopatías/fisiopatología , Cardiomiopatías/virología , Quimiotaxis de Leucocito/fisiología , Circulación Coronaria , Endotelio Vascular/fisiopatología , Endotelio Vascular/virología , Adulto , Biopsia , Cardiomiopatías/patología , Angiografía Coronaria , Ecocardiografía Doppler , Endotelio Vascular/patología , Femenino , Hemodinámica , Humanos , Inmunohistoquímica , Inflamación/virología , Masculino , Microcirculación , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Volumen Sistólico , Carga ViralRESUMEN
BACKGROUND: For a long time, enteroviruses have been considered to be the most common cause of acute viral myocarditis (MC), with possible transition from MC to dilated cardiomyopathy (DCM). Recent investigations have shown, however, that other viruses are also frequently encountered in MC patients, suggesting that persistence of various virus species may play a pathogenic role in the transition from MC to DCM. The purpose of this study was to screen endomyocardial biopsies (EMBs) from patients with "idiopathic" DCM for the presence of viral genomes by using polymerase chain reaction (PCR) to assess the frequency of cardiac viral infections that may be involved in the pathogenesis of the disease. METHODS AND RESULTS: EMBs were obtained for PCR analysis from 245 consecutive patients (median left ventricular ejection fraction, 35.0%; range, 9% to 59%). PCR and reverse transcription-PCR were performed to detect the genomic sequences of enterovirus (EV), adenovirus (ADV), human cytomegalovirus (HCMV), herpes simplex virus, Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), parvovirus B19 (PVB19), and influenza A and B viruses. Myocardial inflammation was assessed by histological and immunohistological analyses. Viral genomes could be amplified from EMBs of 165 (67.4%) of the 245 DCM patients: EV=23 (9.4%), ADV=4 (1.6%), PVB19=126 (51.4%), HHV-6=53 (21.6%), EBV=5 (2.0%), HCMV=2 (0.8%), including n=45 cases (27.3%) with multiple infections. Active or borderline myocarditis according to the Dallas classification did not exist in any case. Lymphocyte and macrophage infiltrates were not significantly different in virus-positive versus virus-negative patients. CONCLUSIONS: Viral genomes were frequently detected in EMBs of patients with systolic left ventricular dysfunction. Our data suggest that myocardial persistence of various viruses, often presenting as multiple infections, may play a role in the pathogenesis of DCM far more frequently than suspected so far.
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Cardiomiopatía Dilatada/virología , Genoma Viral , Corazón/virología , Disfunción Ventricular Izquierda/virología , Virosis/complicaciones , Adulto , Anciano , Biopsia , Cardiomiopatía Dilatada/etiología , Femenino , Humanos , Inflamación , Masculino , Persona de Mediana Edad , Miocarditis/virología , Reacción en Cadena de la Polimerasa , Prevalencia , Disfunción Ventricular Izquierda/etiología , Virosis/fisiopatologíaRESUMEN
BACKGROUND: Myocardial virus persistence is frequently observed in patients with cardiomyopathy. Endothelial dysfunction in patients with cardiomyopathy is associated with inflammatory immunoresponses in myocardial biopsies. The aim of this study was to investigate the impact of myocardial virus persistence on endothelial function. METHODS AND RESULTS: In 124 patients with suspected cardiomyopathy, myocardial biopsies were examined for virus persistence (by polymerase chain reaction) and inflammation (by immunohistology). Endothelial function of the radial artery was examined by high-resolution ultrasound. Diameter changes in response to reactive hyperemia (flow-mediated dilation [FMD]) compared with glycerol trinitrate (GTN-MD) were measured. Mean age of the patients (55 men, 69 women) was 45+/-13 years; ejection fraction was 57+/-17%. In 73 patients, adenovirus, enterovirus, parvovirus, or HHV6 virus (V) was detected; in 51, no virus was detected. FMD was significantly impaired in patients with myocardial virus persistence compared with control subjects (Co): FMD-V, 3.38+/-2.67%; FMD-Co, 7.34+/-3.44 (P<0.001). In 86 patients, myocardial inflammation was confirmed (Inf). Of those, 57 had virus, and 29 did not. FMD was significantly impaired in patients with virus compared with controls: FMD-Inf-V, 3.24+/-2.66%; FMD-Inf-Co, 6.07+/-3.00 (P<0.001). In 38 patients, immunohistology of the myocardial biopsies was normal (Co); of those, 16 had virus, and 22 did not. FMD was impaired in patients with virus compared with control subjects: FMD-Co-V, 3.88+/-2.72%; FMD-Co-Co, 9.00+/-3.32% (P<0.001). Endothelium-independent vasodilation (GTN-MD) was not significantly affected. CONCLUSIONS: Myocardial virus persistence is associated with endothelial dysfunction. Endothelial dysfunction in patients with myocardial virus persistence can occur independently of endothelial activation or myocardial inflammation but is more pronounced in patients with concurrent inflammation.
Asunto(s)
Infecciones por Adenovirus Humanos/fisiopatología , Arterias/fisiopatología , Infecciones por Coxsackievirus/fisiopatología , Endotelio Vascular/fisiopatología , Infecciones por Enterovirus/fisiopatología , Corazón/virología , Miocarditis/virología , Infecciones por Parvoviridae/fisiopatología , Infecciones por Roseolovirus/fisiopatología , Vasodilatación/fisiología , Infecciones por Adenovirus Humanos/sangre , Infecciones por Adenovirus Humanos/virología , Adenovirus Humanos/aislamiento & purificación , Biopsia , Proteína C-Reactiva/análisis , Cardiomiopatías/fisiopatología , Infecciones por Coxsackievirus/sangre , Infecciones por Coxsackievirus/virología , ADN Viral/aislamiento & purificación , Enterovirus/aislamiento & purificación , Infecciones por Enterovirus/sangre , Infecciones por Enterovirus/virología , Hemodinámica , Hemorreología , Herpesvirus Humano 4/aislamiento & purificación , Herpesvirus Humano 6/aislamiento & purificación , Humanos , Miocarditis/sangre , Miocarditis/fisiopatología , Miocardio/patología , Infecciones por Parvoviridae/sangre , Infecciones por Parvoviridae/virología , Parvovirus B19 Humano/aislamiento & purificación , Infecciones por Roseolovirus/sangre , Infecciones por Roseolovirus/virologíaRESUMEN
BACKGROUND: Enteroviruses (EVs) and adenoviruses (ADVs) have been considered common causes of myocarditis and dilated cardiomyopathy. In the present study, we report on the association of parvovirus B19 (PVB19) genomes in the clinical setting of acute myocarditis. METHODS AND RESULTS: This study included 24 consecutive patients admitted to our hospital within 24 hours after onset of chest pain. Acute myocardial infarction had been excluded in all patients by coronary angiography. Endomyocardial biopsies were analyzed by nested polymerase chain reaction/reverse transcriptase-polymerase chain reaction for EV, ADV, PVB19, human cytomegalovirus, Epstein-Barr virus, Chlamydia pneumoniae, influenza virus A and B, and Borrelia burgdorferi genomes, respectively, followed by direct sequencing of the amplification products. All patients presented with acute onset of angina pectoris and ST-segment elevations or T-wave inversion mimicking acute myocardial infarction. Mean baseline peak creatinine kinase and creatine kinase-isoenzyme fraction were 342+/-241 U/L and 32+/-20 U/L, respectively. Mean troponin T was increased to 7.5+/-15.0 ng/mL and C-reactive protein to 91+/-98 mg/mL. Eighteen patients had global or regional wall motion abnormalities (ejection fraction 62.5+/-15.5%). Histological analysis excluded the presence of active or borderline myocarditis in all but one patient. PVB19, EV, and ADV genomes were detected in the myocardium of 12, 3, and 2 patients, respectively (71%). Follow-up biopsies of virus-positive patients (11 of 17) demonstrated persistence of PVB19 genomes in 6 of 6 patients, EV genomes in 2 of 3 patients, and ADV genomes in 1 of 2 patients, respectively. CONCLUSIONS: Virus genomes can be demonstrated in 71% of patients with normal coronary anatomy, clinically mimicking acute myocardial infarction. In addition to EVs and ADVs, PVB19 was the most frequent pathogen.
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Infarto del Miocardio/diagnóstico , Miocarditis/diagnóstico , Infecciones por Parvoviridae/diagnóstico , Parvovirus B19 Humano/aislamiento & purificación , Virus/aislamiento & purificación , Enfermedad Aguda , Adolescente , Adulto , Anciano , Angina de Pecho/etiología , Biopsia , Dolor en el Pecho/etiología , Angiografía Coronaria , ADN Viral/análisis , ADN Viral/genética , Diagnóstico Diferencial , Ecocardiografía , Electrocardiografía , Femenino , Estudios de Seguimiento , Corazón/virología , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Infarto del Miocardio/complicaciones , Infarto del Miocardio/virología , Miocarditis/complicaciones , Miocarditis/virología , Miocardio/patología , Infecciones por Parvoviridae/complicaciones , Infecciones por Parvoviridae/virología , Parvovirus B19 Humano/genética , Reacción en Cadena de la Polimerasa , Recurrencia , Virus/genéticaRESUMEN
BACKGROUND: Viral infections are important causes of myocarditis and may induce cardiac dysfunction and finally lead to dilated cardiomyopathy. We investigated whether interferon (IFN)-beta therapy is safe and may achieve virus clearance and prevent deterioration of left ventricular (LV) function in patients with myocardial virus persistence. METHODS AND RESULTS: In this phase II study, 22 consecutive patients with persistence of LV dysfunction (history of symptoms, 44+/-27 months) and polymerase chain reaction-proven enteroviral or adenoviral genomes were treated with 18x10(6) IU/week IFN-beta (Beneferon) subcutaneously for 24 weeks. Histological and immunohistological analysis of endomyocardial biopsies was used to characterize myocardial inflammation. LV diameters and ejection fraction were assessed by echocardiography and angiography, respectively. During the treatment period, IFN-beta was well tolerated by all patients. No patient deteriorated. Clearance of viral genomes was observed in 22 of 22 of patients after antiviral therapy. Virus clearance was paralleled by a significant decrease of LV end diastolic and end systolic diameters, decreasing from 59.7+/-11.1 to 56.5+/-10.0 mm (P<0.001) and 43.2+/-13.6 to 39.4+/-12.1 mm (P<0.001), respectively. LV ejection fraction increased from 44.6+/-15.5% to 53.1+/-16.8% (P<0.001). CONCLUSIONS: A 6 months, IFN-beta treatment was safe in patients with myocardial enteroviral or adenoviral persistence and LV dysfunction and resulted in elimination of viral genomes (22 of 22 patients) and improved LV function (15 of 22 patients).
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Cardiomiopatía Dilatada/tratamiento farmacológico , Corazón/efectos de los fármacos , Corazón/virología , Interferón beta/uso terapéutico , Disfunción Ventricular Izquierda/tratamiento farmacológico , Adenoviridae/efectos de los fármacos , Adenoviridae/genética , Adenoviridae/aislamiento & purificación , Antivirales/uso terapéutico , Biopsia , Volumen Cardíaco/efectos de los fármacos , Cardiomiopatía Dilatada/complicaciones , Cardiomiopatía Dilatada/virología , Recuento de Células , Progresión de la Enfermedad , Electrocardiografía , Enterovirus/efectos de los fármacos , Enterovirus/genética , Enterovirus/aislamiento & purificación , Femenino , Corazón/fisiopatología , Hemodinámica/efectos de los fármacos , Humanos , Interferón beta/efectos adversos , Masculino , Persona de Mediana Edad , Miocardio/patología , Reacción en Cadena de la Polimerasa , Volumen Sistólico/efectos de los fármacos , Linfocitos T/patología , Resultado del Tratamiento , Disfunción Ventricular Izquierda/complicaciones , Disfunción Ventricular Izquierda/virologíaRESUMEN
OBJECTIVES: The aim of this study was to investigate whether myocardial inflammation (MC) and endothelial activation are associated with clinically detectable endothelial dysfunction. BACKGROUND: In patients with MC, immunohistologic evaluation of myocardial biopsies demonstrates a cellular infiltrate of lymphocytes in the myocardium and endothelial activation, as indicated by enhanced expression of human leukocyte antigen (HLA)-1, HLA-DR and intercellular adhesion molecule (ICAM)-1. This chronic inflammatory process may be associated with endothelial dysfunction. METHODS: In 65 patients with suspected MC, endothelial function of the radial artery was noninvasively assessed. By means of high-resolution ultrasound, diameter changes in response to reactive hyperemia (endothelium-dependent), as compared with glyceroltrinitrate (endothelium-independent), were analyzed. In the myocardial biopsies, MC was confirmed by immunohistology in 53 patients; 12 patients with normal myocardial biopsies served as controls. Endothelial expression of HLA-1, HLA-DR and ICAM-1 was semiquantitatively evaluated by immunohistology. To minimize other factors influencing endothelial function, patients with coronary artery disease, diabetes, severely impaired left ventricular function or more than one arteriosclerotic risk factor were excluded from this study. RESULTS: Endothelial function, as determined by flow-mediated vasodilation (FMD), in patients with MC was impaired (FMD(MC) 4.28%), as compared with controls (FMD(Co) 10.10%). The severity of endothelial dysfunction in patients with MC correlated significantly with the extent of endothelial expression of HLA-1, HLA-DR and ICAM-1 in myocardial biopsies. Endothelium-independent vasodilation was not affected by MC or endothelial activation. CONCLUSIONS: Myocardial inflammation is associated with endothelial dysfunction of peripheral arteries. The severity of endothelial dysfunction correlates with the extent of endothelial activation.
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Arterias/fisiopatología , Endotelio Vascular/fisiopatología , Antígenos HLA/biosíntesis , Molécula 1 de Adhesión Intercelular/biosíntesis , Miocarditis/diagnóstico , Miocardio/patología , Adulto , Factores de Edad , Biopsia , Presión Sanguínea/fisiología , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Miocarditis/metabolismo , Índice de Severidad de la Enfermedad , Estadística como Asunto , Volumen Sistólico/fisiología , Vasodilatación/fisiología , Función Ventricular Izquierda/fisiologíaRESUMEN
BACKGROUND: Effector functions of an aberrant immune response have been implicated in the pathogenesis of idiopathic dilated cardiomyopathy (DCM). The immunologic determinants of myocardial dysfunction, however, remain poorly understood. This study sought to determine the relation of different immunologic responses to hemodynamic dysfunction in DCM. METHODS: Immunoglobulin (Ig) G class/subclass response ELISA (enzyme-linked immunosorbent assay) against cardiac myosin heavy chain, histologic characteristics (DALLAS criteria), immunohistochemistry, plasma interleukin-4 and plasma interferon gamma (IFN-gamma) were determined in patients (n = 76) with clinically suspected myocarditis or DCM. Patients were prospectively evaluated, both clinically and hemodynamically, on admission (baseline) and at 6-month follow-up. RESULTS: Indices of hemodynamic dysfunction (by cardiac catheterization and transthoracic echocardiography) correlated significantly with an Ig subclass response. IgG3 levels correlated with left ventricular ejection fraction (P =.02), pulmonary capillary wedge pressure (P <.0001), left ventricular end-systolic volume index (P =.002), left ventricular end-diastolic volume index (P =.033), left ventricular end-diastolic pressure (P =.04), right ventricular end-diastolic pressure (P =.039), and left ventricular end-systolic dimension and left ventricular end-diastolic dimension (P <.05). Patients positive for IgG3 (predominantly male, P =.01) had depressed left ventricular ejection fraction (< or =45%, relative risk 3.0, 95% CI 1.5-5.7, P =.005) at baseline and 6 months. Mitral-septal separation at follow-up improved in patients negative for IgG3 (P =.018), and the number of patients on conventional therapy in this group declined at 6-month follow-up (P <.05). Lymphocyte counts/high-power field; CD2, CD3, CD4, and CD8 (independent of IgG class/subclass response and left ventricular dysfunction) were significantly higher in patients positive for IFN-gamma (25%). A positive IFN-gamma response was higher in patients positive for IgG3. These patients, positive for IgG3 and IFN-gamma (10%), had significantly shorter duration of clinical symptoms: 0.17 years (0.12-2.36 y) versus 1.01 years (0.49-5.35 y, P =.04). CONCLUSION: IgG3 reactivity correlated with depressed myocardial dysfunction. This may render this subclass Ig a surrogate target for therapeutic intervention in DCM. With IFN-gamma, IgG3 may reflect a more aggressive disease.