RESUMEN
BACKGROUND AND AIMS: Increased potassium intake is related to reduced blood pressure (BP) and reduced stroke rate. The effect of increased dietary potassium on endothelial function remains unknown. The aim was to determine the effect of increased dietary potassium from fruit and vegetables on endothelial function. METHODS AND RESULTS: Thirty five healthy men and women (age 32 ± 12 y) successfully completed a randomised cross-over study of 2 × 6 day diets either high or low in potassium. Flow mediated dilatation (FMD), BP, pulse wave velocity (PWV), augmentation index (AI) and a fasting blood sample for analysis of Intercellular Adhesion Molecule-1 (ICAM-1), E-selectin, asymmetric dimethylarginine (ADMA) and endothelin-1 were taken on completion of each intervention. Dietary change was achieved by including bananas and potatoes in the high potassium and apples and rice/pasta in the low potassium diet. Dietary adherence was assessed using 6 day weighed food diaries and a 24 h urine sample. The difference in potassium excretion between the two diets was 48 ± 32 mmol/d (P = 0.000). Fasting FMD was significantly improved by 0.6% ± 1.5% following the high compared to the low potassium diet (P = 0.03). There were no significant differences in BP, PWV, AI, ICAM-1, ADMA or endothelin-1 between the interventions. There was a significant reduction in E-selectin following the high (Median = 5.96 ng/ml) vs the low potassium diet (Median = 6.24 ng/ml), z = -2.49, P = 0.013. CONCLUSION: Increased dietary potassium from fruit and vegetables improves FMD within 1 week in healthy men and women but the mechanisms for this effect remain unclear. CLINICAL TRIAL REGISTRY: ACTRN12612000822886.
Asunto(s)
Endotelio Vascular/efectos de los fármacos , Potasio en la Dieta/administración & dosificación , Adolescente , Adulto , Anciano , Arginina/análogos & derivados , Arginina/sangre , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Índice de Masa Corporal , Estudios Cruzados , Selectina E/sangre , Endotelina-1/sangre , Femenino , Frutas , Voluntarios Sanos , Humanos , Molécula 1 de Adhesión Intercelular/sangre , Masculino , Persona de Mediana Edad , Cooperación del Paciente , Análisis de la Onda del Pulso , Método Simple Ciego , Urinálisis , Verduras , Adulto JovenRESUMEN
AIMS: To examine whether the prophylactic antianginal agent perhexiline potentiates platelet responsiveness to nitric oxide (NO) in patients with stable angina pectoris (SAP) and acute coronary syndromes (ACS: unstable angina pectoris or non-Q-wave myocardial infarction). METHODS AND RESULTS: Blood samples were obtained from patients before and after initiation of treatment with perhexiline. ADP-induced platelet aggregation and its inhibition by the NO donor sodium nitroprusside (SNP) were determined via impedance aggregometry in whole blood (WB) and platelet-rich plasma (PRP). Intraplatelet cGMP content was assayed by RIA, and superoxide (O(2)(-)) level by lucigenin-derived chemiluminescence. In patients with ACS not receiving perhexiline (n=12), platelet responsiveness to SNP did not vary significantly over the first 3 days post admission to hospital. Therapy with perhexiline for 3 days was associated with increases in SNP-induced inhibition of aggregation from 29+/-2% to 43+/-4% (n=50,P <0.001) in WB and from 20+/-5% to 42+/-7% (n=12, P<0.01) in PRP. Resolution of symptomatic ischaemia (n=39) was associated with significantly greater (P<0.01) increases than non-resolution (n=11). Similar increases in SNP responsiveness (P<0.001) occurred following institution of perhexiline therapy in patients with SAP (n=30), associated with a 85% decrease in anginal frequency. Treatment with perhexiline potentiated the cGMP-elevating effects of SNP in platelets (n=9,P =0.03). Although perhexiline did not alter whole blood O(2)(-) concentration ex vivo, it inhibited (P<0.01) O(2)(-) release from neutrophils in vitro. CONCLUSION: Perhexiline potentiates platelet responsiveness to NO both in SAP and ACS patients; in the latter group this improvement was predictive of resolution of ischaemic symptoms. The predominant mechanism of perhexiline effect is an increase in platelet cGMP responsiveness. Perhexiline also may reduce the potential for NO clearance by neutrophil-derived O(2)(-).
Asunto(s)
Fármacos Cardiovasculares/uso terapéutico , Enfermedad Coronaria/tratamiento farmacológico , Óxido Nítrico/fisiología , Perhexilina/uso terapéutico , Agregación Plaquetaria/efectos de los fármacos , Anciano , Angina de Pecho/tratamiento farmacológico , Plaquetas/metabolismo , GMP Cíclico/metabolismo , Femenino , Humanos , Masculino , Neutrófilos/metabolismo , Donantes de Óxido Nítrico/uso terapéutico , Nitroprusiato/uso terapéutico , Superóxidos/metabolismoRESUMEN
Although the growth factors that regulate megakaryocytopoiesis are well known, the molecular determinants of platelet formation from mature megakaryocytes remain poorly understood. Morphological changes in megakaryocytes associated with platelet formation and removal of senescent megakaryocytes are suggestive of an apoptotic process. Previously, we have established that nitric oxide (NO) can induce apoptosis in megakaryocytoid cell lines. To determine whether there is an association between NO-induced apoptosis and platelet production, we exposed Meg-01 cells to S-nitrosoglutathione (GSNO) with or without thrombopoeitin (TPO) pretreatment and used flow cytometry and electron microscopy to assess platelet-sized particle formation. Meg-01 cells treated with TPO alone produced few platelet-sized particles (<3% of total counts), whereas treatment with GSNO alone produced a significant percentage of platelet-sized particles (22 +/- 4% of total counts); when combined with TPO pretreatment, however, GSNO led to a marked increase in platelet-sized particle production (48 +/- 3% of total counts). Electron microscopy confirmed that Meg-01 cells treated with TPO and GSNO yielded platelet-sized particles with morphological features specific for platelet forms. The platelet-sized particle population appears to be functional, because addition of calcium, fibrinogen, and thrombin receptor-activating peptide led to aggregation. These results demonstrate that NO facilitates platelet production, thereby establishing the essential role of NO in megakaryocyte development and thrombopoiesis.
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Plaquetas/citología , Plaquetas/efectos de los fármacos , Hematopoyesis/efectos de los fármacos , Megacariocitos/citología , Megacariocitos/efectos de los fármacos , Óxido Nítrico/farmacología , Animales , Apoptosis/efectos de los fármacos , Plaquetas/fisiología , Línea Celular , GMP Cíclico/metabolismo , Citocinas/farmacología , Humanos , Megacariocitos/metabolismo , Ratones , Ratones Noqueados , Microscopía Electrónica de Rastreo , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico Sintasa/biosíntesis , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa de Tipo II , Óxido Nítrico Sintasa de Tipo III , S-Nitrosoglutatión/farmacología , Trombopoyetina/farmacologíaRESUMEN
Although heparin is a well-known anticoagulant, in some cases it promotes a prothrombotic state and does so through both antibody-dependent and antibody-independent platelet activation. In this study, heparin was found to reverse the antiplatelet effect of an NO donor. S-nitroso-glutathione (SNO-Glu), with an EC(50) of 1.8 U/mL. Ultraviolet/visible spectral analysis and the Griess assay showed that increasing heparin concentrations on a dose-dependent basis eliminated acidified NO(x) species. Since heparin is a heterogeneous mixture of glycosaminoglycans, the effects of six different heparin disaccharides were compared with various substitutions on the hexose rings to determine which functional group(s) of the polysaccharide interact with acidified NO(x). Among the six disaccharides tested, only types I-S and II-S had the effect, suggesting that the sulfamino-group at the C2 position of the glucosamine moiety was critical for the elimination of acidified NO(x) species. Mass spectrometry experiments gave results consistent with these observations, indicating that only the I-S and II-S heparin disaccharides were modified upon treatment with NaNO(2)/HCl. Negative-ion electro-spray ionization MS and tandem MS analyses of the native compounds and their deuterium-labeled analogs confirmed that the reaction products from nitrosation of these N-sulfated disaccharides had eliminated the C2-sulfamino-moiety and replaced it with methoxide derived from the solvent. Participation of the 6-sulfato-substituent appears to facilitate the elimination reaction. These data show that heparin can impair the antiplatelet properties of nitric oxide by interacting with the nitrosating species, and suggest that heparin-like glycosamino-glycans may interact with endothelium-derived nitric oxide in vivo to regulate the bioactivity of this important antiplatelet and vasorelaxant substance.
Asunto(s)
Anticoagulantes/metabolismo , Heparina/metabolismo , Óxido Nítrico/metabolismo , Anticoagulantes/farmacología , Disacáridos/farmacología , Interacciones Farmacológicas , Heparina/química , Heparina/farmacología , Humanos , Técnicas In Vitro , Espectrometría de Masas , Óxido Nítrico/química , Donantes de Óxido Nítrico/farmacología , Nitritos/metabolismo , Agregación Plaquetaria/efectos de los fármacosRESUMEN
OBJECTIVES: The study examined possible clinical determinants of platelet resistance to nitric oxide (NO) donors in patients with stable angina pectoris (SAP) and acute coronary syndromes (ACS), relative to nonischemic patients and normal subjects. BACKGROUND: We have shown previously that platelets from patients with SAP are resistant to the antiaggregating effects of nitroglycerin (NTG) and sodium nitroprusside (SNP). METHODS: Extent of adenosine diphosphate (1 micromol/liter)-induced platelet aggregation (impedance aggregometry in whole blood) and inhibition of aggregation by NTG (100 micromol/liter) and SNP (10 micromol/liter) were compared in normal subjects (n = 43), nonischemic patients (those with chest pain but no fixed coronary disease, (n = 35) and patients with SAP (n = 82) or ACS (n = 153). Association of NO resistance with coronary risk factors, coronary artery disease (CAD), intensity of angina and current medication was examined by univariate and multivariate analyses. RESULTS: In patients with SAP and ACS as distinct from nonischemic patients and normal subjects, platelet aggregability was increased (both p < 0.01), and inhibition of aggregation by NTG and SNP was decreased (both p < 0.01). Multivariate analysis revealed that NO resistance occurred significantly more frequently with ACS than with SAP (odds ratio [OR] 2.3:1), and was less common among patients treated with perhexiline (OR 0.3:1) or statins (OR 0.45:1). Therapy with other antianginal drugs, extent of CAD, intensity of angina and coronary risk factors were not associated with variability in platelet responsiveness to NO donor. CONCLUSIONS: Patients with symptomatic ischemic heart disease, especially ACS, exhibit increased platelet aggregability and decreased platelet responsiveness to the antiaggregatory effects of NO donors. The extent of NO resistance in platelets is not correlated with coronary risk factors. Pharmacotherapy with perhexiline and/or statins may improve platelet responsiveness to NO.
Asunto(s)
Angina de Pecho/metabolismo , Plaquetas/metabolismo , Enfermedad Coronaria/metabolismo , Óxido Nítrico/metabolismo , Enfermedad Aguda , Adulto , Anciano , Plaquetas/efectos de los fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Nitroglicerina/farmacología , Nitroprusiato/farmacología , Agregación Plaquetaria/efectos de los fármacos , SíndromeRESUMEN
OBJECTIVES: This study constituted a formative evaluation of the relevance of the MSc course to the needs of Hungarian primary health care educators. DESIGN: A qualitative, naturalistic approach using in-depth interviews was used to construct the meaning of the experience of the MSc for the Hungarian participants. Interviews were triangulated using observation and documentary analysis. SETTING: The University of Exeter's Institute of General Practice. SUBJECTS: Eight Hungarian primary health care professionals. RESULTS: The evaluation data revealed that the attitude of the Hungarian students to their role as medical educators had been substantially changed by exposure to western models of adult education. There were a number of 'clashes of expectation' between the Hungarian students and the course staff in relation to the course requirements. Reconciliation of these differing expectations required a sequence of ongoing adjustments to the course content and delivery. CONCLUSIONS: Existing postgraduate courses for health educators can accommodate the needs of medical teachers from countries who are developing their primary health care education systems. Successful accommodation is facilitated by ensuring an adequate preparation in relation to language fluency, academic requirements of the course, familiarization with modern approaches to adult education as well as with the local health care delivery system.
Asunto(s)
Educación de Pregrado en Medicina , Enseñanza , Educación en Salud , Humanos , Hungría , Atención Primaria de Salud , Reino Unido/epidemiologíaRESUMEN
OBJECTIVE: To evaluate the construct validity of the Pain Patient Profile (P-3), a brief self-report instrument designed to measure anxiety, depression, and somatization in patients presenting with pain. DESIGN: Comparison of P-3 scores with previously established measures of depression, anxiety, and somatization, and comparison of P-3 scores of pain patients with those of patients with diabetes. SETTINGS: Hospital-based outpatient pain clinic, family practice clinic, diabetes education group. PATIENTS: Seventy pain patients and 40 patients with diabetes. RESULTS: High positive correlations (.69 to .90) were found between the P-3 scales of Depression, Anxiety, and Somatization and the corresponding measures of these constructs, and high intercorrelations were found among the three P-3 scales. Significant differences were found between pain patients and diabetes patients for the P-3 Depression and Somatization scale scores, but not for the P-3 Anxiety scale scores. CONCLUSIONS: The P-3 is a useful instrument for initial screening of psychological distress in pain patients. Some patients may show elevations on more than one of the clinical scales, which either indicates that the P-3 does not distinguish well among these constructs or reflects the well-established comorbidity of these constructs.
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Dolor/complicaciones , Dolor/psicología , Escalas de Valoración Psiquiátrica/normas , Estrés Psicológico/diagnóstico , Estrés Psicológico/etiología , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Ansiedad/diagnóstico , Ansiedad/etiología , Ansiedad/psicología , Estudios de Casos y Controles , Comorbilidad , Depresión/diagnóstico , Depresión/etiología , Depresión/psicología , Diabetes Mellitus/psicología , Análisis Discriminante , Femenino , Humanos , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Trastornos Somatomorfos/diagnóstico , Trastornos Somatomorfos/etiología , Trastornos Somatomorfos/psicología , Estrés Psicológico/psicologíaRESUMEN
A number of anti-anginal agents (perhexiline, amiodarone, trimetazidine) have been shown to inhibit myocardial carnitine palmitoyltransferase-1, which controls access of long-chain fatty acids to mitochondrial sites of beta-oxidation. In view of clinical data suggesting that perhexiline improves symptomatic status in unstable angina pectoris, and the known role of mitochondrial beta-oxidation in platelet metabolism, we compared the platelet carnitine palmitoyltransferase-1 inhibitory and putative anti-aggregatory effects of perhexiline, amiodarone and trimetazidine with those of specific carnitine palmitoyltransferase-1 inhibitors: etomoxir and hydroxyphenylglyoxylate in both normal subjects and patients with stable angina. All of the compounds examined inhibited platelet carnitine palmitoyltransferase-1 activity; rank order of potency etomoxir > malonyl-CoA > hydroxyphenylglyoxylate > amiodarone > or = perhexiline > trimetazidine. However, only perhexiline, amiodarone and trimetazidine inhibited platelet aggregation. We conclude that (a) the carnitine palmitoyltransferase-1 inhibitors perhexiline, amiodarone and trimetazidine exert significant anti-aggregatory effects which may be therapeutically relevant and, (b) these effects are independent of carnitine palmitoyltransferase-1 inhibition.
Asunto(s)
Plaquetas/enzimología , Fármacos Cardiovasculares/farmacología , Carnitina O-Palmitoiltransferasa/metabolismo , Agregación Plaquetaria/efectos de los fármacos , Adulto , Anciano , Amiodarona/farmacología , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Carnitina O-Palmitoiltransferasa/antagonistas & inhibidores , Estudios de Casos y Controles , Inhibidores Enzimáticos/farmacología , Compuestos Epoxi/farmacología , Ácidos Grasos/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Perhexilina/farmacología , Trimetazidina/farmacología , Vasodilatadores/farmacologíaRESUMEN
In polycythaemia vera (PV; polycythaemia rubra vera, primary proliferative polycythaemia) and primary thrombocythaemia (PT; essential thrombocythaemia), occlusive complications in the microvasculature and larger vessels are a significant cause of morbidity and mortality. Central to the pathogenesis of these complications are the quantitative and qualitative platelet changes present in these myeloproliferative disorders. Aspirin irreversibly inactivates cyclo-oxygenase in platelets. This leads to a reduced production of platelet thromboxane A2 which has vasoconstricting and platelet aggregatory properties. In haematologically normal individuals, aspirin has been shown to reduce thrombo-embolic complications in populations at risk of these events. In PV and PT, aspirin has been shown to specifically eliminate the micro-circulatory and vasomotor manifestations and there is some evidence of a reduction in larger vessel occlusion. Low-dose aspirin has been shown to substantially reduce the raised thromboxane A2 production of platelets in PV and PT patients. The incidence of haemorrhagic side-effects of aspirin are minimized by the use of low doses. Haemorrhagic events are particularly found in patients with platelet counts > 1000 x 10(9)/l and these events are enhanced by aspirin therapy in these patients. Aspirin should be used with caution in patients with dyspeptic symptoms or a history of peptic ulceration or bronchospasm. Precise PCV control (< 0.45) and cytoreduction (platelets < 400 x 10(9)/l) should be used in patients with PV to minimize the vascular occlusion risk but routine cytoreduction is proposed only for those at particular risk of vascular occlusion in PT. In the acute presentation of patients with vascular occlusion, cytoreduction and an aspirin dose of 300 mg a day is proposed, reducing to 75 mg a day with the control of symptoms and signs, while 75 mg a day may play a role as prophylactic therapy in the prevention of thrombosis. However, there are no prospective studies in PT to demonstrate the benefit/risk profile and to confirm these recommendations, while a randomized prospective placebo-controlled study of low-dose aspirin in PV has only recently been initiated.
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Aspirina/uso terapéutico , Inhibidores de la Ciclooxigenasa/uso terapéutico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Policitemia Vera/tratamiento farmacológico , Trombocitemia Esencial/tratamiento farmacológico , Ácido Araquidónico/metabolismo , Humanos , Policitemia Vera/complicaciones , Policitemia Vera/fisiopatología , Trombocitemia Esencial/complicaciones , Trombocitemia Esencial/fisiopatología , Trombosis/fisiopatología , Enfermedades Vasculares/etiologíaRESUMEN
Human immunodeficiency virus (HIV) infection and infective endocarditis are serious complications of injection drug use. To determine whether HIV infection may increase the risk of endocarditis beyond that associated with drug injection, we performed a nested case-control study among injecting drug users taking part in an ongoing cohort. We identified 26 participants with infective endocarditis between cohort enrollment (in 1988-1989) and June 1992, through reviews of medical records and death certificates. We matched each endocarditis case with up to five controls (N = 120) on enrollment date, race/ethnicity, and follow-up time. Data were taken from baseline and from the one follow-up visit: the last visit before the endocarditis occurred for cases and the closest visit (+/- 3 months) for controls. We used conditional logistic regression to quantify the association between HIV serostatus at follow-up and subsequent endocarditis, after adjusting for a history of endocarditis or sepsis before enrollment, injection duration, current injection frequency, and a recent history of abscess at injection sites. Among current injectors at follow-up, the adjusted odds ratio (OR) of developing endocarditis for HIV-seropositive subjects with > or = 350 CD4 cells per microliter, compared with HIV-seronegative subjects, was 2.31 [95% confidence interval (CI) = 0.61-8.78]; the corresponding OR for HIV-seropositive subjects with < 350 CD4 cells per microliter was 8.31 (95% CI = 1.23-56.37). These data indicate that HIV-related immunodeficiency may independently increase the risk of infective endocarditis among injecting drug users.
Asunto(s)
Endocarditis/etiología , Infecciones por VIH/complicaciones , Abuso de Sustancias por Vía Intravenosa/complicaciones , Adulto , Recuento de Linfocito CD4 , Estudios de Casos y Controles , Endocarditis/epidemiología , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Distribución de Poisson , Factores de Riesgo , Sepsis/epidemiología , Sepsis/etiologíaRESUMEN
We tested the hypothesis that utilisation of multiple agonists in physiological concentrations is more appropriate for platelet aggregation in vitro than a single agonist in high concentration. Utilising impedance aggregometry in whole human blood (normal subjects and patients with coronary artery disease) we observed potentiation of pro-aggregatory effects of ADP by the combination of adrenaline, serotonin and thrombin in subthreshold concentrations (multiple agonist approach). In blood samples from the patients, verapamil (Ver, an L-type Ca(2+) channel blocker), nitroglycerine (NTG, a stimulator of cGMP formation) and prostaglandin E(1) (PGE(1) a stimulator of CAMP formation) inhibited platelet aggregation in vitro. With NTG and PGE(1) there was increased sensitivity to multiple agonists in comparison with ADP alone. For example, inhibition of aggregation with 10(-4)M NTG increased from 37 ± 5% with ADP alone to 86 ± 13% (P < 0.01) with multiple agonists. Threshold effects of NTG were seen at 10(-6) M with ADP alone and 10(-7) M with multiple agonists; whilst threshold for PGE(1) was reduced from 10(-10) to 10(-11) M. However, responses to Ver were unchanged by multiple agonists, demonstrating that the potentiation of anti-aggregating effects utilising the multiple agonist approach is not a non-specific phenomenon. The ability of multiple agonists to enhance the anti-aggregating effects of NTG and PGE(1) provides an in vitro experimental method mimicking the in vivo situation.
RESUMEN
As more effective therapies have produced longer survival times for HIV-infected patients, non-infectious complications of late stage HIV infection such as the development of severe global left ventricular dysfunction (dilated heart muscle disease) have emerged. The demographic and clinical characteristics of HIV-infected patients who develop dilated heart muscle disease as well as potential risk factors are, as yet, poorly characterized. Of 174 patients enrolled in a prospective longitudinal study, a total of nine patients, all with CD4 T cell counts < 200 mm-3, developed symptomatic heart disease (congestive heart failure n = 7, sudden cardiac death n = 1 and cardiac tamponade n = 1); three of these patients developed progressive cardiac dysfunction leading to primary cardiac failure and death. An additional 55 HIV-infected patients referred to our Cardiomyopathy Service were found to have global left ventricular dysfunction, with 84% having New York Heart Association Class III or IV congestive heart failure on presentation. Clinical characteristics associated with severe symptomatic cardiac dysfunction included low CD4 T cell counts, myocarditis associated with non-permissive cardiotropic virus infection on endomyocardial biopsy and persistent elevation of anti-heart antibodies. No relationships to any specific HIV risk factor or opportunistic infection were found. These findings suggest that a severe form of HIV-related dilated heart muscle disease is largely a disease of late stage HIV infection. Virus-related myocarditis and cardiac autoimmunity may play a role in the pathogenesis of progressive cardiac injury. Long-term longitudinal studies of larger HIV-infected cohorts are warranted to identify clinical, behavioral and immunologic risk factors.
Asunto(s)
Cardiomiopatía Dilatada/diagnóstico , Seropositividad para VIH/diagnóstico , Miocarditis/diagnóstico , Adulto , Autoanticuerpos/análisis , Biopsia , Recuento de Linfocito CD4 , Taponamiento Cardíaco/patología , Cardiomiopatía Dilatada/patología , Cardiomiopatía Dilatada/fisiopatología , Muerte Súbita Cardíaca/patología , Endocardio/inmunología , Endocardio/patología , Femenino , Seropositividad para VIH/patología , Seropositividad para VIH/fisiopatología , Hemodinámica/fisiología , Humanos , Estudios Longitudinales , Masculino , Miocarditis/patología , Miocarditis/fisiopatología , Miocardio/inmunología , Miocardio/patología , Estudios Prospectivos , Disfunción Ventricular Izquierda/diagnóstico , Disfunción Ventricular Izquierda/patología , Disfunción Ventricular Izquierda/fisiopatología , Función Ventricular Izquierda/fisiologíaRESUMEN
Conflicting patterns of myocardial cell adhesion molecule expression associated with cardiac rejection have emerged from numerous studies of randomly selected cardiac biopsies. We designed a prospective, longitudinal study which reports both qualitative and quantitative levels of myocardial ICAM-1, VCAM-1, E-selectin, and P-selectin expression in sequential human cardiac allograft biopsies. Intense ICAM-1 and VCAM-1 staining was found in all biopsies during the first three weeks after transplant and coincided with elevated serum levels of troponin T, a sensitive marker of ischemic myocyte injury. Baseline ICAM-1 and VCAM-1 expression returned within three to four weeks, as did serum troponin T levels in all patients who did not develop rejection. All 29 rejection episodes encountered were associated with intense ICAM-1 staining, while 24 of the 29 (83%) had intense VCAM-1 staining. Increased ELAM-1 and CD62 staining was only rarely observed. Persistence of increased ICAM-1 and VCAM-1 staining after treated rejection episodes predicted a recurrent rejection episode within two months (75% positive and 100% negative predictive value). Objective quantitative measurements by radioimmunoassay (RIA) confirmed these patterns of induced ICAM-1 and VCAM-1 expression. Thus, longitudinal monitoring of serial biopsies for myocardial ICAM-1 and VCAM-1 expression could be useful in the early detection of rejection episodes and monitoring the efficacy of immunosuppressive therapy.
Asunto(s)
Moléculas de Adhesión Celular/análisis , Rechazo de Injerto/inmunología , Trasplante de Corazón/inmunología , Miocardio/inmunología , Adulto , Biomarcadores , Biopsia , Creatina Quinasa/sangre , Endocardio/inmunología , Endocardio/patología , Rechazo de Injerto/sangre , Rechazo de Injerto/patología , Supervivencia de Injerto , Humanos , Isoenzimas/sangre , Estudios Longitudinales , Persona de Mediana Edad , Miocardio/patología , Estudios Prospectivos , Trasplante Homólogo , Troponina/sangre , Troponina TRESUMEN
OBJECTIVES: The purpose of this study was to characterize the histologic and immunopathologic results of 37 endomyocardial biopsy samples from patients infected with human immunodeficiency virus type 1 (HIV-1) who were evaluated for unexplained global left ventricular dysfunction. BACKGROUND: Recent studies have identified a growing number of patients infected with HIV-1 who develop unexplained left ventricular dysfunction and congestive heart failure. Myocarditis has been confirmed at autopsy in small numbers of such patients, although a pathogenic opportunistic infectious agent can rarely be identified. METHODS: All patients had moderate to severe global left ventricular hypokinesia on two-dimensional echocardiography. Endomyocardial biopsy samples were evaluated by standard histologic studies, immunoperoxidase staining and in situ hybridization for cytomegalovirus and HIV-1 gene sequences. RESULTS: Twenty-eight patients presented with New York Heart Association functional class III or IV congestive heart failure. Four patients had myocarditis secondary to known etiologies (opportunistic infection n = 2; drug-induced hypersensitivity myocarditis n = 2). Of the remaining 33 samples, 17 (51%) showed histologic evidence of idiopathic active or borderline myocarditis. Immunohistologic findings revealed induced expression of major histocompatibility class I antigen on myocytes and increased numbers of infiltrating CD8+ T lymphocytes. Specific hybridization within myocytes was observed in 5 of 33 samples with the HIV-1 antisense riboprobe and in 16 of 33 samples with the cytomegalovirus immediate early (IE-2) antisense riboprobe. All but one patient with specific myocyte hybridization presented with congestive heart failure; all patients had myocarditis and CD4+ cell counts < 100/mm3. CONCLUSIONS: This study demonstrates that cardiotropic virus infection and myocarditis may be important in the pathogenesis of symptomatic HIV-associated cardiomyopathy.
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Infecciones Oportunistas Relacionadas con el SIDA/complicaciones , Infecciones por Citomegalovirus/complicaciones , Infecciones por VIH/complicaciones , Miocarditis/complicaciones , Disfunción Ventricular Izquierda/complicaciones , Infecciones Oportunistas Relacionadas con el SIDA/patología , Adulto , Biopsia , Estudios de Cohortes , Infecciones por Citomegalovirus/patología , Ecocardiografía , Femenino , Infecciones por VIH/patología , Humanos , Inmunohistoquímica , Hibridación in Situ , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Miocarditis/patología , Miocardio/patología , Estudios Prospectivos , Disfunción Ventricular Izquierda/patologíaAsunto(s)
Cardiomiopatía Dilatada/inmunología , Infecciones por VIH/complicaciones , VIH-1/patogenicidad , Miocarditis/inmunología , Autoinmunidad , Cardiomiopatía Dilatada/etiología , Cardiomiopatía Dilatada/patología , Citocinas/fisiología , ADN Viral/análisis , Corazón/microbiología , Humanos , Hibridación in Situ , Interleucina-6/sangre , Miocarditis/etiología , Miocarditis/patologíaRESUMEN
The prevalence and incidence of left ventricular (LV) dysfunction was examined in patients infected with the human immunodeficiency virus (HIV). Sixty-nine randomly selected patients diagnosed with HIV infection who were followed in HIV clinics were prospectively evaluated by 2-dimensional echocardiography. Mean follow-up duration was 11 months. Additionally, 39 consecutive HIV-infected patients referred to the Cardiomyopathy Service and found to have LV dysfunction by 2-dimensional echocardiography were also studied. Of the 39 referred patients, 34 (87%) were referred for recent onset, unexplained, congestive heart failure. During this time, the HIV clinic population comprised 1,819 alive and actively followed patients; the 39 cardiomyopathy referrals therefore constituted a crude rate of 2.1% for this population. Of the 69 prospectively studied patients without clinical heart disease, a 14.5% prevalence of global LV hypokinesia and an incidence of 18%/patient-year were found. During a maximal 18-month follow-up period, 4 prospective patients (5.8%) developed symptoms of congestive heart failure. A greater proportion of prospective and referred patients with LV dysfunction had CD4 counts < 100/mm3 (62 and 79%, respectively) than did that of those without LV dysfunction (35%). In conclusion, the high rate of unexpected LV dysfunction in this HIV-infected population suggests that early cardiac contractile abnormalities may involve a significant number of patients, most of whom have low CD4 counts. A subgroup of these patients appears to progress to symptomatic congestive heart failure.
Asunto(s)
Cardiomiopatía Dilatada/epidemiología , Cardiomiopatía Dilatada/fisiopatología , Infecciones por VIH/complicaciones , Función Ventricular Izquierda , Adulto , Cardiomiopatía Dilatada/diagnóstico por imagen , Ecocardiografía , Femenino , Infecciones por VIH/fisiopatología , Humanos , Incidencia , Masculino , Prevalencia , Estudios ProspectivosAsunto(s)
Cardiomiopatías/diagnóstico por imagen , Seropositividad para VIH , Enfermedades de las Válvulas Cardíacas/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Abuso de Sustancias por Vía Intravenosa/complicaciones , Adulto , Cardiomiopatías/epidemiología , Cocaína , Estudios de Cohortes , Ecocardiografía , Femenino , Enfermedades de las Válvulas Cardíacas/epidemiología , Dependencia de Heroína/complicaciones , Humanos , Hipertrofia Ventricular Izquierda/epidemiología , Masculino , Contracción Miocárdica/fisiología , PrevalenciaRESUMEN
OBJECTIVE: Recent clinical and echocardiographic studies have identified dilated cardiomyopathy in 10-20% of HIV-infected adults. The purpose of this study was to determine the role of cardiotropic cytomegalovirus (CMV) infection in the development of HIV-associated cardiomyopathy. DESIGN: We generated sense and antisense digoxigenin-labeled riboprobes derived from the CMV immediate-early (IE) and delayed-early (DE) genes and applied them retrospectively to endomyocardial biopsy samples and control autopsy cardiac samples from HIV-infected patients. SETTING: Tertiary care, referral hospital. PATIENTS: Twelve consecutive HIV-infected patients with global left ventricular hypokinesis demonstrated on two-dimensional echocardiography; eight randomly selected control autopsy cardiac samples from HIV-infected patients without cardiac disease during life. MEASUREMENTS AND MAIN RESULTS: Of the 12 endomyocardial biopsy specimens, six (50%) were found to have specific myocyte nuclear and perinuclear hybridization for transcripts of the CMV IE gene, consistent with non-permissive or latent infection. Similar patterns were not found in any of the eight autopsy control samples. All six patients presented with unexplained congestive heart failure and had CD4 counts less than 100 x 10(6)/l; all six biopsy samples had immunohistochemical evidence of increased myocardial major histocompatibility complex (MHC) class I expression, a finding typical of non-HIV myocarditis. None of the endomyocardial biopsy samples had characteristic CMV inclusions and no specific hybridization was noted with the DE gene riboprobe, suggesting that no active viral DNA replication was present. Only two of the six patients with myocyte hybridization with the IE riboprobe had clinical evidence of solid organ infection with CMV at the time of cardiovascular presentation. CONCLUSIONS: This study is the first to demonstrate the expression of the IE gene of CMV within myocytes from HIV-infected patients with cardiomyopathy, suggesting a non-permissive infection of myocytes without classical intranuclear inclusions. Myocyte infection may be necessary to trigger cellular and humoral-mediated cardiac injury and may be best identified using in situ hybridization techniques.