Differential actions of eplerenone and spironolactone on the protective effect of testosterone against cardiomyocyte apoptosis in vitro.

INTRODUCTION AND OBJECTIVES: Testosterone deficiency is associated with a poor prognosis in patients with heart failure. It is not clear whether testosterone reduces cardiomyocyte apoptosis or whether the effect of spironolactone, an aldosterone receptor blocker with progestogenic and anti-androgen activity, differs from that of the selective aldosterone blocker eplerenone. METHODS: Apoptosis induced by hyperosmotic stress in the embryonic rat heart cell line H9c2 was monitored by measuring cell viability, DNA fragmentation and caspase-3, -8 and -9 activation. The effect of testosterone was investigated in the presence or absence of spironolactone and eplerenone. RESULTS: Exposure to sorbitol (0.6 M, 3 h) decreased cell viability and increased DNA fragmentation and caspase-3, -8 and -9 activation. These effects were all significantly reduced by testosterone, 100 nM (P< .01). Pretreatment with spironolactone, 10 .M, blocked the effects of testosterone, decreased cell viability (P< .01) and increased caspase activation (P< .01). In contrast, eplerenone, 10 .M, increased cell viability (P< .001) without altering the effect on caspase activation. These actions were not modified by the androgen receptor blocker flutamide. They were mediated by SAPK/JNK and ERK1/2 signaling pathways (P< .01). CONCLUSIONS: Testosterone appears to have a protective effect against cardiomyocyte apoptosis which is antagonized by spironolactone but not by eplerenone. These effects await confirmation in in vivo models, but their presence could have clinical and therapeutic implications.

Efecto diferencial de espironolactona frente a eplerenona sobre el papel protector in vitro de testosterona en la apoptosis de cardiocitos / Differential actions of eplerenone and spironolactone on the protective effect of testosterone against cardiomyocyte apoptosis in vitro

Introducción y objetivos. La deficiencia de testosterona se asocia a un peor pronóstico en pacientes con insuficiencia cardiaca. Se desconoce si la testosterona disminuye la apoptosis de cardiomiocitos y si la espironolactona, bloqueador del receptor de aldosterona con actividad progestogénica y antiandrogénica, tiene un efecto diferencial respecto al bloqueo selectivo con eplerenona. Métodos. En la línea de cardiomioblastos de rata H9c2, se cuantificó la apoptosis inducida por estrés hiperosmótico mediante análisis de viabilidad celular, fragmentación del ADN y activación de caspasa 3, 8 y 9. Se estudiaron los efectos de testosterona, en presencia o ausencia de espironolactona y eplerenona. Resultados. La exposición al sorbitol (0,6 M, 3 h) disminuyó la viabilidad celular e incrementó la fragmentación del ADN y la activación de caspasa 3, 8 y 9. Estos efectos fueron disminuidos significativamente por la testosterona (100 nM) (p < 0,01). El pretratamiento con espironolactona (10 μM) bloqueó los efectos de la testosterona, disminuyó la viabilidad celular (p < 0,01) e incrementó la activación de caspasas (p < 0,01); por el contrario, la eplerenona (10 μM) incrementó la viabilidad (p < 0,001) sin alterar el efecto en las caspasas. Estas acciones no se modificaron por el bloqueo del receptor de andrógenos con flutamida y fueron mediadas por las rutas de señalización SAPK/JNK y ERK1/2 (p < 0,01). Conclusiones. La testosterona parece tener un efecto protector contra la apoptosis de células cardiacas, que la espironolactona contrarresta, pero no la eplerenona. Estos hallazgos precisan confirmación en modelos in vivo, pero de estar presentes podrían tener implicaciones clínicas y terapéuticas (AU)

Introduction and objectives. Testosterone deficiency is associated with a poor prognosis in patients with heart failure. It is not clear whether testosterone reduces cardiomyocyte apoptosis or whether the effect of spironolactone, an aldosterone receptor blocker with progestogenic and anti-androgen activity, differs from that of the selective aldosterone blocker eplerenone. Methods. Apoptosis induced by hyperosmotic stress in the embryonic rat heart cell line H9c2 was monitored by measuring cell viability, DNA fragmentation and caspase-3, -8 and -9 activation. The effect of testosterone was investigated in the presence or absence of spironolactone and eplerenone. Results. Exposure to sorbitol (0.6 M, 3 h) decreased cell viability and increased DNA fragmentation and caspase-3, -8 and -9 activation. These effects were all significantly reduced by testosterone, 100 nM (P < .01). Pretreatment with spironolactone, 10 μM, blocked the effects of testosterone, decreased cell viability (P < .01) and increased caspase activation (P < .01). In contrast, eplerenone, 10 μM, increased cell viability (P < .001) without altering the effect on caspase activation. These actions were not modified by the androgen receptor blocker flutamide. They were mediated by SAPK/JNK and ERK1/2 signaling pathways (P < .01). Conclusions. Testosterone appears to have a protective effect against cardiomyocyte apoptosis which is antagonized by spironolactone but not by eplerenone. These effects await confirmation in in vivo models, but their presence could have clinical and therapeutic implications (AU)

Sex hormone-binding globulin: a new marker of disease severity and prognosis in men with chronic heart failure.

INTRODUCTION AND OBJECTIVES: Sex hormone-binding globulin (SHBG) is a key regulator of the actions of anabolic steroids. Chronic heart failure (HF) has been associated with anabolic steroid deficiency, but its relationship with SHBG is not known. METHODS: The study involved 104 men (53+/-11 years) with HF (i.e. left ventricular ejection fraction [LVEF] <40%) attending a specialist clinic on optimum treatment and in a stable condition. At enrolment, the median and interquartile range (IQR) SHBG level was determined, associated hormone levels were measured, and known risk factors were recorded. The study end-point was cardiac death within 3 years. RESULTS: At enrolment, the SHBG level (median 34.5 nmol/L, IQR 27-50 nmol/L) was correlated with the N-terminal probrain natriuretic peptide level (r=0.271, P=.005), LVEF (r=-0.263, P=.007), body mass index (r=-0.199, P=.020) and total testosterone level (r=0.332, P=.001). The median SHBG level was higher in the 16 patients (15.4%) who died, at 48.5 nmol/L (IQR 36-69.5 nmol/L) vs. 33 nmol/L (IQR 25.3-48.7 nmol/L; P=.001), and a high level was associated with an increased risk of death (hazard ratio [HR]=1.045, 95% confidence interval [CI] 1.021-1.069; P< .001). The association remained significant after adjustment in Cox multivariate regression modeling, at HR=1.049 (95% CI 1.020-1.079; P=.001). Analysis by SHBG tertiles showed mortality was 30% in the third tertile, 14% in the second, and 4% in the first (log rank 0.007; HR=3.25, 95% CI 1.43-7.34; P=.004). CONCLUSIONS: The SHBG level correlated with measures of HF severity and was associated with a higher risk of cardiac death. Further studies are needed to clarify whether SHBG plays a role in HF pathophysiology.

Globulina transportadora de hormonas sexuales: nuevo marcador de severidad y pronóstico en varones con insuficiencia cardiaca crónica / Sex hormone-binding globulin: a new marker of disease severity and prognosis in men with chronic heart failure

Introducción y objetivos. La globulina transportadora de hormonas sexuales (SHBG) es una molécula clave en la regulación del efecto de los esteroides anabolizantes. En la insuficiencia cardiaca crónica se ha descrito un deterioro anabólico, pero se desconoce el valor de la SHBG. Métodos. Se incluyeron 104 varones (53 ± 11 años) con insuficiencia cardiaca (FEVI < 40%) atendidos en una consulta especializada, con tratamiento optimizado y situación clínica estable. A la inclusión, se midieron los niveles de SHBG (mediana [rango intercuartil]), otras hormonas relacionadas y factores de riesgo conocidos. Se estudió la aparición de muerte cardiaca a los 3 años. Resultados. A la inclusión, los niveles de SHBG (34,5 [27-50] nmol/l) se correlacionaron con los de NT-proBNP (r = 0,271; p = 0,005), la FEVI (r = -0,263; p = 0,007), el ín-dice de masa corporal (r = -0,199; p = 0,020) y la testosterona total (r = 0,332; p = 0,001). Los niveles de SHBG fueron mayores (48,5 [36-69,5] frente a 33 [25,3-48,7] nmol/l; p = 0,001) en pacientes que fallecieron (n = 16 [15,4%]) y se asociaron a un mayor riesgo de muerte (HR = 1,045; IC del 95%, 1,021-1,069; p < 0,001), que fue significativo tras el ajuste en un modelo multivariable de Cox (HR = 1,049; IC del 95%, 1,020-1,079; p = 0,001). El análisis por terciles mostró una mortalidad del 30% en el tercer tercil; el 14% en el segundo y el 4% en el primer tercil (log rank test, 0,007; HR = 3,25; IC del 95%, 1,43-7,34; p = 0,004). Conclusiones. Los niveles de SHBG se correlacionan con medidas de severidad de la insuficiencia cardiaca y se asocian a un mayor riesgo de muerte cardiaca. Nuevos estudios deben aclarar si la SHBG tiene un papel en la fisiopatología de la insuficiencia cardiaca (AU)

Introduction and objectives. Sex hormone-binding globulin (SHBG) is a key regulator of the actions of anabolic steroids. Chronic heart failure (HF) has been associated with anabolic steroid deficiency, but its relationship with SHBG is not known. Methods. The study involved 104 men (53±11 years) with HF (i.e. left ventricular ejection fraction [LVEF] <40 attending a specialist clinic on optimum treatment and in stable condition at enrolment the median interquartile range iqr shbg level was determined associated hormone levels were measured known risk factors recorded study end-point cardiac death within 3 years results 34 5 nmol l 27-50 correlated with n-terminal probrain natriuretic peptide r="0.332," p lvef body mass index total testosterone higher 16 patients 15 4 who died 48 36-69 vs 33 25 3-48 7 high an increased of hazard ratio hr 95 confidence interval ci 1 021-1 069 <.001). The association remained significant after adjustment in Cox multivariate regression modeling, at HR=1.049 (95% CI 1.020-1.079; P=.001). Analysis by SHBG tertiles showed mortality was 30% in the third tertile, 14% in the second, and 4% in the first (log rank 0.007; HR=3.25, 95% CI 1.43-7.34; P=.004). Conclusions. The SHBG level correlated with measures of HF severity and was associated with a higher risk of cardiac death. Further studies are needed to clarify whether SHBG plays a role in HF pathophysiology (AU)

Pulmonary surfactant protein B in the peripheral circulation and functional impairment in patients with chronic heart failure.

INTRODUCTION AND OBJECTIVES: Surfactant protein B (SP-B) is a marker of damage to the alveolar-capillary barrier that could be useful for monitoring functional impairment in patients with chronic heart failure (HF). METHODS: Dyspnea-limited cardiopulmonary exercise testing was carried out in 43 outpatients with chronic HF (age 51+/-10 years, 77% male, left ventricular ejection fraction [LVEF] 33+/-11%). Peripheral blood serum samples were obtained at rest and during the first minute of peak exercise. The presence and concentration of SP-B in the serum samples were determined by Western blot analysis. RESULTS: At rest, SP-B was detected in 35 (82%) patients compared with only six (23%) healthy volunteers in a control group (n=26, age 51+/-10 years, 77% male). The median circulating SP-B level was higher in HF patients, at 174 [interquartile range, 70-283] vs. 77 [41-152] (P< .001) in the control group. In HF patients, the presence of circulating SP-B was associated with a lower LVEF (31.4+/-9.6% vs. 41.8+/-15%; P=.01). Multivariate analysis showed that the resting SP-B level correlated with a greater VE/VCO2 slope (beta=1.45; P=.02). The peak-exercise SP-B level correlated almost perfectly with the resting level (r=0.980; P< .001), but there was no significant increase with exercise (P=.164). Nor was there a correlation with any other exercise parameter. CONCLUSIONS: In patients with chronic HF, the level of pulmonary surfactant protein B in the peripheral circulation is increased and is correlated with ventilatory inefficiency during exercise, as indicated by the VE/VCO2 slope.

Proteína surfactante pulmonar tipo B en circulación periférica y deterioro funcional en pacientes con insuficiencia cardiaca crónica / Pulmonary Surfactant Protein B in the Peripheral Circulation and Functional Impairment in Patients With Chronic Heart Failure

Introducción y objetivos. La proteína surfactante tipo B (PS-B) es un marcador de daño en la barrera alveolocapilar y podría ser útil en la monitorización del deterioro pulmonar asociado a la insuficiencia cardiaca crónica (ICC). Métodos. Se estudió a 43 pacientes ambulatorios con ICC (edad, 51 ± 10 años; el 77% varones; fracción de eyección del ventrículo izquierdo [FEVI], 33% ± 11%) a los que se realizó una prueba de esfuerzo cardiopulmonar limitada por disnea. Se obtuvieron muestras de sangre periférica en reposo y en el primer minuto tras el máximo esfuerzo. La presencia y la cantidad de PS-B en suero sanguíneo se analizaron mediante análisis Western blot. Resultados. En reposo, se detectó PS-B circulante en 35 (82%) pacientes, frente a sólo 6 (23%) voluntarios sanos de una muestra control (n = 26; edad, 51 ± 10 años; el 77% varones), con mayores concentraciones circulantes en pacientes con ICC (mediana [intervalo intercuartílico], 174 [70-283]) frente al grupo control (77 [41-152]; p < 0,001). En pacientes con ICC, la presencia de PS-B circulante se asoció a una menor FEVI (31,4% ± 9,6% frente a 41,8% ± 15%; p = 0,01). Tras el ajuste multivariable, la cantidad de PS-B en reposo se correlacionó con una mayor pendiente VE/VCO2 (β = 1,45; p = 0,02). Los valores de PS-B en el esfuerzo máximo se correlacionaron casi perfectamente con las cifras en reposo (r = 0,980; p < 0,001), pero no se incrementaron significativamente con el esfuerzo (p = 0,164) ni se correlacionaron con los parámetros de ejercicio. Conclusiones. En pacientes con ICC, la proteína surfactante pulmonar tipo B está incrementada en la circulación periférica y se correlaciona con la ineficiencia ventilatoria en el ejercicio expresada como pendiente VE/VCO2

Introduction and objectives. Surfactant protein B (SP-B) is a marker of damage to the alveolar-capillary barrier that could be useful for monitoring functional impairment in patients with chronic heart failure (HF). Methods. Dyspnea-limited cardiopulmonary exercise testing was carried out in 43 outpatients with chronic HF (age 51±10 years, 77% male, left ventricular ejection fraction [LVEF] 33±11%). Peripheral blood serum samples were obtained at rest and during the first minute of peak exercise. The presence and concentration of SP-B in the serum samples were determined by Western blot analysis. Results. At rest, SP-B was detected in 35 (82%) patients compared with only six (23%) healthy volunteers in a control group (n=26, age 51±10 years, 77% male). The median circulating SP-B level was higher in HF patients, at 174 [interquartile range, 70-283] vs. 77 [41-152] (P<.001) in the control group. In HF patients, the presence of circulating SP-B was associated with a lower LVEF (31.4±9.6% vs. 41.8±15%; P=.01). Multivariate analysis showed that the resting SP-B level correlated with a greater VE/VCO2 slope (β=1.45; P=.02). The peak-exercise SP-B level correlated almost perfectly with the resting level (r=0.980; P<.001), but there was no significant increase with exercise (P=.164). Nor was there a correlation with any other exercise parameter. Conclusions. In patients with chronic HF, the level of pulmonary surfactant protein B in the peripheral circulation is increased and is correlated with ventilatory inefficiency during exercise, as indicated by the VE/VCO2 slope

Comparison of late mortality in hospitalized patients >70 years of age with systolic heart failure receiving beta blockers versus those not receiving beta blockers.

Beta blockers are underprescribed to elderly patients with systolic heart failure (HF). We studied whether the prescription of a beta blocker is associated with a survival benefit in a nonselected population of patients >70 years of age hospitalized with acute HF and systolic dysfunction. We studied 272 consecutive patients >70 years (median 77.0, interquartile range 73.4 to 81.1) hospitalized with acute HF (left ventricular ejection fraction 34 +/- 8%) during a 2-year period. At discharge, beta-blocker therapy was prescribed in 139 patients (51.1%). A propensity score for the likelihood of receiving beta-blocker therapy was developed and showed a good performance (c-statistic = 0.825 and Hosmer-Lemeshow p = 0.820). After discharge, 120 patients (44.1%) died during the follow-up (median 31 months, interquartile range 12 to 46). Cox regression analysis showed a lower risk of death associated with beta-blocker prescription (p <0.001, hazard ratio [HR] 0.450, 95% confidence interval [CI] 0.310 to 0.655), which persisted after risk adjusting for the propensity score (HR 0.521, 95% CI 0.325 to 0.836, p = 0.007). In a propensity-matched cohort of 130 patients, there was a significantly lower mortality in patients receiving beta blockers (log rank 0.009, HR 0.415, 95% CI 0.234 to 0.734, p = 0.003). Risk reduction associated with beta blockade was observed with both high doses (HR 0.472, 95% CI 0.300 to 0.742, p = 0.001) and low doses (HR 0.425, 95% CI 0.254 to 0.711, p = 0.001). In conclusion, beta-blocker prescription at discharge in a nonselected population >70 years of age hospitalized with systolic HF is associated with a significantly lower risk of death even at low doses. This benefit remains consistent after adjustment for potential confounders.

Hyperuricaemia and long-term outcome after hospital discharge in acute heart failure patients.

BACKGROUND: Uric acid (UA) may be involved in chronic heart failure (HF) pathogenesis, entailing a worse outcome. The purpose of this study was to examine the role of hyperuricaemia as a prognostic marker after hospital discharge in acute HF patients. METHODS: We studied 212 patients consecutively discharged after an episode of acute HF with LVEF<40%. Blood samples for UA measurement were extracted in the morning prior to discharge. The evaluated endpoints were death and new HF hospitalization. RESULTS: Mean UA levels were 7.4+/-2.4 mg/dl (range 1.6 to 16 mg/dl), with 127 (60%) of patients being within the range of hyperuricaemia. Hyperuricaemia was associated with a higher risk of death (n=48) (HR 2.0, 95% CI 1.1-3.9, p=0.028), new HF readmission (n=67) (HR 1.8, 95% CI 1.1-3.1, p=0.023) and the combined event (n=100) (HR 1.9, 95% CI 1.2-2.9, p=0.004). At 24 months, cumulative event-free survival was lower in the two higher UA quartiles (36.9% and 40.7% vs. 63.5% and 59.5%, log rank=0.006). After adjustment for potential confounders, hyperuricaemia remains an independent risk factor for adverse outcomes (HR 1.6, 95% CI 1.1-2.6, p=0.02). CONCLUSIONS: In hospitalized patients with acute HF and LV systolic dysfunction, hyperuricaemia is a long-term prognostic marker for death and/or new HF readmission.

[Implementation of the new diagnostic criteria for myocardial infarction]. / Utilización de los nuevos criterios diagnósticos de infarto de miocardio.

The extent of implementation in daily clinical practice of the new definition of myocardial infarction is unknown. The purpose of the present study was to describe the use of the new definition in patients discharged from a cardiology department. We analyzed the clinical records of 277 patients admitted because of acute coronary syndromes and discharged from the cardiology department between 1 March 2001 and 31 August 2001. The final clinical diagnosis based on the presence of classical or only new diagnostic criteria was studied. 127 patients (46%) satisfied the new definition (61% classical criteria and 39% only new criteria). Only 98 (77%) of the patients with myocardial infarction according to the new definition were discharged with this diagnosis (96% of the group that satisfied classical criteria and 48% of the group that satisfied only new criteria). The diagnosis of myocardial infarction is still based predominantly on classical criteria; the new criteria have been only partially implemented.

Utilización de los nuevos criterios diagnósticos de infarto de miocardio / Implementation of the new diagnostic criteria for myocardial infarction

La nueva definición del infarto de miocardio tiene implicaciones en múltiples campos de la cardiología. Su grado real de aplicación es actualmente desconocido. Este trabajo se propone conocer la utilización de la nueva definición en los pacientes dados de alta de un servicio de cardiología. Analizamos el historial clínico de los 277 pacientes dados de alta de un servicio de cardiología entre el 1 de marzo y el 31 de agosto de 2001 tras ingresar por un síndrome coronario agudo. Estudiamos el juicio diagnóstico final atendiendo al cumplimiento de los criterios clásicos o actuales de infarto. Cumplieron la nueva definición 127 pacientes (46 por ciento), 61 por ciento con criterios clásicos y 39 por ciento sin ellos. Sólo 98 (77 por ciento) de los pacientes con infarto según la nueva definición recibieron este diagnóstico en el momento del alta hospitalaria (el 48 por ciento si no existían criterios clásicos de infarto). Los criterios clásicos siguen siendo determinantes para el diagnóstico del infarto de miocardio. Los nuevos criterios se aplican sólo parcialmente (AU)

[Effect of time elapsed from spontaneous syncope on the diagnostic performance of the head-up tilt table test]. / Efecto del tiempo transcurrido tras el síncope sobre el rendimiento diagnóstico de la prueba de basculación.

OBJECTIVES: The propensity for spontaneous and tilt-induced neurocardiogenic syncope may exhibit temporal variations. Therefore the diagnostic performance of the head-up tilt test could be improved if it were performed soon after the occurrence of spontaneous syncope. The objective of this study was to assess whether the time interval between the last syncopal episode and tilt table testing influenced the outcome of the test. PATIENTS AND METHOD: Three hundred and fifteen patients undergoing diagnostic tilt table testing potentiated with nitroglycerin for suspected neurocardiogenic syncope were included in the study. The time between the last spontaneous syncope and the tilt table test was recorded and its relationship with the results of the test was analyzed. RESULTS: The tilt table test was positive in 211 patients (67.0%). The time from syncope to test was similar for patients with positive and negative tilt table test results: 28 (1-500) vs 32 (2-700) days (NS). No significant relation was observed between the results of the test and the occurrence of spontaneous syncope during the week, the month or the three months previous to the procedure. However, in men and in patients older than 50 years a higher rate of positive tests was observed if the tilt test was performed within the first month after the last spontaneous syncope. CONCLUSIONS: The time from the last previous spontaneous syncope to the head-up tilt test does not have a significant impact on test outcome in the overall population with suspected neurocardiogenic syncope. However, the rate of positivity might decrease in men and patients older than 50 years if the test is performed later than one month after the spontaneous syncopal episode.

Efecto del tiempo transcurrido tras el síncope sobre el rendimiento diagnóstico de la prueba de basculación / Effect of time elapsed from spontaneous syncope on the diagnostic performance of the head-up tilt table test

Introducción y objetivos. La propensión a sufrir síncopes neuromediados parece modificarse con el tiempo, por lo que el rendimiento diagnóstico de la prueba de basculación podría mejorar si se efectúa pronto tras el episodio sincopal. El objetivo del estudio es determinar si el tiempo transcurrido desde el síncope espontáneo hasta la realización de la prueba de basculación modifica la tasa de positividad de la misma. Pacientes y método. Se incluye a 315 pacientes a los que se practicó una prueba de basculación diagnóstica potenciada con nitroglicerina por sospecha de síncope vasovagal. Se registró el tiempo desde el síncope hasta la realización de la prueba y se analizó su relación con el resultado de la misma. Resultados. La basculación fue positiva en 211 pacientes (67,0 por ciento). El tiempo síncope-basculación fue similar en los pacientes con resultado positivo y negativo (28 [1-500] frente a 32 [2-720] días; NS). Globalmente, no existió una relación significativa entre el resultado de la prueba y la existencia de síncope durante la semana, el mes o los 3 meses previos. Sin embargo, en los varones y en mayores de 50 años, la tasa de positividad fue mayor en los pacientes con un tiempo síncope-basculación inferior a un mes. Conclusiones. El tiempo transcurrido desde el último síncope espontáneo no afecta significativamente el resultado del test de basculación en una población global evaluada para diagnóstico de síncope, pero la tasa de positividad puede disminuir en varones y en mayores de 50 años si la prueba se efectúa después de un mes del último síncope (AU)