Mechanism of vascular toxicity in rats subjected to treatment with a tyrosine kinase inhibitor

Sunitinib (Su) is a tyrosine kinase inhibitor with antiangiogenic and antineoplastic effects that is recommended therapy for renal cell carcinoma, gastrointestinal stromal tumors, and pancreatic neuroendocrine tumors. Arterial hypertension is one of the adverse effects observed in the treatment with Su. The aim of this work was to deepen our understanding of the underlying mechanisms involved in the development of this side effect. Studies on endothelial function, vascular remodeling and nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) system were carried out in thoracic aortas from rats treated with Su for three weeks. Animals subjected to Su treatment presented with increased blood pressure and reduced endothelium-dependent vasodilation, the latter being reverted by NADPH oxidase blockade. Furthermore, vascular remodeling and stronger Masson trichrome staining, together with enhanced immunofluorescence signal for collagen 1 alpha 1 (Col1ff1), were observed in aortas from treated animals. These results were accompanied by a significant elevation in superoxide anion production and the activity/protein/gene expression of NADPH oxidase isoforms (NOX1, NOX2, and NOX4), which was also prevented by NOX inhibition. Furthermore, a decrease in nitric oxide (NO) levels and endothelial nitric oxide synthase (eNOS) activation was observed in aortas from Su-treated animals. All these results indicate that endothelial dysfunction secondary to changes in vascular remodeling and oxidative stress might be responsible for the typical arterial hypertension that develops following treatment with Su.Junta de Andalucía 2017/44

Benefit of tolvaptan in the management of hyponatraemia in patients with diuretic‐refractory congestive heart failure: the SEMI‐SEC project

Aims: Hyponatraemia is an electrolyte disorder that occurs in advanced congestive heart failure (HF) and worsens prognosis. We explored the usefulness of tolvaptan, which has shown promising results in the treatment of this condition. Methods and results: This study is based on a retrospective national registry (2011-15) of patients hospitalized with refractory HF and hyponatraemia who agreed to receive tolvaptan when standard treatment was ineffective. The benefit of tolvaptan was analysed according to the following criteria: normalization ([Na+] >= 135mmol/L) or increased sodium levels [Na+] >= 4mEq/L on completion of treatment, and increase in urine output by 300 or 500mL at 48h. Factors associated with tolvaptan benefit were explored. A total of 241 patients were included, 53.9% of whom had ejection fraction = 4mEq/L and/or +300mL in urine output (54.4% both). Conclusions: An increase in sodium levels and/or improvement in urine output was observed in patients admitted for HF and refractory hyponatraemia under tolvaptan treatment. Tolvaptan may be useful in this setting, in which no effective proven alternatives are available

Cancer Impacts Prognosis on Mortality in Patients with Acute Heart Failure: Analysis of the EPICTER Study

Introduction: Heart failure (HF) and cancer are currently the leading causes of death worldwide, with an increasing incidence with age. Little is known about the treatment received and the prognosis of patients with acute HF and a prior cancer diagnosis. Objective: to determine the clinical characteristics, palliative treatment received, and prognostic impact of patients with acute HF and a history of solid tumor. Methods: The EPICTER study (“Epidemiological survey of advanced heart failure”) is a cross-sectional, multicenter project that consecutively collected patients admitted for acute HF in 74 Spanish hospitals. Patients were classified into two groups according to whether they met criteria for acute HF with and without solid cancer, and the groups were subsequently compared. A multivariable logistic regression analysis was conducted, using the forward stepwise method. A Kaplan–Meier survival analysis was performed to evaluate the impact of solid tumor on prognosis in patients with acute HF. Results: A total of 3127 patients were included, of which 394 patients (13%) had a prior diagnosis of some type of solid cancer. Patients with a history of cancer presented a greater frequency of weight loss at admission: 18% vs. 12% (p = 0.030). In the cancer group, functional impairment was noted more frequently: 43% vs. 35%, p = 0.039). Patients with a history of solid cancer more frequently presented with acute HF with preserved ejection fractiono (65% vs. 58%, p = 0.048) than reduced or mildly reduced. In-hospital and 6-month follow-up mortality was 31% (110/357) in patients with solid cancer vs. 26% (637/2466), p = 0.046. Conclusion: Our investigation demonstrates that in-hospital mortality and mortality during 6-month follow-up in patients with acute HF were higher in those subjects with a history of concomitant solid tumor cancer diagnosis

Chronic Obstructive Pulmonary Disease in Elderly Patients with Acute and Advanced Heart Failure: Palliative Care Needs—Analysis of the EPICTER Study

Introduction: There are studies that evaluate the association between chronic obstructive pulmonary disease (COPD) and heart failure (HF) but there is little evidence regarding the prognosis of this comorbidity in older patients admitted for acute HF. In addition, little attention has been given to the extracardiac and extrapulmonary symptoms presented by patients with HF and COPD in more advanced stages. The aim of this study was to evaluate the prognostic impact of COPD on mortality in elderly patients with acute and advanced HF and the clinical manifestations and management from a palliative point of view. Methods: The EPICTER study (Epidemiological survey of advanced heart failure) is a cross-sectional, multicenter project that consecutively collected patients admitted for HF in 74 Spanish hospitals. Demographic, clinical, treatment, organ-dependent terminal criteria (NYHA III-IV, LVEF <20%, intractable angina, HF despite optimal treatment), and general terminal criteria (estimated survival <6 months, patient/family acceptance of palliative approach, and one of the following: evidence of HF progression, multiple Emergency Room visits or admissions in the last six months, 10% weight loss in the last six months, and functional impairment) were collected. Terminal HF was considered if the patient met at least one organ-dependent criterion and all the general criteria. Both groups (HF with COPD and without COPD) were compared. A Kaplan-Meier survival analysis was performed to evaluate the presence of COPD on the vital prognosis of patients with HF. Results: A total of 3100 patients were included of which 812 had COPD. In the COPD group, dyspnea and anxiety were more frequently observed (86.2% vs. 75.3%, p = 0.001 and 35.4% vs. 31.2%, p = 0.043, respectively). In patients with a history of COPD, presentation of HF was in the form of acute pulmonary edema (21% vs. 14.4% in patients without COPD, p = 0.0001). Patients with COPD more frequently suffered from advanced HF (28.9% vs. 19.4%; p < 0.001). Consultation with the hospital palliative care service during admission was more frequent when patients with HF presented with associated COPD (94% vs. 6.8%; p = 0.036). In-hospital and six-month follow-up mortality was 36.5% in patients with COPD vs. 30.7% in patients without COPD, p = 0.005. The mean number of hospital admissions during follow-up was higher in patients with HF and COPD than in those with isolated HF (0.63 +/- 0.98 vs. 0.51 +/- 0.84; p < 0.002). Survival analysis showed that patients with a history of COPD had fewer survival days during follow-up than those without COPD (log Rank chi-squared 4.895 and p = 0.027). Conclusions: patients with HF and COPD had more severe symptoms (dyspnea and anxiety) and also a worse prognosis than patients without COPD. However, the prognosis of patients admitted to our setting is poor and many patients with HF and COPD may not receive the assessment and palliative care support they need. Palliative care is necessary in chronic non-oncologic diseases, especially in multipathologic and symptom-intensive patients. This is a clinical care aspect to be improved and evaluated in future research studies

Cancer impact prognosis on mortality in patients with acute heart failure: analysis of the epicter study

Introduction: Heart failure (HF) and cancer are currently the leading causes of death worldwide, with an increasing incidence with age. Little is known about the treatment received and the prognosis of patients with acute HF and a prior cancer diagnosis. Objective: to determine the clinical characteristics, palliative treatment received, and prognostic impact of patients with acute HF and a history of solid tumor. Methods: The EPICTER study ('Epidemiological survey of advanced heart failure') is a cross-sectional, multicenter project that consecutively collected patients admitted for acute HF in 74 Spanish hospitals. Patients were classified into two groups according to whether they met criteria for acute HF with and without solid cancer, and the groups were subsequently compared. A multivariable logistic regression analysis was conducted, using the forward stepwise method. A Kaplan-Meier survival analysis was performed to evaluate the impact of solid tumor on prognosis in patients with acute HF. Results: A total of 3127 patients were included, of which 394 patients (13%) had a prior diagnosis of some type of solid cancer. Patients with a history of cancer presented a greater frequency of weight loss at admission: 18% vs. 12% (p = 0.030). In the cancer group, functional impairment was noted more frequently: 43% vs. 35%, p = 0.039). Patients with a history of solid cancer more frequently presented with acute HF with preserved ejection fraction (65% vs. 58%, p = 0.048) than reduced or mildly reduced. In-hospital and 6-month follow-up mortality was 31% (110/357) in patients with solid cancer vs. 26% (637/2466), p = 0.046. Conclusion: Our investigation demonstrates that in-hospital mortality and mortality during 6-month follow-up in patients with acute HF were higher in those subjects with a history of concomitant solid tumor cancer diagnosis

Estudio de las alteraciones del metabolismo fosfo-cálcico y sus consecuencias en la enfermedad hepática difusa

En la evolución de la hepatopatía crónica y del etilismo puede aparecer como complicación una enfermedad ósea metabólica, Osteoporosis (OP) u Osteomalacia (OM), que en el caso de la cirrosis se ha denominado Osteodistrofia Hepática (ODH). Su etiopatogenia no está del todo aclarada, y se ha dado por muchos autores una gran importancia a alteraciones en el metabolismo de la vitamina D. En nuestro medio se desconoce su incidencia, así como el tipo de enfermedad ósea predominante y los factores implicados en su aparición, por ello nos planteamos realizar el presente trabajo. Hemos estudiado un total de 212 personas divididas en cuatro grupos: Controles (88), Hepatitis Agudas (12), etílicos Crónicos sin Hepatopatía (49), y Cirróticos (63); estos últimos subdivididos en función de la etiología y el grado de insuficiencia hepática. A todos ellos se les realizó medición de masa ósea lumbar mediante Absorciometría Fotónica Doble (AFD), y a 82 casos pertenecientes a los diferentes grupos se les realizó el protocolo del estudio completo, que incluía: historia clínica digestiva y ósea, hábitos dietéticos, ingesta de etanol y tratamiento farmacológicos realizados, estudios radiográficos y de medición de masa ósea, estudios bioquímicos y hormonales relacionados con el metabolismo fosfo-cálcico, y valoración de la absorción intestinal de calcio, grasas y vitamina D. Nuestros resultados indican que la enfermedad ósea metabólica que predomina en nuestro medio, tanto en los cirróticos como en los alcohólicos crónicos, es la OP, y dados los niveles de Osteocalcina sérica (BGP) en dichos pacientes, pensamos que se trata de una OP de “bajo tournover”, Dicha OP se aprecia tanto en el hueso trabecular como en el cortical. La incidencia de valores de Densidad Mineral Ósea (BMD) a nivel lumbar inferiores a 2 desviaciones standard (DS) por debajo de la media del grupo control fue del 19% en los cirróticos y del 12% en los etílicos, y con respecto al porcentaje de Área Cortical (PCA) metacarpiano fue del 35% en cirróticos y del 15% en etílicos. La mayor incidencia de síntomas (dolores óseos) la presentaron los cirróticos de origen etílico (29%), y, mientras que la prevalencia de fracturas vertebrales fue similar en todos los grupos de cirróticos y en los etílicos (entre 7 y 12%), otras fracturas no vertebrales fueron mucho más frecuentes en los enfermos alcohólicos que en los que no lo eran, estando esto quizás relacionado con los frecuentes traumatismos que sufren. Por lo que respecta a la etiopatogenia de la OP en estos pacientes, parece ser multifactorial. Las alteraciones que hemos encontrado en los cirróticos son: una actividad física baja, una dieta inadecuada baja en calcio y vitamina D, una escasa exposición solar, deficiente estado de nutrición, malabsorción de calcio, déficit de magnesio, hipocalciuria (en los cirróticos con ascitis), niveles bajos de PTH y 25-OH-D, pero con niveles normales de 1,25-(OH)2-D3. También en los alcohólicos sin cirrosis encontramos algunas de estas alteraciones, y el etilismo por sí solo produce alteraciones en la absorción intestinal de calcio y a nivel metabólico que acaba originando igualmente OP. CONCLUSIONES: 1. La incidencia de síntomas de enfermedad ósea (dolor óseo) en nuestro estudio ha sido del 22% en los etílicos crónicos, y del 21 al 29% en los distintos grupos de cirróticos, siendo la más elevada la de los cirróticos de origen etílico. 2. La prevalencia de fracturas vertebrales fue similar en etílicos y cirróticos, oscilando entre el 7% y el 12%. En cambio, los alcohólicos y los cirróticos de origen etílico presentaron una prevalencia de otras fracturas 2 a 4 veces superior que los cirróticos no etílicos, hecho que puede explicarse por su elevado número de traumatismos 3. La mayor tasa de síntomas y de fracturas vertebrales en el grupo de cirróticos de origen etílico sugiere que la asociación de hábito etílico y enfermedad hepática incrementa el riesgo de padecer enfermedad ósea metabólica. 4. Con los métodos empleados para el estudio óseo 8radiografías, radiogrametría y AFD) no encontramos evidencias de Osteomalacia (OM) en ninguno de los pacientes, pero si de Osteoporosis (OP), tanto cortical como trabecular, siendo el PCA metacarpiano y el BMD lumbar significativamente inferiores en etílicos y cirróticos con respecto al grupo control. 5. La elevación de la fosfatasa alcalina carece de utilidad como índice de actividad osteoblástica en los cirróticos si no se determinan las isoenzimas óseas y hepáticas. La Osteocalcina sérica (BGP) es más útil como marcador del remodelamiento óseo, y ya que sus valores fueron bajos o normales en el 100% de los alcohólicos y en el 90% de los cirróticos, pensamos que la OP de estos enfermos corresponde al tipo denominado de “bajo tournover”. 6. La falta de ejercicio físico, una baja exposición a la luz solar, el etilismo, la desnutrición, una dieta pobre en calcio y vitamina D, y los trtamientos con diuréticos y antiácidos, son factores que contribuyen a la pérdida de masa ósea y deben ser tenidos en cuenta como causa de la OP en nuestros pacientes. 7. La absorción intestinal de calcio está significativamente disminuida en los alcohólicos y más aun en los cirróticos, siendo más ineficaz a medida que empeora la función hepática. Ello puede deberse a déficit de 1,25-(OH)2-D3 en los cirrótico, a una resistencia a la acción de esta hormona, a un efecto tóxico del etanol sobre el enterocito, y a factores locales digestivos y de la mucosa intestinal, siendo estos últimos importantes en los grados avanzados de cirrosis, que es cuando también disminuye la absorción de grasas y de vitamina D. 8. El calcio total corregido para la albúmina, el calcio iónico y el fósforo séricos son normales en todos los grupos estudiados. El magnesio sérico está bajo en los cirróticos, pero solo significativamente en los que tienen ascitis. El hallazgo de hipomagnesemia en el 21% de los alcohólicos y en el 40% de los cirróticos sugiere la existencia de un déficit de magnesio total e intracelular en estos enfermos, que puede tener repercusiones sobre el metabolismo fosfo-cálcico. 9. La calciuria fue más baja en etílicos y cirróticos que en sanos, y estaba significativamente disminuida en los cirróticos con ascitis, lo cual va a favor de que la hipocalciuria esté en relación con los mecanismos renales implicados en la formación de la ascitis, que originan una hiperreabsorción de sodio, y esta a su vez de calcio. La fosfaturia fue también inferior en los cirróticos, pero el resto de los parámetros del manejo renal del fósforo fueron normales. 10. La Calcitonina sérica está elevada en los cirróticos, aumentando a medida que empeora la función hepática, lo que se debe probablemente a una disminución del catabolismo hepático de esta hormona más que a una alteración con implicaciones metabólicas. 11. La PTH intacta sérica está significativamente disminuida en los cirróticos y en los alcohólicos respecto al grupo control, esto puede deberse a una inhibición de su síntesis y/o secreción relacionadas con un déficit de magnesio, con un efecto tóxico del etanol o con otras causas no conocidas. No encontramos evidencias de hiperparatiroidismo secundario en nuestros enfermos, excepto en un caso que fue dudoso. 12. En todos los grupos del estudio encontramos variaciones estacionales de los niveles séricos de 25-OH-D, siendo más elevados en los meses de verano; el 1,25-(OH)2-D3 no presentó dichas variaciones. Los cirróticos tienen valores más bajos de 25-OH-D que los controles, sobre todo lo que tienen ascitis, pero solo este último grupo es el que tiene niveles de 1,25-(OH)2-D3 inferiores al del grupo control, aunque dentro del rango normal. Esto puede explicar la ausencia de OM en nuestro medio. 13. La ausencia de correlaciones de importancia entre los parámetros bioquímicos y hormonales del metabolismo fósforo-cálcico, el grado de hepatopatía, la ingesta etílica y la cuantía de pérdida de masa ósea sugiere la existencia de una etiología multifactorial en la ODH, siendo no obstante el etilismo uno de los factores causales de mayor importancia. 14. De lo dicho anteriormente puede resumirse que la enfermedad ósea metabólica que presentan los etílicos crónicos y los cirróticos es fundamentalmente una OP de “bajo tournober”, que afecta al hueso cortical y al trabecular, y cuya etiología es multifactorial influyendo el tipo de vida y alimentación, tóxicos y fármacos, trastornos digestivos, renales y alteraciones metabólicas. 15. Finalmente, el tratamiento que debe recomendarse a estos enfermos es, hoy por hoy, fundamentalmente preventivo, evitando el sedentarismo y los hábitos tóxicos, favoreciendo la exposición a la luz solar y una dieta equilibrada, y administrando suplementos vitamínicos y minerales

Hyponatremia as predictor of worse outcome in real world patients admitted with acute heart failure

Background: Our aim was to determine if hyponatremia, defined as serum sodium level &lt; 135 mmol/L, is a predictor of worse outcome in a cohort of real-world patients with heartfailure (HF).Methods: We used data of the National registry of HF (RICA) from Spain, an ongoing multicenter, prospective cohort study. The patients were assigned to two groups regarding sodium levels. Primary end-point was first all-cause readmission, or death by any cause. Secondary end-points were the number of days hospitalized, and the presence of complications.Results: We identified 973 patients, 147 (15.11%) with hyponatremia. The median age of patients enrolled was 77.25 ± 8.79 years-old, the global comorbidity measured by Charlson comorbidity index (CCI) was upper 3 points and preserved ejection fraction was present in67.1% of them. Clinical complications during admission were significantly higher in the patients with hyponatremia (35.41%, p &lt; 0.001) and this remained as significant predictor after logistic regression adjustment (OR 1.08, p &lt; 0.01). Also mortality and readmissions were more frequent in patients with hyponatremia (20.69% and 22.41%, respectively) but after Cox regression adjustment hyponatremia in our cohort was not associated with increase in 90-day all-cause mortality and readmissions, and only CCI remained significant for primaryend-point (HR 1.08, p &lt; 0.001).Conclusions: Hyponatremia is an independent predictor of complications during hospitalization in our real-world cohort, but was not associated with 90 days mortality or readmissions. Global comorbidity, however, played an important role, and could influence the mortality and readmissions of our patients