Molecular Alterations of Nucleocytoplasmic Transport in Patients on the Heart Transplantation Waiting List and Its Correlation With the Severity and Etiology of Heart Failure.

OBJECTIVES: To evaluate whether the levels of some molecules implicated in nucleocytoplasmic transport in human cardiomyocytes are related to the severity of heart failure (HF) in patients on the heart transplantation (HT) waiting list, and to determine whether there is a differential pattern of molecular alteration between ischemic cardiomyopathy (ICM) and non-ischemic dilated cardiomyopathy (DCM). METHODS: Sixty-three blood samples collected before HT were analyzed to identify the levels of IMPORTIN5 (IMP5); IMPORTINalpha2; ATPaseCaTransp (ATPCa); NUCLEOPORIN153kDa (Nup153); NUCLEOPORIN160kDa (Nup160); RANGTPaseAP1 (RanGAP1) and EXPORTIN4 (EXP4). These data were then compared between patients with advanced HF with or without the need for ventricular support with extracorporeal membrane oxygenation (ECMO) as a bridge for HT, as well as between patients with non-ischemic DCM and patients with ICM. RESULTS: Thirty-three patients had ICM, 26 had non-ischemic DCM, and 4 had heart disease. Seventeen patients required ventricular assistance as a bridge to HT. The levels of ATPCa, RanGAP1, and IMP5 were significantly higher in patients with ECMO, while EXP4 was significantly higher in patients without ECMO. Patients with DCM showed higher levels of IMP5, RanGAP1, and Nup153 than those with ICM. CONCLUSION: Patients with advanced HF in critical condition (with ECMO as a bridge for HT) presented with significantly higher levels of ATPCa, RanGAP1, and IMP5, while patients with DCM had significantly higher levels of RanGAP1, IMP5, and Nup153. It remains to be clarified whether the determination of these molecules would facilitate the early identification of this group or if their alteration occurs as consequence of circulatory support with ECMO.

Relaxin activates AMPK-AKT signaling and increases glucose uptake by cultured cardiomyocytes.

PURPOSE: Many evidences show that the hormone relaxin plays a pivotal role in the physiology and pathology of the cardiovascular system. This pleiotropic hormone exerts regulatory functions through specific receptors in cardiovascular tissues: in experimental animal models it was shown to induce coronary vasodilation, prevent cardiac damage induced by ischemia/reperfusion and revert cardiac hypertrophy and fibrosis. A tight relationship between this hormone and important metabolic pathways has been suggested, but it is at present unknown if relaxin could regulate cardiac metabolism. Our aim was to study the possible effects of relaxin on cardiomyocyte metabolism. METHODS: Neonatal rat cardiomyocytes were treated with relaxin and (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assays (MTT) were performed to assess metabolic activity; while 2-deoxy-D-[3H] glucose and BODIPY-labelled fatty acid incorporations were analyzed to measure glucose and fatty acid uptakes, and western blot was utilized to study the intracellular signaling pathways activated by the hormone. RESULTS: We observed that relaxin at 10 ng/ml was able to increase the level of metabolic activity of cultured neonatal rat cardiomyocytes; the rate of 2-deoxy-D-[3H]glucose incorporation demonstrated that relaxin also induced an increase in glucose uptake. First evidence is also offered that relaxin can activate the master energy sensor and regulator AMPK in cardiomyocytes. Moreover, the treatment of cardiomyocytes with relaxin also induced dose-dependent increases in ERK1/2, AKT, and AS160 phosphorylation. That raise in AS160 phosphorylation induced by relaxin was prevented by the pretreatment with AMPK and AKT pathways inhibitors, indicating that both molecules play important roles in the relaxin effects reported. CONCLUSION: Relaxin can regulate cardiomyocyte metabolism and activate AMPK, the central sensor of energy status that maintains cellular energy homeostasis, and also ERK and AKT, two molecular sensing nodes that coordinate dynamic responses of the cell's metabolic responses.

20 years of leptin: Role of leptin in cardiomyocyte physiology and physiopathology.

Since the discovery of leptin in 1994 by Zhang et al., there have been a number of reports showing its implication in the development of a wide range of cardiovascular diseases. However, there exists some controversy about how leptin can induce or preserve cardiovascular function, as different authors have found contradictory results about leptin beneficial or detrimental effects in leptin deficient/resistant murine models and in wild type tissue and cardiomyocytes. Here, we will focus on the main discoveries about the leptin functions at cardiac level within the last two decades, focusing on its role in cardiac metabolism, remodeling and contractile function.

Long-term prognostic implications of metabolic syndrome in heart transplant recipients.

BACKGROUND: Metabolic syndrome (MS) increases the risk of cardiovascular events due to endothelial dysfunction. There are few studies evaluating the impact of MS on the survival of heart transplantation (HTx) patients. AIM: The aim of this study was to study the impact of MS in the early period and on the long-term survival after HTx. MATERIALS AND METHODS: We studied 196 HTx patients with a minimum survival of 1 year post-HTx. A diagnosis of MS was made at 3 months after HTx, if at least 3 of the following criteria were met: triglyceride levels ≥150 mg/dL (or drug treatment for hypertriglyceridemia); high-density lipoprotein cholesterol (HDL-C) <40 mg/dL in men and <50 mg/dL in women (or drug treatment to raise HDL-C levels); diabetes mellitus on drug treatment or fasting glucose levels ≥100 mg/dL; blood pressure ≥130/85 mm Hg (or on antihypertensive drug treatment); and body mass index (BMI) ≥30. We used the Kaplan-Meier method (log-rank test) to calculate long-term survival and Student t and chi-square tests for comparisons. RESULTS: Among 196 patients, 96 developed MS. There were no differences between the groups with versus without MS in recipient gender, underlying etiology, smoking, pre-HTx diabetes, or immunosuppressive regimen. However, differences were observed between groups in age (MS: 53 ± 9 vs non-MS: 50 ± 12 years; P = .001); pre-HTx creatinine (MS: 1.2 ± 0.3 vs non-MS: 1.0 ± 0.4 mg/dL; P = .001); BMI (MS: 27.3 ± 4 vs non-MS: 24.6 ± 4; P = .001); pre-HTx hypertension (MS: 48% vs non-MS: 17%; P < .001); and dyslipidemia (MS: 53% vs non-MS: 37%; P = .023). Long-term survival was better among the non-MS group, but the difference did not reach significance (MS: 2381 ± 110 vs non-MS: 2900 ± 110 days; P = .34). CONCLUSIONS: The development of MS early after HTx is a common complication that affects nearly 50% of HTx patients. The prognostic implication of this syndrome on overall survival might occur in the long term.

The role of the nuclear lamins in the pathogenesis of heart failure in patients undergoing cardiac transplantation.

The nuclear lamins A/C play a critical role in maintaining the structure of the nuclear lamina and the organization of various proteins, such as emerin. These protein levels may play roles in the pathogenesis and clinical evolution of both ischemic (ICM) and dilated (DCM) cardiomyopathy. We evaluated the nuclear morphology of cardiomyocytes and determine lamins A/C and emerin levels among DCM and ICM heart failure patients compared with control human hearts. We determined protein levels by Western blots using mouse monoclonal antibodies in 23 explanted human hearts. Lamin A was increased in failing hearts but significantly different only among the DCM compared with the control group: mean, 236 +/- 51 vs 100 +/- 34; (P < .05). However, lamin C in the DCM group was near control values and significantly decreased in the ICM cohort compared to controls 75 +/- 7 versus 100 +/- 3 (P < .05). No alterations in emerin levels were observed in ICM or DCM, compared with controls. In conclusion, hearts with ICM or DCM showed different alterations in the nuclear morphology of cardiomyocytes; ICM patients had decreased lamin C, whereas DCM patients had increased lamin A. These changes affecting nuclear structure and function may have prognostic implications, for cardiomyopathy etiology.

[Urinary levels of B-type natriuretic peptide (BNP) and ventricular systolic dysfunction in heart failure patients]. / Niveles urinarios de péptido natriurético tipo B (BNP) y disfunción ventricular sistólica en pacientes con insuficiencia cardiaca.

BACKGROUND: It was aimed to compare urine B-type natriuretic peptide (BNP) according to left ventricular systolic dysfunction and to investigate its diagnostic value in heart failure (HF) patients. MATERIAL AND METHODS: A total of 90 HF outpatients (61 men, age 66 +/- 12) and 30 age- and gender-matched controls were studied. RESULTS: An increase in urine BNP was observed in patients with EF 40% (p < 0.0001), and controls (p < 0.0001). Significant correlations between urinary BNP and left ventricular functional parameters were obtained. A multivariate regression analysis was performed and the best model associated with urine BNP included plasma BNP (p < 0.0001), EF (p = 0.02) and LV volume indexes (p < 0.0001). The ROC for detection of EF

Niveles urinarios de péptido natriurético tipo B (BNP) y disfunción ventricular sistólica en pacientes con insuficiencia cardiaca / Urinary levels of B-type natriuretic peptide (BNP) and ventricular systolic dysfunction in heart failure patients

Introducción. Comparar niveles de péptido urinario tipo B (BNP) en orina según la presenciade disfunción sistólica ventricular izquierda e investigar su valor diagnóstico enpacientes con insuficiencia cardiaca (IC).Material y métodos. Hemos estudiado a 90 pacientes ambulatorios con IC (61 hombres,edad 66 ± 12) y 30 sujetos control apareados por edad y género.Resultados. Se encontró un aumento en los niveles urinarios de BNP en los pacientes con fracciónde eyección (FE) <= 40% comparados con los de FE > 40% (p < 0,0001) y con los controles(p < 0,0001). Se obtuvieron correlaciones signifi cativas entre los niveles urinarios de BNP ylos parámetros funcionales del ventrículo izquierdo. Se realizó un análisis multivariado y elmejor modelo asociado con los niveles urinarios de BNP incluyó a los niveles de BNP en plasma(p < 0,0001), FE (p = 0,02) y volúmenes del ventrículo izquierdo (p < 0,0001). La curvaROC para la detección de FE <= 40% usando BNP urinario mostró un área bajo la curva de0,74 ± 0,05, (p < 0,0001). A partir de la curva ROC, el punto óptimo de corte (2,30 pg/ml)tuvo una sensibilidad del 60% y una especifi cidad del 90%. Finalmente, se realizó unaregresión binaria logística para la detección de FE <= 40%, y los niveles urinarios de BNPmostraron un buen valor predictivo con una odds-ratio de 21.Discusión. Los niveles urinarios de BNP se correlacionan con los parámetros funcionalesdel ventrículo izquierdo, demostrando que este marcador biológico es útil para el diagnósticode la disfunción ventricular izquierda en pacientes con insufi ciencia cardiaca(AU)

Background. It was aimed to compare urine B-type natriuretic peptide (BNP) according toleft ventricular systolic dysfunction and to investigate its diagnostic value in heart failure(HF) patients.Material and methods. A total of 90 HF outpatients (61 men, age 66 ± 12) and 30 age- andgender-matched controls were studied.Results. An increase in urine BNP was observed in patients with EF<= 40% compared toEF> 40% (p < 0.0001), and controls (p < 0.0001). Signifi cant correlations between urinaryBNP and left ventricular functional parameters were obtained. A multivariate regressionanalysis was performed and the best model associated with urine BNP included plasmaBNP (p < 0.0001), EF (p = 0.02) and LV volume indexes (p < 0.0001). The ROC fordetection of EF <= 40% using urine BNP levels showed an area under the curve of 0.74 ±0.05, (p < 0.0001). From the ROC curve, the optimal cut-off value (2.30 ng/l) had a 60%sensitivity and 90% specifi city. Finally, we performed a binary logistic regression fordetection of EF <= 40%, and urine BNP was shown to be a strong predictor with an oddsratioof 21.Discussion. Urine BNP levels correlated with left ventricular functional parameters. Thisbiomarker is a useful tool for detecting and diagnosing left ventricular systolic dysfunctionin heart failure(AU)