Metástasis mandibular por carcinoma hepático: un infrecuente caso con severa hemorragia

El carcinoma hepatocelular (CH) es relativamente infrecuente en Europa y Estados Unidos, a pesar de que en este último país se diagnostican más de 13.000 nuevos casos cada año. Las metástasis mandibulares por CH son inusuales, recogiéndose en la literatura hasta el momento, 50 casos. En el presente trabajo se documenta un nuevo caso, correspondiente a un varón de 54 años que presentó una metástasis por HC en el cuerpo mandibular derecho, al año del tratamiento de su tumor primario. El curetaje-biopsia de la lesión se acompañó de una profusa hemorragia. El paciente falleció a los seis meses de la biopsia, con múltiples metástasis. Se describen las posibles vías de diseminación hematógena de la enfermedad.Hepatocellular carcinoma (HCC) is quite uncommon in Europe and USA, although in this last country more than 13,000 new cases are diagnosed every year. Mandibular metastases are unusual, with only 50 cases documented. In this article, we present a 54 year-old male patient with a metastasis of HCC in right mandibular body, one year after treating the primary tumor. Curettage and biopsy of the lesion was performed, followed by a profuse hemorrhage. The patient expired six months after the biopsy, with multiple metastases. We describe the different paths for hematogenic dissemination of the process

Disfunción microvascular coronaria e inflamación crónica

La disfunción microvascular coronaria asociada a disfunción endotelial está presente en diferentes contextos de la enfermedad cardiovascular, incluyendo los factores de riesgo cardiovascular clásicos, y la inflamación podría jugar un papel esencial en todo este epifenómeno. De hecho, actualmente la aterosclerosis es vista como un proceso inflamatorio activo e inmuno-mediado en el cual leucocitos y factores solubles (anticuerpos, factores de complemento activados, citoquinas) participan en el progreso de la enfermedad. Los pacientes con enfermedades inflamatorias sistémicas autoinmunes, como la artritis reumatoide y el lupus eritematoso sistémico presentan una elevada morbilidad y mortalidad de origen cardiovascular secundaria a aterosclerosis acelerada y enfermedad coronaria prematura. El exceso de riesgo observado en estos pacientes parece estar relacionado con los efectos deletéreos de la inflamación sistémica en la vasculatura. Por otro lado se especula que un estado inflamatorio de bajo grado podría ser relevante en la patogénesis del síndrome X cardiaco, enfermedad caracterizada por episodios anginosos típicos con isquemia miocárdica transitoria a pesar de no presentar lesiones angiográficas en la coronariografía, en los cuales la disfunción microvascular se ha mostrado como causante de la isquemia miocárdica. El objetivo de la presente tesis es demostrar la posible relación entre inflamación crónica y disfunción microvascular coronaria. Especulamos con que el grado de disfunción de la microcirculación está directamente relacionado con el tiempo de exposición a la inflamación e incluso contemplamos el potencial papel de la inflamación en la modulación de la respuesta microvascular coronaria en algunos pacientes.Background. Coronary microvascular dysfunction associated with endothelial dysfunction is often found in many cardiac conditions, including cardiovascular risk factors, and inflammation would be playing a key role in all this epiphenomenon. Actually, atherosclerosis is seen as an active inflammatory and immune-mediated process in which leukocytes and soluble factors (antibodies, activated complement, cytokines) play a role in accelerating vessel pathology. Patients with systemic inflammatory, autoimmune disease, such as rheumatoid arthritis (AR) and systemic lupus erythematosus (SLE), suffer from increased cardiovascular morbidity and mortality owing to accelerated atherosclerosis and premature coronary disease. The excess risk observed in these patients appears to be driven by the damaging effects of systemic inflammation on the vasculature. A low grade of inflammation could also play a role in the pathogenesis of cardiac syndrome X (ie typical angina and transient myocardial ischemia despite normal coronary arteries) in which coronary microvascular dysfunction has been show to lead myocardial ischemia. Aims. To demonstrate that exposure to chronic inflammation results in coronary microvascular dysfunction (CMD). We speculate that the degree of CMD is directly related to time exposed to inflammation and also hypothesise a potential role of inflammation in the modulation of coronary microvascular responses in some patients. Methods. We carried out 2 separated studies in which systemic inflammatory (AR and LES) patients and CSX patients were analyzed by using positron emission tomography. Resting and hyperaemic (adenosine, 140 μg/Kg/min) myocardial blood flow (MBF) was measured in both groups of patients and in matched healthy volunteers as controls. Results. Although resting MBF was similar in patients (AR/LES and CSX) and controls, abnormalities of the coronary microvascular function were found in both studies, with reduced coronary flow reserve (CFR). CSX patients with C reactive protein levels higher of 3 mg/L at study entry had more severe impairment of CFR. In AR/SLE patients, CFR was inversely related to disease duration (r=-0.65; p<0.001). In both groups of patients, we also found that patients showing ischaemic electrocardiographic changes during adenosine induced hyperaemia, had lower CFR and longer disease duration (AR/LES patients) or higher CRP levels (CSX patients) when compared with patients without changes. Conclusions. Chronic inflammation in the absence of significant coronary disease and traditional cardiovascular risk factors is associated with severe abnormalities of coronary microcirculation, and the degree of this CMD is related with the exposure time to inflammation. We suggest a role for inflammation in the modulation of coronary responses in patients with CSX. This may represent an early marker of cardiovascular disease which precedes and contributes to accelerated atherogenesis

Impact of Vitamin D Supplementation on Arterial Vasomotion, Stiffness and Endothelial Biomarkers in Chronic Kidney Disease Patients

Background: Cardiovascular events are frequent and vascular endothelial function is abnormal in patients with chronic kidney disease (CKD). We demonstrated endothelial dysfunction with vitamin D deficiency in CKD patients; however the impact of cholecalciferol supplementation on vascular stiffness and vasomotor function, endothelial and bone biomarkers in CKD patients with low 25-hydroxy vitamin D [25(OH)D] is unknown, which this study investigated. Methods: We assessed non-diabetic patients with CKD stage 3/4, age 17–80 years and serum 25(OH)D ,75 nmol/L. Brachial artery Flow Mediated Dilation (FMD), Pulse Wave Velocity (PWV), Augmentation Index (AI) and circulating blood biomarkers were evaluated at baseline and at 16 weeks. Oral 300,000 units cholecalciferol was administered at baseline and 8-weeks. Results: Clinical characteristics of 26 patients were: age 50614 (mean61SD) years, eGFR 41611 ml/min/1.73 m2, males 73%, dyslipidaemia 36%, smokers 23% and hypertensives 87%. At 16-week serum 25(OH)D and calcium increased (43616 to 84629 nmol/L, p,0.001 and 2.3760.09 to 2.4260.09 mmol/L; p = 0.004, respectively) and parathyroid hormone decreased (10.868.6 to 7.464.4; p = 0.001). FMD improved from 3.163.3% to 6.163.7%, p = 0.001. Endothelial biomarker concentrations decreased: E-Selectin from 566662123 to 525662058 pg/mL; p = 0.032, ICAM-1, 3.4560.01 to 3.1061.04 ng/mL; p = 0.038 and VCAM-1, 54633 to 42633 ng/mL; p = 0.006. eGFR, BP, PWV, AI, hsCRP, von Willebrand factor and Fibroblast Growth Factor-23, remained unchanged. Conclusion: This study demonstrates for the first time improvement of endothelial vasomotor and secretory functions with vitamin D in CKD patients without significant adverse effects on arterial stiffness, serum calcium or FGF-23. Trial Registration: ClinicalTrials.gov NCT0200571

Methotrexate-mediated activation of an AMPK-CREB-dependent pathway: a novel mechanism for vascular protection in chronic systemic inflammation

Aims Premature cardiovascular events complicate chronic inflammatory conditions. Low-dose weekly methotrexate (MTX), the most widely used disease-modifying drug for rheumatoid arthritis (RA), reduces disease-associated cardiovascular mortality. MTX increases intracellular accumulation of adenosine monophosphate (AMP) and 5-aminoimidazole-4-carboxamide ribonucleotide which activates AMP-activated protein kinase (AMPK). We hypothesised that MTX specifically protects the vascular endothelium against inflammatory injury via induction of AMPK-regulated protective genes. Methods/results In the (NZW×BXSB)F1 murine model of inflammatory vasculopathy, MTX 1 mg/kg/week significantly reduced intramyocardial vasculopathy and attenuated end-organ damage. Studies of human umbilical vein endothelial cells (HUVEC) and arterial endothelial cells (HAEC) showed that therapeutically relevant concentrations of MTX phosphorylate AMPKαThr172, and induce cytoprotective genes including manganese superoxide dismutase (MnSOD) and haem oxygenase-1 (HO-1). These responses were preserved when HUVECs were pretreated with tumour necrosis factor-α to mimic dysfunctional endothelium. Furthermore, MTX protected against glucose deprivation-induced endothelial apoptosis. Mechanistically, MTX treatment led to cyclic AMP response element-binding protein (CREB)Ser133 phosphorylation, while AMPK depletion attenuated this response and the induction of MnSOD and HO-1. CREB siRNA inhibited upregulation of both cytoprotective genes by MTX, while chromatin immunoprecipitation demonstrated CREB binding to the MnSOD promoter in MTX-treated EC. Likewise, treatment of (NZW×BXSB)F1 mice with MTX enhanced AMPKαThr172 phosphorylation and MnSOD, and reduced aortic intercellular adhesion molecule-1 expression. Conclusions These data suggest that MTX therapeutically conditions vascular endothelium via activation of AMPK-CREB. We propose that this mechanism contributes to the protection against cardiovascular events seen in patients with RA treated with MTX

Outcomes and factors associated with mortality in patients with atrial fibrillation and heart failure: FARAONIC study

Background: Heart failure (HF) and atrial fibrillation (AF) are common and coexistent conditions. Hypothesis: To investigate the adverse events and mortality risk factors in patients with AF and HF treated with rivaroxaban in Spain. Methods: Multicenter, prospective and observational study with a follow-up of 2 years, that included adults, with a diagnosis of nonvalvular AF and chronic HF, anticoagulated with rivaroxaban at least 4 months before being enrolled. Results: A total of 672 patients from 71 Spanish centers were recruited, of whom 658 (97.9%) were included in the safety analysis and 552 (82.1%) in the per protocol analysis. At baseline, the mean age was 73.7 +/- 10.9 years, 65.9% were male, 51.3% had HF with preserved ejection fraction and 58.7% were on New York Heart Association functional class II. CHA2DS2-VASc was 4.1 +/- 1.5. During the follow-up, 11.6% of patients died and around one-quarter of patients were hospitalized or visited the emergency department, being HF worsening/progression the main cause (51.1%), with a 2.9% of thromboembolic events and 2.0% of acute coronary syndromes. Major bleeding occurred in 3.1% of patients, with 0.5% experiencing intracranial bleeding but no fatalities. Compliance with HF treatment was associated with a lower risk of death (hazard ratio: 0.092; 95% confidence interval: 0.03-0.31). Conclusions: Among patients with HF and AF anticoagulated with rivaroxaban, incidences of thromboembolic or hemorrhagic complications were low. The most important factor for improving survival was compliance with HF drugs, what strengths the need for early treatment with HF disease-modifying therapy and anticoagulation

Ergocalciferol and Microcirculatory Function in Chronic Kidney Disease and Concomitant Vitamin D Deficiency: An Exploratory, Double Blind, Randomised Controlled Trial

Vitamin D deficiency and endothelial dysfunction are non-traditional risk factors for cardiovascular events in chronic kidney disease. Previous studies in chronic kidney disease have failed to demonstrate a beneficial effect of vitamin D on arterial stiffness, left ventricular mass and inflammation but none have assessed the effect of vitamin D on microcirculatory endothelial function.We conducted a randomised controlled trial of 38 patients with non diabetic chronic kidney disease stage 3-4 and concomitant vitamin D deficiency (<16 ng/dl) who received oral ergocalciferol (50,000 IU weekly for one month followed by 50,000 IU monthly) or placebo over 6 months. The primary outcome was change in microcirculatory function measured by laser Doppler flowmetry after iontophoresis of acetylcholine. Secondary endpoints were tissue advanced glycation end products, sublingual functional capillary density and flow index as well as macrovascular parameters. Parallel in vitro experiments were conducted to determine the effect of ergocalciferol on cultured human endothelial cells.Twenty patients received ergocalciferol and 18 patients received placebo. After 6 months, there was a significant improvement in the ergocalciferol group in both endothelium dependent microcirculatory vasodilatation after iontophoresis of acetylcholine (p = 0.03) and a reduction in tissue advanced glycation end products (p = 0.03). There were no changes in sublingual microcirculatory parameters. Pulse pressure (p = 0.01) but not aortic pulse wave velocity was reduced. There were no significant changes in bone mineral parameters, blood pressure or left ventricular mass index suggesting that ergocalciferol improved endothelial function independently of these parameters. In parallel experiments, expression of endothelial nitric oxide synthase and activity were increased in human endothelial cells in a dose dependent manner.Ergocalciferol improved microcirculatory endothelial function in patients with chronic kidney disease and concomitant vitamin D deficiency. This process may be mediated through enhanced expression and activity of endothelial nitric oxide synthase.Clinical trials.gov NCT00882401

Effectiveness and safety of rivaroxaban in patients with atrial fibrillation and heart failure in clinical practice: an indirect comparison of national and international registries

Background The objective of the study was to analyze and compare the effectiveness and safety of rivaroxaban in patients with atrial fibrillation (AF) and heart failure (HF).Methods The clinical profile and outcomes of the FARAONIC study were indirectly compared with those of the ROCKET-AF trial and other national and international observational registries.Results In FARAONIC, the median age was 73.7 years, 34.1% were women, and the median CHA2DS2-VASc was 4.1. In the rivaroxaban arm of ROCKET-AF in patients with HF, these statistics were 72 years, 39.1%, and 5.1, respectively. In the national/international registries of patients with HF receiving rivaroxaban, these statistics were 74.0-75.3 years, 40.8%-41.4%, and 3.2-4.5, respectively. In the GLORIA-AF (dabigatran) and ETNA-AF (edoxaban) trials, these numbers were 69.9-75.3 years, 39.3%-41.6%, and 3.8-4.4, respectively. Among the HF populations, annualized rates of stroke or systemic embolism were 0.75% in FARAONIC (vs. 1.90% in ROCKET-AF, 0.92%-1.2% in national/international registries with rivaroxaban, 0.82% in GLORIA-AF, and 0.88% in ETNA-AF). Rates of major bleeding in FARAONIC were 1.55% (vs. 1.4%-3.86% in the national/international registries with rivaroxaban, 1.20% in GLORIA-AF, and 1.65% in ETNA-AF).Conclusion In clinical practice, AF patients with HF, anticoagulated with rivaroxaban are old, have many comorbidities and have a high thromboembolic risk. Despite this, rates of adverse events are low

Practical Approaches to the Management of Cardiorenal Disease beyond Congestion

Background: The coexistence of heart and kidney diseases, also called cardiorenal syndrome, is very common, leads to increased morbidity and mortality, and poses diagnostic and therapeutic difficulties. There is a risk-Treatment paradox, such that patients with the highest risk are treated with lesser disease-modifying medical therapies. Summary: In this document, different scientific societies propose a practical approach to address and optimize cardiorenal therapies and related comorbidities systematically in chronic cardiorenal disease beyond congestion. Cardiorenal programs have emerged as novel models that may assist in delivering coordinated and holistic management for these patients. Key Messages: (1) Cardiorenal disease is a ubiquitous entity in clinical practice and is associated with numerous barriers that limit medical treatment. (2) The present article focuses on the practical approaches to managing chronic cardiorenal disease beyond congestion to overcome some of these barriers and improve the treatment of this high-risk population

Haemodynamic Balance in Acute and Advanced Heart Failure: An Expert Perspective on the Role of Levosimendan

Acute and advanced heart failure are associated with substantial adverse short- and longer-term prognosis. Both conditions necessitate complex treatment choices to restore haemodynamic stability and organ perfusion, relieve congestion, improve symptoms and allow the patient to leave the hospital and achieve an adequate quality of life. Among the available intravenous vasoactive therapies, inotropes constitute an option when an increase in cardiac contractility is needed to reverse a low output state. Within the inotrope category, levosimendan is well suited to the needs of both sets of patients since, in contrast to conventional adrenergic inotropes, it has not been linked in clinical trials or wider clinical usage with increased mortality risk and retains its efficacy in the presence of beta-adrenergic receptor blockade; it is further believed to possess beneficial renal effects. The overall haemodynamic profile and clinical tolerability of levosimendan, combined with its extended duration of action, have encouraged its intermittent use in patients with advanced heart failure. This paper summarises the key messages derived from a series of 12 tutorials held at the Heart Failure 2019 congress organised in Athens, Greece, by the Heart Failure Association of the European Society of Cardiology

Congestion as a crucial factor determining albuminuria in patients with cardiorenal disease

Background: Albuminuria could potentially emerge as a novel marker of congestion in acute heart failure. However, the current evidence linking albuminuria and congestion in patients with congestive heart failure (CHF) remains somewhat scarce. This study aimed to evaluate the prevalence of albuminuria in a cohort of patients with CHF, identify the independent factors associated with albuminuria and analyse the correlation with different congestion parameters. Methods: This is a subanalysis of the Spanish Cardiorenal Registry, in which we enrolled 864 outpatients with heart failure and a value of urinary albumin:creatinine ratio (UACR) at the first visit. Results: The median age was 74 years, 549 (63.5%) were male and 438 (50.7%) had a reduced left ventricular ejection fraction. A total of 350 patients (40.5%) had albuminuria. Among these patients, 386 (33.1%) had a UACR of 30–300 mg/g and 64 (7.4%) had a UACR >300 mg/g. In order of importance, the independent variables associated with higher UACR were estimated glomerular filtration rate determined by the Chronic Kidney Disease Epidemiology Collaboration equation (R2 = 57.6%), systolic blood pressure (R2 = 21.1%), previous furosemide equivalent dose (FED; R2 = 7.5%), antigen carbohydrate 125 (CA125; R2 = 6.1%), diabetes mellitus (R2 = 5.6%) and oedema (R2 = 1.9%). The combined influence of oedema, elevated CA125 levels and the FED accounted for 15.5% of the model's variability. Conclusions: In patients with chronic stable heart failure, the prevalence of albuminuria is high. The risk factors of albuminuria in this population are chronic kidney disease and hypertension. Congestion parameters are also associated with increased albuminuria