Anemia de las enfermedades crónicas: fisiopatología, diagnóstico y tratamiento / Anaemia of chronic diseases: Pathophysiology, diagnosis and treatment

La anemia de las enfermedades crónicas (AEC) se genera por la activación del sistema inmune por autoantígenos, moléculas microbianas o antígenos tumorales, que dan lugar a la liberación de citocinas que originan una elevación de la hepcidina sérica, hiposideremia, supresión de la eritropoyesis, disminución de la eritropoyetina (EPO) y acortamiento de la vida media de los hematíes. La anemia suele ser normocítica/normocrómica, es la más prevalente, después de la anemia ferropénica, y es la más frecuente en los ancianos y en los pacientes hospitalizados. Si la anemia es grave, la calidad de vida del paciente se deteriora y puede tener un impacto negativo en la supervivencia. El objetivo del tratamiento va dirigido a controlar la enfermedad de base y a corregir la anemia. En ocasiones se ha utilizado hierro endovenoso y EPO, pero el futuro terapéutico va dirigido contra la hepcidina, que es la diana responsable final de la anemia. (AU)

Anaemia of chronic disease (ACD) is generated by the activation of the immune system by autoantigens, microbial molecules or tumour antigens resulting in the release of cytokines that cause an elevation of serum hepcidin, hypoferraemia, suppression of erythropoiesis, decrease in erythropoietin (EPO) and shortening of the half-life of red blood cells. Anaemia is usually normocytic and normochromic, which is the most prevalent after iron deficiency anaemia, and it is the most frequent in the elderly and in hospitalized patients. If the anaemia is severe, the patient's quality of life deteriorates, and it can have a negative impact on survival. Treatment is aimed at controlling the underlying disease and correcting anaemia. Sometimes intravenous iron and EPO have been used, but the therapeutic future is directed against hepcidin, which is the final target of anaemia. (AU)

Anaemia of chronic diseases: Pathophysiology, diagnosis and treatment. / Anemia de las enfermedades crónicas: fisiopatología, diagnóstico y tratamiento.

Anaemia of chronic disease (ACD) is generated by the activation of the immune system by autoantigens, microbial molecules or tumour antigens resulting in the release of cytokines that cause an elevation of serum hepcidin, hypoferraemia, suppression of erythropoiesis, decrease in erythropoietin (EPO) and shortening of the half-life of red blood cells. Anaemia is usually normocytic and normochromic, which is the most prevalent after iron deficiency anaemia, and it is the most frequent in the elderly and in hospitalized patients. If the anaemia is severe, the patient's quality of life deteriorates, and it can have a negative impact on survival. Treatment is aimed at controlling the underlying disease and correcting anaemia. Sometimes intravenous iron and EPO have been used, but the therapeutic future is directed against hepcidin, which is the final target of anaemia.

Estado actual del metabolismo del hierro: implicaciones clínicas y terapéuticas / Current status of iron metabolism: clinical and therapeutic implications

La hepcidina es el principal regulador del metabolismo del hierro y el factor patogénico más importante en sus trastornos. La deficiencia de hepcidina provoca sobrecarga de hierro, mientras que su exceso da lugar o contribuye al desarrollo de anemias por déficit o restricción de hierro en las enfermedades crónicas. Conocemos los mecanismos implicados en la síntesis de hepcidina y, en condiciones fisiológicas, hay un equilibrio entre las señales activadoras e inhibidoras que regulan su síntesis. Las primeras incluyen las relacionadas con la concentración plasmática de hierro y con las enfermedades inflamatorias. Las señales inhibidoras más importantes están relacionadas con la eritropoyesis activa y con la matriptasa-2. Conocer cómo se sintetiza la hepcidina ha servido para diseñar nuevos tratamientos farmacológicos cuya diana principal es la hepcidina. En un futuro próximo, se dispondrá de tratamientos eficaces dirigidos a corregir el defecto de muchos de los trastornos del metabolismo del hierro (AU)

Hepcidin is the main regulator of iron metabolism and a pathogenic factor in iron disorders. Hepcidin deficiency causes iron overload, whereas hepcidin excess causes or contributes to the development of iron-restricted anaemia in chronic inflammatory diseases. We know the mechanisms involved in the synthesis of hepcidin and, under physiological conditions, there is a balance between activating signals and inhibitory signals that regulate its synthesis. The former include those related to plasmatic iron level and also those related to chronic inflammatory diseases. The most important inhibitory signals are related to active erythropoiesis and to matriptase-2. Knowing how hepcidin is synthesised has helped design new pharmacological treatments whose main target is the hepcidin. In the near future, there will be effective treatments aimed at correcting the defect of many of these iron metabolism disorders (AU)

Current status of iron metabolism: Clinical and therapeutic implications. / Estado actual del metabolismo del hierro: implicaciones clínicas y terapéuticas.

Hepcidin is the main regulator of iron metabolism and a pathogenic factor in iron disorders. Hepcidin deficiency causes iron overload, whereas hepcidin excess causes or contributes to the development of iron-restricted anaemia in chronic inflammatory diseases. We know the mechanisms involved in the synthesis of hepcidin and, under physiological conditions, there is a balance between activating signals and inhibitory signals that regulate its synthesis. The former include those related to plasmatic iron level and also those related to chronic inflammatory diseases. The most important inhibitory signals are related to active erythropoiesis and to matriptase-2. Knowing how hepcidin is synthesised has helped design new pharmacological treatments whose main target is the hepcidin. In the near future, there will be effective treatments aimed at correcting the defect of many of these iron metabolism disorders.

Serial Changes in Cognitive Function Following Transcatheter Aortic Valve Replacement.

BACKGROUND: Data regarding the mid- to long-term cognitive trajectory of transcatheter aortic valve (TAVR) recipients are scarce. OBJECTIVES: Changes in global cognition and specific cognitive domains up to 1 year post-TAVR were evaluated. METHODS: Fifty-one patients (median age 80.0 [interquartile range: 72.0 to 85.0] years; 37% women) underwent TAVR and prospective assessment of cognitive function using the Montreal Cognitive Assessment (MoCA) at baseline, short-term (30 days), and 1 year post-TAVR. Processing speed and executive cognitive functions were further evaluated with the digit-symbol substitution test (DSST), Trail Making Tests (TMT), and verbal fluency tests at the same time points. Cognitive decline (CD) was determined by changes in mean scores and as a rate using practice-corrected reliable change index (RCI). RESULTS: The baseline mean total MoCA score was 22.71 ± 3.84. Twenty patients (39.2%) were considered cognitively impaired using a cutoff of <23 of 30 points. Mean total MoCA score improved at short-term post-TAVR and remained stable at 1 year (p = 0.022). On the basis of the RCI of total MoCA score, 4 patients (7.8%) presented with short-term CD, which persisted at 1 year in 1 patient (2.0%). Four patients (7.8%) exhibited cognitive improvement at 1 year, increasing to 15% among those with baseline cognitive impairment. No significant changes were observed over time in the mean DSST, TMT, and verbal fluency test scores. On the basis of the RCI, 10 of 40 patients (25%) presented with a reduction in performance of at least 1 test at 30 days that persisted at 1 year in 4 patients (10%). CONCLUSIONS: TAVR was associated with global improvement in cognitive status, more pronounced among those with cognitive impairment pre-TAVR. However, early decline in some complex cognitive functions was observed in one-quarter of TAVR recipients, persisting at 1 year in 10% of patients.

Prognostic Value of Fat Mass and Skeletal Muscle Mass Determined by Computed Tomography in Patients Who Underwent Transcatheter Aortic Valve Implantation.

Body composition (fat mass [FM] and skeletal muscle mass [SMM]) predicts clinical outcomes. In particular, loss of SMM (sarcopenia) is associated with frailty and mortality. There are no data on the prevalence and impact of FM and SMM in patients undergoing transcatheter aortic valve implantation (TAVI). The objective of this study is to determine body composition from pre-TAVI computed tomography (CT) and evaluate its association with clinical outcomes in patients who underwent TAVI. A total of 460 patients (mean age 81 ± 8 years, men: 51%) were included. Pre-TAVI CTs of the aorto-ilio-femoral axis were analyzed for FM and SMM cross-sectional area at the level of the third lumbar vertebrae (L3). Regression equations correlating cross-sectional area at L3 to total body FM and SMM were used to determine prevalence of sarcopenia, obesity, and sarcopenic obesity in patients (64%, 65%, and 46%, respectively). Most TAVI procedures were performed through a transfemoral approach (59%) using a balloon-expandable valve (94%). The 30-day and mid-term (median 12 months [interquartile range 6 to 27]) mortality rates were 6.1% and 29.6%, respectively. FM had no association with clinical outcomes, but sarcopenia predicted cumulative mortality (hazard ratio 1.55, 95% confidence interval 1.02 to 2.36, p = 0.04). In conclusion, body composition analysis from pre-TAVI CT is feasible. Sarcopenia, obesity, and sarcopenic obesity are prevalent in the TAVI population, with sarcopenia predictive of cumulative mortality.

Clinical impact and evolution of mitral regurgitation following transcatheter aortic valve replacement: a meta-analysis.

OBJECTIVES: Mitral regurgitation (MR) is a common entity in patients with aortic stenosis undergoing transcatheter aortic valve replacement (TAVR), but its influence on outcomes remains controversial. The purpose of this meta-analysis was to assess the clinical impact of and changes in significant (moderate-severe) MR in patients undergoing TAVR, overall and according to valve design (self-expandable (SEV) vs balloon-expandable (BEV)). METHODS: All national registries and randomised trials were pooled using meta-analytical guidelines to establish the impact of moderate-severe MR on mortality after TAVR. Studies reporting changes in MR after TAVR on an individual level were electronically searched and used for the analysis. RESULTS: Eight studies including 8015 patients (SEV: 3474 patients; BEV: 4492 patients) were included in the analysis. The overall 30-day and 1-year mortality was increased in patients with significant MR (OR 1.49, 95% CI 1.16 to 1.92; HR 1.32, 95% CI 1.12 to 1.55, respectively), but a significant heterogeneity across studies was observed (p<0.05). The impact of MR on mortality was not different between SEV and BEV in meta-regression analysis for 30-day (p=0.360) and 1-year (p=0.388) mortality. Changes in MR over time were evaluated in nine studies including 1278 patients. Moderate-severe MR (SEV: 326 patients; BEV: 192 patients) improved in 50.5% of the patients at a median follow-up of 180 (30-360) days after TAVR, and the degree of improvement was greater in patients who had received a BEV (66.7% vs 40.8% in the SEV group, p=0.001). CONCLUSIONS: Concomitant moderate-severe MR was associated with increased early and late mortality following TAVR. A significant improvement in MR severity was detected in half of the patients following TAVR, and the degree of improvement was greater in those patients who had received a BEV.

Myocardial injury following transcatheter aortic valve implantation: insights from delayed-enhancement cardiovascular magnetic resonance.

AIMS: The aim of this study was to evaluate the presence, localisation and extent of myocardial injury as determined by late gadolinium enhancement (LGE) on cardiovascular magnetic resonance (CMR) imaging in patients undergoing transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS: A total of 37 patients, who underwent successful TAVI with a balloon-expandable valve (transapical [TA], n=11; non-TA, n=26), were included. Cardiac biomarker (CK-MB and cTnT) levels were determined at baseline and following TAVI. CMR was performed within a week before and within 30 days following TAVI. Some increase in cardiac biomarkers was detected in 97% of the patients as determined by a rise in cTnT, and in 49% of the patients as determined by a rise in CK-MB. Following TAVI, no new myocardial necrosis defects were observed with the non-TA approach. Nonetheless, all patients who underwent TAVI through the TA approach had new focal myocardial necrosis in the apex, with a median myocardial extent and necrotic mass of 5% [2.0-7.0] and 3.5 g [2.3-4.5], respectively. CONCLUSIONS: Although some increase in cardiac biomarkers of myocardial injury was systematically detected following TAVI, new myocardial necrosis as evaluated by CMR was observed only in patients undergoing the procedure through the TA approach, involving ~5% of the myocardium in the apex.

Myocardial Injury After Transaortic Versus Transapical Transcatheter Aortic Valve Replacement.

BACKGROUND: The release of cardiac biomarkers of myocardial injury after transcatheter aortic valve replacement (TAVR) is common, but no data exist on patients undergoing TAVR through a transaortic approach. We aimed to evaluate the incidence and prognostic significance of the increase in cardiac biomarkers in nontransfemoral TAVR candidates, comparing transaortic and transapical approaches. METHODS: After excluding patients deemed suitable for transfemoral TAVR, 251 consecutive patients (transaortic, 45; transapical, 206) were prospectively evaluated. Creatine kinase-myocardial band and cardiac troponin T levels were measured at baseline and at 6, 12, 24, 48, and 72 hours after TAVR. Baseline and 6- to 12-month echocardiographic and clinical follow-up were performed. RESULTS: After TAVR, cardiac troponin T increased above the upper normal values in all patients (peak value 0.64 µg/L [IQR, 0.39 to 1.03 µg/L]), whereas creatine kinase-myocardial band levels increased in 88% of patients (transaortic 51%, transapical 96%, p < 0.001; peak value 20.1 µg/L [interquartile range, 14.3 to 31.6 µg/L]). Compared with the transaortic approach, the transapical approach was associated with a greater rise in both cardiac biomarkers (p < 0.001 for both), and a lesser improvement in left ventricular ejection fraction (p = 0.058) and global longitudinal strain (p = 0.039) at 6- to 12-month follow-up. Greater increases of cardiac troponin T levels were independently associated with 30-day and 1-year overall and cardiovascular mortality (p < 0.001 for all). A 15-fold rise in cardiac troponin T levels was the optimal threshold for determining poorer outcomes (p < 0.001). CONCLUSIONS: Periprocedural TAVR-related myocardial injury in nontransfemoral candidates was demonstrated in all patients, but the transapical approach was associated with significantly greater myocardial injury compared with the transaortic approach. A higher degree of myocardial injury translated into reduced left ventricular function improvement and lower early and midterm survival rates.

Transcatheter mitral "valve-in-ring" implantation: a word of caution.

Transcatheter mitral valve-in-valve and valve-in-ring procedures have emerged as a potential alternative for patients with failed mitral bioprosthesis or mitral valve repair who are at very high or prohibitive surgical risk. However, transcatheter mitral valve-in-ring implantation (TMViRI) remains a challenging procedure, partially because of the oval shape of mitral rings, which may lead to prosthesis dysfunction when the ring is not able to adopt the circular shape of the transcatheter valve. We present a case of failed TMViRI in a dysfunctional mitral homograft. The potential factors leading to procedural failure are discussed.

Prosthetic valve endocarditis after transcatheter valve replacement: a systematic review.

OBJECTIVES: The aim of this review is to describe the incidence, features, predisposing factors, and outcomes of prosthetic valve endocarditis (PVE) after transcatheter valve replacement (TVR). BACKGROUND: Very few data exist on PVE after TVR. METHODS: Studies published between 2000 and 2013 regarding PVE in patients with transcatheter aortic valve replacement (TAVR) or transcatheter pulmonary valve replacement (TPVR) were identified through a systematic electronic search. RESULTS: A total of 28 publications describing 60 patients (32 TAVRs, 28 TPVRs) were identified. Most TAVR patients (66% male, 80 ± 7 years of age) had a very high-risk profile (mean logistic EuroSCORE: 30.4 ± 14.0%). In TPVR patients (90% male, 19 ± 6 years of age), PVE was more frequent in the stenotic conduit/valve (61%). The median time between TVR and infective endocarditis was 5 months (interquartile range: 2 to 9 months). Typical microorganisms were mostly found with a higher incidence of enterococci after TAVR (34.4%), and Staphylococcus aureus after TPVR (29.4%). As many as 60% of the TAVR-PVE patients were managed medically despite related complications such as local extension, embolism, and heart failure in more than 50% of patients. The valve explantation rate was 57% and 23% in balloon- and self-expandable valves, respectively. In-hospital mortality for TAVR-PVE was 34.4%. Most TPVR-PVE patients (75%) were managed surgically, and in-hospital mortality was 7.1%. CONCLUSIONS: Most cases of PVE post-TVR involved male patients, with a very high-risk profile (TAVR) or underlying stenotic conduit/valve (TPVR). Typical, but different, microorganisms of PVE were involved in one-half of the TAVR and TPVR cases. Most TPVR-PVE patients were managed surgically as opposed to TAVR patients, and the mortality rate was high, especially in the TAVR cohort.

Effect on outcomes and exercise performance of anemia in patients with aortic stenosis who underwent transcatheter aortic valve replacement.

The objectives of this study were to determine the causes and impact of anemia and hemoglobin level on functional status, physical performance, and quality of life in the preprocedural evaluation and follow-up of transcatheter aortic valve replacement (TAVR) candidates. A total of 438 patients who underwent TAVR were included. Anemia was defined as a hemoglobin level <12 g/dl in women and <13 g/dl in men. Before TAVR, anemia was encountered in 282 patients (64.4%). A potential treatable cause of anemia was detected in 90.4% of patients and was attributed to iron deficiency in 53% of them. The occurrence of anemia was an independent predictor of poorer performance in the 6-minute walk test (6MWT), a lower Duke Activity Status Index score, and Kansas City Cardiomyopathy Questionnaires overall, clinical, and social limitation scores (p <0.05 for all). A lower hemoglobin level was associated with a higher prevalence of New York Heart Association class III to IV (p <0.001) and correlated negatively with the results of all functional tests (p <0.02 for all). At follow-up, anemia was found in 62% of patients and was associated with poorer performance in the 6MWT (p = 0.023). A lower hemoglobin level after TAVR was a predictor of poorer New York Heart Association class (p = 0.020) and correlated negatively with the distance walked in the 6MWT (r = -0.191, p = 0.004) and Duke Activity Status Index score (r = -0.158, p = 0.011) at 6-month follow-up. In conclusion, anemia was very common in TAVR candidates and was attributed to iron deficiency in more than half of them. The presence of anemia and lower hemoglobin levels determined poorer functional status before and after the TAVR procedure. These results highlight the importance of implementing appropriate measures for the diagnosis and treatment of this frequent co-morbidity to improve both the accuracy of preprocedural evaluation and outcomes of TAVR candidates.

The transradial approach during transcatheter structural heart disease interventions: a review.

AIMS: To review the safety and feasibility of a transradial (TR) approach during transcatheter structural or congenital heart disease interventions when utilized as either as a primary or secondary arterial access site. METHODS AND RESULTS: Studies and case reports published between 2002 and 2014 utilizing the TR access during transcatheter structural and congenital heart disease interventions during alcohol septal ablation (ASA), ventricular septal defect (VSD), renal denervation (RD), paravalvular leak (PVL) closure, transcatheter aortic valve implantation (TAVI, secondary access) and endovascular repair of aortic coarctation (ERAC, secondary access) were evaluated. Access-site (femoral vs. TR) vascular and bleeding complications were assessed. Femoral access complications ranged from 0.16% to 40%, with an overall incidence of 2.2% (56/2521). There were 18 reports or studies specifically evaluating the utility of TR access in the context of transcatheter structural heart disease interventions (ASA: 3; VSD: 1; RD: 3; PVL closure: 1; TAVI: 7, ERAC: 3). The use of TR access either as primary or secondary access site was feasible and allowed the completion of the procedure in all cases. The overall incidence of access-site complications following a TR approach was 0.5% (2/406 patients), with no major vascular or bleeding complications. CONCLUSIONS: A TR approach during transcatheter structural heart disease interventions appears to be a safe, effective means of delivering high procedural success accompanied by lower bleeding complications compared with the transfemoral approach.

Left atrial decompression through unidirectional left-to-right interatrial shunt for the treatment of left heart failure: first-in-man experience with the V-Wave device.

AIMS: Elevated filling pressures of the left atrium (LA) are associated with poorer outcomes in patients with chronic heart failure. The V-Wave is a new percutaneously implanted device intended to decrease the LA pressure by the shunting of blood from the LA to the right atrium. This report describes the first-in-man experience with the V-Wave device. METHODS AND RESULTS: A 70-year-old man with a history of heart failure of ischaemic origin, left ventricular dysfunction (LVEF: 35%, pulmonary wedge: 19 mmHg), no right heart dysfunction, NYHA Class III and orthopnoea despite optimal treatment, was accepted for V-Wave device implantation. The device consists of an ePTFE encapsulated nitinol frame that is implanted at the level of the interatrial septum and contains a trileaflet pericardium tissue valve sutured inside which allows a unidirectional LA to right atrium shunt. The procedure was performed through a transfemoral venous approach under fluoroscopic and TEE guidance. The device was successfully implanted and the patient was discharged 24 hours after the procedure with no complications. At three-month follow-up a left-to-right shunt through the device was confirmed by TEE. The patient was in NYHA Class II, without orthopnoea, the Kansas City Cardiomyopathy index was 77.6 (from 39.1 at baseline) and NT-proBNP was 322 ng/mL (from 502 ng/mL at baseline). The QP/QS was 1.17 and the pulmonary wedge was 8 mmHg, with no changes in pulmonary pressure or right ventricular function. CONCLUSIONS: Left atrial decompression through a unidirectional left-to-right interatrial shunt represents a new concept for the treatment of patients with left ventricular failure. The present report shows the feasibility of applying this new therapy with the successful and uneventful implantation of the V-Wave device, which was associated with significant improvement in functional, quality of life and haemodynamic parameters at 90 days.

Arrhythmia burden in elderly patients with severe aortic stenosis as determined by continuous electrocardiographic recording: toward a better understanding of arrhythmic events after transcatheter aortic valve replacement.

BACKGROUND: This study sought to evaluate the prevalence of previously undiagnosed arrhythmias in candidates for transcatheter aortic valve replacement (TAVR) and to determine the impact on therapy changes and arrhythmic events after the procedure. METHODS AND RESULTS: A total of 435 candidates for TAVR underwent 24-hour continuous ECG monitoring the day before the procedure. Newly diagnosed arrhythmias were observed in 70 patients (16.1%) before TAVR: paroxysmal atrial fibrillation (AF)/atrial tachycardia (AT) in 28, advanced atrioventricular block or severe bradycardia in 24, nonsustained ventricular tachycardia in 26, and intermittent left bundle-branch block in 3 patients. All arrhythmic events but one were asymptomatic and led to a therapy change in 43% of patients. In patients without known AF/AT, the occurrence of AF/AT during 24-hour ECG recording was associated with a higher rate of 30-day cerebrovascular events (7.1% versus 0.4%; P=0.030). Among the 53 patients with new-onset AF/AT after TAVR, 30.2% had newly diagnosed paroxysmal AF/AT before the procedure. In patients who needed permanent pacemaker implantation after the procedure (n=35), 31.4% had newly diagnosed advanced atrioventricular block or severe bradycardia before TAVR. New-onset persistent left bundle-branch block after TAVR occurred in 37 patients, 8.1% of whom had intermittent left bundle-branch block before the procedure. CONCLUSIONS: Newly diagnosed arrhythmias were observed in approximately a fifth of TAVR candidates, led to a higher rate of cerebrovascular events, and accounted for a third of arrhythmic events after the procedure. This high arrhythmia burden highlights the importance of an early diagnosis of arrhythmic events in such patients to implement the appropriate therapeutic measures earlier.

Impact of the use of transradial versus transfemoral approach as secondary access in transcatheter aortic valve implantation procedures.

No data exist on the impact of vascular complications related to the secondary access site in transcatheter aortic valve implantation (TAVI). The objectives of this nonrandomized study were to determine the rate of vascular complications related to the secondary access site in TAVI procedures and to evaluate the clinical impact of using the radial versus femoral approach as a secondary access in such procedures. A total of 462 consecutive patients (mean age 79 ± 9 years, 50% men) who underwent TAVI were included. The femoral approach (FA) was used as the secondary access (for the insertion of a 5F pigtail catheter) in 335 patients and the radial approach (RA) in 127 patients. Thirty-day events were prospectively collected. There were no baseline differences between groups, except for a higher prevalence of women and peripheral disease in the FA group (p <0.05 for both). A total of 74 vascular access site complications occurred in 70 patients (15%), and 23% of them (29% in the FA group) were related to the secondary access. The use of FA as secondary access was associated with a higher rate of vascular complications (5.0% vs 0% in the RA group, p = 0.005, adjusted p = 0.014). All major vascular complications related to the secondary access occurred in the FA group (3% vs 0% in the RA group, p = 0.040, adjusted p = 0.049), and this translated into a higher rate of major and/or life-threatening bleeding events related to the secondary access in the FA group (3% vs 0% in the RA group, p = 0.040, adjusted p = 0.049). In conclusion, about 1/4 of vascular access site complications in TAVI are related to the secondary access. The use of the RA as a secondary access was associated with a major reduction in vascular complications. These results highlight the impact of secondary access vascular complications in TAVI procedures and support the use of the RA as the preferred secondary access.