Manuel Gómez-Bueno

Genetic basis of end‐stage hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is characterized by a heterogeneous presentation and clinical course. A minority of HCM patients develop end‐stage HCM and require cardiac transplantation. The genetic basis of end‐stage HCM is unknown but small series, isolated case reports and animal models have related the most aggressive heart failure course with the presence of multiple mutations.

Treatment of allograft vasculopathy in heart transplantation

Cardiac allograft vasculopathy remains one of the main causes of morbidity and mortality after heart transplantation, although its impact is becoming somewhat smaller as prophylactic measures are implemented. Advances in the understanding of the molecular and cellular mechanisms involved in the genesis and development of cardiac allograft vasculopathy are opening ways for new diagnostic and therapeutic strategies. Successful prophylaxis of the early stages of the disease has been demonstrated with the use of newer immunosuppressive agents, such as sirolimus and everolimus, that will probably be included in future protocols. For most patients with established cardiac allograft vasculopathy, currently available revascularisation methods and retransplantation are not appropriate options. Antiproliferative agents could provide significant improvement in terms of symptom relief and prognosis, but their definite value must be proven in well-designed trials.

Natural History and Prognostic Factors in Alcoholic Cardiomyopathy

OBJECTIVES This study sought to determine the natural history of contemporary alcoholic cardiomyopathy (ACM), to compare it with that of idiopathic dilated cardiomyopathy (IDCM), and to identify risk factors for poor outcome. BACKGROUND ACM is a common cause of dilated cardiomyopathy (DCM), but little is known about its natural history or the effect of reducing alcohol intake on disease progression. METHODS We studied the clinical characteristics and outcomes of 94 consecutive patients with ACM and 188 with IDCM, evaluated over the period between 1993 and 2011. RESULTS After a median follow-up of 59 months (interquartile range: 25 to 107 months), 14 ACM patients (15%) had died from cardiovascular causes (6 from heart failure and 8 from sudden cardiac death), 14 (15%) underwent heart transplantation, 35 (37%) experienced recovery in left ventricular function, and 31 (33%) remained clinically stable without improvement in systolic function. Transplantation-free survival was higher in ACM patients than in IDCM patients (p = 0.002), and ACM was associated with a favorable outcome on multiple analysis of the entire cohort (odds ratio [OR]: 0.4; 95% confidence interval [CI]: 0.2 to 0.8; p = 0.01). Independent predictors of death or heart transplantation in ACM identified by multiple logistic regression analysis were atrial fibrillation (OR: 9.7; 95% CI: 2.56 to 36.79; p = 0.001); QRS duration >120 ms (OR: 7.2; 95% CI: 2.02 to 26; p = 0.002), and lack of beta-blocker therapy (OR: 4.4; 95% CI: 1.35 to 14.49; p = 0.014). ACM patients who reduced their alcohol intake to moderate levels exhibited similar survival (p = 0.22) and cardiac function recovery (p = 0.8) as abstainers. CONCLUSIONS ACM has a better prognosis than IDCM. Atrial fibrillation, QRS width >120 ms, and the absence of beta-blocker therapy identify patients with a poor outcome. Alcohol abstainers and those who reduce intake to a moderate degree show similar clinical outcomes.

Genetics in dilated cardiomyopathy

Discoveries made during the last 20 years have revealed a genetic origin in many cases of dilated cardiomyopathy (DCM). Currently, over 40 genes have been associated with the disease. Mutations in DCM-causing genes induce the condition through a variety of different pathological pathways with complex and not completely understood mechanisms. Genes that encode for sarcomeric, cytoskeletal, nuclear membrane, dystrophin-associated glycoprotein complex and desmosomal proteins are the principal genes involved. In this review we discuss the most frequent DCM-causing genes. We propose a classification in which DCM genes are considered as being major or minor genes according to their mutation frequency and the available supporting evidence. The main phenotypic characteristics associated with each gene are discussed.

Papel de la gammagrafía cardiaca con 99mTc-DPD en la discriminación del subtipo de amiloidosis cardiaca

INTRODUCTION AND OBJECTIVES We investigated the diagnostic accuracy of (99m)Tc-3,3-diphosphono-1,2 propanodicarboxylic acid ((99m)Tc-DPD) scintigraphy in differentiating between monoclonal immunoglobulin light chain and transthyretin-related cardiac amyloidosis. METHODS Nineteen patients with documented cardiac amyloidosis were included: 8 with transthyretin-related amyloidosis (group A) and 11 with light chain amyloidosis (group B). All the patients underwent scintigraphy with (99m)Tc-DPD and (99m)Tc-methylene diphosphonate ((99m)Tc-MDP). RESULTS On visual scoring, cardiac (99m)Tc-DPD uptake could be characterized as moderate to severe (scores of 2-3), with ventricular or biventricular distribution, in all group A patients (transthyretin-related cardiac amyloidosis), and was absent or mild (scores of 0-1) and diffusely distributed in all group B patients (monoclonal immunoglobulin light chain cardiac amyloidosis). (99m)Tc-DPD uptake was also absent (score of 0) among unaffected controls and in 2 unaffected relatives of patients with hereditary transthyretin-related amyloidosis who harbor a mutation in the TTR gene. With (99m)Tc-MDP, all the patients had a myocardial uptake score of 0-1. In our series, selective myocardial uptake of (99m)Tc-DPD provided 100% accuracy (95% confidence interval, 97.37%-100%) for the differentiation between transthyretin-related and monoclonal immunoglobulin light chain cardiac amyloidosis. CONCLUSIONS We conclude that (99m)Tc-DPD scintigraphy is a useful test for the differential diagnosis of transthyretin vs monoclonal immunoglobulin light chain etiology in patients with cardiac amyloidosis.

Withdrawal of proliferation signal inhibitors due to adverse events in the maintenance phase of heart transplantation

BACKGROUND The increasing use of proliferation signal inhibitors (PSIs) has raised the issue of their risk profile. We sought to determine the causes, incidence, risk factors, and consequences of withdrawal due to adverse events of PSIs in maintenance heart transplantation. METHODS This was a retrospective study from 9 centers of the Spanish Registry for Heart Transplantation. Demographic, clinical, analytic, and evolution data were obtained for patients in whom a PSI (sirolimus or everolimus) was used between October 2001 and March 2009. RESULTS In the first year, 16% of 548 patients could not tolerate PSIs. This incidence rate stabilized to 3% to 4% per year thereafter. The most frequent causes for discontinuation were edema (4.7%), gastrointestinal toxicity (3.8%), pneumonitis (3.3%), and hematologic toxicity (2.0%). In multivariate analysis, withdrawal of PSI was related to the absence of statin therapy (p = 0.006), concomitant treatment with anti-metabolites (p = 0.006), a poor baseline renal function (p = 0.026), and multiple indications for PSI use (p = 0.04). Drug discontinuation was associated with a decline in renal function (p = 0.045) but not with an excess in mortality (p = 0.42). CONCLUSIONS In this large cohort of maintenance heart transplant recipients taking a PSI, 16% withdrew treatment in the first year, and 25% had stopped PSI due to severe adverse events by the fourth year. This high rate of toxicity-related PSI withdrawal could limit the clinical utility of this otherwise novel class of immunosuppressive agents.

Use of mTOR inhibitors in chronic heart transplant recipients with renal failure: Calcineurin-inhibitors conversion or minimization?

BACKGROUND In the last decade, mTOR inhibitors (mTOR-is) have become the cornerstone of the calcineurin inhibitor (CNI)-reduced/free regimens aimed to the preservation of post-transplant renal function. We compared utility and safety of the total replacement of calcineurin inhibitors with a mTOR-i with a strategy based on calcineurin inhibitor minimization and concomitant use of m-TOR-i. METHODS In a retrospective multi-center cohort of 394 maintenance cardiac recipients with renal failure (GFR<60 mL/min/1.73 m(2)), we compared 235 patients in whom CNI was replaced with a mTOR-i (sirolimus or everolimus) with 159 patients in whom mTOR-is were used to minimize CNIs. A propensity score analysis was carried out to balance between group differences. RESULTS Overall, after a median time of 2 years from mTOR-i initiation, between group differences for the evolution of renal function were not observed. In a multivariate adjusted model, improvement of renal function was limited to patients with mTOR-i usage within 5years after transplantation, particularly with the conversion strategy, and in those patients who could maintain mTOR-i therapy. Significant differences between strategies were not found for mortality, infection and mTOR-i withdrawal due to drug-related adverse events. However, conversion group tended to have a higher acute rejection incidence than the minimization group (p=0.07). CONCLUSION In terms of renal benefits, our results support an earlier use of mTOR-is, irrespective of the strategy. The selection of either a conversion or a CNI minimization protocol should be based on the clinical characteristics of the patients, particularly their rejection risk.

Comentarios a la guía de práctica clínica de la ESC sobre diagnóstico y tratamiento de la insuficiencia cardiaca aguda y crónica 2012. Un informe del Grupo de Trabajo del Comité de Guías de Práctica Clínica de la Sociedad Española de Cardiología

El Comite de Guias de Practica Clinica de la SEC formo un grupo de trabajo integrado por cardiologos clinicos, electrofisiologos, cirujanos cardiacos y personal de enfermeria, expertos en los diversos aparta-dos de la IC que cubre la guia de la ESC, propuestos por la Seccion de Insuficiencia Cardiaca y Trasplante y el Grupo de Trabajo sobre Resin-cronizacion Cardiaca de la SEC y por la Asociacion Espanola de Enfer-meria Cardiovascular, con el objetivo general de revisar las evidencias y recomendaciones aportadas por la guia europea sobre IC antes citada

Abordaje familiar en la amiloidosis cardiaca hereditaria por transtiretina

Cardiac amyloidosis is a disease of complex diagnosis and treatment. Some subtypes of cardiac amyloidosis are inherited. Among these, the most common variant is caused by mutations in the transthyretin gene. Correct identification of amyloidosis produced by a genetic defect is of great importance because it modifies the diagnostic and therapeutic approach in patients and their families. We describe our experience in the evaluation of two families with hereditary transthyretin cardiac amyloidosis. We discuss a number of considerations related to the evaluation of these patients and the diagnostic and therapeutic approach to perform in relatives.

Sildenafil for improving outcomes in patients with corrected valvular heart disease and persistent pulmonary hypertension: a multicenter, double-blind, randomized clinical trial

Abstract Aims We aimed to determine whether treatment with sildenafil improves outcomes of patients with persistent pulmonary hypertension (PH) after correction of valvular heart disease (VHD). Methods and results The sildenafil for improving outcomes after valvular correction (SIOVAC) study was a multricentric, randomized, parallel, and placebo-controlled trial that enrolled stable adults with mean pulmonary artery pressure ≥ 30 mmHg who had undergone a successful valve replacement or repair procedure at least 1 year before inclusion. We assigned 200 patients to receive sildenafil (40 mg three times daily, n = 104) or placebo (n = 96) for 6 months. The primary endpoint was the composite clinical score combining death, hospital admission for heart failure (HF), change in functional class, and patient global self-assessment. Only 27 patients receiving sildenafil improved their composite clinical score, as compared with 44 patients receiving placebo; in contrast 33 patients in the sildenafil group worsened their composite score, as compared with 14 in the placebo group [odds ratio 0.39; 95% confidence interval (CI) 0.22–0.67; P < 0.001]. The Kaplan–Meier estimates for survival without admission due to HF were 0.76 and 0.86 in the sildenafil and placebo groups, respectively (hazard ratio 2.0, 95% CI = 1.0–4.0; log-rank P = 0.044). Changes in 6-min walk test distance, natriuretic peptides, and Doppler-derived systolic pulmonary pressure were similar in both groups. Conclusion Treatment with sildenafil in patients with persistent PH after successfully corrected VHD is associated to worse clinical outcomes than placebo. Off-label usage of sildenafil for treating this source of left heart disease PH should be avoided. The trial is registered with ClinicalTrials.gov, number NCT00862043.