F. Pérez-Villa

Prognostic value of serum cytokines in patients with congestive heart failure

BACKGROUND Increased levels of circulating cytokines have been previously reported in patients with congestive heart failure; however, whether they have prognostic implications is still unknown. The aim of this study was to assess the prognostic implications of elevated serum cytokines in patients with heart failure and to identify the predictors of cytokine activation. METHODS AND RESULTS We assessed neurohormonal determinations, circulating cytokines, ejection fraction (EF) and end-diastolic and end-systolic left ventricular lengths in 87 patients (aged 57 +/- 9 years) with left ventricular dysfunction (EF 24% +/- 6%). In 48 patients, we also assessed cytokine receptors. During follow-up (mean, 14 +/- 9 months), 8 patients died and 12 had new heart failure episodes that required hospital admission, 5 of whom underwent heart transplantation. The univariate predictors of these events were serum interleukin-6 (IL-6) (p = 0.00001), New York Heart Association (NYHA) functional class (p = 0.0004), tumor necrosis factor-soluble receptor I (p = 0. 001), atrial natriuretic peptide (p = 0.002), tumor necrosis factor-soluble receptor II (p = 0.004), angiotensin II (p = 0.006), serum interleukin-1 beta (p = 0.01), and plasma renin activity (p = 0.02). Increased serum interleukin-6 (>10 pg/ml) was a significant predictor of death or new heart failure episodes according to the Kaplan-Meier survival method by log-rank test (p = 0.004). By Cox regression analysis, serum IL-6 (p = 0.0005) and the NYHA functional class (p = 0.005) were identified as independent predictors of prognosis. CONCLUSIONS In patients with congestive heart failure, increased serum IL-6 was identified as a powerful independent predictor of the combined end point: death, new heart failure episodes, and need for heart transplantation.

Serum interleukin-6 in congestive heart failure secondary to idiopathic dilated cardiomyopathy

Increased serum interleukin-6 (IL-6) was associated with a higher incidence of New York Heart Association functional classes III to IV and worse left ventricular function during follow-up. Patients with elevated serum IL-6 had poor prognosis. These results reinforce the concept that increased serum IL-6 may also play an important role in disease progression.

Influence of Cytomegalovirus Disease in Outcome of Solid Organ Transplant Patients

INTRODUCTION Despite recent advances in prevention and treatment, cytomegalovirus (CMV) is still a major complication in transplant patients. This study sought to analyze the incidence of CMV disease and its impact on patient and graft survival. METHODS Between June 2003 and December 2009, we included all kidney, liver, heart, and double transplant patients who underwent solid organ transplantation. They had 1-year posttransplant follow-up. RESULTS Among the 1427 patients who received kidney (n = 661), liver (n = 494), heart (n = 89), or double (n = 183) transplants, 103 (7.2%) displayed CMV disease. The incidence by type of transplant was: heart (n = 17, 19%), liver (n = 35, 7%), kidney (n = 41, 6.2%), or double transplant (n = 10, 5.5%; P < .001). In 59% of cases, the infection developed during the first 3 months after transplantation. CMV infections ranged from viral syndrome (n = 47, 45%) to tissue-invasive disease (n = 56, 55%), including 38% with gastrointestinal involvement. Relapsing episodes occurred in 12 patients (11%). Discordant donor/recipient CMV serology was present in 151 patients (donor positive/receptor negative), including 34 (22.5%) who developed primary CMV disease (P < .001). Coinfections mostly bacterial, were diagnosed in 38% of patients. An acute rejection episode was present in 31% of patients with CMV disease compared to 20% without this complication (P = .017). Crude mortality was significantly higher among patients with CMV disease (n = 18 patients [18%] vs 92 patients [7%]; P < .001). CONCLUSION Our data confirmed that CMV disease was associated with worse transplant outcomes, with higher incidences of acute rejection episodes and mortality.

Epidemiology and risk factors for late infection in solid organ transplant recipients

C. Cervera, M. Fernández‐Ruiz, A. Valledor, L. Linares, A. Antón, M. Ángeles Marcos, G. Sanclemente, I. Hoyo, F. Cofán, M.J. Ricart, F. Pérez‐Villa, M. Navasa, T. Pumarola, A. Moreno. Epidemiology and risk factors for late infection in solid organ transplant recipients.
Transpl Infect Dis 2011: 13: 598–607. All rights reserved

Immunohistochemically proven cytomegalovirus end-organ disease in solid organ transplant patients: clinical features and usefulness of conventional diagnostic tests.

Abstract: We studied the main clinical features, outcome, and laboratory parameters in a group of solid organ transplant (SOT) patients with immunohistochemically proven cytomegalovirus (CMV) disease. Confirmed CMV cases were obtained through databases. Demographics, clinical data, transplantation type, immunosuppressive regimens, donor and recipient CMV serostatus, therapy, outcome and laboratory results, pp65 antigenemia, and qualitative polymerase chain reaction (PCR) for CMV were analyzed. From 1995 to 2004, 31 cases with complete medical records were identified. Disease appeared between 24 and 2538 days after transplantation but most cases presented in the first 100 days. Gastrointestinal CMV disease was the most frequent form (71%), while thrombocytopenia was present in 50% of cases, and leukopenia was less common (35.5%). CMV pp65 antigenemia was positive in 58% of patients, but its sensitivity increased to 71% if performed during the first 6 months. A qualitative CMV PCR technique gave similar results during this period (71.4%). Most patients were treated with intravenous ganciclovir (n=25; 80.6%). In 4 cases (19.4%), use of foscarnet alone or a sequential regimen with ganciclovir–foscarnet was deemed necessary. Surgical procedures were necessary in 5 patients (16%). The death rate reached 13%. CMV end‐organ disease can be a life‐threatening infection in SOT patients. Gastrointestinal disease was the most frequent end‐organ disease. CMV antigen detection is best suited for the early period after transplantation.

Tuberculosis in Solid Organ Transplant Recipients at a Tertiary Hospital in the Last 20 Years in Barcelona, Spain

OBJECTIVE Mycobacterium tuberculosis (TB) is a serious opportunistic infection in solid organ transplant recipients. The TB incidence is 20 to 74 times greater than that among the general population. Our aim was to determine the incidence as well as the clinical, radiological, and microbiological features and outcomes of TB in these patients. MATERIALS AND METHODS We reviewed the clinical records of subjects with posttransplant TB from January 1988 to December 2007. A definite TB case was defined by a positive culture; probable TB by a positive smear or histological finding; and disseminated TB when 2 organs were involved. We noted an early diagnosis as ones in the first year posttransplantation. Outcomes were classified following the WHO recommendation and mortality related defined by death during treatment. RESULTS Among 4634 recipients (2757 kidney, 1334 liver, 361 double kidney-pancreas, and 182 heart), 21 (0.45%) developed posttransplant TB: namely, 0.47%, 0.22%, 1.1%, and 0.54%, respectively. In 2 cases M. tuberculosis did not grow upon culture; the diagnosis was established by positive acid-fast bacilli on a sputum smear or by histological findings on biopsy. The mean posttransplantation time to TB diagnosis was 21 months (48% early TB). Two patients had a previous history of TB. Fever was the most common symptom (71%). Pulmonary tuberculosis represented 47.6% of cases; extrapulmonary, 28.6%; and disseminated, 23.8%. Among the cases of pulmonary TB, 60% had unilateral infiltrates and 10% cavitations on X ray. Eighteen patients completed treatment. Five patients displayed adverse events, 3 of which were liver toxicity. Four patients died, with 3 deaths related to TB. CONCLUSIONS The incidence of TB in this cohort was higher than that among the general population (450 cases/100,000 recipients). TB was associated with adverse effects of treatment and significant mortality.

Left atrial dysfunction relates to symptom onset in patients with heart failure and preserved left ventricular ejection fraction

AIMS Pathophysiology of heart failure (HF) with preserved ejection fraction (HFPEF) remains unclear. Left atrial (LA) function has been related to HF symptoms. Our purpose is to analyse LA function in outpatients with new onset symptoms of HF. METHODS AND RESULTS An observational study was performed including 138 consecutive outpatients with suspected HF referred to a one-stop clinic. Final diagnosis [HF with reduced EF (HFREF), HFPEF, or non-HF] was established according to current recommendations. Echocardiography was performed in all patients. LA function was analysed using strain derived from speckle tracking in sinus rhythm patients (n = 83). Results were analysed with ANOVA and Bonferroni statistical tests. Receiver operating characteristic (ROC) curves were constructed to investigate the predictive ability of LA parameters for the final diagnosis of HF. Patients were 75 ± 9 years and 63% women. Final diagnosis was 23.2% HFREF, 45.7% HFPEF, and 31.2% non-HF. Left ventricular strain rate showed no differences between non-HF and HFPEF groups, but both groups showed differences with the HFREF group. LA strain rate (A- and S-waves) was significantly reduced in both HF groups (without differences among them) when compared with the non-HF group. LA strain rate and indexed volume showed significant accuracy for HF diagnosis in ROC curves. CONCLUSIONS In outpatients with new-onset symptoms of HF, LA dysfunction was observed. It might be the initial mechanism in the development of symptoms in HFPEF patients. These findings support the relationship of LA dysfunction with HFPEF, suggesting that the analysis of LA function may be useful in sinus rhythm patients with new-onset dyspnoea.

Survival in New York Heart Association class IV heart failure patients treated with cardiac resynchronization therapy compared with patients on optimal pharmacological treatment

AIMS Although the benefit of cardiac resynchronization therapy (CRT) in selected patients with heart failure is well established, its effect on mortality in New York Heart Association (NYHA) class IV patients remains unclear. Our study evaluated the effect of CRT on urgent transplant-free survival in NYHA class IV patients treated with CRT, compared with medication-only treatment. METHODS AND RESULTS Forty NYHA class IV patients treated with CRT (80% men, 62.5% ischaemic, mean age of 65) were matched 1:1 by age, gender and aetiology of cardiomyopathy with patients treated with optimal medical therapy (OPT group). No significant differences were found between the groups in left ventricular diastolic diameter (71 +/- 6 vs. 73 +/- 9 mm), left ventricular systolic diameter (58 +/- 7 vs. 61 +/- 11 mm), and left ventricular ejection fraction (23 +/- 5 vs. 22 +/- 6%). Mean follow-up was 13.2 +/- 9.5 months for the CRT group and 17.3 +/- 11.6 months for the OPT group. Time to all-cause death or urgent transplantation [hazard ratios (HR), 1.29; 95% CI: 0.59-2.83; P = 0.52] or to cardiovascular death or urgent transplantation (HR, 1.53; 95% CI: 0.64-3.67; P = 0.34) was not reduced significantly in patients treated with CRT. CONCLUSION In this study, CRT did not significantly improve survival of NYHA class IV heart failure patients compared with pharmacological therapy.

Protein arginine methyl transferases-3 and -5 increase cell surface expression of cardiac sodium channel

The α‐subunit of the cardiac voltage‐gated sodium channel (NaV1.5) plays a central role in cardiomyocyte excitability. We have recently reported that NaV1.5 is post‐translationally modified by arginine methylation. Here, we aimed to identify the enzymes that methylate NaV1.5, and to describe the role of arginine methylation on NaV1.5 function. Our results show that protein arginine methyl transferase (PRMT)‐3 and ‐5 methylate NaV1.5 in vitro, interact with NaV1.5 in human embryonic kidney (HEK) cells, and increase NaV1.5 current density by enhancing NaV1.5 cell surface expression. Our observations are the first evidence of regulation of a voltage‐gated ion channel, including calcium, potassium, sodium and TRP channels, by arginine methylation.

Identification of N-terminal protein acetylation and arginine methylation of the voltage-gated sodium channel in end-stage heart failure human heart.

The α subunit of the cardiac voltage-gated sodium channel, NaV1.5, provides the rapid sodium inward current that initiates cardiomyocyte action potentials. Here, we analyzed for the first time the post-translational modifications of NaV1.5 purified from end-stage heart failure human cardiac tissue. We identified R526 methylation as the major post-translational modification of any NaV1.5 arginine or lysine residue. Unexpectedly, we found that the N terminus of NaV1.5 was: 1) devoid of the initiation methionine, and 2) acetylated at the resulting initial alanine residue. This is the first evidence for N-terminal acetylation in any member of the voltage-gated ion channel superfamily. Our results open the door to explore NaV1.5 N-terminal acetylation and arginine methylation levels as drivers or markers of end-stage heart failure.