Pedro L. Tornel

Soluble ST2 for Predicting Sudden Cardiac Death in Patients With Chronic Heart Failure and Left Ventricular Systolic Dysfunction

OBJECTIVES We studied whether the measurement of the soluble form of ST2 (sST2), an interleukin-1 receptor family member, could identify heart failure (HF) patients at risk of sudden cardiac death (SCD). BACKGROUND The prediction of SCD remains an important challenge in patients with mild-to-moderate chronic HF. Concentrations of sST2 have been found increased and related to worse long-term outcomes in patients with acute HF. Whether sST2 has a prognostic role in SCD is unknown. METHODS A nested case-control study was performed on 36 cases of SCD and 63 control patients (matched for age, sex, and left ventricular ejection fraction) obtained from the MUSIC (MUerte Súbita en Insuficiencia Cardíaca) registry, a 3-year multicenter registry of ambulatory HF patients (New York Heart Association functional class II to III, left ventricular ejection fraction < or =45%). Demographic, clinical, echocardiographic, electrical, and biochemical data were collected at enrollment. RESULTS Concentrations of sST2 were greater among decedents (0.23 ng/ml [interquartile range 0.16 to 0.43 ng/ml] vs. 0.12 ng/ml [interquartile range 0.06 to 0.23 ng/ml], p = 0.001) and were predictive of experiencing SCD (+0.1 ng/ml, odds ratio: 1.39, 95% confidence interval: 1.09 to 1.78, p = 0.006). On the basis of a combined biomarker status, only 4% of patients experienced SCD for neither sST2 nor N-terminal pro-B-type natriuretic peptide (NT-proBNP) above receiver-operator characteristic-derived cut-off points (0.15 ng/ml and 2,000 ng/l, respectively), 34% for either biomarker above, and 71% for both biomarkers above (p < 0.001 for trend). This combined variable added incremental prognostic value to the multivariable regression model (p < 0.001). CONCLUSIONS Elevated sST2 concentrations are predictive of SCD in patients with chronic HF and provide complementary information to NT-proBNP levels. A combined biomarker approach may have an impact on clinical decision-making.

Inhibition of poly(ADP-ribose) polymerase attenuates the severity of acute pancreatitis and associated lung injury

The severity of acute pancreatitis results from the transmigration and activation of leukocytes within the pancreas and the local synthesis and release of proinflammatory-soluble mediators that transform a local injury into a systemic inflammatory response. Poly(ADP-ribose)polymerase-1 (PARP-1) is a nuclear DNA-binding protein that has been shown to play a relevant role in cell necrosis and organ failure in various diseases associated with inflammation. Therefore, we set out to investigate whether the genetic deletion of PARP-1 or PARP-2 (a new member of the PARP family) genes, or pharmacological inhibition of PARP activity might affect the development and severity of acute pancreatitis and pancreatitis-associated lung injury. Secretagogue-induced acute pancreatitis was achieved by 12 hourly intraperitoneal injections of cerulein in mice deficient in PARP-1 or PARP-2 genes, and wild-type (WT) littermate mice untreated or treated with PARP activity inhibitors. The severity of pancreatitis was assessed by measurements of serum amylase, lipase, interleukin-1β and IL-6, pancreatic water content, histologic grading and pancreas myeloperoxidase (MPO) activity. Lung injury was evaluated by quantifying MPO activity and morphological changes. We found that the severity of acute pancreatitis and pancreatitis-associated lung injury was significantly attenuated in mice lacking PARP-1, but not PARP-2, compared with WT mice. Interestingly, administration of PARP inhibitors, 3-aminobenzamide or PJ34 (N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethyacetamide HCl), in WT mice markedly decreased acute pancreatitis severity and pulmonary-associated injury in a larger extension than genetic deletion of PARP-1. Our results support the potential therapeutic application of PARP inhibitors in the development and severity of acute pancreatitis and associated lung injury.

Serum ionized magnesium monitoring during orthotopic liver transplantation

During orthotopic liver transplantation (OLT) citrate accumulates and magnesium can be chelated, which can lead to ionized hypomagnesemia and cardiovascular dysfunction. Our aim was to study the serum ionized magnesium (Me2+) evolution and establish its relation to serum total Mg and citrate levels during OLT. We studied 58 adult patients undergoing OLT. The serum Me2+ level dropped significantly at the end of the preanhepatic phase, and remained low until the end of the procedure. Furthermore, the Me2+ levels remained below the range of reference from the beginning of the anhepatic phase onward. There was an inverse correlation between Me2+ and citrate for all patients. Me2+, like ionized calcium (Ca2+), is chelated by citrate and its evolution is a mirror image of that of citrate. In our patients, we did not observe any significant dysrhythmias that could be directly attributed to ionized hypomagnesemia. In conclusion, low preoperative levels, together with the massive transfusion of blood products and the increase in renal losses, cause progressive ionized hypomagnesemia in OLT patients. We propose that it he routinely monitored and treated accordingly, as is already done with Ca2+.

Ricinus communis agglutinin I reacting and non-reacting butyrylcholinesterase in human cerebrospinal fluid

Differences in glycosylation of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in human brain, plasma and cerebrospinal fluid (CSF) have been investigated by means of their interaction with agarose-immobilized lectins. Most of the AChE in brain and CSF was associated to concanavalin A (Con A), Lens culinaris (LCA) and Triticum vulgaris (WGA) agglutinins, but little activity was adsorbed to Ricinus communis agglutinin I (RCAI). Brain, plasma and CSF BuChE was almost fully bound to Con A, LCA and WGA-agarose. Brain BuChE was unable to react with RCA (RCA-BuChE), the plasma enzyme was completely bound to the lectin (RCA+BuChE) and BuChE from CSF of normal children was partially fixed to RCA (RCA +/- BuChE). BuChE in CSF of children with meningitis fully reacts with the lectin. The data suggest that the proportion of RCA+BuChE in CSF of children with meningitis is increased, this enzyme probably coming from plasma.

Anabolic Status and Functional Impairment in Men With Mild Chronic Heart Failure

The purpose of this study was to establish the role of hormonal anabolic deficiencies in exercise intolerance in patients with chronic heart failure One hundred four consecutive men (mean age 53.1 ± 10.6 years) with established diagnoses of chronic heart failure were included. At enrollment, blood samples were taken, and echocardiography and cardiopulmonary exercise testing were carried out. Exercise capacity was expressed as peak oxygen consumption (Vo₂), predicted peak Vo₂, and the ventilatory response to exercise (VE/Vco₂) slope. The mean left ventricular ejection fraction was 29.7 ± 11.9%, and most patients (86%) were in New York Heart Association class I or II, with a mean peak Vo₂ of 18 ml/min/kg. According to the age-adjusted reference values, hormonal deficiencies were present in 29% for total testosterone, 39% for estimated free testosterone, 34% for insulin-like growth factor-1, and 61% for dehydroepiandrosterone sulfate. Dehydroepiandrosterone sulfate showed a significant correlation with peak Vo₂ (r = 0.29, p = 0.007), predicted peak Vo₂ (r = 0.28, p = 0.006), and VE/Vco₂ slope (r = -0.39, p <0.001), whereas total testosterone, estimated free testosterone, and insulin-like growth factor-1 were not significantly correlated. After adjusting in a multivariable model, dehydroepiandrosterone sulfate remained an independent predictor of each exercise parameter. In conclusion, in a cohort of patients with mild chronic heart failure, exercise capacity objectively measured using cardiopulmonary exercise testing was related to anabolic impairment of the adrenal rather than the somatotropic or peripheral axis.

Sex Hormone-Binding Globulin: A New Marker of Disease Severity and Prognosis in Men With Chronic Heart Failure

INTRODUCTION AND OBJECTIVES Sex hormone-binding globulin (SHBG) is a key regulator of the actions of anabolic steroids. Chronic heart failure (HF) has been associated with anabolic steroid deficiency, but its relationship with SHBG is not known. METHODS The study involved 104 men (53+/-11 years) with HF (i.e. left ventricular ejection fraction [LVEF] <40%) attending a specialist clinic on optimum treatment and in a stable condition. At enrolment, the median and interquartile range (IQR) SHBG level was determined, associated hormone levels were measured, and known risk factors were recorded. The study end-point was cardiac death within 3 years. RESULTS At enrolment, the SHBG level (median 34.5 nmol/L, IQR 27-50 nmol/L) was correlated with the N-terminal probrain natriuretic peptide level (r=0.271, P=.005), LVEF (r=-0.263, P=.007), body mass index (r=-0.199, P=.020) and total testosterone level (r=0.332, P=.001). The median SHBG level was higher in the 16 patients (15.4%) who died, at 48.5 nmol/L (IQR 36-69.5 nmol/L) vs. 33 nmol/L (IQR 25.3-48.7 nmol/L; P=.001), and a high level was associated with an increased risk of death (hazard ratio [HR]=1.045, 95% confidence interval [CI] 1.021-1.069; P< .001). The association remained significant after adjustment in Cox multivariate regression modeling, at HR=1.049 (95% CI 1.020-1.079; P=.001). Analysis by SHBG tertiles showed mortality was 30% in the third tertile, 14% in the second, and 4% in the first (log rank 0.007; HR=3.25, 95% CI 1.43-7.34; P=.004). CONCLUSIONS The SHBG level correlated with measures of HF severity and was associated with a higher risk of cardiac death. Further studies are needed to clarify whether SHBG plays a role in HF pathophysiology.

The value of polymorphonuclear elastase in adult respiratory distress syndrome

The clinical usefulness of quantitative plasma polymorphonuclear elastase (PMN-elastase) determinations as prognostic markers of adult respiratory distress syndrome (ARDS) in polytraumatized patients was analyzed. PMN-elastase and C-reactive protein (CRP) levels were determined in 55 polytraumatized patients admitted into the Intensive Care Unit. Eight patients developed ARDS and 47 patients did not. These parameters were also analyzed in a control group (n = 34). PMN-elastase levels in ARDS cases reached significantly higher values than in patients who did not develop this syndrome (P < 0.01). We conclude that the increase in plasma PMN-elastase levels can be useful in predicting the development of ARDS in polytraumatized patients, in instituting prophylactic actions and monitoring the course of the disease in these high risk patients. This test is easily adaptable to the routine of any hospital laboratory.

Letter by Pascual-Figal et al Regarding Article, “Anabolic Deficiency in Men With Chronic Heart Failure: Prevalence and Detrimental Impact on Survival”

To the Editor: We read with interest the article by Jankowska et al,1 who show that anabolic hormone deficiency is common in heart failure (HF) patients. The article does not mention the proportion of patients treated with spironolactone, a steroid chemically related to the mineralocorticoid aldosterone, which acts as an antiandrogen that competes with dihydrotestosterone at the androgen-receptor level. Spironolactone also increases metabolic clearance and inhibits androgen production.2–4 This drug has long been used in …

Inhibition of cholinesterases by the zwitterionic detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS)

Abstract 3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), a zwitterionic detergent, behaves as a reversible inhibitor of several cholinesterases. Human and horse serum cholinesterases were more sensitive to inhibition by the detergent than the enzyme from Electrophorus electricus or human erythrocyte. Thus, CHAPS binds with butyrylcholinesterase in preference to acetylcholinesterase. Noncompetitive inhibition kinetics were observed with all enzymes tested; the apparent inhibition constants were 0.4, 2.5, 5.8, and 7.5 m m for the cholinesterases from human serum, horse serum, Electrophorus electricus , and human erythrocyte, respectively. The rate of phosphorylation of the cholinesterases by diisopropyl phosphorofluoridate was significantly reduced in assays performed in the presence of CHAPS; however, the detergent was unable to fully protect the cholinesterases from the inactivation by the organophosphate. These results indicate that the detergent binds in a noncompetitive manner to cholinesterases and this reduces the capacity of the enzymes to react with both the substrate and the organophosphate.

Copper metabolism and biliary secretion in patients receiving orthotopic liver transplantation

BACKGROUND The quantitative aspects of biliary copper excretion in health and disease have not been fully defined yet. The aim of the study was to evaluate copper metabolism and biliary excretion of patients who have received an orthotopic liver transplant (OLT) during the immediate postoperative period. METHODS We have studied retrospectively 16 patients undergoing primary OLT and eight undergoing cholecystectomy, and measured serum concentration of copper and its secretion in bile and urine by flame atomic absorption spectrometry (FAAS). RESULTS We found a progressive increase of biliary copper secretion rates and a corresponding lowering of urinary copper during the postoperative period. Thus, in OLT patients, the mean of biliary copper secretion on day 1 is 0.7+/-0.2 micromol/day compared with 2.3+/-1.1 micromol/day on day 7 (p<0.01) and 6.1+/-2.5 micromol/day on day 15 (p<0.0001). The rate of copper output on day 5 after surgery is about one sixth of the value reported for patients who had undergone cholecystectomy. In patients suffering an acute rejection episode, there was an abrupt fall in bile flow (<15 ml/day) and excretion of biliary copper (<1 micromol/day), accompanied by an increase of urine copper excretion (>3 micromol/day), and both were recovered when the rejection episode was solved. We found an inverse relationship between the serum bilirubin (Bt), alkaline phosphatase (ALP) and the biliary copper excretion (p<0.01), and a direct relationship with urinary copper excretion (p<0.01). CONCLUSIONS The copper measurements in urine and bile are non-invasive techniques, of low cost, rapid and easy to accomplish, and available in hospitals accredited for hepatic transplantation. These characteristics make these methods helpful in the monitoring of patients submitted to OLT for assessment of graft quality and subsequent outcome.