Hyponatraemia and congestive heart failure refractory to diuretic treatment. Utility of tolvaptan. / Hiponatremia e insuficiencia cardiaca congestiva refractaria a tratamiento diurético. Utilidad del tolvaptán.

Heart failure (HF) is currently one of the most significant healthcare problems in Spain and has a continuously increasing prevalence. Advances in our understanding of the various biological responses that promote cardiac remodelling and pulmonary venous congestion constitute the basis of current treatment. This article, prepared by members of the HF groups of the Spanish Society of Cardiology and the Spanish Society of Internal Medicine, discusses the current therapeutic strategies for patients with congestion refractory to diuretic treatment. The article includes our clinical experience with the use of tolvaptan as an additional treatment for congestion associated with hyponatraemia. To this end, we propose an algorithm for the use of tolvaptan in patients with congestive HF, natraemia <130mEq/l and poor response to conventional diuretic treatment.

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.

Andalusian registry of heart transplantation: first official adult heart transplant report 2010.

This is the first official report of the Andalusian Registry of Heart Transplantation. Since 1986, two centers in the community have been authorized to perform adult heart transplantation. Until 2010, 854 adult heart transplantation procedures were performed, which constitute the basis of the present report. Clinical features and survival are analyzed. The leading reason for heart transplantation was ischemic cardiomyopathy (34%) and nonischemic dilated cardiomyopathy (34%). The mean age of the recipients was 46 ± 16 years and the mean age of the donors was 29 ± 13 years. After a median follow-up of 106 months, the mean survival was 13.4 ± 0.6 years.

Detection of transplant heart rejection by analysis of endomyocardial voltage.

These studies seek an alternative method with myocardial biopsy for rejection diagnosis. A pacemaker (Biotronik model Logos) was implanted into 16 patients to detect intramyocardial voltage. The recordings were classified in two groups according to results of myocardial biopsy. The results of the biopsy were classified according to the recommendations of the International Society for Heart and Lung Transplantation: namely, Group I: rejection < 2 (52 recordings) and Group II: rejection > or = 2 (9 recordings). The sensitive parameter for rejection detection was Tslew, which was deduced from the paced intracardial potential in the monopolar mode. The results were significant in both groups; the medium value of Tslew in group I was 96.7%, and the value for group II was 87.13% (P=.022). The sensitivity value in our patient group for detection of treatedable rejection was 78%; the negative predictive value was 95%. In conclusion the method is useful for rejection detection, but is necessary to make several recordings for the same patients during the first month post transplant, to obtain an individual baseline value.

New strategies of cyclosporine monitoring in heart transplantation: initial results.

The aim of this study was to evaluate cyclosporine (CyA) absorption profiles in heart transplantation to establish the most adequate monitoring strategy and determine the optimal therapeutic range for AUC(0-4) or C2 levels. A total of 22 full pharmacokinetic studies were performed at steady-state in 22 adult heart transplant recipients (18 men, 4 women). Twelve studies were performed during the first month posttransplant (group I), and 10 studies were done after 1 month (group II). In 9 outpatients we performed an abbreviated AUC(0-4). The mean age of the patients was 49+/-15 years (range, 15-72 years), and the mean weight was 70.4+/-10.8 kg (mean, 54-98 kg). The CyA dosage had been adjusted to maintain trough levels (C0) in the putative target ranges of 200 to 400 ng/mL in group I and between 100 to 300 ng/mL in group II. Blood samples were drawn prior to and at 0.5, 1, 2, 4, 6, 8, and 12 hours after the morning dose. The CyA blood levels were measured by the AxSYM cyclosporine assay. The AUC was calculated by the trapezoidal rule. Multiple linear regression was done to evaluate the predictive ability of various limited sampling strategies. The C0 correlated poorly, either with the full AUC (r2=0.64) or the AUC(0-4) (r2=0.43), while C2 seemed to be the most accurate single predictor of drug exposure (r2=0.92 for AUC(0-12); r2=0.74 for AUC(0-4)). For both AUC(0-4) and AUC(0-12), all 2- or 3-point strategies had r2 values approaching that of the C2 value. In conclusion, C2 is a simple, fast, and accurate value to predict AUC(0-4) in routine clinical practice. Its implementation must focus on ensuring the commitment of all unit staff, thus ensuring that patients are sampled on time and minimizing the impact on workload.

Clinical pharmacokinetics of tacrolimus in heart transplantation: new strategies of monitoring.

The aim of this study was to investigate the absorption profile of tacrolimus (TAC) in heart transplant patients in order to find the best sampling time to predict the total exposure and to explore the target range for optimal clinical immunosuppression. Twenty-five full pharmacokinetic studies were performed in 22 heart transplant patients (11 men and 7 women) at less than 1 year posttransplant. The immunosuppressive treatment was steroids plus azathioprine or mycophenolate mofetil and TAC. The mean age was 55 years (36-64 years) and the mean weight 70.49 kg (50-111 kg). After three days of receiving the same dose, eight blood samples were collected at 0.5, 1, 2, 4, 6, 8, and 12 hours postmorning dose. TAC concentrations were measured by microparticle enzyme immunoassay (IMx). Area under the concentration-time curve(AUC(0-12)) was calculated by the trapezoidal rule. Using 0-4 hours TAC blood concentrations, a projected 12 hours AUC (extrapolated AUC(0-4)) was calculated assuming C0 and C12 were comparable. A high interpatient TAC pharmacokinetics variability that was greater during the absorption phase was observed. A Cmax (30.5+/-13.8 ng/mL) was reached at 2.3+/-1.5 h. When target trough levels were achieved (10-20 ng/mL), the mean tacrolimus exposure was 230.6+/-59.2 ng h/mL (120.14-327.7) (n=19). Correlation between AUC(0-12) and C0 was relatively good (r2=0.74). Between individual time points, C4 showed the best correlation (r2=0.88). In any case the best strategy to monitor is to obtain the extrapolated AUC(0-4) (r2=0.98), as a good approach to patients with a poor response to treatment.

Genetic variations of the apolipoprotein E gene determine the plasma triglyceride levels after heart transplantation.

OBJECTIVES: To study whether the presence of the polymorphism in the apolipoprotein E (apo E) gene influences the lipid profile in heart-transplant recipients. METHODS: A cohort of 103 recipients of heart transplant (93 men and 10 women, with a mean age of 47 +/- 13 years) under triple immunosuppressive therapy were submitted to a genetic study of the apo E gene region. Anthropometric and analytical data, including lipid profile and arterial blood pressure were collected prior to transplantation and 3, 6, 12, and 24 months after it. RESULTS: 65 subjects present the genotype E3E3, 27 the genotype E3E4, 6 the genotype E2E3, and 5 the genotype E2E4. Carriers of the E2 allele (that is, genotypes E3E2 and E4E2) had higher total plasma triglyceride (TG) levels after 3 months (3.47 +/- 1.88 mmol/liter p < 0.001) and after 1 year of transplantation (3.13 +/- 1.77 mmol/liter p < 0.05) than the other genotypes. There were no differences in the plasma levels of total cholesterol (TC), LDL-cholesterol (LDL-C), and HDL-cholesterol (HDL-C). Multiple regression analysis revealed that the apoprotein E gene polymorphism determines 5% (p = 0.0425) and age 8.7% (p < 0.009) of the variants in TG levels. CONCLUSIONS: The presence of the E2 allele in heart-transplant recipients produces a greater rise in total TG plasma levels than the other genotypes.

[Influence of genetic variation at apoprotein A-1 gene promoter region on plasma lipid levels in heart transplantation patients]. / Influencia de la variación genética en la región promotora del gen de la apoproteína A-I sobre las concentraciones de lípidos en pacientes con transplante de corazón.

BACKGROUND: To study if the presence of the G/A polymorphism at the apo A-I gene promoter region could determine the lipid profile in patients with hyperlipidemia after heart transplantation, or if it is related with the type of heart disease that determined the transplantation. PATIENTS AND METHODS: This study included 31 patients with hyperlipidemia after heart transplantation. Anthropometric parameters, basic analytic and lipid study were measured in these subjects. Identification of the G/A mutation in the promoter region of the apo A-I gene was performed. RESULTS: 22 patients had the G/G genotype and 9 the G/A. 14 were transplanted by coronary heart disease and 17 by non ischemic heart disease. Patients with the A allele had higher cHDL (63 [SD 15] vs 53 [10]; p = 0.034) and apo A-I plasma levels (156 [34] vs 132 [24]; p = 0.040) than G/G subjects. The A allele was present in the 18% of the patients transplanted by ischemic heart disease and in the 43% of the transplanted by another etiology (p = 0.073). CONCLUSIONS: The presence of the G/A genotype in the promoter region of the apo A-I gene determines higher plasma levels of cHDL in patients with hyperlipidemia after heart transplantation.

[William's syndrome. Report of a case with family involvement]. / Síndrome de Williams. Presentación de un caso de afectación familiar.

Williams' syndrome (WS) is a rare genetic condition of autosomal dominant inheritance with varying penetrance, which consists of supravalvular aortic stenosis, a characteristic dysmorphic facies named "elf face", mental retardation and other clinical manifestations including transient infantile idiopathic hypercalcemia, growth retardation, and frequent dental problems. It usually presents sporadically, and there are only a few cases of family involvement reported in the literature. Recent studies show that mutations in the elastin gene at chromosome 7q11.23, which occur approximately in 90% of cases, could be the cause of the different clinical manifestations in this syndrome. In this paper we report a case of family involvement with five family members involved with WS (three siblings, the mother, and the siblings' maternal uncle) and all had cardiac structural disorders (supravalvular aortic stenosis being the most frequent), a characteristic face and a low intellectual coefficient. The complementary tests included blood chemistry, chest X-ray, and echocardiogram, which led to the diagnosis of the associated valve pathology. Three patients required therapeutic catheterism with Stent valve implant and valve prosthetic replacement to control cardiac manifestations.

[Value of a short (7 days) prophylactic course of ganciclovir in the prevention of cytomegalovirus disease after heart transplantation]. / Valor de una pauta profiláctica corta (7 días) de ganciclovir en la prevención de la enfermedad por citomegalovirus tras el trasplante cardíaco.

BACKGROUND: The incidence of cytomegalovirus disease remains important after heart transplantation, mainly in the first months after transplantation. We undertook a study to evaluate a short (7 days) prophylactic administration of ganciclovir to prevent cytomegalovirus disease after heart transplantation. PATIENTS AND METHODS: There were two groups of patients: patients transplanted in 1993 (37) and patients transplanted in 1992 (38). In the first group, ganciclovir was given intravenously at a dose of 10 mg per kilogram of body weight every day from postoperative day 1 through day 7. In the second group, ganciclovir was not given. Similar regimens of immunosuppression (ATG, deflazacort, azathioprine and cyclosporine) were given. RESULTS: Age, sex, serology in recipients and donors and incidence of acute rejection were comparable between both groups. Mortality was slightly higher in ganciclovir group (35%) than in control group (26%), although this difference was not statistically significant. There were two cases of cytomegalovirus disease in the ganciclovir group (6%) and nine cases in the control group (27%) (p < 0.05), all of them treated successfully. Cytomegalovirus disease in ganciclovir group occurred in two children, who were seronegative before transplantation. The incidence of cytomegalovirus disease in the pediatric recipients of ganciclovir group were 50% (2 of 4) and 100% in the control group (1 of 1). The incidence of cytomegalovirus disease were therefore 0% in the adult subgroup of ganciclovir group and 24% in the adult subgroup of control group. CONCLUSIONS: A short (7 days) prophylactic administration of ganciclovir reduces the incidence of cytomegalovirus disease. In the pediatric group, the effectiveness is lower.

Repetitive nontreated episodes of grade 1B or 2 acute rejection impair long-term cardiac graft function.

BACKGROUND: Episodes of grade 1B or 2 acute heart rejection are usually not treated, and most of them resolve spontaneously. METHODS: With the aim to assess long-term outcome in patients with repetitive nontreated episodes of low-grade (1B, 2) acute rejection, we have studied 141 heart transplant recipients in whom the evolutive pattern of acute rejection during the first 6 months after transplantation could be determined. RESULTS: Forty-four patients (31%) had only grade 0 or 1A acute rejection episodes (pattern A); 23 patients (16%) had three or more episodes of grade 1B or 2 acute rejection without 3A or more advanced rejection (pattern B); 48 patients (34%) had one or two episodes of grade 3A, 3B, or 4 acute rejection only during the first 6 months after transplantation (pattern C); and 26 patients (19%) had three or more episodes of grade 3A, 3B, or 4 acute rejection (pattern D). Overall mortality was 11%, 26%, 19%, and 46% for patients with patterns A, B, C, and D, respectively. No difference was found among patterns with regard to incidence of graft atherosclerosis. Left ventricular ejection fraction at 1 year after transplantation was significantly lower (p < 0.05) for patients with pattern B (50% +/- 5% versus 59% +/- 7%, 59% +/- 11%, and 56% +/- 6% for patterns A, C, and D, respectively); cardiac index also was lower for patients with pattern B than for those with pattern A (3.6 +/- 0.6 versus 4.1 +/- 0.6 L/min/m2, p < 0.05). CONCLUSIONS: Although mortality was higher for patients with more severe episodes of acute rejection, only repetitive nontreated episodes of grade 1B or 2 rejection significantly impaired long-term graft function.

Lovastatin versus bezafibrate for hyperlipemia treatment after heart transplantation.

BACKGROUND: Elevation in total and low-density lipoprotein cholesterol levels and a decrease in high-density lipoprotein cholesterol plasma concentrations are common in heart transplant recipients. The pathogenesis of this hyperlipemia after heart transplantation is complex. Currently available antilipemic agents are difficult to use because their adverse effects are potentiated by immunosuppressor treatment. The present investigation was carried out to test the safety and efficacy of lovastatin and bezafibrate in 18 patients with hyperlipemia after heart transplantation. METHODS: In this crossover study, after 3 months of dietary recommendations, the subjects were randomly assigned to an 8-week period of lovastatin treatment (10 mg/day) followed by an additional 8-week period of treatment with bezafibrate (400 mg/day) or vice versa. The two treatments were separated by an 8-week washout period. RESULTS: Both drugs reduced total and low-density lipoprotein cholesterol and apoprotein B concentrations. High-density lipoprotein cholesterol was only increased with bezafibrate. The total cholesterol/high-density lipoprotein cholesterol and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratios were decreased under both treatments, but these changes were greater with bezafibrate. Apo AI levels increased with lovastatin. Bezafibrate produced a rise in high-density lipoprotein cholesterol and reduced total and very low-density lipoprotein triglycerides and very low-density lipoprotein cholesterol. Both drugs decreased intermediate density lipoprotein cholesterol and triglyceride levels, but the effect of bezafibrate on intermediate-density lipoprotein triglycerides was significantly greater. The two drugs were well tolerated and liver enzymes, creatine kinase, and renal function remained stable.

[The echocardiographic findings in patients with brain death. The implications for their selection as heart transplant donors]. / Hallazgos ecocardiográficos en pacientes con muerte cerebral. Implicaciones para su selección como donantes para trasplante cardíaco.

INTRODUCTION AND AIMS: Brain death causes myocardial impairment by some mechanisms not yet well understood. The aim of this work was to assess the echocardiographic features found in these patients and their implication in donor selection for heart transplantation. METHODS: With this aim, we have studied 38 consecutive patients with brain death assessed as possible donors for heart transplant in our hospital in the last 3 years. Age was 23 +/- 13 years; 77% were male. No history of cardiac disease was present in any patient. An adequate transthoracic echocardiogram was obtained in 74% of patients; transesophageal view was used in the remaining 26%. RESULTS: Echocardiogram was strictly normal in only 14 patients (37%). Mild valvular alterations were found in 5 patients (13%); a dilated aortic root in 1 (3%); moderate concentric left ventricular hypertrophy in 5 (14%); mild pericardial effusion in 1 (3%); mild septal hypokinesia with normal left ventricular ejection fraction in 4 (10%); abnormal left ventricular diastolic function in 7 (18%); and diffuse hypokinesia with ejection fraction less than 60% in 14 (37%). In 7 patients (18%) ejection fraction was lower than 40% (one of them was cocaine-addict). Mean ejection fraction was 59 +/- 15% (23 to 83%). Only 2 of the 19 (10%) donor hearts implanted in our hospital showed early dysfunction after transplant, but no relation to pretransplant ejection fraction was found. Ejection fraction increased from 62% pretransplant to 73% at one week after transplant in the other 17 cases. CONCLUSIONS: Brain death commonly causes alterations of left ventricular function, and this impairment is severe in almost 20% of cases. These echocardiographic features must be known when selection of donors for heart transplantation is concerned.

Visceral Kaposi's sarcoma without mucocutaneous involvement in a heart transplant recipient.

Kaposi's sarcoma has been occasionally reported in heart transplant recipients, but its occurrence without mucocutaneous involvement is extremely rare. In these uncommon cases, the tumor can be indistinguishable from opportunistic infections, making diagnosis difficult. The case of a patient in whom visceral Kaposi's sarcoma was diagnosed by necropsy 6 months after heart transplantation is reported.

Influence of heart transplantation on the natural history of patients with severe congestive heart failure.

In an attempt to study the influence of heart transplantation on the natural history of patients with severe congestive heart failure, we have reviewed our experience with 240 consecutive patients who were New York Heart Association class IV or III/IV, who had left ventricular ejection fraction less than 35%, who were younger than 65 years of age, and who were assessed for heart transplantation in our hospital since May 1986. Mean age was 47 +/- 12 years. Left ventricular ejection fraction was 20% +/- 6%. Eighty-seven percent were male. New York Heart Association class was IV in 88% and III/IV in 12%. The cause was ischemic heart disease in 35% of patients, valvular heart disease in 13% of patients, and primary dilated cardiomyopathy in 52% of patients. At initial assessment, heart transplantation was considered to be not indicated in 30% of patients, indicated in 51% of patients, and contraindicated in 19% of patients. During a follow-up of 13 +/- 13 months (2 to 64 months), 110 patients underwent transplantation (46%). Posttransplantation actuarial probability of survival was 70% at 3 years. Three-year probability of survival free from transplantation was significantly lower for patients older than 55 years of age (p < 0.05), for those with left ventricular ejection fraction less than 20% (p < 0.05), ischemic causes (p < 0.05), New York Heart Association class IV (p < 0.001), and indication/contraindication for transplantation (p < 0.001); no difference was noted for gender.(ABSTRACT TRUNCATED AT 250 WORDS)

[Patients with an acute myocardial infarct treated in a coronary unit or in a general cardiology ward A comparative study]. / Pacientes con infarto agudo de miocardio tratados en unidad coronaria o en sala general de cardiología. Un estudio comparativo.

INTRODUCTION AND OBJECTIVES: Coronary care units have been accepted as the standard location for treatment for patients with acute myocardial infarction. Nevertheless, controversy over their clinical impact, current role and cost-effectiveness still remains. Due to the increased incidence of coronary artery disease in Spain, coronary care units are often full, and patients with acute myocardial infarction must be cared for in a general cardiology ward. METHODS: We have studied the features and results of 420 patients with acute myocardial infarction consecutively admitted to our hospital and compared patients cared for in the coronary care unit (329 [78%]) with those cared for in the cardiology ward (91 [22%]). Admission to cardiology ward or coronary care unit was based on the clinical judgment of emergency room physicians and the bed availability. No differences in age, sex, risks factors, prior history of coronary heart disease, blood pressure on admission, extension and complications of myocardial infarction were found between both groups. RESULTS: The percentage of patients with evolved and non-Q wave acute myocardial infarction, and admission electrocardiogram not suggestive of infarction was significantly higher in ward group (23 versus 2.4%, p < 0.001; 19 versus 11%, p < 0.01; and 43 versus 15%, p < 0.01; respectively). Although patients admitted to the coronary care unit underwent intravenous thrombolysis and coronary artery revascularization procedures in a higher proportion, mortality was similar in both groups (14% for ward patients and 17% for coronary care unit patients). When patients with evolved or non-Q wave infarctions and those with admission electrocardiograms not suggestive of infarction were excluded from the analysis, mortality rates remained similar. Subgroups mortality was in general similar for patients cared for in cardiology ward or in coronary care unit, although patients without shock, with Killip class I or II, and older than 70 years, had a slightly lesser mortality when treated in the Cardiology ward (5 versus 11%, 6 versus 11%, and 14 versus 28%, respectively). By contrast, patients with shock, Killip class III or IV, and electrocardiogram at admission not suggestive of infarction, had a lesser mortality when cared for in coronary care unit. CONCLUSIONS: We conclude that some subgroups of patients with acute myocardial infarction can be, if needed, effective and safely cared for in cardiology ward.