Rejection after conversion to a proliferation signal inhibitor in chronic heart transplantation.

We sought to determine the incidence, risk factors, and consequences of acute rejection (AR) after conversion from a calcineurin inhibitor (CNI) to a proliferation signal inhibitor (PSI) in maintenance heart transplantation. Relevant clinical data were retrospectively obtained for 284 long-term heart transplant recipients from nine centers in whom CNIs were replaced with a PSI (sirolimus or everolimus) between October 2001 and March 2009. The rejection rate at one yr was 8.3%, stabilizing to 2% per year thereafter. The incidence rate after conversion (4.9 per 100 patient-years) was significantly higher than that observed on CNI therapy in the pre-conversion period (2.2 per 100 patient-years). By multivariate analysis, rejection risk was associated with a history of late AR prior to PSI conversion, early conversion (<5 yr) after transplantation and age <50 yr at the time of conversion. Use of mycophenolate mofetil was a protective factor. Post-conversion rejection did not significantly influence the evolution of left ventricular ejection fraction, renal function, or mortality during further follow-up. Conversion to a CNI-free immunosuppression based on a PSI results in an increased risk of AR. Awareness of the clinical determinants of post-conversion rejection could help to refine the current PSI conversion strategies.

Transplantation for complex congenital heart disease in adults: a subanalysis of the Spanish Heart Transplant Registry.

BACKGROUND: Congenital heart diseases (CHDs) have high infant mortality in their severe forms. When adulthood is reached, a heart transplant (HTx) may be required. Spanish adult population transplanted for CHD was analyzed and compared with the most frequent causes of HTx and between different subgroups of CHD. MATERIALS AND METHODS: A total of 6048 patients (HTx 1984-2009) were included. Pediatric transplants (<15 yr), combined transplants, reHTx, and HTx for heart diseases other than idiopathic dilated cardiomyopathy (IDCM) and ischemic heart disease (IHD) were excluded. Total patients included: 3166 (IHD = 1888; IDCM = 1223; CHD = 55). Subgroups were studied as follows: (1) single ventricle with pulmonary stenosis (n = 18), (2) single ventricle with tricuspid atresia and Glenn/Fontan surgery (n = 10), (3) congenitally corrected transposition of the great vessels (TGV) or with switch atrial surgery (n = 10), and (4) CHD with right ventricle overload (n = 17). RESULTS: Survival probability was different between groups (p = 0.0001). Post hoc analysis showed some differences between groups (CHD vs. IHD, p = 0.05; CHD vs. IDCM, p = 0.5; IHD vs. IDCM, p = 0.0001). Early mortality was different between CHD subgroups (group 1 = 19%, group 2 = 40%, group 3 = 0%, group 4 = 29%; p < 0.001); however, overall mortality did not show differences between subgroups (p = 0.5). CONCLUSIONS: The percentage of Spanish adult HTx patients for CHD is low (1%). The survival curve is better than for other HTx causes (IHD). Nevertheless, early mortality was higher, particularly in some subgroups (Fontan).

Centres of excellence in heart failure: results of an accreditation programme in Spain (2017-2021).

AIMS: To describe logistics and outcomes of the accreditation program of centres of excellence in heart failure (HF) developed in Spain by the Spanish Society of Cardiology (SEC) between 2016 and 2021. METHODS AND RESULTS: A scientific committee created by the SEC defined three types of HF units (community, specialized, and advanced), depending on the characteristics of the hospital and their portfolio of services and equipment, as well as the quality standards required for the accreditation of excellence. The units were required to submit to the SEC a document certifying compliance with the requirements and quality standards. Once verified these, the unit received accreditation of excellence from the SEC. Between 2017 and October 2021, 78 HF units spread throughout Spain applied for accreditation. This represents 50.6% of all Spanish national health system centres with cardiology departments. Accreditation was definitive in 56.4% of the applicant centres and provisional in the remaining 43.6%. Of the 78 units, 19 were community units, 44 specialized, and 15 advanced. Of the 34 units that received provisional accreditation for failure to meet any of the required quality standards, all resolved these deficits within 6 months of the initial evaluation, subsequently receiving definitive accreditation. CONCLUSIONS: Our experience indicates that implementation of an accreditation programme for excellence and quality of care of HF units at the national level by a scientific society is feasible and sustainable over time, leading the majority of HF units in the country to apply for accreditation and to meet the required quality standards.

Gene variants in the NF-KB pathway (NFKB1, NFKBIA, NFKBIZ) and risk for early-onset coronary artery disease.

The nuclear-factor kappa-beta (NF-KB) is a driver of inflammation, and plays an important role in the pathogenesis of atherosclerosis and coronary artery disease (CAD). Early-onset CAD is defined as a coronary ischaemic episode at an age ≤55 years, and in our population was strongly associated with male sex and smoking. Our aim was to determine whether common variants in three NF-KB genes were associated with early-onset CAD. We studied 609 patients with early-onset CAD and 423 healthy controls, all male. Allele and genotype frequencies for the NFKB1 rs28362491 (-94 delATTG) and NFKBIA rs8904 were not significantly different between the two groups. For the NFKBIZ rs3217713, the deletion allele was significantly more frequent in the patients than in controls (0.27 vs. 0.22; p = 0.004). Deletion-carriers were more frequent in the patients (p < 0.001), with an OR = 1.48 (95%CI = 1.15-1.90). We performed a multiple logistic regression (linear generalized model) with smoking, hypercholesterolemia, type 2 diabetes, hypertension, and the rs3217713 deletion carriers remained significantly associated with early-onset CAD (p = 0.01). In our population, the NFKBIZ variant was an independent risk factor for developing early-onset CAD.

The predictive value of soluble major histocompatibility complex class I chain-related molecule A (MICA) levels on heart allograft rejection.

BACKGROUND: Recently the presence of a soluble form of major histocompatibility complex class I chain-related molecule A (sMICA) has been detected in the sera of patients with tumors. Shedding of sMICA by tumor cells downregulates NKG2D-mediated antitumor immunity. The aim of this investigation was to study the possible involvement of sMICA in the allograft acceptance after heart transplantation (HTX). METHODS: We monitored the levels of sMICA by specific enzyme-linked immunosorbent assay (ELISA) in a total of 146 serum samples obtained from 34 heart transplantation patients followed up during the first year post-HTX. RESULTS: The persistence of sMICA expression was correlated with the clinical evolution of these patients. sMICA was detected in the serum of 21 of 34 patients (61.70%) between 15 and 20 days after implantation and was practically absent in pretransplant serum samples. Twenty of these 21 patients (95.24%) with sMICA did not experience episodes of severe rejection during this period (P = 0.0001), whereas sMICA was practically absent in patients with manifestations of severe acute rejection. The longitudinal study of these patients revealed that the presence of sMICA was consistently maintained in 75% of the patients with good graft status during the period of observation. CONCLUSION: This has led us to believe that the presence of levels of sMICA during the first year post-HTX may contribute to allograft acceptance. Additionally, functional studies indicate that sMICA downregulates NKG2D surface expression, which may lead to a functional impairment of cell-mediated cytolysis. These data suggest a significant correlation between the presence of sMICA and a lower incidence of rejection.

A randomized multicenter comparison of basiliximab and muromonab (OKT3) in heart transplantation: SIMCOR study.

BACKGROUND: Antilymphocytic antibodies have been long used for the prevention of acute rejection early after heart transplantation (HTx), but their adverse effects have limited their widespread use. Our aim was to evaluate the safety, tolerability, and efficacy of the novel anti-CD25 antibody basiliximab (BAS) compared with muromonab (OKT3). PATIENTS AND METHODS: In this multicenter study, 99 patients were randomly assigned to receive either BAS or OKT3 in the early post-HTx period. The primary endpoint was safety and tolerability. Specific safety variables were predefined for a better comparison of adverse effects. Secondary endpoints concerning anti-rejection efficacy were also evaluated. RESULTS: No adverse events related to study medication were found in the BAS group, whereas 23 were observed among patients receiving OKT3 (P<0.0001). The proportion of patients with predefined adverse events day 4 post-HTx was much higher with OKT3 than with BAS (43% vs. 4%; P<0.0001). Fever, acute pulmonary edema, hypotension, and other complications accounted for most of the difference. At 1-year follow-up, biopsy-proven rejection episodes grade>or=3A had occurred in 39.6% of BAS patients versus 40.4% of OKT3 patients (P=0.87). There were no differences in terms of severity and timing of acute rejection episodes. The number of infectious episodes, complications not related to study medication, and actuarial survival were similar in both groups. CONCLUSION: In this HTx study, induction therapy with BAS was safer and better tolerated than OKT3, without significant differences in efficacy outcomes.

[Myocardial Infarction Registry in Asturias: the RIMAS project]. / Registro del Infarto de Miocardio en Asturias: proyecto RIMAS.

BACKGROUND AND OBJECTIVE: Spanish hospital registers of myocardial infarction (MI) are not uniform. The RIMAS project is trying to know the real situation of myocardial infarction in Asturias and to observe possible differences among hospitals and with other registers. PATIENTS AND METHOD: It was a cohorts study using a hospital registry of patients with MI. All cases arriving alive to all public and private-public Asturian hospitals during 1998 were included. Demographic data, cardiovascular risk factors, delays, evolution, treatments and techniques used, were all registered. RESULTS: 875 cases were registered with a coverage rate of 77%. The average age was 66.5 years (45.6% older than 70 years) and women represented 29.1%. Sixty three per cent of the patients had tobacco consumption, 43% had arterial hypertension, and 22.3% were diabetics. The extrahospital delay was 135 min and thrombolysis delay was 180 min. Thrombolytic therapy was administered to 34.1% of patients and 4% were treated with primary angioplasty. Intrahospital mortality was 14.4%. At discharge, antiagregant therapy was administrated to 94%, betablockers to 43.2%, ACE inhibitors to 33.3% and hypolipemiants to 25% of treated patients. CONCLUSIONS: People attended in Asturias with a MI are older and there is a higher percentage of women. There are delays which include the start of thrombolytic therapy. However, there are significant differences with regard to the adhesion to clinical practice guidelines between different hospitals.

Management and risk factors for mortality in very elderly patients with acute myocardial infarction.

AIM: Elderly patients often remain underrepresented in clinical trials. The aim of our study was to analyze the treatment, clinical outcome and risk factors for mortality in patients aged ≥85 years with ST-segment elevation myocardial infarction (STEMI). METHODS: From 2005-2011, 102 patients aged ≥85 years with STEMI admitted to a coronary care unit were retrospectively reviewed. Clinical data, treatment and outcome were recorded. Reperfusion strategy and its influence in hospital morbidity and mortality were evaluated. Morbidity was defined as the presence of heart failure (Killip-Kimball >1), arrhythmias, mechanical complications, stroke or major bleeding. Risk factors for mortality were assessed by multivariate analysis. RESULTS: The mean age was 87.5±2.5 years (range 85-96). Therapeutic strategy on admission was: primary-angioplasty (PCI) for 33 patients (32.3%) fibrinolysis for 30 patients (29.4%) and conservative treatment for 35 patients (34.3%). In the four remaining patients, rescue angioplasty was required. A total of 29 patients (28.4%) died, and morbidity was seen in 63 patients (61.7%). The morbidity and mortality rates in the conservative treatment group (77.1% and 48.5%) were higher than that found in the reperfusion strategy group (primary-PCI and fibrinolysis; 53.7% and 17.9%; P=0.02 and P=0.002, respectively). Regarding mortality, the univariate analysis showed that heart failure on admission (P=0.0001) and previous coronary artery disease (P=0.01) were prognostic variables. Only heart failure was an independent risk factor for mortality (odds ratio=3.64, 95% CI 0.78-21.87, P<0.0001). CONCLUSIONS: Mortality and morbidity in very elderly patients with STEMI are very high, especially in those not receiving reperfusion therapies. Heart failure on admission was an independent risk factor for hospital mortality.

Left ventricle non-compaction cardiomyopathy: different clinical scenarios and magnetic resonance imaging findings.

Left ventricle non-compaction cardiomyopathy is currently considered as a well-defined individual entity. However, it includes a broad spectrum of clinical, radiological and pathophysiological findings. In this review we describe 3 different scenarios of this entity: an isolated case with severe left ventricle dysfunction, an "associated" case in a patient with previous atrial septum defect and pulmonary stenosis and finally, as a finding in a patient with a transient cerebrovascular ischemic attack. In the 2 last cases, both asymptomatic, morphological criteria of left ventricle non-compaction were found but, ventricular function was normal and cardiac-MRI showed no late gadolinium hyperenhancement. Periodical follow-up and familial screening were recommended. Natural history and prognosis factors of this disease are still not well known. Further and longer series of patients with this diagnosis are needed to completely define radiological criteria, clinical presentation and evolution.

Primary graft failure after heart transplantation: characteristics in a contemporary cohort and performance of the RADIAL risk score.

BACKGROUND: Primary graft failure (PGF) is the leading cause of early heart transplantation (HT) mortality. Our aim was to analyze PGF currently and explore the ability of a dedicated score for PGF risk stratification. METHODS: After applying a dedicated PGF definition, we analyzed its incidence, mortality, and associated factors in a multicenter cohort of 857 HTs performed in 2006 to 2009. We used the following criteria: recipient right (R) atrial pressure ≥ 10 mm Hg; age (A) ≥ 60 years; diabetes (D) mellitus, and inotrope (I) dependence; donor age (A) ≥ 30 years, and length (L) of ischemia ≥ 240 minutes to calculate the RADIAL score for PGF risk prediction. RESULTS: PGF incidence was 22%. The right ventricle was almost always affected, alone (45%) or as part of biventricular failure (47%). Mechanical circulatory support was used in 55%. Mortality attributable to PGF was 53% and extended through the third month after HT, but thereafter, PGF had little influence in long-term outcome. The RADIAL score was higher in PGF patients (2.78 ± 1.1 vs. 2.42 ± 1.1, p = 0.001) and stratified 3 groups with incremental PGF incidence: low risk (12.1%), intermediate risk (19.4%), and high risk (27.5%, p = 0.001). CONCLUSIONS: PGF had a strong impact, with an incidence of 22% and a mortality exceeding 50% that extends through the third post-HT month. The RADIAL score classified patients into 3 groups with incremental risk for PGF and may be useful for its prevention and early therapy.

Resequencing the whole MYH7 gene (including the intronic, promoter, and 3' UTR sequences) in hypertrophic cardiomyopathy.

MYH7 mutations are found in ~20% of hypertrophic cardiomyopathy (HCM) patients. Currently, mutational analysis is based on the sequencing of the coding exons and a few exon-flanking intronic nucleotides, resulting in omission of single-exon deletions and mutations in internal intronic, promoter, and 3' UTR regions. We amplified and sequenced large MYH7 fragments in 60 HCM patients without previously identified sarcomere mutations. Lack of aberrant PCR fragments excluded single-exon deletions in the patients. Instead, we identified several new rare intronic variants. An intron 26 single nucleotide insertion (-5 insC) was predicted to affect pre-mRNA splicing, but allele frequencies did not differ between patients and controls (n = 150). We found several rare promoter variants in the patients compared to controls, some of which were in binding sites for transcription factors and could thus affect gene expression. Only one rare 3' UTR variant (c.*29T>C) found in the patients was absent among the controls. This nucleotide change would not affect the binding of known microRNAs. Therefore, MYH7 mutations outside the coding exon sequences would be rarely found among HCM patients. However, changes in the promoter region could be linked to the risk of developing HCM. Further research to define the functional effect of these variants on gene expression is necessary to confirm the role of the MYH7 promoter in cardiac hypertrophy.

Clinical recommendations for the use of everolimus in heart transplantation.

Proliferation signal inhibitors (PSIs), everolimus (EVL), and sirolimus are a group of immunosuppressor agents indicated for the prevention of acute rejection in adult heart transplant recipients. Proliferation signal inhibitors have a mechanism of action with both immunosuppressive and antiproliferative effects, representing an especially interesting treatment option for the prevention and management of some specific conditions in heart transplant population, such as graft vasculopathy or malignancies. Proliferation signal inhibitors have been observed to work synergistically with calcineurin inhibitors (CNIs). Data from clinical trials and from the growing clinical experience show that when administered concomitantly with CNIs, PSIs allow significant dose reductions of the latter without loss of efficacy, a fact that has been associated with stabilization or significant improvement in renal function in patients with CNI-induced nephrotoxicity. The purpose of this article was to review the current knowledge of the role of PSIs in heart transplantation to provide recommendations for the proper use of EVL in cardiac transplant recipients, including indications, treatment regimens, monitoring, and management of the adverse events.

Clinical utility of NT-proBNP levels in late heart transplantation patients.

BACKGROUND: The present work was aimed to describe NT-proBNP levels in heart transplant patients after the first year postsurgery. METHODS: NT-proBNP concentration was measured in 1231 samples from 142 patients when a routine four-month follow-up was carried out, including other biochemical and clinical examinations. Endomyocardial biopsies were performed only upon clinical suspicion of acute rejection. RESULTS: NT-proBNP concentrations were not significantly correlated to post-transplantation time, though differences were observed according to clinical symptoms (Kruskal-Wallis test, p<0.001). Although multivariate analysis revealed statistically significant association between NT-proBNP concentration and some qualitative (cardiac allograft vasculopathy-CAV-, sex, diabetes) and quantitative (creatinine, hematocrit, age) variables, only moderately relevant contribution was observed for creatinine and CAV. Patients with rejection showed noticeable increases in serum NT-proBNP concentrations, above more than 2.5 times the reference change value (97%). NT-proBNP concentrations higher than 1000ng/L increased in 3.5 times (95%CI: 2.4-5) the risk of death in less than one year. CONCLUSIONS: After the first year from surgery, NT-proBNP concentrations were not associated to post-transplantation time and NT-proBNP could be a useful diagnostic marker for rejection, whenever serial measurements are made. A NT-proBNP cutoff value of 1000ng/L was identified for classifying patients at risk of death after one year.

Left ventricle non-compaction cardiomyopathy: Different clinical scenarios and magnetic resonance imaging findings / Miocardiopatía no compactada: diferentes escenarios clínicos y hallazgos en cardiorresonancia magnética

Left ventricle non-compaction cardiomyopathy is currently considered as a well-defined individual entity. However, it includes a broad spectrum of clinical, radiological and pathophysiological findings. In this review we describe 3 different scenarios of this entity: an isolated case with severe left ventricle dysfunction, an "associated" case in a patient with previous atrial septum defect and pulmonary stenosis and finally, as a finding in a patient with a transient cerebrovascular ischemic attack. In the 2 last cases, both asymptomatic, morphological criteria of left ventricle non-compaction were found but, ventricular function was normal and cardiac-MRI showed no late gadolinium hyperenhancement. Periodical follow-up and familial screening were recommended. Natural history and prognosis factors of this disease are still not well known. Further and longer series of patients with this diagnosis are needed to completely define radiological criteria, clinical presentation and evolution.

La miocardiopatía no compactada está considerada actualmente como una entidad independiente y bien definida. Sin embargo, presenta un espectro amplio de hallazgos clínicos, radiológicos y fisiopatológicos. En la presente revisión describimos 3 escenarios clínicos diferentes de dicha entidad: un caso con disfunción ventricular severa, un caso como entidad «asociada¼ a una cardiopatía congènita en un pacientes con un defecto del septo interauricular previo y estenosis pulmonar, y finalmente, como un hallazgo casual en un paciente con un accidente cerebrovascular transitorio. En estos 2 últimos casos se encontraron criterios morfológicos de miocardiopatía no compactada con función ventricular normal y sin presencia de realce tardío de gadolinio en el estudio de cardio-RM. En todos ellos se recomendó estudio familiar. La historia natural y el pronóstico de esta anatomía patológica no son todavía del todo conocidos. Series mayores y seguimiento más largos son necesarios para definir completamente los criterios radiológicos, la presentación clínica y la evolución de esta fascinante entidad.

Comparison of cytomegalovirus pp-65 antigenemia assay and plasma DNA correlation with the clinical outcome in transplant recipients.

The relationship between quantitative antigenemia and plasma DNAemia was studied for monitoring cytomegalovirus (CMV) viremia in CMV infection (CMVI) or disease (CMVD), in 20 transplant recipients (13 CMD, seven CMVI). A total of 142 samples of blood were assayed for CMV-DNA and pp-65 antigenemia (CMV-Ag). A quantitative correlation between both markers was found (P < 0.0001). First CMV antigenemia as well as first plasma DNA viral load was similar in CMVI and CMVD (29 vs. 24 CMV-Ag+ cells/10(5) PMN; and 7445 vs. 12407 CMV-DNA copies/ml). The maximum antigenemia was higher in CMVD than in CMVI (146 +/- 87 vs. 61 +/- 54 +cells/10(5) PMN, P < 0.05), but the highest CMV plasma viral load was similar in both groups (62592 +/- 33000 vs. 42055 +/- 38600 copies/ml). In nine patients, maximum antigenemia coincided with highest plasma DNA viral load, but in 10 highest DNAemia occurred 6 days later. On the contrary, antigenemia declined faster than CMV-DNAnemia, after treatment.

Assay of cytomegalovirus susceptibility to ganciclovir in renal and heart transplant recipients.

Ganciclovir (GCV) prophylaxis or pre-emptive therapy significantly reduce the rate of cytomegalovirus (CMV) disease and viremia, but increase the potential for emergence of ganciclovir-resistant CMV strains. The inhibitor concentration at 50% (IC(50)) of GCV from 156 CMV isolates from 59 renal or heart transplant recipients was calculated by means of a rapid phenotypic susceptibility assay. Twenty-seven strains were from 14 patients undergoing GCV therapy. The IC(50) was higher in patients under the prophylaxis regimen. One CMV strain, from a heart transplant recipient, became GCV-resistant after 1 month of therapy (IC(50)=13.7 micromol/l). These data, together with clinical and virological markers, suggested that a switch to foscarnet was necessary, and good evolution was observed. Thus, assay of CMV susceptibility to GCV could be helpful in clinical management.