Cancer Incidence in Heart Transplant Recipients With Previous Neoplasia History.

Neoplasm history increases morbidity and mortality after solid organ transplantation and has disqualified patients from transplantation. Studies are needed to identify factors to be considered when deciding on the suitability of a patient with previous tumor for heart transplantation. A retrospective epidemiological study was conducted in heart transplant (HT) recipients (Spanish Post-Heart Transplant Tumor Registry) comparing the epidemiological data, immu-nosuppressive treatments and incidence of post-HT tumors between patients with previous malignant noncardiac tumor and with no previous tumor (NPT). The impact of previous tumor (PT) on overall survival (OS) was also assessed. A total of 4561 patients, 77 PT and 4484 NPT, were evaluated. The NPT group had a higher proportion of men than the PT group (p < 0.001). The incidence of post-HT tumors was 1.8 times greater in the PT group (95% confidence interval [CI] 1.2-2.6; p < 0.001), mainly due to the increased risk in patients with a previous hematologic tumor (rate ratio 2.3, 95% CI 1.3-4.0, p < 0.004). OS during the 10-year posttransplant period was significantly lower in the PT than the NPT group (p = 0.048) but similar when the analysis was conducted after a first post-HT tumor was diagnosed. In conclusion, a history of PT increases the incidence of post-HT tumors and should be taken into account when considering a patient for HT.

The falling incidence of hematologic cancer after heart transplantation.

BACKGROUND: A number of changes in the management of heart transplantation (HT) patients have each tended to reduce the risk of post-HT hematologic cancer, but little information is available concerning the overall effect on incidence in the HT population. METHODS: Comparison of data from the Spanish Post-Heart-Transplantation Tumour Registry for the periods 1991-2000 and 2001-2010. RESULTS: The incidence among patients who underwent HT in the latter period was about half that observed in the former, with a particularly marked improvement in regard to incidence more than five yr post-HT. CONCLUSIONS: Changes in HT patient management have jointly reduced the risk of hematologic cancer in the Spanish HT population. Long-term risk appears to have benefited more than short-term risk.

Lung cancer after heart transplantation: results from a large multicenter registry.

In this study we analyzed Spanish Post-Heart-Transplant Tumour Registry data for adult heart transplantation (HT) patients since 1984. Median post-HT follow-up of 4357 patients was 6.7 years. Lung cancer (mainly squamous cell or adenocarcinoma) was diagnosed in 102 (14.0% of patients developing cancers) a mean 6.4 years post-HT. Incidence increased with age at HT from 149 per 100 000 person-years among under-45s to 542 among over-64s; was 4.6 times greater among men than women; and was four times greater among pre-HT smokers (2169 patients) than nonsmokers (2188). The incidence rates in age-at-diagnosis groups with more than one case were significantly greater than GLOBOCAN 2002 estimates for the general Spanish population, and comparison with published data on smoking and lung cancer in the general population suggests that this increase was not due to a greater prevalence of smokers or former smokers among HT patients. Curative surgery, performed in 21 of the 28 operable cases, increased Kaplan-Meier 2-year survival to 70% versus 16% among inoperable patients.

Malignancy after heart transplantation: incidence, prognosis and risk factors.

The Spanish Post-Heart-Transplant Tumour Registry comprises data on neoplasia following heart transplantation (HT) for all Spanish HT patients (1984-2003). This retrospective analysis of 3393 patients investigated the incidence and prognosis of neoplasia, and the influence of antiviral prophylaxis. About 50% of post-HT neoplasias were cutaneous, and 10% lymphomas. The cumulative incidence of skin cancers and other nonlymphoma cancers increased with age at HT and with time post-HT (from respectively 5.2 and 8.9 per 1000 person-years in the first year to 14.8 and 12.6 after 10 years), and was greater among men than women. None of these trends held for lymphomas. Induction therapy other than with IL2R-blockers generally increased the risk of neoplasia except when acyclovir was administered prophylactically during the first 3 months post-HT; prophylactic acyclovir halved the risk of lymphoma, regardless of other therapies. Institution of MMF during the first 3 months post-HT reduced the incidence of skin cancer independently of the effects of sex, age group, pre-HT smoking, use of tacrolimus in the first 3 months, induction treatment and antiviral treatment. Five-year survival rates after first tumor diagnosis were 74% for skin cancer, 20% for lymphoma and 32% for other tumors.

Comparison of the effectiveness of lovastatin therapy for hypercholesterolemia after heart transplantation between patients with and without pretransplant atherosclerotic coronary artery disease.

With the aim of assessing the effectiveness and safety of lovastatin in patients with hypercholesterolemia after heart transplantation, as well as the potential differences in the lipid-lowering effect of lovastatin between patients with or without pretransplant coronary artery disease (CAD), we studied 63 heart transplant patients who had serum total cholesterol > 250 mg/dl in spite of dietary therapy. Mean age of subjects was 47 +/- 2 years. Triple-drug immunosuppressive therapy consisted of cyclosporine, azathioprine, and steroids. Thirty-nine patients (62%) had pretransplant CAD and 24 (38%) did not. Pretreatment serum lipid levels were: total cholesterol, 302 +/- 32 mg/dl; low-density lipoprotein (LDL) cholesterol, 201 +/- 35 mg/dl; high-density lipoprotein (HDL) cholesterol, 60 +/- 19 mg/dl; triglycerides, 205 +/- 86 mg/dl; and total/HDL cholesterol ratio, 5.4 +/- 1.6. Patients received 10 to 40 mg/day of lovastatin (mean dose 17 +/- 6) for 13 +/- 4 months. There were no serious adverse events. At 3 months, lovastatin decreased total cholesterol by 15% (p < 0.001), LDL cholesterol by 21% (p < 0.001), triglycerides by 17% (p < 0.05), and total/HDL cholesterol ratio by 17% (p < 0.001), and increased HDL cholesterol by 3% (NS). Although lovastatin was effective in both patients with pretransplant CAD and non-CAD, analysis of its effect in each subgroup (CAD and non-CAD) revealed that its lipid-lowering effect was higher for non-CAD patients (-20% vs -12% for total cholesterol, and -27% vs -17% for LDL cholesterol, both p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Detection of herpesvirus-like sequences in Kaposi's sarcoma from heart transplant recipients.

BACKGROUND: Herpesvirus-like DNA sequences have been found in lesions from patients with Kaposi's sarcoma in its several forms, suggesting that this tumor may be caused by a new herpesvirus, referred to as Kaposi's sarcoma-associated herpesvirus or human herpesvirus 8. METHODS: We analyzed DNA from skin and lung lesions, healthy skin, and peripheral blood mononuclear cells of three heart transplant recipients with Kaposi's sarcoma. We also studied DNA from normal skin and from peripheral blood of Kaposi's sarcoma-free heart transplant recipients. Samples were analyzed by polymerase chain reaction with specific primers to amplify the KS 330 sequence. RESULTS: The KS 330 fragment was found in Kaposi's sarcoma tissue of all three patients, in normal skin of one of them, and in peripheral blood of two. It was not detected in any of the samples from skin or peripheral blood of heart transplant recipients not affected by Kaposi's sarcoma. DNA extracted from a peripheral blood sample of one patient before transplantation showed that the KS 330 sequence was already detectable at that time. CONCLUSIONS: These findings suggest that Kaposi's sarcoma-associated herpesvirus may play a significant role in the pathogenesis of all forms of Kaposi's sarcoma. The development of the tumor in transplant recipients may be related, at least in some cases, to transplantation-associated immunosuppression, rather than to the acquisition of the virus from the donor.

Efficacy of low-dose OKT3 as cytolytic induction therapy in heart transplantation.

BACKGROUND: The need for prophylactic cytolytic treatment in heart transplantation is a controversial issue. Its use, however, might prevent the onset of cellular rejection in the immediate postoperative period, facilitating patient management. It has recently been suggested that the administration of these products at low doses might have the same immunologic impact and would reduce secondary effects and the cost of treatment. METHODS: In a nonrandomized retrospective study, we assessed 45 consecutive patients who underwent orthotopic heart transplantation in 1992 and 1993. Six patients who died before receiving the complete OKT3 dose were excluded. Twenty-three patients were treated with 5mg/day doses of OKT3 for 7 consecutive days. Another 16 patients received 2.5 mg of OKT3 for 7 consecutive days. RESULTS: There were no significant differences between the two groups with respect to CD3 counts on days 2 (0.1% +/- 0.3% versus 0.04% +/- 0.25%; p > 0.05) and 6 (0.2% +/- 0.45% versus 0.1% +/- 0.3%; p > 0.05), number of rejection episodes (1.45% +/- 0.8% per year of follow-up versus 1.7% +/- 1.2%, p = 0.66), number of infectious complications (8 versus 3, p > 0.05), total methylprednisolone dose used to treat rejection crises (3900 +/- 2765 versus 3600 +/- 1963 mg; p = 0.71), adverse effects attributed to OKT3 (two versus none), or length of the postoperative hospital stay (36.8 +/- 19 versus 30.2 +/- 20.9 days). CONCLUSIONS: As cytolytic induction therapy in heart transplantation, a daily regimen of 2.5 mg of OKT3 for 7 days achieves the same clinical and immunologic effect as the conventional 5 mg/day dose. In addition, it results in a considerable reduction in the cost of treatment.

High incidence of severe infections in heart transplant recipients receiving tacrolimus.

BACKGROUND: Tacrolimus (FK) is being increasingly used as an alternative to cyclosporine (CyA) in heart transplantation (HTx). It is believed to engender slightly more powerful protection against acute rejection. However, the increased immunosuppression could result in an excess of infectious complications. METHODS: Our study compared the incidence of major infections (MInf), defined as life-threatening infectious episodes requiring admission and intravenous (IV) antimicrobial therapy, among a series of HTx recipients treated with either FK (n=30) or CyA (n=84). RESULTS: A total of 21 patients received FK in an elective protocol and 9 patients initially treated with CyA were converted to FK. Tacrolimus was combined with azathioprine and prednisone in 21 cases, and with mycophenolate mofetil and steroids in 8 recipients. After a follow-up between 6 and 37 months, 11 patients (37%) in the FK group developed 13 episodes of MInf, most (85%) occurring during the first posttransplant year. Conversely, CyA patients (n=84), a group with similar characteristics and follow-up, showed a MInf incidence of 12% (P<.05). Among the FK group, the most common site of MInf was pulmonary (69%). A variety of opportunistic agents caused MInf in 54% of cases, whereas the remaining ones were attributed to nosocomial bacteria. There were three deaths (27% of all MInf), all in azathioprine-treated patients with initial FK therapy. CONCLUSIONS: Tacrolimus therapy seems to be associated with an increased incidence of severe infections in HTx recipients. We recommend aggressive diagnostic and therapeutic approaches for patients on FK who develop signs or symptoms of infection in the first year after HTx.

[The heart transplantation in Spain. Organization and results]. / El trasplante cardíaco en España. Organización y resultados.

Heart transplantation has achieved a great development in Spain. With 8 heart transplantation procedures per million of inhabitants per year, we are the second ranking country, after the U.S.A., in this therapeutic activity. A relative adequacy between the number of available donors and the number of receptors included on the waiting list help to reduce the delays and the mortality rates in expecting patients, compare to other countries, which demonstrated the efficiency of the system. From 1984 to 1998, 2,756 heart transplantations were performed in Spain, in 16 authorized hospitals. In 56 cases (2%) the procedures were re-transplantation. Cardiomyopathy with ischemic origin was the most frequent pathology in determining the intervention, affecting to the 37% of the receptors, followed by idiopathic dilated cardiomyopathy with a 35%. Compared to other countries, a high proportion of cardiopathies (11%) of rheumatic origin stands out.20% of the heart transplantations were performed in a maximum emergency situation of the receptors. Assigning donors priority on a national scale. In a 2, 9% of the cases, extra procedures of circulatory assistance devises were used. The actuarial survival of the whole series is 74% at the end of the first year; 62% after five years and 46% after ten years. The mean survival of the grafts was 9.5 years. These data do not differ substantially from those of the Registry of the International Society of Heart and Lung Transplantation. The most important causes of early mortality were the graft primary failure, the infections and the rejection. Among the causes of late morbidity, cancer, with a prevalence of 6,1%, and vascular disease of the graft, present in 8,4% of the receptors, stand out. These results support the so-called Spanish Model for Solid Organ Transplantation, which, according to the health authorities of the European Union, should be implemented in all the member countries. The keys to the success of the Spanish Model are based on three factors, in order of importance: a) to have a public professionalized institution for the detection of donors, the allocation of the grafts, and the coordination of the extraction and transportation force. The Transplant National Organization is the name of this complex force in our country; b) the high rates of road and labour mortality in Spain, and c) to provide incentives for the professionals in charge of the whole process.

[Heart transplantation]. / El trasplante cardíaco.

Heart transplantation is presently the only treatment capable of substantially changing the natural history of endstage heart failure, achieving a 5-year survival rate of 60%. The relative scarcity of available donors is the main limitation to this procedure. The standard surgical technique is that referred to as "orthotopic", described by Shumway and Lower. Research efforts now focus on the design of more efficient methods of preservation that will permit longer storage periods once the grafts have been harvested. Rejection and infection are the most common causes of post-transplantation mortality. The "attenuation" of the immune response to prevent graft loss is achieved by administration of drugs such as cyclosporine A, azathioprine, steroids and antilymphocytic globulins, which constitute the basis for most immunosuppression protocols. Despite numerous proposals of methods for detecting rejection, endomyocardial biopsy continues to be the fastest and most efficient procedure and constitutes a standard tool for monitoring rejection. Graft vascular pathology or chronic rejection is the greatest threat to long-term survival of transplant recipients, 30% of whom are affected by this process after 5 years. Prospects for the future point in three different directions: research to design more powerful and selective immunosuppressive drugs, the development of totally implantable and autonomous artificial ventricular assist systems and the use of xenografts that have undergone genetic manipulations that eliminate interspecies immunological barriers.

[Practice guidelines of the Spanish Society of Cardiology. Cardiac and heart-lung transplants]. / Guías de actuación clínica de la Sociedad Española de Cardiología. Trasplante cardíaco y de corazón-pulmones.

Cardiac transplantation is the only therapy that is able to substantially modify the natural evolution of patients with severe heart failure, along with angiotensin converting enzyme inhibitors. Nevertheless, because of the limited number of donors, its impact is scarce compared to the magnitude of the problem. Up to the end of 1998, 48,541 orthotopic cardiac transplantations and about 2,510 heart and both lung transplantations have been registered throughout the world. In Spain 2,780 procedures have been performed in the last 15 years. The survival expectations for a transplanted patient is 75% after the first year and 60% the following 5 years. The average duration of the graft is 8 years and 6 months. Cardiac transplantation is indicated for young and middle-age patients with irreversible cardiac process in bad clinical condition, with no other possibility of medical or surgical management and with a limited life expectancy. The major debate when choosing this therapy appears with the critical patients, patients older than 65 years, and some patients with systemic diseases. The great demand of transplantation obliges the teams to enlarge the criteria for donors' acceptance. At the same time, the increase of the knowledge about the transmission of some infections, mainly viral, forces to review those criteria day-to-day. The use of different immunosuppressive strategies pursues the control of rejection. The most commonly used is the so-called triple therapy (cyclosporine-azathioprine and steroids). The use of antilymphocytic antibodies such as cytolytic induction treatment is not unanimously accepted. Some of the new immunosuppressive agents such as myphenolate-mofetil and tacrolimus seem to offer advantages mainly due to their greater potency. Since transplantation is a limited procedure, of which its practise has an effect on the whole health system of a country, a perfect planning and adequacy of the Centers is compulsory, as well as the setting-up of clear rules for the use of donors and priority of transplantation. Finally, the patient must be informed clearly and comprehensively at length of the risks, limitations and expectations of these complex procedures.

[Right ventricular arrhythmogenic dysplasia. The role of heart transplantation in its management]. / Displasia arritmogénica ventricular derecha. El papel del trasplante cardíaco en su manejo.

Arrhythmogenic right ventricular dysplasia is a rare disease that usually presents with ventricular arrhythmias and sometimes with heart failure. Rarely symptoms become severe and refractory to conventional therapy. We present the case of a 36-year-old man with this disease who had sustained ventricular arrhythmias and severe right heart failure. Because these symptoms were poorly controlled with medical therapy, cardiac transplantation was finally chosen as definitive treatment. The patient had a favorable course and now leads near-normal life.

[Heart transplantation in a patient with rheumatoid arthritis]. / Trasplante cardíaco en un paciente con artritis reumatoide.

A 56 year-old woman with rheumatoid arthritis was diagnosed with idiopathic dilated cardiomyopathy. She developed progressive heart failure that was refractory to conventional medical management. Heart transplantation was performed bearing in mind the controversy that surrounds its use in patients with a systemic disease. Transplant and rheumatoid arthritis were favorable at 33 month evolution. The immunosuppressive therapy required for the transplant helped the control of her articular disease.

[Experimental endocarditis. Pathological anatomy of human endocarditis]. / Endocarditis experimental. Anatomía patológica de la endocarditis humana.

Experimental reproduction of human endocarditis in animal models has been based on the induction of structural lesions in valve endocardium using different methods. The primary lesion caused in this way is the so called non-bacterial thrombotic endocarditis. Its colonization is then induced by inoculation of microorganisms in the bloodstream. Freedman's modified method has been the most widespread model of this type. It has mainly been performed in rabbits with inoculation of Staphylococcus aureus or alpha-hemolitic Streptococcus. Experimental models of endocarditis have contributed to our knowledge of the pathogenic mechanisms, causative agents and predisposing factors of endocarditis. They have also allowed us to develop appropriate diagnostic, therapeutic and prophylactic measures for its management.

[Dilated cardiomyopathy in infants and children]. / Miocardiopatía dilatada en lactantes y niños.

Three cases of dilated cardiomyopathy manifested at 2, 5, and 13 months of age are reported. The clinical, radiographic, electrocardiographic, echocardiographic and angiocardiographic findings are analyzed. The follow up during 11, 14 and 16 years is described. After several years of the onset, 2 patients recovered a normal cardiac function. The third patient required a cardiac transplant when he was 9 years old, and now, after 2 and a half years, he is healthy, without congestive heart failure. Current references about indications of cardiac transplant in this disease are reviewed. We got the following conclusion: In patients with dilated cardiomyopathy, at least in those who begin before 2 years, the indication and the time of the cardiac transplant have to be established by individual valuation of each case, considering the follow up of the risk's criteria, mainly the congestive heart failure.

[Angina pectoris in the heart transplant recipient: evidence of reinnervation]. / Angina de pecho en el paciente con trasplante cardíaco: una evidencia de reinervación.

Heart transplantation involves the removal of a sick heart together with its innervation and replacement with a donor heart isolated from the control of the autonomous nervous system of the recipient, therefore being, functionally dennervated. Dennervation conditions several alterations in cardiac physiology, such as the inability to experience pain during myocardial ischemia, so that theoretically these patients cannot present angina pectoris. However, several reports have shown evidence of reinnervation with isolated cases of transplanted patients with angina pectoris having been reported. We describe the case of a transplanted patient who showed typical effort angina, vascular disease of the graft and data of sympathetic reinnervation demonstrated by cardiac gammagraphy with metayodo-benzilguanidina-I-123.

[Neurological complications in a series of 205 orthotopic heart transplant patients]. / Complicaciones neurológicas en una serie de 205 trasplantes cardíacos ortotópicos.

INTRODUCTION: A heart transplant is the only effective therapeutic option open to many patients with severe heart failure and performing such an intervention is not free of complications. Little is known about the risk factors for neurological complications after a heart transplant. AIMS: The aim of this study was to identify the risk factors for neurological complications following a heart transplant and, more especially, those associated with epileptic seizures, encephalopathy, cerebrovascular accidents (CVA) and headaches. PATIENTS AND METHODS: We conducted a retrospective review of the records of 205 orthotopic heart transplant patients and collected clinical, haemodynamic and laboratory data before, during and after the intervention, using a standardised protocol. RESULTS: 95 patients (48%) presented neurological complications. Their frequencies were as follows: encephalopathy (16.6%), epileptic seizures (13.6%), neuromuscular disorders (10.6%), headaches (10.6%), CVA (10.1%), psychiatric disorders (2.2%) and infection of the central nervous system (2.2%). The risk factors for encephalopathy were post-transplant renal failure (RR: 4.6; CI 95%: 1.4-15), post-transplant hepatic failure (RR: 5.6; CI 95%: 1.5-22) and pre-transplant haemodynamic instability (RR: 4.3; CI 95%: 1.3-14); for epileptic seizures they were a cardiac index of < or = 2 L/min/m2 (RR: 23.8; CI 95%: 2-247) and extracorporeal circulation time > or = 115 min (RR: 11.3; CI 95%: 1-79); and for CVA the risk factor was post-transplant hepatic failure (RR: 12.9; CI 95%: 2.5-66). CONCLUSIONS: Neurological complications often occur after a transplant and are transient. Perioperative haemodynamic instability giving rise to cerebral ischemia and the metabolic disorders secondary to multiple organ failure are determining factors of encephalopathy, epileptic seizures and CVA.

Genetic testing of candidate genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia.

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a rare cardiac genetic disease characterized by the presence of structural alterations in the right ventricle which may cause ventricular arrhythmias and may induce sudden cardiac death. ARVC/D has been associated with mutations in genes encoding myocyte adhesion proteins. However, only 30%-50% of patients have mutations in these genes. Genetic testing is useful in obtaining a diagnosis, particularly in individuals who do not completely fulfill clinical criteria, thereby also enabling the undertaking of preventive strategies in family members. The main goal of this study was to identify mutations in candidate genes associated with intercalate disks that could be potentially involved in ARVC/D pathogenesis. We analyze a cohort of 14 Spanish unrelated patients clinically diagnosed with ARVC/D without any genetic alteration in all previously known responsible genes. Thus, a genetic screening has been performed in 7 additional potential candidate genes (ACTC1 -actin alpha cardiac muscle 1-, CDHN -cadherin 2 type 1 or N-cadherin-, CTNNA1 -catenin alpha 1-, Cx43 or GJA1 -gap junction protein alpha 1-, MVCL -Metavinculin-, MYL2 -myosin light chain 2- and MYL3 -myosin light chain 3-) by direct sequencing analysis. Our genetic analysis did not identify any disease-causing mutation. Thirty single nucleotides polymorphisms were found, six of them novel. In conclusion, our ARVC/D Spanish cohort has not shown any mutations in the analyzed candidate genes despite their involvement in formation and maintenance of the intercalated disk.

The prognosis of noncutaneous, nonlymphomatous malignancy after heart transplantation: data from the Spanish Post-Heart Transplant Tumour Registry.

INTRODUCTION: Malignancy is a major complication in the management of solid organ transplant patients. Skin cancers show a better prognosis than other neoplasms, but not all others are equal: Ideally, patient management must take into account the natural history of each type of cancer in relation to the transplanted organs. We sought to determine the prognosis of various groups of noncutaneous nonlymphomatous (NCNL) cancers after heart transplantation (HT). METHODS: We retrospectively analyzed the records of the Spanish Post-Heart-Transplant Tumour Registry, which collects data on posttransplant tumors in all patients who have undergone HT in Spain since 1984. Data were included in the study up to December 2008. We considered only the first NCNL post-HT tumors. RESULTS: Of 4359 patients, 375 developed an NCNL cancer. The most frequent were cancers of the lung (n=97; 25.9%); gastrointestinal tract (n=52; 13.9%); prostate gland (n=47; 12.5%; 14.0% of men), bladder (n=32; 8.5%), liver (n=14; 3.7%), and pharynx (n=14; 3.7%), as well as Kaposi's sarcoma (n=11; 2.9%). The corresponding Kaplan-Meier survival curves differed significantly (P<.0001; log-rank test), with respective survival rates of 47%, 72%, 91%, 73%, 36%, 64%, and 73% at 1 year versus 26%, 62%, 89%, 56%, 21%, 64%, and 73% at 2 years; and 15%, 51%, 77%, 42%, 21%, 64%, and 52% at 5 years post-diagnosis, respectively. CONCLUSION: Mortality among HT patients with post-HT NCNL solid organ cancers was highest for cancers of the liver or lung (79%-85% at 5 years), and lowest for prostate cancer (23%).