Apoptosis in heart failure

A characteristic feature of heart failure is the progressive worsening of ventricular function over months or years despite the absence of clinically apparent intercurrent adverse events. The mechanism or mechanisms responsible for this hemodynamic deterioration are not known but may be related to progressive intrinsic contractile dysfunction of residual viable cardiac myocytes, or to ongoing degeneration and loss of myocytes, or both. This report will address the concept of ongoing cardiac myocyte loss that may occur during the course of evolving heart failure viewed from the perspective of apoptosis or "programmed cell death" as the potential mediator of cardiac muscle cell loss. In recent years, several studies have shown that constituent myocytes of failed explanted human hearts and hearts of animals with experimentally induced heart failure undergo apoptosis. Recent studies have shown that cardiac myocyte apoptosis also occurs after acute myocardial infarction, as well as in the hypertrophied heart and the aging heart, conditions frequently associated with the development of heart failure. Considerable work has also been conducted and novel concepts advanced to explain potential molecular triggers of cardiac myocyte apoptosis in heart failure. Although available data support the existence of myocyte apoptosis in the failing heart, questions essential to our understanding of the importance of myocyte apoptosis in this disease process remain unanswered. Lacking are studies aimed at identifying physiological factors inherent to heart failure that trigger myocyte apoptosis. Also lacking are studies that address the importance of myocyte apoptosis in the progression of left ventricular dysfunction. If loss of cardiac myocytes through apoptosis can be shown to be an important contributor to the progression of heart failure, and if factors that trigger apoptosis in the heart can be identified, such knowledge can potentially lead to the development of novel therapeutic modalities aimed at preventing, or at the very least retarding, the process of progressive ventricular dysfunction and the ultimate transition toward end-stage, intractable heart failure.     

Apoptosis in the failing heart

Apoptosis is a tightly regulated, energy-requiring process of programmed cell death. While necrosis is a form of cell death that results from acute cellular injury, apoptosis is controlled autodigestion of the cell that occurs through activation of endogenous proteases. This process results in the cleavage of chromatin into oligonucleosome-length DNA fragments and its multiples. This DNA fragmentation demonstrates a characteristic laddering pattern on DNA agarose gel electrophoresis. The heart undergoes extensive remodeling during embryogenesis wherein apoptosis significantly contributes to the development of the cardiac chambers and correct routing of the great vessels. Pathologic stimuli can also result in apoptosis and include ischemia, hypoxia, inflammation, cytokines, growth factors, and toxic agents. Better understanding of the molecular mechanisms responsible for regulating apoptosis in the failing myocardium may soon lead to strategies aimed at preventing further myocyte loss and enhancing myocyte replacement through regulated cell growth.     

Apoptosis in the failing human heart

BACKGROUND: Loss of myocytes is an important mechanism in the development of cardiac failure of either ischemic or nonischemic origin. However, whether programmed cell death (apoptosis) is implicated in the terminal stages of heart failure is not known. We therefore studied the magnitude of myocyte apoptosis in patients with intractable congestive heart failure. METHODS: Myocardial samples were obtained from the hearts of 36 patients who underwent cardiac transplantation and from the hearts of 3 patients who died soon after myocardial infarction. Samples from 11 normal hearts were used as controls. Apoptosis was evaluated histochemically, biochemically, and by a combination of histochemical analysis and confocal microscopy. The expression of two proto-oncogenes that influence apoptosis, BCL2 and BAX, was also determined. RESULTS: Heart failure was characterized morphologically by a 232-fold increase in myocyte apoptosis and biochemically by DNA laddering (an indicator of apoptosis). The histochemical demonstration of DNA-strand breaks in myocyte nuclei was coupled with the documentation of chromatin condensation and fragmentation by confocal microscopy. All these findings reflect apoptosis of myocytes. The percentage of myocytes labeled with BCL2 (which protects cells against apoptosis) was 1.8 times as high in the hearts of patients with cardiac failure as in the normal hearts, whereas labeling with BAX (which promotes apoptosis) remained constant. The near doubling of the expression of BCL2 in the cardiac tissue of patients with heart failure was confirmed by Western blotting. CONCLUSIONS: Programmed death of myocytes occurs in the decompensated human heart in spite of the enhanced expression of BCL2; this phenomenon may contribute to the progression of cardiac dysfunction.     

Alternatives to heart transplantation

This paper is about the alternatives of curing the drug-refractory heart failure with the exception of cardiac transplantation. It includes even the newest methods mostly being in the phase of animal experiment in the meantime. The authors give a review on the different possibilities of skeletal muscle autotransplantation for cardiac support, such as cardiomyoplasty which has already been done in Hungary too, externally powered mechanical devices for long-term support, molecular and cellular cardiomyoplasty. The partial ventriculectomy and transmyocardial laser revascularization are mentioned as well. Although, most part of the enumerated procedures is not available in Hungary at this time, they are expected to enter the arsenal of medicine in the future.     

Anesthesia for heart transplantation

Heart transplantation, as a therapeutic possibility, has been available since 1992 in Hungary. The authors present the anaesthetic aspects and clinical experiences of this worldwide used therapeutic method. The specialties of the narcosis, the importance of the aseptic techniques, and the treatment of the denervated heart are emphasised.     

Hyperlipoproteinemia in patients after heart transplantation

Hyperlipidaemia is one of the most frequent metabolic disorders after heart transplantation (HTx). The significance of hyperlipidaemia is stressed mainly in relation to graft vascular disease (GVD) which is the leading cause of death more than one year after transplantation. Recently the evidence on the role of hyperlipidaemia (HLP) in the pathogenesis of GVD is growing. Total cholesterol (TC), triglycerides (TAG) HDL-cholesterol (HDL-C) and LDL-cholesterol (LDL-C) were analysed cross-sectionally in 35 patients (30 males), aged 20-64 (median 40) years, more than one year after HTx. In 25 patients HTx was performed because of dilated cardiomyopathy (D-KMP), in 10 because of coronary artery disease (CAD). TC more than 5.6 mmol/l was detected in 29 (83%), TAG > 2.3 mmol/l in 15 (43%), LDL-C >3.6 mmol/l in 28 (80%) and HDL-C < 1.4 mmol/l in 25 (75%) of patients. There were no statistically significant differences in evaluated parameters found between the groups of patients operated on because of CAD and D-CMP, with and without glucose tolerance disorder and groups treated with higher (> 5 mg/D) and lower (.5 mg/D) dose of prednisone. Significant linear correlation of body mass index (BMI) and TAG or BMI and HDL/C resp. was confirmed. Pathogenesis of HLP after HTx is complex. Except of obesity, no unambiguous evidence of the role of glucose tolerance disorder or prednisone dose in immunosuppressive treatment were found. (Tab. 2, Fig. 3, Ref. 21.)     

Indications for heart transplantation

Heart transplantation may have a considerable impact on the fate of the patient in the end stage of heart failure. A successful procedure requires the existence of a sophisticated programme combining the expertise of top departments of cardiology and cardiac surgery working in conjunction with the transplant centre directly responsible for removing the organ. One of the factors playing an important role in a favourable outcome is the correct indication for the procedure. The information on patient selection and criteria for the heart donor, presented in this paper, become increasingly important even for the practitioner in cardiology referring their patients to specialized departments. The paper also offers background information on the heart transplant programme in the Czech Republic suggesting the need for expanding the availability of the therapeutic method in this country.     

Protein catabolism after lung transplantation and heart transplantation

Any surgical intervention is associated with an activation of protein catabolism, the extent of which is dependent on the severity of surgical trauma. There is a paucity of reports on protein catabolism after transplantation of chest organs (lung transplantation (LTX) and heart transplantation (HTX)). The aim of the present study was to quantify and compare the extent of postoperative protein catabolism and associated metabolic perturbations in patients after LTX and HTX. Eighteen consecutive patients after LTX and 15 consecutive patients after HTX who required postoperative intensive care for more than 4 days, constituted the study population. The nitrogen balance (assessed on the basis of the urea nitrogen production rate and nitrogen intake) was assessed retrospectively and correlated with insulin requirements, immunosuppression and the clinical course. Within the first 5 days the nitrogen balance became progressively negative in both groups, reaching a maximum on the 5th day. Thereafter the nitrogen balance of patients following LTX remained negative, whereas the nitrogen balance of patients following HTX tended to improve. The evolution of nitrogen balance significantly differed between both groups (p < 0.01). The mean nitrogen loss was -0.29 +/- 0.17g/kg BW/day after LTX versus -0.22 +/- 0.12g/kg BW/day after HTX. Smaller amounts of glucocorticoids were used for immunosuppression in patients after HTX than in patients after LTX; nevertheless, heart transplant recipients required higher doses of insulin to maintain normoglycemia. A regression analysis revealed that the duration of stay at the intensive care unit (p < 0.001) and the amount of glucocorticoids (p < 0.01) negatively affected the nitrogen balance, whereas an increased protein intake (p < 0.001) exerted a positive effect. Compared to other major surgical procedures, protein catabolism is excessively elevated in patients after thoracic transplantation. Immunosuppressive therapy with glucocorticoids contributes to protein degradation; the nitrogen balance after LTX is more negative than that after HTX because of higher glucocorticoid requirements following LTX. More aggressive nutritional intervention and especially an increased nitrogen intake might help to reduce protein losses in these patients.     

Combined heart and single-lung transplantation in complex congenital heart disease

We present a patient with a history of tricuspid and pulmonary atresia who underwent a classic Glenn shunt and a Potts shunt during childhood, resulting in different right and left pulmonary physiology. Because of progression of cardiopulmonary disease and the fact that the right lung was "protected," the patient underwent combined heart-left single-lung transplantation. The postoperative course was uneventful. Potential early and late advantages of this approach include simplifying of the operative procedure and mitigating the potential effects of obliterative bronchiolitis.     

Clinical experience with heart transplantation in infants

Patients with typical symptoms of biliary tract disease but no gallstones on ultrasonography may benefit from cholecystectomy for presumed chronic acalculous cholecystitis. We retrospectively analyzed the outcome of 50 patients with a preoperative diagnosis of chronic acalculous cholecystitis based upon history (chronic or recurrent, postprandial right upper quadrant abdominal pain), the absence of acid-peptic disease, and normal biliary sonography treated with laparoscopic cholecystectomy (LC) and transcholecystic cholangiography from 1991 to 1996. All patients had preoperative cholecystokinin-stimulated hepatobiliary scintigraphy (CCK-HBS). There were 42 women and 8 men with a mean age of 43 years. CCK-HBS was abnormal in 45 patients (< or = 35 per cent gallbladder ejection fraction or nonfilling of the gallbladder). There was no postoperative mortality and one morbidity (urinary retention). All patients had microscopic evidence of chronic cholecystitis. At mean follow-up of 30 months, (range, 7-62 months) 39 patients (78%) were free of abdominal pain. Thirty-five of 45 patients with abnormal CCK-HBS were pain free (positive predictive value, 0.78). Four of five patients with normal CCK-HBS were pain free (negative predictive value, 0.20). The positive and negative likelihood ratios for CCK-HBS were 0.99 and 1.13, respectively, confirming that this test was not useful for predicting benefit from LC. Seven patients with persistent right upper quadrant pain had abnormal postoperative sphincter of Oddi manometry; they improved after endoscopic sphincterotomy. Patients with symptoms typical of biliary colic with normal gallbladder sonography and absence of acid-peptic disease benefit from LC in the majority of cases. Those who remain symptomatic after LC may benefit from endoscopic retrograde cholangiopancreatography with sphincter of Oddi manometry and endoscopic sphincterotomy when manometry is abnormal.     

The role of gender in heart transplantation

The position of chief information officer (CIO) is gaining popularity, especially in the health care field. The results of an informal electronic and telephone survey indicate that few medical librarians have made a career move to CIO even though this might seem like a logical step. This paper examines the qualities required of an effective information management executive, the role CIOs play within organizations, and the career advancement strategies for librarians interested in becoming CIOs. Questionnaire responses are reported from three medical librarians who have made the transition to CIO-type positions, and a case study illustrates the responsibilities of CIOs in health care organizations.     

Aortic mismatch in heart transplantation: readaptation

Great vessel mismatch between donor and recipient is very usual in heart transplantation. Different procedures have been used to manage this situation. A tailoring aortoplasty is described, as a technical alternative, in cases of considerable size incongruence between donor and recipient aortic diameters.     

Psychological aspects of heart transplantation

The aim of our work was to stress the role of some psychologic and psychosocial factors participating significantly in the emotional experiencing, in the period before and after heart transplantation, respectively. The uniqueness of the patients personality is emphasized with the aim to sensitively and competently help them to improve their experiencing and quality of life. The author tried to acquaint the general health public with various approaches to this very complex problem. Main interest was focused on the predictors of successful heart transplantation, the criteria and contraindications of HTx, the waiting period for transplantation. The problems of depression, anxiety, denial, noncompliance and the selection of appropriate coping mechanisms--which are the most frequently occurring psychological factors directly influencing the behaviour and experiencing of the patient--HTx candidate were presented. In conclusion specific problems of HTx (the approach to the patient when informing him about the necessity of HTx and the relations of patients with the donor family) are discussed. (Tab. 2, Fig. 4, Ref. 34.)     

Psychiatric aspects of heart transplantation

This article, part of a series on organ transplantation, will review psychiatric aspects of heart transplantation, starting with a brief summary of medical aspects. The authors then review psychiatric symptoms and syndromes frequently encountered pre-, peri-, and posttransplantation; the selection of candidates; and treatment of psychopathology.     

Hematologic aspects of heart transplantation

Heart transplantation is an accepted therapeutic method for end-stage heart failure. The aim of the presented paper is to provide a short review of haematologic problems of heart transplantation. Haemostatic disorders, cytopenias and lymphoproliferative diseases are the most frequent haematologic complications of this highly sophisticated procedure. Perioperative bleeding tendency is due to cardiopulmonary bypass, both qualitative and quantitative platelet disorders and hyperfibrinolysis are the main causes. Incidence of cytopenias (mono- and/or bi- and/or tricytopenia) reaches up to 70%. They are multifactorial as to etiology and coincidence with viral infection, antimicrobial and immunosuppressive therapy. Lymphoproliferative disease affects about 1.2% of patients during the first year after transplantation. Posttransplant lymphoproliferative diseases are highly variable as to manifestation and prognosis-ranging from indolent course to rapid, aggressive growth. Routine cytostatic therapy is generally ineffective. Crucial therapeutic measure is to turn off immunosuppressive therapy. (Tab. 3, Fig. 2, Ref. 41).     

Chylous ascites following heart transplantation

BACKGROUND: Hepatocellular carcinoma is highly refractory to most chemotherapeutic agents. Clofazimine, a riminophenazine compound used to treat leprosy since 1962, inhibits various cancer cell lines, including hepatocellular carcinoma cell lines, via phospholipase A2 dependant processes. Clofazimine also inhibits p170-glycoprotein, the mdr1 gene product. PATIENTS AND METHODS: Thirty patients (26 males and four females) with unresectable (25) or metastatic (5) hepatocellular carcinoma received oral clofazimine 600 mg daily for two weeks, followed by 400 mg daily until progression or death. RESULTS: There were three responses (10%)--one of a soft tissue metastasis, and two of local disease, with 13 patients disease stabilizing for up to 20 months. The overall median survival was 13 weeks. Adverse events included hyperpigmentation, eczematous skin rashes and palpitations. CONCLUSIONS: Although only three patients had an objective response (10%), the 13 patients with stable disease for up to 20 months, and an overall median survival of 13 weeks, suggest that clofazimine, or other riminophenazine compounds may prove to be of value in hepatocellular carcinoma.