| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Ann Thorac Surg 1997;64:1661-1668
© 1997 The Society of Thoracic Surgeons
Deutsches Herzzentrum Berlin, Klinik für Herz-, Thorax- und Gefässchirurgie, Berlin, and Medizinische Hochschule Hannover, Hannover, Germany
 |
Abstract |
|---|
 TopFootnotes Abstract IntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
|---|
Patients and Methods. Seventy-seven of 182 patients who received transplants between July 1983 and January 1988 in Hannover (1983–1985; n = 69 patients) and Berlin (1986–1988; n = 113 patients) have survived up to now, 9 to 13 years after transplantation (mean, 10 years 4 months). The patients and their medical records (eg, cardiac catheter studies, echocardiography) were examined to assess their somatic status. Psychologic, social, and occupational status and quality of life data were assessed by combination of self-rating questionnaires (the Short Form Health Survey Questionnaire, Giessener Beschwerdebogen [the Giessen Subjective Complaints List], the Sickness Impact Profile, and the Hospital Anxiety and Depression Scale) and semistructured interviews.
Results. Ninety-one percent of the patients were in New York Heart Association functional class I (70%) or II (21%). The results of the psychologic investigation revealed a definite impact of the side effects of chronic immunosuppression; however, overall, the quality of life rating was within the normal range. Sixty-seven (86%) patients were married, 51 (66%) patients were retired, 17 (22%) worked full-time or part-time, and 9 (12%) were housewife or houseman. Four male patients have fathered five healthy children 1 to 10 years after the transplantation. More than 75% of the patients had normal systolic ventricular function (mean left ventricular ejection fraction, 0.63). Coronary angiograms were normal or with minor wall irregularities in 86% (n = 66 patients), and revealed severe obstructions in 14% (n = 11). Normal function of all valves was found in one-third of the patients, tricuspid valve incompetence was not found or was insignificant in 87% (n = 67 patients) and severe in 8% (n = 10). Six patients had undergone tricuspid valve replacement, invariably for structural valve defects attributable to biopsy injuries. Fifty-eight patients (75%) exhibited various degrees of compensated renal insufficiency, 7 of them were on chronic hemodialysis, and 2 patients have undergone kidney transplantation. Hepatic function was normal in 68% (n = 52) of the patients, and 1 patient has developed liver cirrhosis. Osteoporosis was diagnosed of the discrete form in 7 (9%) and of a significant degree in 24 patients (31%); 38.5% (n = 30) complained of symptoms of polyneuropathy.
Conclusions. The patients surviving 9 to 13 years after orthotopic heart transplantation are mostly in good physical status, the quality of life is comparable to the general population, and only a few of them have significantly limited in their life style. They do show the substantial chronic side effects of long-term immunosuppression, remaining treatment-dependent for a lifetime.
|
Introduction |
|---|
|
TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
|---|
During the recent decade, heart transplantation has become a well-established treatment modality for end-stage heart disease. The Registry of the International Society for Heart and Lung Transplantation has included data on 30,297 heart transplant procedures reported through February 15, 1995, with a present annual rate of some 3,000 operations, which constitute the vast majority of transplant cases worldwide [1]. Mid- and long-term survival rates for all patients and for subgroups of many aspects have been calculated from the data of the Registry and from single center experience. However, except for a few chance reports on patients living longer periods after the transplantation [2], there are very few publications dealing with the somatic, psychologic, social, and occupational status of patients living long term [3–6]. This report includes data obtained from 77 patients transplanted between July 1983 and January 1988 who have survived up to now, 9 to 13 years after transplantation.
|
Patients and Methods |
|---|
|
TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
|---|
There has been a complete follow-up of all patients with a mean of 10 years 4 months, and none has been lost to follow-up. Data acquisition was facilitated by the fact that the majority of patients were followed in the outpatient departments of Berlin or Hannover, as well as those departments with continuing cooperation with our transplant center (departments of internal medicine in Duisburg, Ludwigsburg, and Kaiserslautern). Three patients who live in other countries were visited by our investigation team for the examinations reported in this study.
At the time of transplantation, the entire group of the first 182 transplanted patients (groups A and B together) consisted of 152 male patients and 30 women. The ages ranged from 3 months to 64 years (mean, 43.3 years). Indication for transplantation were dilated cardiomyopathy of various origin in 112 patients (61.5%), ischemic cardiomyopathy in 60 (33%) with 16 patients having previous coronary bypass operation, valvular disease in 9, and congenital heart disease in 1 patient.
The actuarial survival curve of the entire group of 182 patients indicated a 1-year survival rate of 71%, 5-year survival of 60%, 9-year survival of 46%, 10-year survival of 42% and 12- and 13-year survival of 40% (Fig 1
). The respective figures for the groups A and B were 78% and 67% at 1 year, 61% and 59% at 5 years, 43% and 47% at 9 years, and 38% and 45% at 10 years, respectively (log-rank test for the survival curves, p = 0.69). From the entire group of the first 182 patients (groups A and B together) transplanted between July 1983 and January 1988, 77 patients (42%; 61 men and 16 women) are presently alive and these 77 patients are the subject of this investigation.
|
Operative Technique
All operations were performed according to the standard technique of Lower and Shumway [8, 9] with the modified incision of the right donor atrium for the anastomosis [10]. The donor hearts were arrested with 2,000 or 3,000 mL of cold Bretschneider cardioplegic solution, which was infused initially at a pressure of 80 to 100 mm Hg until cessation of the heart contractions and subsequently by gravity over a 8- to 12-minute period.
Immunosuppression and Rejection Monitoring
Immunosuppression consisted of a high dose of cyclosporine A monotherapy in the first 24 patients, which then was followed by various regimens of triple immunosuppression including cyclosporine A, azathioprine, steroids, and inductive cytolytic treatment. Follow-up investigations included routine transvenous endomycardial biopsies according to a regimen of weekly visits for the first 3 months, subsequent protracted intervals up to 3 months and, finally, 6 months in the long-term follow-up. During 1986 the routine use of telemetric surveillance of the endomyocardial electrogram was instituted, which, however, in this early group did not have a significant impact on the number of biopsies. During the later years these tapered to only the occasional invasive investigation [11, 12].
Measurements and Data Collection
Details of cardiac functions were derived from routine, yearly cardiac catheter studies including left ventricular and coronary angiography. The left ventricular function values were calculated from the catheterization data from the last year, or, if the catheterization examination was older than 1 year, from the most recent echocardiographic examination performed within the last year. Valvular functions were assessed by the last echocardiography. The catheter studies performed in the last year were available in 46 patients. In 27 patients the last catheter studies dated back to 2 years and in 4 patients up to 4 years.
The relevant follow-up medical data were considered extensively, such as the present data on immunosuppressive and other chronic medications, renal and hepatic function, concomitant diseases such as diabetes mellitus and thyroid dysfunction, and characteristic side effects of chronic medication such as osteoporosis, polyneuropathy, and tumors. Information has been compiled on surgical procedures of various kinds that the patients had undergone since transplantation.
Psychologic, social, and occupational status and quality of life data were assessed by a combination of self-rating questionnaires and semistructured interviews. All patients received four questionnaires, and in addition, all of them were interviewed by a specialized psychiatrist actively involved in the care of heart transplant patients (WA). The interviews focused extensively on the psychologic, psychosocial, and occupational status, for example, all domains of health-related quality of life were evaluated. The following four tests were applied: the Short Form Health Survey Questionnaire, Giessener Beschwerdebogen (the Giessen Subjective Complaints List), the Sickness Impact Profile, and the Hospital Anxiety and Depression Scale. The 36-item Short Form Health Survey Questionnaire is an instrument for measuring general health concepts referring to the most important quality of life domains [13]. Giessener Beschwerdebogen allows assessment of subjective suffering from symptoms [14]. The Sickness Impact Profile assesses the impact of sickness on daily activities and behavior of patients [15]. The Hospital Anxiety and Depression Scale evaluates the extent of anxiety and depression [16].
Statistical Analysis
Long-term survival was calculated by the Kaplan-Meier method and compared with the log-rank test. The Student's t test was used for assessment of differences between the mean values for the domains of the quality of life tests. A value of p less than 0.05 was considered to be significant.
|
Results |
|---|
|
TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
|---|
). At present, 2 patients from the group of children and adolescents younger than 16 years (33% of the whole group) are alive. Ten (56%) of the young adults, 54 (41%) of the middle-age adults (30 to 55 years), and 11 (41%) of the older patient group (>55 years) have also survived up to now. Seventy-seven patients have been living longer than 9 years, 48 longer than 10 years, 25 longer than 11 years, and 12 more than 12 years. The longest living patients just recently (January 25, 1997) completed 13 years after transplantation.
|
Cardiac Function
LEFT VENTRICULAR EJECTION FRACTION.
Mean left ventricular ejection fraction for the entire group was 0.63 ± 0.12 (Table 1). This indicates that systolic ventricular function remained normal in more than three fourths of the patients and was severely depressed in only 2 patients.
|
). This finding, however, is limited by the fact that in 31 patients the angiographic studies date back to between 1 and 4 years.
|
). The most prominent site of cardiac valve incompetence was the tricuspid valve. It showed incompetence of various degrees in two-thirds of the patients, yet was insignificant or minor in most (87%). Using the grading scale of valve incompetence from grade 0 to IV, no tricuspid valve incompetence (grade 0) was found in 26 patients (34%), grade I in 28 (36%), and grade II in 13 (17%). Tricuspid valve incompetence of grade III was found only in 9 patients (12%) and valve incompetence of grade IV was identified only in 1 patient (1%). Six patients had undergone tricuspid valve replacement, invariably for structural valve defects due to biopsy injuries.
|
SECONDARY CARDIAC INTERVENTIONS.
As mentioned, 6 patients had undergone tricuspid valve replacement, invariably for structural valve defects due to biopsy injuries. The other procedures were aortocoronary vein bypass graft in 1 patient, percutaneous transluminal coronary angioplasty alone in 5, and percutaneous transluminal coronary angioplasty combined with stent implantation in 2 patients. One patient had been subject to another heart transplantation 4.5 years after the primary transplant in 1987.
Present Medication
The majority of the patients (75%) continue to take the standard triple immunotherapy consisting of cyclosporine A, azathioprine, and steroids, and another 20% take cyclosporine A combined with steroids. Only 5% are not taking steroids. The mean doses of the immunosuppressive drugs at the time of the examination were (standard deviation) 201 ± 71 mg/day (range, 77 to 400 mg/day) for cysclosporine A, 6 ± 3.1 mg/day (range, 1.5 to 20 mg/day) for steroids, and 60 ± 40 mg/day (range, 4 to 150 mg/day) for azathioprine. All patients are on antihypertensive drugs, mostly angiotensin-converting enzyme inhibitors, allopurinol, and almost all take diuretics.
Renal Function
Twelve patients have no indication of renal dysfunction, 58 have various degrees of compensated renal insufficiency with a mean (standard deviation) serum creatinine level of 2.09 ± 1.5 mg/dL. Slightly elevated serum creatinine (<1.5 mg/dL) was found in 23, and more than 1.5 mg/dL in 35 patients. Seven patients are on chronic hemodialysis and 2 patients have undergone kidney transplantation in 1986, 1 and 2 years after heart transplantation, respectively.
Hepatic Function
In 68% of the patients normal liver function laboratory findings were obtained, the others display minor to moderate elevation of liver enzymes, and 1 patient has developed liver cirrhosis. Hepatitis B was identified in 3 patients and hepatitis C in 6 patients.
Associated Diseases
Diabetes mellitus is present in 9 patients, 2 of whom take insulin. Multinodular goiter was found in 6 patients and 2 have signs of hyperthyroid disease. Radiologic studies revealed osteoporosis of the discrete form in 7 patients (9%) and of a significant degree in 24 patients (31%). The other patients were free from this sequelae. Sixteen patients had suffered spontaneous bone fractures of various localization. Tumors were found frequently; benign skin tumors in 2 patients and malignant or potentially malignant tumors in 18 patients. Three patients have other malignancies. A substantial proportion of the patients (38.5%) have complaints relating to symptoms of polyneuropathy.
Noncardiac Surgical Procedures
Major operations for a variety of noncardiac diseases and organ localization were performed occasionally during the follow-up period. This includes major vascular (aortic, carotid, and peripheral) procedures in 7 patients, abdominal visceral operations in 9, and other operations (hip replacement, thyroid resection, etc.) in 3 patients.
Social and Occupational Status
The marital status of the patients shows that a high proportion of patients are married (86%) and only few (5%) are single or divorced (9%). Four male patients have fathered five healthy children, 1 to 10 years after the transplantation. Retirement, combined with full activities, is enjoyed by 51 (66%) of the patients, 17 (22%) are working full-time or part-time, and 9 (12%) are occupied as housewife or houseman.
HEALTH-RELATED QUALITY OF LIFE.
The results of the Short Form Health Survey Questionnaire are depicted in Figure 3. For comparison the respective values obtained in the various health concept domains from a representative United States sample population are also shown. Statistically significant differences were seen in four of eight domains of the test: physical functions, role functioning limited by physical impairment, bodily pain, and general health. The scores of these patients were inferior in comparison to the healthy probands. The question as to how the patients estimate their overall health (1 of the 36 questions) were answered with "good to excellent" by 79% patients, "less good" by 14%, and "bad" by 7%. As assessed by the Giessener Beschwerdebogen, the four most frequent complaints were (in order of frequency) bone and joint pain, back pain, oversensitivity to cold, and hirsutism. The influence of being a heart transplant patient with regard to quality of life was assessed by the Sickness Impact Profile. When compared with the general population, the results were insignificant for most of the subcategories except for "work behavior" and "recreation and pastimes." However, the overall score of dysfunction in all subcategories was within the normal range (Fig 4). The Hospital Anxiety and Depression Scale in the transplant patients was compared to the established values in a healthy German sample population [17] and a group of German heart disease outpatients; the anxiety data did not differ significantly within the three groups with a maximum found in the heart disease patients (Fig 5). In contrast, depression scaled highest in the transplant cohort, reaching statistical significance when compared with the healthy probands (Fig 5).
|
|
|
|
Comment |
|---|
|
TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
|---|
Heart transplantation has been established as a promising treatment modality for patients with terminal heart failure for whom both life expectancy and quality of life have been reduced to a minimum. Hardly any other treatment of a life-threatening disease has a similarly dramatic impact on both these categories as heart transplantation. However, only a limited number of the patients needing this treatment can be transplanted due to the specific limitations of donor organ availability and specialized center capacity. Having an extraordinary public interest, this operation has raised many questions regarding the long-term outcome both in terms of lifetime gain and quality of life. Viable answers to these questions are imperative, particularly in a health-care reimbursement system such as exists in Germany, where substantial costs of such treatment have to be carried by the entire population.
Survival in our patient group is favorably comparable with the data given in the Internation Society for Heart and Lung Transplantation Registry [1], indeed a few percent points better, probably due to very close follow-up of all our patients that was performed in most cases by our outpatient department or in some cases by several cooperating departments spread across the country in which the same diagnostic and treatment regimens have been applied.
In contrast to short-term heart transplant survivors where rejection and infection play a dominant role in mortality and morbidity, the predominant causes in long-term survivors are coronary artery disease with a consecutive cardiac event [4, 18–20] and side effects of immunosuppressive medication [4]. The therapy that enables the transplant patients to attain extended posttransplant times causes the very problem in this period [21]. The side effect of individual immunosuppressive agents, such as nephrotoxicity with consecutive arterial hypertension, hepatotoxicity, hirsutism, neurotoxicity caused by chronic cyclosporine A therapy, or cushingoid habitus, glucose intolerance, and osteoporosis as sequelae of corticosteroids mark the late posttransplant period [4, 18, 19, 21, 22]. Osteoporosis leading to vertebral collapse and vascular necrosis of the hip and other weight-bearing joints has become one of the leading causes of disability in this phase [21]. As expected, the consequence of permanent immunosuppressive medication and its side effects were observed in many patients and some had undergone secondary significant treatment such as chronic dialysis, renal transplant, and treatment of fractures and tumors. Still, although repeatedly requested by several of our long-term surviving patients, withdrawal of immunosuppression has not been justified up to now.
Graft atherosclerosis is the major limiting factor for long-term survival. Patients with angiographic evidence of coronary artery disease define a high-risk group for subsequent cardiac events. The rate of cardiac events increases markedly after a period of time. Sudden death during the late period is mostly a sequela of unrecognized myocardial infarction [18]. The reported incidence differs between 5% at 1 year and as high as 70% within 7 years after transplantation [3–5, 18, 19, 21, 22]. Graft atherosclerosis seen in the angiograms developed in a significantly stenotic form in less than 15% of our patients. This, of course, does not qualify to estimate the real degree of the usually diffuse and peripheral nature of chronic graft disease. A substantial proportion of patients can have a cardiac event but with no evidence of coronary artery disease in angiographic examination [19]. Therefore, more adequate methods, such as the intravascular ultrasound, have been introduced only recently and will allow a more precise judgment of this most important long-term transplant sequela once all the patients have undergone this type of study. More important, however, it becomes obvious that in the later period after heart transplantation a certain degree of immunologic tolerance toward the graft had developed with complete disappearance of acute rejection and only slow, if at all, progression of chronic vascular changes.
Most of our patients indicated a very good physical work ability, confirmed by a high proportion of asymptomatic patients (70%) or with only minor limitations (New York Heart Association functional class II in 20%). This corresponds with the mostly well-preserved left ventricular systolic function as expressed by normal left ventricular ejection fraction in 76% and moderate left ventricular ejection fraction impairment in 21% of our patients, which corresponds well with the reported results [3, 4, 21, 23]. Although this introduces a methodical inconsistency, the data document the obviously minimally destructive influence of acute rejection episodes and atherosclerotic coronary artery changes in the great majority of these hearts after many years. Quite certainly, diastolic function will show more discrete changes, which are presently being considered in ongoing studies.
Tricuspid incompetence, which has been found at a high rate by several other groups [24–26], was now present in two-thirds of our patients; however, only in a very small proportion had this valve dysfunction reached a significant degree. The patients who had undergone tricuspid valve replacement for severe incompetence invariably had displaced structural damage to the valve components as a result of biopsy injury. Therefore, we have continued to apply the original atrial anastomotic technique. Thus, together with the almost complete elimination of cardiac biopsy and the adherence to noninvasive rejection monitoring using telemetry of electrophysiologic parameters [11, 12], we believe that significant tricuspid incompetence can be avoided.
A disproportionately high number of the patients are married and only a few live single or are divorced. This fact may be related to the better care within a family and to the higher compliance of patients with social obligations. The present work status of the patients shows a high proportion of retired persons, and only one-fifth of the group are working full or parttime. The discrepancy of early retirement and full physical ability must be looked at in the light of a dense social insurance network such as in Germany.
The greatest effort of this study was invested to elucidate the psychologic and psychosocial situation of the patients, both by asking the patients to fill out defined test questionnaires and an extended interview conducted by a professional psychiatrist. This interview was ranked at high value to make sure that the self-rating answers of the questionnaires could be confirmed. The applied tests were selected according to our vast experience in psychologic care for large groups of patients before and after heart transplantation and such patients on mechanical assist devices [27]. The results of the psychologic investigation revealed a definite impact of the side effects of chronic immunosuppression. This holds true for all four domains where the patients estimated their well-being as inferior in comparison to the U.S. sample population and which are all related to somatic qualities. However, when rating overall quality of life (Sickness Impact Profile), this was still within the normal range. When looking at the intensity of anxiety, which surprisingly was stated not higher in comparison to healthy probands, we would assume a certain amount of denial as a coping mechanism. Depression, in contrast, was significantly elevated when compared with healthy persons. This, we believe, has to be seen in conjunction with the uncertain outlook toward life. Most remarkable, coming to terms with the fact of living with a heart of another person obviously has been overcome by most of the patients. This fact may, however, regain vital importance when brought back to the patients through their social interactions, for example the refusals of potential parents-in-law to give their permission to the marriage of their daughter with an otherwise fully working, asymptomatic young male heart transplant recipient.
Now, as longer times of survival after heart transplantation have been attained, several questions have to be considered regarding the further fate of these patients. The most important question certainly is what the life expectancy will be once the patients have reached 10 years of new life. This question is most significant for those patients requiring transplantation during childhood or early adult life, with respect to establishing partnerships and families, the ability to earn a living, and fulfillment of personal life concepts in general. When extrapolating both the survival curves of the International Society for Heart and Lung Transplantation [1] and our experience [7], one would arrive at a maximum survival time of approximately 18 to 20 years. Because this estimate, however, does not take into account the normal age-related life risks and the impact of newly emerging therapy concepts, we tend to assume a longer future, at least for these young patients. Thus, our policy has been to advise these patients in a more optimistic fashion.
|
Acknowledgments |
|---|
|
TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
|---|
|
Footnotes |
|---|
|
TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
|---|
Address reprint requests to Prof Hetzer, Deutsches Herzzentrum Berlin, Klinik für Herz-, Thorax- und Gefässchirurgie, Augustenburger Platz 1, D-13353 Berlin, Germany.
|
References |
|---|
|
TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
|---|
Related Article
This article has been cited by other articles:
|
|
 |
|
  B. H.A. von Rahden, H. J. Stein, G. Schmidt, H. Bartels, M. Overbeck, and J. R. Siewert Esophageal Cancer Surgery in Heart Transplant Patients Ann. Thorac. Surg., October 1, 2005; 80(4): 1510 - 1512. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. M. Mueller Drug immunosuppression therapy for adult heart transplantation. Part 1: immune response to allograft and mechanism of action of immunosuppressants Ann. Thorac. Surg., January 1, 2004; 77(1): 354 - 362. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Wilhelmi, K. Pethig, M. Wilhelmi, H. Nguyen, M. Struber, and A. Haverich Heart transplantation: echocardiographic assessment of morphology and function after more than 10 years of follow-up Ann. Thorac. Surg., October 1, 2002; 74(4): 1075 - 1079. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. John, H. A. Rajasinghe, J. M. Chen, A. D. Weinberg, P. Sinha, D. M. Mancini, Y. Naka, M. C. Oz, C. R. Smith, E. A. Rose, et al. Long-term outcomes after cardiac transplantation: an experience based on different eras of immunosuppressive therapy Ann. Thorac. Surg., August 1, 2001; 72(2): 440 - 449. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Drews, M. Loebe, E. Hennig, F. Kaufmann, J. Muller, and R. Hetzer The 'Berlin Heart' assist device Perfusion, July 1, 2000; 15(4): 387 - 396. [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ANN THORAC SURG | ASIAN CARDIOVASC THORAC ANN | EUR J CARDIOTHORAC SURG |
| J THORAC CARDIOVASC SURG | ICVTS | ALL CTSNet JOURNALS |
