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Outcome of Exercise Electrocardiography in Familial Amyloidotic Polyneuropathy Patients, Portuguese Type, Under Evaluation for Liver Transplantation

Posted on: Sunday, 31 October 2004, 03:00 CST

KEY WORDS: amyloid neuropathies, familial, heart disease, ischmie, electrocardiograph}*, exercise, liver transplantation

ABBREVIATIONS: ECG= electrocardiograph)': FAP=Jamilial amyloidotic poly neuropathy: PND score = polyneuropathy disability score: TTR = transthyretin

Abstract

Familial amyloidolic polyneuropathy (FAP) is a dominantly inherited systemic amyloidosis caused by mutated transthyretin (TTR). Liver transplantation is currently the only available treatment that halts the progress of the disease. Cardiovascular complications are common in FAP, and cardiac arrhythmias are typical complications in FAP Val30Met. For patients with late onset FAP, as the Swedish patients, coronary heart disease has been found in several patients, and a QS complex is not an uncommon finding in FAP- patients ECG raising the suspicion of coronary heart disease. The aim of this study was to evaluate exercise ECG in FAP patients before transplantation with regard to mortality and morbidity. Thirty-eight FAP patients who underwent examination by exercise ECG, as part of the evaluation for liver transplantation were included in the study. Of these, 30 patients were transplanted, and the surviving patients were followed for at least 2 years. Exercise ECG was performed on bicycles with standard 12 leads. Nonparametric statistical analyses were used in all calculations.

Six patients died 0-5.5 years after transplantation. They were older than the survivors (p < 0.01), but their duration of disease did not deviate from that of survivors (p = 0.8). They were also less able to increase their heart rates during exercise than the survivors (p < 0.05). For all transplanted patients, a significant relationship was found between patients ' increase of heart rate, blood pressure and maximal workload, and the duration of disease and also for the PND-score, signifying that the outcome of exercise ECG predominantly was related to the patients autonomie and motor function, and not to their heart function.

Introduction

Familial amyloidotic polyneuropathy, Portuguese type (FAP), is a rare autosomal dominantly inherited systemic amyloidosis caused by mutated transthyretin (TTR) in which valine is exchanged for methionine at position 30 (ATTR VaBOMet). More than 100 amyloidogenic mutations of TTR are known of which ATTR Val30Mct is the most common and most studied neuropathic form of TTR amyloidosis.' TTR is normally a tetramer functioning as the carrier for thyroid hormone and retinol binding protein. It has been suggested that separation of TTR into monomers is required for amyloid formation, and that the monomer undergoes conformational changes and thereafter assembles into amyloid fibrils.2

FAP is characterized by a progressive neuropathy complicated by cardiac, gastrointestinal and kidney impairment, leading to death for Swedish patients within 12 to 13 years after onset.3,4 The first symptoms usually emanate from the peripheral nervous system, where amyloid infiltration and destruction of the nerves are observed. Amyloid also infiltrates other organs such as the gastrointestinal tract, the kidneys and the cardiovascular system.4-6 Visual impairment caused by amyloid deposits in the corpus vitrium is often noted.7 The gastrointestinal disturbances, such as constipation and later diarrhea lead to fecal incontinence and the patients develop a marked malnutrition.3 The kidney dysfunction is caused by amyloid deposits in the kidneys and also by bladder dysfunction with urinary retention.8,9 Cardiovascular complications are common and even though cardiomyopathy is observed, the main complication in FAP is arrhythmia attributed to conduction disturbances due to amyloid infiltration of the conductive system.10 Syncope and sudden death have been observed in FAP patients, and pacemaker treatment is often needed.4'11'12 Abnormal resting ECG was recorded in 87% of Portuguese FAP-patients, and QS pattern in V1-V3 and low voltage was the most frequent findings." In an elderly FAP-population such as the Swedish, QS pattern raises the suspicion of coronary heart disease. Exercise ECG is routinely used to diagnose ischmie heart disease, but the findings on exercise ECG in FAP patients has not been reported.

TTR is primarily produced by the liver, and currently liver transplantation is the only available treatment that seems to halt the progress of the disease.13 The first liver transplantation on a FAP patient was performed in Sweden in 1990,14 and up to the present approximately 60 patients with FAP have been transplanted in Sweden. However, liver transplantation is a major surgical procedure that carries a considerable risk. Circulatory instability some with fatal outcome has been reported and appears to be caused by autonomie disturbances.15 The finding of QS-pattern on ECG has often raised the suspicion of coronary heart disease, and necessitated further investigations.

All transplant candidates since 1992 have been subjected to resting and exercise ECGs to disclose exercise induced arrhythmias and ischmie heart disease. However, the outcome of an exercise ECG test is dependent not only on the heart function but also on the autonomie regulation of the heart and blood pressure, the lung function, and the patients muscle strength.

The aim of this study was to evaluate the value of exercise ECG in FAP patients as a part of routine investigation of patients submitted for liver transplantation.

Patients and methods

Patients

Thirty-eight FAP-patients between 1992 and 2001 have undergone exercise ECG examination as a part of the routine investigation program before liver transplantation. All were included in the study. Of these, 30 patients had liver transplantations and were followed for 2 years or longer after transplantation (Table 1). The remaining 8 patients were not accepted or submitted for transplantation for the following reasons: 3 patients declined transplantation after information on the procedure and the risk involved. Three patients were not accepted, because of advanced disease (1 patient) or previously known coronary heart disease and heart infarction (2 patients), and 2 patients because of an unusual slow progressing disease, and relatively advanced age.

Table 1. Clinical data of transplanted patients

The diagnosis of FAP was in all cases substantiated by the finding of the ATTR Va30Met mutation and the presence of amyloid deposits in intestinal biopsies or subcutaneous fat.

All patients were evaluated by resting and exercise ECGs, 24-h Holier electrocardiography, echo-Doppler cardiography and lung function tests (Table 1). The outcome of the investigations were not re-examined for the study, thus the interpretation of the results are those obtained from the laboratory of clinical physiology according to routine laboratory practice.

Resting and exercise ECG examination

The examinations were performed according to the standard procedures at the Umc University Hospital.16 The exercise testing was performed on bicycle. Standard 12 leads ECG were recorded with an increase in workload by 10 watts each minute. Blood pressure and heart rate were measured before exercise (after 10 min lying down), and repeatedly during work, and at maximal workload. The test was interrupted if the patient was unable to carry on due to exhaustion or chest pain, or if the examiner noted ECG changes or fall of blood pressure. The term block was used for atrio-ventricular block (AV- block) and/or sino-atrial block (SA-block). Arrhythmia was designated for ventricular extra-cystoles and ventricular tachycardia during exercise. The interpretation of ECG changes suggestive of ischemia on resting and exercise ECG was evaluated by the examining doctor of the Department of Clinical Physiology according to defined standard criteria, 17,18 and the result expressed as suspect or definitively abnormal.

Twenty-four hours hotter ECG recording

Continuous ambulatory 24-h ECG recordings were performed by a standard recorder unit (Tracker II, Reynolds Medical Ltd, UK, or Braemer DL 700, Braemer Inc. Burnsvillc, MN, USA). The patients recorded their physical activities, palpitations, dizziness and tiredness in a diary during the recording period. All recordings were analysed by a PC-based Holler system (Danica Holier Replay Unit, Danica, Borlnge, Sweden), and checked and edited by a physician according Io rouline laboratory practice.

Ech o-Doppler cardiography

The examination was performed al lhe Department of Clinical Physiology as previously oullined.19 The seplal thickness was measured in all palienls.

Lung function test

This was performed according to the standard practice. The following measurements were performed: diffusion capacity, lung volume, airway resistance, forced expiratory volume 1.0 s.

Clinical scoring

The polyneuropathy disability scoring system (PND) was used to assess the patients motor function, where 0 denotes patients without any impairment; I sensory disturbances, but preserved walking capability; II impaired walking, but able to walk without stick or crutches; IIIA walking with the help of one stick or crutch; IIIB walks with the help of 2 sticks or crutches, and IV confined to a wheel chair or bedridden.20

Statistics

Differences between groups were calculated by Mann-Whitney test. Correlations wer\e calculated by Spearman's rank correlation test. Linear regression was used for multiple regression analysis. For statistical analyses, Statistica, version 4.1 for Macintosh (Stat Soft Inc, Tulsa, OK, USA) and SPSS, version 11.01 (SPSS Inc., Chicago, USA) was used. A p-value below 0.05 was accepted as statistically significant.

Results

In 4 of the non-transplanted patients exercise, ECG was abnormal with changes (ST segment depression during exercise) suggestive of coronary heart disease. However, for two patients, the heart disease was known, and for one of the remaining, coronary angiography showed a 50% narrowing of the left anterior descending artery not sufficient for coronary bypass or dilatation, and for the other, coronary angiography could not verify the presence of coronary heart disease.

The PND score and data from the exercise ECG are summarized in Table 1.

Six patients died 0-5.5 years after transplantation, (Table 2). Deceased patients, both those who died in conjunction with the transplantation (3 patients), and those who died later (3 patients), were all older than the median age of the transplanted patients, The duration of their disease was not different from that of survivors. The patients who died had generally a poorer performance on exercise ECG, than those who survived. They were less able to increase their heart rates, and their maximal workload tended to be lower as did their ability to increase blood pressure (p < 0.05, p = 0.07 and 0.06 respectively). However, the PND-score of deceased patients deviated not significantly from that of survivors (p = 0.14). In only one of the deceased patients (Male, 52) was an abnormal exercise ECG with ventricular extra systoles found before transplantation.

The patients' capability of cycling correlated as expected with their disease duration, PND-score and age, but age at transplantation was not correlated with duration of disease, thus, older patients were not more severely sick than the younger (Table 3). Multiple regression analysis with age, PND-score and duration of disease disclosed that PND score had a significant impact on exercise ECG maximal work load (p < 0.02).

Males exhibited a higher workload, resting heart rate and systolic blood pressure than females (p < 0.05 for all 3 parameters). No such differences were found in the ability to increase heart rate and blood pressure during exercise (p = 0.97 and p = 0.2 respectively). No difference was found between females and males for PND-score.

Two patients had hypertrophie cardiomyopathy as defined by a septal thickness of 15 mm or more. Six patients had a septal thickness > 12 mm. No correlation was noted between septum thickness and outcome of exercise ECG, neither had patients with arrhythmia during the test an increased septal thickness.

In 1 of 8 patients who later received a pacemaker (female age 40) an episode of AV-block II, type 1, was detected by the exercise ECG, and contributed to the implantation of a permanent pacemaker.

Holler ECG examination disclosed conduction disturbances in the form of an AV-block I in one patient, AV block II in one patient and SA block in 3 patients. Ventricular arrhythmias in the form of short episodes of ventricular tachycardia was noted in 3 patients of which one also had AV block I, Three patients had episodes of ventricular extrasystoles in bigemini. In approximately 50% of the patients, Holier ECG were normal.

Pulmonary function tests (lung volumes and diffusion capacities) were without any significant abnormalities. In 4 patients, marginal decrease of diffusion capacities were observed, and for 5 patients minor obstructive changes were noted, but an abnormal lung function test was not related to poor performance on exercise ECG in any patient.

Table 2. Clinical data of transplanted patients who died after or during transplantation

Discussion

Coronary heart disease is recognized as a problem in patients undergoing liver transplantation at an age above 50, and evaluation for coronary heart disease is recommended for all presenting with risk factors such as diabetes mellitus.21 Exercise ECG is a powerful predictor of major ischmie heart disease even in asymptomatic individuals,22 so it appears reasonable to include it in the investigation of FAP-patients under evaluation for liver transplantation. Although ischemic heart disease is not an absolute contraindication to liver transplantation, it has a substantial impact on morbidity and mortality.23 In this study, exercise ECG did not detect ischemic heart disease in any patient in whom it was not previously diagnosed. It is notable that for one patient (female age 65, Table 2) with minor ST-segment depression and pre-cordial pain during exercise, suggestive of coronary heart disease, the angiographie examination did not substantiate the suspicion. It is tempting to speculate that the ECG changes originated from amyloid deposits in the myocardium.

Autonomic dysfunction is a risk factor for circulatory disturbances during liver transplantation,15 In our study, non- survivors were less able to increase their heart rate during exercise and their ability to increase their blood pressure tended also to be lower compared with survivors. However, only 3 patients died in connection or shortly after transplantation, for the remaining, other complications not likely to have a connection with autonomie disturbances were the cause of death (Table 3). Changes suggestive of ischmie heart disease were not detected on any of the 6 deceased patients' exercise ECG. One deceased patient had ventricular extrasystoles during exercise of doubtful relevance to the outcome (Table 3).

Table 3. Relationship between the outcome of exercise ECG and duration of the disease, PND* score and age at transplantation

Not surprisingly, PND score had a high impact on exercise ECG performances. Likewise had age, and duration of disease. Thus, the outcome of exercise ECG appears mainly to be dependent on non- cardiac factors in FAP-patients. Autonomie dysfunction is a well- known complication of the disease.24 Spectral analysis of RRintervals is a recognized test in autonomie neuropathy, but cardiac arrhythmia precludes inteipretation of the result in approximately 25-30% of the patients.25'26 Thus, impaired increase of pulse rate and blood pressure on exercise ECG may point towards autonomie neuropathy, so exercise ECG could serve as a complement to RRintcrval measurements, especially in patients with arrhythmias.

Contrary to our expectations, septal thickness had no impact on performance on exercise ECG or on arrhythmia, though it must be emphasized, that hyperthrophic cardiomyopathy was found only in 2 patients.

In conclusion, exercise ECG has limited value in the routine investigation of FAP-patients that are under evaluation for liver transplantation. The outcome reflects mostly the patients' autonomie and motor impairment, and contributes to the overall estimation of the patient's status. In our experience, few if any patients are rejected as transplantation candidates because of unexpected findings on exercise ECG.

Acknowledgments

The study was supported by grants from the Swedish Medical Research Council (2003-4485), the patients association FAMY/AMYE, Umc University and the Bengt Ihre Foundation.

References

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Kristina Juneblad, Anna Nslund, Bert-Ove Olofsson and Ole B. Suhr

Department of Public Health and Clinical Medicine, Ume University Hospital, Umearing;, Sweden

Correspondence: Dr. Ole B. Suhr. Department of Medicine, Umc University Hospital, SE 901 85 Ume, Sweden

Tel: +46 907851383 Fax: +46 90 143986 E-mail: ole.suhr@mcdicin.umu.se

Submitted: December 18, 2003 Revision Accepted: May 21, 2004

Copyright CRC Press Sep 2004

Source: Amyloid

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