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Clinical genetic care in diseases predisposing to sudden cardiac death
van Langen, I.M.
Publication date
2005
Link to publication
Citation for published version (APA):
van Langen, I. M. (2005). Clinical genetic care in diseases predisposing to sudden cardiac
death.
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Chapter
Familiar disease with a risk on
sudden d e a t h :
A l o n g i t u d i n a l study of the psychological
consequences of predictive t e s t i n g for
long QT syndrome
KSWH Hendriks, IM van Langen, MMWB Hendriks, E Birnie, FJM Grosfeld, AMM Wilde, J van den Bout, JP van Tintelen, HFJ ten Kroode
Abstract
Background: From 1996 electrocardiographic (ECG) and molecular screening in families with long QT syndrome (LQTS), a potentially life-threatening but treatable cardiac arrhythmia syndrome has been performed in the Netherlands. We examined the psychological influence of predictive ECG and molecular screening in these families.
Method: In a prospective study the extent and course of anxiety and depression associated with two seguential screening tests: first ECG, second DNA, are described in applicants and their partners from the first consultation until 18 months after disclosure of the DNA-results. Findings: Seventy-seven applicants and 57 partners completed measures of distress at three time points. Both ECG findings and DNA results were associated with increased depression, anxiety and disease related distress in short term. Highest scores of distress were found in those who received inconclusive ECG results. In the long-term the high levels of distress were restored. In carriers, however, the scores of disease related anxiety remained increased. Interpretation: In predictive two step testing in LQTS, applicants are responding to risk information, whether from ECG or DNA.This finding highlights the importance of proper initial pre-test counselling before ECG testing.
A L O N G I T U D I N A L P S Y C H O L O G I C A L S T U D Y IN L Q T S P R E D I C T I V E T E S T I N G
Introduction
Just a decade ago, the first genes for cardiac arrhythmia syndromes (primary electrical diseases) were identified. Eight genes associated with the long QT syndrome (LQTS) have since been cloned. Symptoms in untreated carriers consist of cardiac ventricular arrhythmias, leading to dizziness, fainting spells and, in up to 5% of symptomatic cases yearly, to sudden death. Clinical manifestations usually occur before the age of 40, frequently even before adulthood. Triggers for symptoms are dependent of the type of LQTS, physical or emotional stress, loud noises, swimming or rest. Clinical diagnosis in symptomatic patients is made by cardiologie screening (ECG-recording, exercise test, holter-ECG), in relationship to clinical symptoms and family data. Approximately 50% of mutation carriers never display any symptoms of LQTS and in 15% of mutation carriers the ECG shows no signs of the disease [1-5]. Carriers with clearly abnormal ECG's are at highest risk. Treatment consists in most cases of prophylactic medication (beta blockers) and, in rare cases, of implantation of a pacemaker or internal cardioverter defibrillator (ICD). Strict rules of living such as avoiding QT prolonging medication, and avoiding physical exhaustion from sports and work and emotional arousal are prescribed. When prophylactic measures are followed strictly morbidity and mortality rates can be reduced substantially in carriersofa LQTS causing mutation [6,7],Therefore the clinical benefits of identifying mutation carriers for LQTS are potentially great, provided carriers follow the recommendation to reduce their risks.
In 1996 systematic predictive genetic testing by cardiac and molecular screening in LQTS families was set up in the Netherlands. This is being performed in cardiogenetic outpatient clinics, situated in university hospitals, in which combined consultations of specialised cardiologists and clinical geneticists take place. The counselling and testing protocols are derived from those in predictive genetic testing in neurogenetics (Huntington's disease) and oncogenetics, adapted to the needs of families with cardiologie diseases [8]. One unique feature of this protocol is the two-step procedure in revealing the results of the genetic test, firstly by the interpretation of the clinical and (particularly) the ECG-data at the first consultation and secondly and by disclosing the results of the DNA-test 6 to 8 weeks afterwards.
Almost from the start in 1996, this prospective psychological research was initiated to investigate the extent and course of distress associated with by this new form of predictive genetic testing. To examine the influence of the ECG-results on one hand and of the genetic risk status (being a mutation carrier or not) on the other we analysed the course of distress in applicants and their partners from the first consultation until 18 months after disclosure of the DNA-results.
Methods
Participants (n=77) were close relatives of LQTS index patients in whom a causative mutation in one of the three major genes was detected. These participants actively responded to an invitation for counselling and testing by a family letter written by the medical team, distributed
by the index patient. Nearly all relatives whom received a letter applied for testing.These relatives applied for predictive genetic testing for themselves in one of the cardiogenetic outpatients clinics of Amsterdam, Utrecht or Groningen (1997-2001). No one was clinically diagnosed with LQTS before. Their partners (n=57) were also included. Applicants below 16 years of age and those who had insufficient mastery of the Dutch language were excluded.
Procedure
During the first combined consultation, the features of LQTS and the possible medical and psychosocial consequences of carriership and the predictive diagnostic procedures were explained to the applicants and their partners (Table 1). If agreed to (all cases), an ECG was made and judged and based on results and the clinical and family data a presumptive diagnosis was given because of the possible immediate threat of cardiac arrhythmia symptoms. Blood for DNA-testing was drawn at the first session after informed consent.
Table I. Protocol for predictive testing in LQTS during this study
1. Invitation for counselling and testing by a family letter written by the medical team, distributed by the index patient.
2. After appr. 2 weeks after application: First visit at cardiogenetic outpatient clinic (cardiologist and clinical geneticists): explanation, medical history, family history, ECG- testing and result (normal, abnormal, uncertain), blood taking for DNA-testing, offer of psychosocial help
4. In case of a clearly abnormal ECG: immediate referral for further cardiologie testing and treatment 3. After appr. 6-8 weeks: Revelation of results of DNA-testing at the cardiogenetic outpatient clinic, followed
by a letter summarizing results, rules of living and (if applicable) advises for testing of relatives (children). 4. Referral of carriers to cardiologist for further cardiologie testing and treatment
5. If desired or indicated: referral of carriers for further psychosocial help.
Three outcomes of the clinical (ECG-) screening were possible: 1.normal (no signs of LQTS), 2.inconclusive (LQTS possible) and 3. abnormal (LQTS very probable). In case of a clearly positive ECG test result and/or clinical symptoms of LQTS, additional cardiologie examination followed and prophylactic treatment was started before the definitive results of the DNA-test were disclosed (n= 10). In all other cases the DNA-test results were awaited. After disclosure of carriershipofthefamiliar mutation, the personal medical and social implications werediscussed again in a second combined consultation. Referral to a cardiologist for further cardiologie examination and prophylactic treatment followed. If indicated, psychosocial help of a social worker was offered during or after DNA-testing.
The counselling team introduced this psychological study at the end of the first consultation. The applicants received a take home letter with a brief description of the study. Due to the potential immediate threat of cardiac arrhythmia symptoms the time lag was too short
A L O N G I T U D I N A L P S Y C H O L O G I C A L STUDY IN L Q T S P R E D I C T I V E T E S T I N G
between the application of a first consult and the actual appointment with the cardiologist and the clinical geneticist to introduce the psychological study before the first visit.
Design and measures
Questionnaires were sent to the applicants, after they gave their written consent.The prospective design consisted of data assessments within two weeks of the first consultation (Tl), and two weeks (T2) and 18 months (T3) after DNA-test result disclosure. Applicants and their partners were asked to complete and return the questionnaire by mail within two weeks.
This study was approved by the Medical Ethical Review Committee of the University Medical Centre Utrecht.
At three time points, the Impact of Event Scale (IES), the Spielberger State Anxiety Inventory (STAI-s) and Beck Depression Inventory (BDI) were administered. Disease related anxiety was assessed with the 15-item IES. This instrument measures specific anxiety as a result of a distressing event, in this study being at risk for LQTS. Scores of 0-8 indicate a minor, 9-19 a moderate and above 20 a clinically important reaction [9,10]. General situational anxiety was assessed with the widely used 20-item STAl-s [11]. The average norm of a Dutch population of general practitioner patients is 34.8 (SD 9.8). Depression was assessed with the 21-item BDI. Scores 0-9 are considered normal, 10-16 suggest mild depression symptoms and scores higher than 16 suggest moderate to severe depression symptoms. The average norm is 4.7 (SD 5.0) for a non-clinical sample [12,13].
Socio-demographic variables were assessed with a questionnaire compiled by the authors. To assess coping we used the Utrecht Coping List (UCL) measuring active coping, social support seeking and avoidance reactions [14]. All these questionnaires are validated.
Statistical analysis
In this study four, instead of the potential six, different clinical groups can be distinguished: (a) carriers with an abnormal ECG at Tl, (b) carriers with an inconclusive ECG, (c) noncarriers with a normal ECG and (d) noncarriers with an inconclusive ECG (the other two possibilities: carriers with a normal ECG and noncarriers with an abnormal ECG did not occur). Differences between these four groups with respect to demographic and clinical characteristics were analysed with chi-square tests.
Repeated measures analysis was used to examine the effect of genetic risk status and ECG results on distress and the influence of time on levels of distress of applicants and partners. Restricted Maximum Likelihood (REML) estimation was used to estimate the effects of time, genetic risk status and ECG results in such a repeated measures model, for all three psychological tests. REML was preferred over other estimation methods, since it is able to handle designs with incomplete cases. Significant effects were found in the repeated measures analysis therefore pair wise comparisons between the four groups at each time point were executed. No additional effect of early started prophylactic treatment (before T2) on distress was found. Differences between the second and third assessments were assessed using paired sample
t-tests. Cutoff scores of high distress (IES > 26;STAI m/v > 38/39; BDI > 10) were used to describe psychological morbidity.
Results
Demographic characteristics
Sociodemographiccharacteristicsofthe study groups of applicants and partners are represented in Table 2a&b. No significant differences between the study groups were observed with regard to any of the demographic variables. The seven participants (drop-out = 5%) who did not want to participate in the follow-up of the psychological study have a less active coping style in comparison to the participants (t = -.147, p=. 036). From the 134 participants who continued participation in the follow-up study, 33 participants did not return their questionnaire at one of the three assessments. This resulted in 8.9% of the total number of scores missing.
Psychological characteristics of the applicants
Carriers
Compared to the normal population both groups of carriers expressed moderate disease related anxiety at all three assessments.The mean scores for the carriers with an inconclusive ECG were even in the clinical range at the first assessment (Figures 1 to 3). The group of carriers with an abnormal ECG had general anxiety and depression scores that were comparable with the normal population, for all assessments. The group of carriers with an inconclusive ECG showed significantly higher depression scores in comparison with the normal population at T1 (T=2.9, p=.017) and their general anxiety scores were significantly higher atT2 (T=3.23, p=.008).
The time course of distress is presented in Table 3. The clinical important disease related anxiety scores of those with an inconclusive ECG did not change significantly over time and
Fig. 1 Mean scores on the disease related anxiety (IES) for the four study groups at each
assessment.
Carriers with an ECG " • with LQTS featues
Carriers with an uncertain ECG
^-^-» Noncarriers with a normal ECG
Noncarriers with an uncertain ECG
A L O N G I T U D I N A L P S Y C H O L O G I C A L S T U D Y IN L Q T S P R E D I C T I V E T E S T I N G
Fig. 2 Mean scores on the general anxiety (STAI)
50 |
-Carriers with an ECG with LQTS featues
Carriers with an uncertain ECG
Noncarriers with a normal ECG Noncarriers with
an uncertain ECG
Fig. 3 Mean scores for depression (BDI)
16 14 12 10 8 6 4 2 0
X
Carriers with an ECG with LQTS featues
Carriers with an uncertain ECG
Noncarriers with a norma! ECG Noncarriers with
an uncertain ECG
thus stayed high. Their high levels of general anxiety at T1 andT2 showed a significant decline and were comparable with a normal population at the third assessment. Their depression scores showed a significant decline atT2 and remained the same in the long term. In the group of carriers with an abnormal ECG the same moderate disease related anxiety scores and low depression scores were found at all three assessments and no significant incline or decline could be found. For this group the general anxiety remained high at the first two assessments and was comparable with a normal population atT3.
Applying cut off scores of high distress revealed that up to fifty percent of carriers showed clinically relevant distress at T1 (Figure 4). At T2 there was a decline in the number of carriers with an abnormal ECG with such high specific and general distress scores to 33%. However, the percentage of high scores even increased atT2 among those carriers having received an inconclusive ECG result at first visit: from 50% to 78%. After 18 months (T3) this percentage declined in this group to a still high percentage of 36 and in the group carriers with an abnormal ECG to 20%.
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At T1, the noncarriers had disease related anxiety scores which were increased (Figure 1 to 3). The other mean distress scores were within the normal limits at all assessments. For the noncarriers, distress measures showed a decline from T1 toT2. Although the general distress scores showed an incline from T2 to T3, the scores remained low at the last assessment.
The incidence of clinically high distress scores was high at the first assessment in the group of prospective noncarriers with an inconclusive ECG. After DNA disclosure this percentage dropped from 50% to 20% and remained at this level at T3 (Figure 4).
Fig. 4 Percentages of applicants with high distress scores (IES > 26, STAI m/v > 38/39,
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T1 T2 T3
non-carriers
Comparisons between the four subgroups
Figure 1 to 3 show mean distress scores of the four study groups in time. At the first assessment, applicants with an inconclusive ECG test result showed higher depression scores than applicants who had a normal or an abnormal ECG irrespective of future carrier status. Shortly after DNA disclosure (T2), noncarriers had significantly lower mean scores of anxiety compared to carriers, in particular in comparison with those carriers who were given an inconclusive ECG result at first visit. After 18 months, carriers showed higher disease related anxiety in comparison with noncarriers.
Psychological characteristics of the partners
Partners of carriers
Mean scores for disease related anxiety, general anxiety and depression before and after DNA disclosure are presented in Table 4. Both groups of partners of carriers had on average disease related anxiety scores, which are indicative for moderate impact at all three assessments. Their
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Fig 5. Percentage of partners with high distress scores
50
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general anxiety and depression scores were comparable with a normal population.
Disease related anxiety, general anxiety and depression scores did not change over time. As shown in Figure 5, the percentage of partners of carriers with an abnormal ECG with high distress scores decreased with each follow-up assessment. The partners of carriers with an inconclusive ECG did not show this pattern however. After DNA disclosure, the percentage with high distress scores doubled from 17% at Tl to 42% at follow-up and slightly decreased to 25% at T3.
Partners ofnoncarriers
Partners of the noncarriers had disease related anxiety, general anxiety and depression scores which were within the normal range and these did not change over time.
Comparisons between the four subgroups of partners
There were no significant differences between the groups in general anxiety and depression scores at all assessments (Table 4).There was also no difference in disease related anxiety at the first two assessments. At the third assessment the disease related anxiety was, however, higher in those whose partners proved to be carriers of LQTS.
Discussion
This is the first longitudinal study addressing the psychological conseguences of predictive testing for an inherited arrhythmia syndrome, the long QT syndrome. Our results show that the testing procedure leads to significant distress, especially in mutation carriers who initially receive an inconclusive ECG-result, but also in carriers with clearly abnormal ECG-results and
in spouses of carriers. Disease related anxiety scores remain relatively high in particular in the group of carriers whose ECG-results were inconclusive at the first visit, even at long term. This may not only be caused by the testing procedure as such, but may well be a result of the subsequent prophylactic treatment, including rules of living and the immediate threats of dying suddenly and of having passed the mutation to ones children. More than one third of the carriers showed high distress scores at long term, a substantial proportion which was not previously reported in other studies on genetic testing or in studies reporting on the impact of receiving a diagnosis of a chronic disease [15,16-19]. Our findings also suggest that the way of revelation of the ECG test result at first visit had an effect on the psychological distress levels of the applicants. Applicants who received an inconclusive ECG result were more distressed than applicants who were given clearly normal or abnormal results.
Some weeks after DNA disclosure, the distress levels in the group of carriers remained high. The initial cardiologie testing already leads to emotional distress and the results of the following molecular testing seemed to have lost most of its impact as mentioned in other studies [15,20,21-25]. In both groups of noncarriers, however, molecular testing decreased the emotional distress associated with the clinical assessment. Comparable to other studies, noncarriers felt relieved immediately after receiving the normal DNA-test results [21,26,27].
The present study indicates that the general distress levels in the applicants were largely restored within 18 months, returning to levels comparable to those of the normal population. The DNA test outcome (as well as the ECG-outcome) was therefore not predictive of general distress 18 months after testing. This is in line with the findings of a systematic review and reported in more recent studies on predictive testing in neuro- and oncogenetics [19,28,29]. However we have to be cautious with drawing this conclusion since relatively more applicants who are using a less active coping style are lost during follow-up. A recent study states that studies reporting few harmful effects may have underestimated the real impact due to the dropouts who are less resourceful and less emotionally robust [30].
The specific (disease related) distress scores in carriers remained (mildly) increased at 18 months. To be able to answer the needs of these applicants, psychosocial care is probably important. Additional studies will have to examine possible individual predictors for distress in applicants and partners, to identify those participants who are especially in need of timely support. Further studies are needed to develop and evaluate the type of care that would be most effective at preventing high levels of distress for these more vulnerable individuals. In these studies the role of the cardiologist caring for these (mostly asymptomatic) carriers also needs to be taken into account.
Partners of applicants were also included in this study; compared with non-carriers' partners, carrier partners had higher levels of disease related anxiety at all three assessments. These findings indicate that the risk status of one's partner may also influence the daily life of the individual and his (future) offspring.This finding stresses the need to involve partners in the genetic testing counselling procedure.
In our study, ECG-testing can be seen as'genetic testing'because the genetic status of the applicant was (partly) revealed. Since ECG assessment took place before our first psychological assessment, a baseline distress measure was lacking. As described, due to the procedure, no
A L O N G I T U D I N A L P S Y C H O L O G I C A L S T U D Y IN L Q T S P R E D I C T I V E T E S T I N G
psychological studies were possible before the first visit. Even if this had been possible, this would not have revealed the genuine baselines as all applicants are aware of their increased risk of long QT syndrome due to their family histories.
Predictive genetic testing in long QT syndrome is an important part of prevention, because it enables timely prophylactic measures in mutation carriers and therefore helps to reduce sudden death at young age. Not withstanding this, the testing procedure, including ECG-assessment, leads to distress which substantially decreases over time. Disease-related anxiety however persists in a subgroup of carriers, which stresses the need for ongoing psychosocial care in them and their relatives.
Acknowledgements
This study is supported by the Netherlands Heart Foundation project no.99.115. We thank all the participants and the clinical genetic centers in Utrecht, Amsterdam and Groningen.
We thank the social workers Oda Berkhout and Alma Schiphorst for their contribution to this study.
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