E-health Treatment of Stress and Anxiety in Stockholm Myocardial Infarction With Non-obstructive Coronaries Study
Phase: NA
Conditions: Myocardial Infarction
Sponsor: Per Tornvall

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e-Health treatment of stress and anxiety in Stockholm 
Myocardial Infarction with Non-obstructive 
Coronaries study 
e-SMINC 
 
Registered in ClinicalTrials.gov No. 20191111 
 
Version 1.3 
August 24, 2023 
 
 
 

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Funding 
 Vetenskapsrådet 
(Swedish Medical Research Council) 
Grant 2018-02655 
Hjärt-Lungfonden 
(Swedish Heart and Lung Foundation) 
 Grant 20200221 
Riksförbundet Hjärt-Lung 
(The Swedish Heart and Lung Association) 
Grant FA 2019:41 and 2020:21 
Sponsor 
Uppsala Universitet 
Box 256, 751 05 Uppsala, Sweden 

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Table of content 
1. Steering committee 
2. Background and rationale 
3. Objectives and design 
4. Study setting 
5.  Inclusion criteria 
6.  Exclusion criteria 
7. Intervention 
8. Outcomes 
8:1 Primary outcome 
8:2 Secondary outcomes 
9. Flow chart of study time-line 
10. Sample size 
11. Methods 
11:1 Assignment of treatment 
11:2 Questionnaires 
11:3 Stress test 
11:4 Biological stress measures 
11:5 Data collection and management 
11:6 Statistical methods 
12. Monitoring 
13. Ethics 
14. References 

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1. Steering committee  
Per Tornvall, Stockholm, chair 
Department of Clinical Science and Education Södersjukhuset, Karolinska Institutet 
Sjukhusbacken 10, 118 83 Stockholm, Sweden, E-mail: per.tornvall@ki.se 
Erik Olsson, Uppsala, co-chair 
Department of Women’s and Children’s Health, Uppsala University 
Akademiska hospital, 751 85 Uppsala, Sweden, E-mail: erik.olsson@kbh.uu.se 
Claes Held, Uppsala 
Department of Medical Sciences, Cardiology, Uppsala University, Akademiska hospital, 751 
85 Uppsala, Sweden, E-mail: claes.held@ucr.uu.se 
Patrik Lyngå, Stockholm 
Department of Clinical Science and Education Södersjukhuset, Karolinska Institutet 
Sjukhusbacken 10, 118 83 Stockholm, Sweden, E-mail: patrik.lynga@ki.se 
Anna Nordenskjöld, Örebro 
Hjärt-lung-fysiologiska kliniken, University Hospital Örebro, Södra Grev Rosengatan, 701 85 
Örebro, Sweden, E-mail: anna.nordenskjold@regionorebrolan.se 
Fredrika Norlund, Uppsala 
Department of Women’s and Children’s Health, Uppsala University 
Akademiska hospital, 751 85 Uppsala, Sweden, E-mail: fredrika.norlund@kbh.uu.se 
Elisabet Rondung, Östersund 
Department of Psychology and Social Work, Mid Sweden University, Kunskapens väg 8, 831 
25 Östersund, Sweden, E-mail: elisabet.rondung@miun.se 
Jonas Spaak, Stockholm 
Department of Clinical Sciences Danderyd sjukhus, Karolinska Institutet, Danderyds sjukhus, 
182 88 Stockholm, Sweden, E-mail: jonas.spaak@ki.se 
 

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Örjan Sundin, Östersund 
Department of Psychology and Social Work, Mid Sweden University, Kunskapens väg 8, 831 
25 Östersund, Sweden, E-mail: orjan.sundin@miun.se 
Anders Ulvenstam, Östersund 
Medicinkliniken, Östersunds sjukhus, 831 83 Östersund, Sweden, E-mail: 
anders.ulvenstam@regionjh.se 
Lena Kövamees, Stockholm 
Patient representative, E-mail: lena@kovamees.com 
 
2. Background and rationale 
Recent advances in diagnostics of acute coronary syndromes, such as high sensitive troponin 
assays and coronary angiography, have revealed a new entity of patients. Approximately six 
percent (5-15%) of all patients fulfilling the diagnostic criteria for myocardial infarction have 
no obvious cause in the coronary arteries i.e. < 50% stenosis (1). These events were recently 
labelled Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA) that should 
be considered as a working diagnosis, which requires further investigation (2). Examples of 
diagnoses revealed during investigation of MINOCA are myocarditis, takotsubo syndrome and 
myocardial infarction due to plaque rupture or erosion. The most recent 4th definition of 
myocardial infarction have refined the final diagnosis of myocardial infarction to only include 
patients fulfilling the diagnostic criteria for myocardial infarction with a coronary cause, for 
example plaque disruption (3). Consequently, the troponin increase in myocarditis is 
described as myocardial injury and takotsubo syndrome is considered a separate entity. The 
management of MINOCA as a working diagnosis is not clear and there are no separate 
guidelines but one European position paper (2) and one American scientific statement (4). 
Recently, diagnosis and management of MINOCA was mentioned as a separate entity in the 
European Society of Cardiology guidelines for acute coronary syndromes in patients 
presenting without persisting ST-segment elevation (5). All emphasize the importance of 
further diagnostic investigations, in particular the use of Cardiac Magnetic Resonance (CMR) 
imaging and recommended treatment depending on the final diagnosis.  

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Patients with MINOCA often report anxiety due to the lack of a firm explanation for their 
illness and in many cases mental or physical stress are contributing parts to the syndrome. 
Patients with the working diagnosis MINOCA, including takotsubo syndrome, have a 
decreased health-related Quality-of-Life (QoL) compared to healthy subjects. Their QoL is 
similar and in some dimensions worse (mental stress and vitality) than patients with 
myocardial infarction due to Coronary Artery Disease (CAD)(6). Furthermore, anxiety and 
depressive symptoms are as prevalent in MINOCA as in myocardial infarction due to CAD (7). 
As described above, takotsubo syndrome is part of the working diagnosis of MINOCA but a 
separate final diagnosis. The above mentioned studies of the working diagnosis MINOCA (6,7) 
also describe sub-group analyses of patients with takotsubo syndrome showing exaggerated 
mental stress and anxiety when compared with MINOCA patients without takotsubo. 
Increased mental stress and anxiety in takotsubo patients have been confirmed in qualitative 
interview studies (8,9). One recent study of MINOCA (10) showed that patients, in particular 
women, rate their stress high on the Perceived Stress 14 Item Scale (PSS-14). Unpublished 
data from the Stockholm Myocardial Infarction with Normal Coronaries (SMINC)-2 study (11) 
showed that 60% of the patients with a working diagnosis of MINOCA report high levels of 
stress and/or anxiety, as determined by the questionnaires PSS-14 and HADS, during 
admission. At present there are no randomised studies of any treatment of MINOCA, including 
the final diagnoses of MINOCA and takotsubo syndrome. There is an urgent need for non-
pharmacological alternatives aiming at relieving stress and anxiety considering the high 
mental stress and anxiety levels in MINOCA, including takotsubo syndrome, leading to 
decreased QoL. Cognitive Behavioural Therapy (CBT) aiming at reducing mental stress has 
been shown to be effective regarding prognosis in patients with CAD (12). The current protocol 
describes a randomized controlled trial evaluating an internet-based CBT program for 
reduction of stress and anxiety in patients with increased mental stress and/or anxiety and a 
final diagnosis of either MINOCA or takotsubo syndrome. 
3. Objectives and design 
The overall aim is to study the effects of an internet-based CBT intervention on perceived 
stress and anxiety in patients with MINOCA and takotsubo syndrome compared to controls 

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receiving usual care. A secondary aim is to compare immediate CBT intervention (start within 
2-4 weeks) with late intervention (start within 12-14 weeks). 
4. Study setting 
Academic hospitals in Stockholm and other selected sites with an interest in MINOCA, Sweden 
5. Inclusion criteria 
Inclusion criteria are: 
➢ a suspected diagnosis of MINOCA or takotsubo syndrome with coronary angiography 
without diameter stenosis ≥50%  
➢ age ≥ 35 years 
➢ PSS-14 ≥ 25 and/or HADS-A ≥ 8 during admission 
➢ reading and writing proficiency in Swedish 
➢ computer/Internet access and literacy 
6. Exclusion criteria 
Exclusion criteria are: 
➢ strong clinical suspicion of myocarditis 
➢ spontaneous coronary artery dissection 
➢ acute pulmonary embolism  
➢ acute myocardial infarction type 2 
➢ cardiomyopathy other than takotsubo syndrome 
➢ a previous myocardial infarction due to CAD 
➢ expected poor compliance to behavioural therapy 
➢ not likely to survive > one year due to for example cancer 
7. Intervention 

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The intervention is a nine-step psychologist-guided internet-delivered self-help program, 
based on CBT. It will be delivered via a secure on-line platform, the portal, using secure 
authentication for log in. All nine intervention steps include short informative texts and 
examples, as well as assignments that the participant report in the portal. The self-help 
material also include both audio and video files. Participants will be encouraged to complete 
one step in the self-help program each week. 
The first step includes written medical information about MINOCA and filmed interviews with 
patient and health-care personnel. Diagnosis and recommended treatments are covered and 
common reactions after a cardiac event are presented. Participants are asked to describe their 
cardiac event and how it has influenced their lives.  
The following four steps, focus on stress. Step 2 is mainly psycho-educative, and introduces 
self-monitoring of stressors and stress reactions. In Step 3 specific and personal stress 
situations are identified, including a discussion on short- and long-term consequences of stress 
behaviors. Step 4 focuses on recovery and relaxation. In Step 5 central personal values are 
identified and behaviors in line with these values are encouraged. 
In Step 6, the concept of heart-related fear, worry or anxiety is introduced. Participants 
recognizing these kinds of worries are encouraged to work through steps 7-8, including 
psycho-education relating to fear, worry and anxiety, self-monitoring of difficult situations and 
avoidance behaviors, formulation of an exposure hierarchy, and heart-related exposure 
training. Participants that do not experience heart-related fear, worry or anxiety can go 
directly to Step 9. 
In the last step of the program, Step 9, the participants will be working on a summary of what 
they have learned during the intervention, and how these advances can be maintained or 
further developed.   
On completion of the first intervention step, the psychologist will contact each participant by 
phone to establish report and discuss treatment goals. Throughout the rest of the program, 
participants will receive personalized written assignment feedback from their psychologist. 
The participants will also be able to contact their psychologist using a text message function 
within the portal.  
8. Outcomes 

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8:1 Primary outcome 
Self-rated stress and/or anxiety, as a categorical measure, 12-14 weeks after the index event 
8:2 Secondary outcomes 
Self-rated stress, anxiety, QoL, cardiac anxiety and post-traumatic symptoms, as continuous 
measures, 10, 20 and 50 weeks after randomisation 
Biological stress 10 weeks after randomisation 
Physiological recovery after stress 10 weeks after randomisation 
Self-reported total number of sick-leave days 10, 20 and 50 weeks after randomisation 
Self-reported total number of health-care visits 10, 20 and 50 weeks after randomisation 
9. Flow chart of study time-line 
 
10. Sample size 
By including 90 patients (45+45 patients) we will be able to detect a 30% absolute difference 
in the number of patients per group that have normalized the scores on PSS-14 and/or HADS-A 
(80% power, p < 0.05) taking into account that 45% of patients receiving usual care had 
                                          
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normalized their PSS-14 and/or HADS-A at 6 months (unpublished results). 90 patients 
compensate for a loss of 10 patients missing follow-up measurements.  
11. Methods 
The secure web-platform, the portal described above, will be used to collect information 
about background factors such as patient characteristics and history as well as for the 
questionnaires and information about health-care contacts and sick-leave. Thus, the majority 
of information is self-reported rather than investigator-reported with the exception of the 
biological stress measures.  
11:1 Assignment of treatment 
All patients will be introduced to the study by the study site. Randomisation will be made by 
computer-generated random numbers in blocks of 6 within the internet-portal described 
above. The treatment will be guided by psychologists involved in the trial within the portal. 
11:2 Questionnaires 
Self-related stress will be determined by Perceived Stress Scale (PSS-14) which is a self-
reported questionnaire measuring levels of stress and coping (13). PSS-14 contains 14 items 
that are rated on a 5-point Likert scale, from 0 (never) to 4 (very often) with a total score 
between 0 and 56. High scores indicate more perceived stress. The threshold for increased 
levels of stress is 25. PSS 14 has two subscales where seven of the items measures stress, while 
the other seven items measures coping ability. The Swedish version of PSS-14 has been shown 
to be reliable and valid in patients with or without known stress-related conditions (14). 
Self-rated anxiety will be determined by Hospital and Anxiety Depression Scale (HADS) which 
is an instrument for assessment of symptoms of anxiety and depression (15). It has two 
subscales, one for anxiety (HADS-A), and one for depression (HADS-D), each consisting of 
seven items that are rated on a 4-point Likert scale (0-3) with a total score between 0 and 21. 
A cut-off point of 8 can be used to identify potential cases of anxiety and depression. HADS 
has been validated in a Swedish population and shown to have a reliable factor structure (16) 
and been frequently used in several studies on different CAD groups in Sweden and elsewhere. 

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Self-rated cardiac anxiety will be determined by Cardiac Anxiety Questionnaire (CAQ) which 
is an instrument used to measure heart-related anxiety developed for patients with chest pain 
(17). It consists of three domains: fear of cardiovascular sensations, avoidance of activities 
that may trigger them and heart-focused attention. The scale comprises 18 statements rated 
on a Likert type scale ranging from 0 (never) to 4 (always) with a total score between 0 and 
72. CAQ has demonstrated good reliability and validity and been used in several Swedish 
patient groups including patients with chest pain with or without CAD and is associated with 
psychological distress (18). 
Self-related QoL will be determined by Rand-36 that is a free version of the generic QoL 
questionnaire Short Form-36. It contains 36 items in eight domains of QoL and gives a range 
between 0-100 where a higher value indicates better QoL. The Swedish version of Rand-36 
has been validated in cardiac patients (19). 
Self-rated post-traumatic symptoms will be determined by Impact of Event Scale 6 item 
version (IES-6) which is a short form version of the Impact of Event Scale Revised version (IES-
R)(19). It is a brief measure capturing symptoms of post-traumatic stress relating to a specified 
event. The IES-6 includes two IES-R intrusion items, two avoidance items, and two 
hyperarousal items all rated on a Likert type scale ranging from 0 (not at all) to 5 (very much) 
with a total score between 0 and 30. The IES-6 accounted for 91% of the variance in the full 
IES-R and possessed screening properties similar to the IES-R when compared to the 
posttraumatic stress disorder checklist (20). The Swedish version of IES-R has been shown to 
have good properties as a screening tool for PTSD (21). 
The following questionnaires will be used at admission to investigate possible predictors of 
mental stress and anxiety: 
Intolerance of Uncertainty Scale (IUS 12) is a brief self-report tool for evaluating general 
intolerance of uncertainty (22). The 12 items are rated on a Likert type scale ranging from 1 
(not at all characteristic of me) to 5 (entirely characteristic of me). The total score (12-60) 
indicates general intolerance of uncertainty with higher scores reflecting greater reports of 
intolerance. The scale can also be divided into two factors: Prospective anxiety (fear and 
anxiety based on future events) comprising 7 items and inhibitory anxiety (uncertainty 
inhibiting action or experience) comprising 5 items. The English version of the IUS 12 has 

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shown strong internal consistency and high correlations with the original IUS and related 
measures of anxiety and worry (23), while the Swedish translation is yet to be validated. 
Difficulties in Emotion Regulation Scale (DERS 16) is a brief assessment of overall emotion 
regulation difficulties (24). It consists of 16 items that assess six dimensions of emotion 
regulation difficulties: non-acceptance of negative emotions, inability to engage in goal-
directed behaviors when distressed, difficulties controlling impulsive behaviors when 
distressed, limited access to emotion regulation strategies perceived as effective, and lack of 
emotional clarity. Respondents are asked to rate the extent to which each item applies to 
them on a 5-point Likert-type scale from 1 (almost never) to 5 (almost always), giving the 
DERS-16 a range of 16 to 80, with higher scores reflecting greater levels of emotion 
dysregulation. The Swedish version of DERS 16 has shown very good psychometric properties, 
with excellent internal consistency, good test-retest reliability, and good convergent and 
discriminant validity (24). 
Global/general attachment subscale of the Experiences in Close Relationship-Relationships 
Structure (ECR-RS) questionnaire is an instrument for brief evaluation of an individual’s 
global adult attachment (25). In nine items, participants are asked to rate how they generally 
think and feel in close relationships. Each item is rated on a 7-point Likert scale from 1 
(strongly disagree) to 7 (strongly agree). The first six items tap attachment-related avoidance 
(i.e. how comfortable the individual is with closeness and dependency) and the three 
remaining items capture attachment-related anxiety (i.e. the extent to which an individual is 
concerned about being rejected by others). High scores on either of the two subscales 
reflects higher levels of attachment-related avoidance and/or anxiety. The Swedish version 
of ECR-RS has shown good internal consistency, as well as good convergent and discriminant 
validity, and multi-group invariance tests for gender and age showed no violations to 
invariance (26). 
 
11:3 Stress test 
There are many different mental stress provocations used to test the balance between vagal 
and sympathetic activity. The mental stress test presented below has been used previously in 
patients with takotsubo syndrome (27). The first part, known to increase sympathetic activity, 

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consists of two tasks, presented in one block, starting by an anger recall interview where the 
patient is asked to recall an upsetting situation during the last few months prior to the 
investigation and then speak about that situation for a 2-3 minutes. Follow-up questions about 
this upsetting situation are asked by the interviewer. The anger recall interview is immediately 
followed by a mental arithmetic task in which the patient is asked to subtract 7 from a 4 digit 
number in consecutive steps as fast as possible. This part of the test is performed under 
increased stress induced by the test-leader by asking the patient to count faster. The second 
part of the mental stress test consists of a recovery phase potentiated by an imagery task 
(comprising a secure place or person) shown to increase vagal activity (28). Recovery time is 
defined as the time it takes for the patient to reach baseline levels of heart rate and blood 
pressure. 
11:4 Biological stress measures 
Cortisol is a method to measure biological stress (29). Traditionally, cortisol measurements 
made in blood, saliva or urine gives an estimate of the most recent stress including both 
mental and physical stress, hence saliva cortisol will be used to measure acute stress before 
and after the planned stress test. Long-term stress can be measured by frequent samples of 
saliva cortisol, including 2-5 samples/day, repeated several days during the whole time-period 
of interest or by hair cortisol. One centimeter of hair taken from the scalp reflect one month 
of cortisol exposure. Hair cortisol will be measured at randomization and after the 
intervention. Hair and saliva cortisol will be measured by RIA-technique. 
Heart-Rate-Variability (HRV) is a method to measure autonomic activity (30). HRV is caused 
by the balance between vagal and sympathetic nerve activity, reflected in alterations in heart 
rate, i.e. heart-beat intervals. In general, increased HRV reflect a relative increase in vagal to 
sympathetic nerve activity and is associated to low mental stress. HRV can be assessed by 
time-domain, frequency domain and non-linear methods. HRV will be determined after the 
intervention before and after the mental stress test from a 10 minutes ECG-recording, both in 
the time-domain (SD, SDNN and others), frequency domain (HF, LF and VLF), and by nonlinear 
methods (such as Poincaré plots). The ECG will be recorded as a single-lead ECG with very high 
resolution (10 000 Hz; PowerLab, ADInstruments) using a specific electrode positioning that 
also enable us to measure skin sympathetic nerve activity as a surrogate of cardiac 
sympathetic nerve activity, as previously described (31).  

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11:5 Data collection and management 
All data, with the exception for the biological stress measures, will be collected by the secure 
platform, the portal, hosted by Uppsala University. All personal data will be handled according 
to GDPR.  
11:6 Statistical methods 
Continuous data will be presented as median with interquartile range or by mean and 
standard deviation, and categorical data as numbers and percentages. Comparison of 
continuous data will be made by linear regression or mixed models with post-measures as 
outcome and, group allocation and pre-measures as covariates. Calculations of effect size will 
be performed by Cohens d. Categorical data will be analyzed by Chi2-test. The outcomes will 
primarily be analyzed as intention-to-treat. As a post-hoc analysis, patients who completed ≥5 
steps of the intervention will be compared with treatment as usual. The outcomes will be 
analyzed by Chi2-test of normalization of PSS-14 and/or HADS-A (categorical data) and by 
linear regression or mixed models (continuous outcomes) using the measurements made at 
randomisation (2-4 weeks) as pre-measures. Clinical significance will be determined according 
to the method by Jacobson and Truax (32). 
12. Monitoring 
There will be no data monitoring since data are self-reported and the patients with active 
treatment will be followed continuously by psychologists involved in the trial. There will be an 
audit of the recruitment process by independent monitors from Södersjukhuset at the end of 
the trial. 
13. Ethics  
The study has applied and received permission (December 17, 2018) to perform the trial from 
the Regional Ethics Committee in Stockholm (2018/1434-31/1).  
The permission includes oral and written informed consent from all included patients. All 
personal data will be saved securely by Uppsala University according to GDPR. Only the 
members of the steering committee and doctoral students will have full access to the data.  

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The results of the study will be presented at national and international conferences and 
published in an open access peer-reviewed journal including authorship by all members of the 
steering committee and selected doctoral students. 
 
 

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