Norwegian Danish Spontaneous Coronary Artery Dissection Exercise Study

Spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic cause of acute coronary syndrome that predominantly affects younger, otherwise healthy women. It is characterized by a dissection and/or intramural hematoma in the coronary artery wall, leading to impaired coronary blood flow and myocardial infarction. SCAD typically occurs in women around the perimenopausal period, but a substantial proportion of patients are even younger, and SCAD is a leading cause of pregnancy-associated myocardial infarction. Traditional cardiovascular risk factors are often absent, whereas conditions such as fibromuscular dysplasia and migraine are more common. Emotional stress, and to a lesser extent physical stress, is frequently reported around the time of the event. This profile makes SCAD a distinctly sex-related cardiovascular disease: female-dominated, closely linked to hormonal transitions, non-atherosclerotic, and often preceded by severe psychosocial stress.

In contrast to other forms of coronary disease, evidence-based guidance on exercise and cardiac rehabilitation after SCAD is lacking. Most recommendations are extrapolated from atherosclerotic coronary disease and do not reflect the different risk profile and rehabilitation needs of SCAD survivors. Many patients are advised to avoid high-intensity exercise based on precaution rather than data, and structured rehabilitation is frequently omitted. Observational data suggest that fewer than half of SCAD patients meet general physical activity recommendations, and preliminary findings from the Norwegian Spontaneous Coronary Artery Dissection study (NOR-SCAD) indicate that many have lost physical fitness and do not reach age-expected peak oxygen uptake (VO2peak, ml/kg/min). Restrictive advice may therefore contribute to inactivity, loss of fitness, weight gain, persistent symptoms, and psychological distress, including fear of exertion and anxiety about recurrence. Importantly, there are no robust data demonstrating that usual physical activity increases the risk of recurrent SCAD. This combination of a predominantly female, younger patient group, a strong need for rehabilitation, and limited evidence on exercise safety creates a major gap in sex-specific cardiovascular care.

The Norwegian Spontaneous Coronary Artery Dissection Exercise trial (NOR-SCAD-Ex) is a randomized controlled trial conducted in Norway to address this evidence gap. Adult women and men aged ≥18 years with prior, confirmed SCAD at least 12 weeks before enrollment, who are medically stable and cleared for cardiopulmonary exercise testing (CPET) and supervised exercise, are eligible. After baseline assessments, participants are randomized 1:1 to either a 12-week supervised, treadmill-based high-intensity interval training (HIIT) program or usual care with an upper intensity restriction. All participants receive guideline-directed medical therapy and standard clinical follow-up independent of group allocation. CPET is performed at baseline and at 12 weeks using standardized procedures for calibration, performance, and quality control. VO2peak is defined as the highest 30-second average of oxygen uptake (ml/kg/min) during CPET. In addition to CPET, participants undergo blood pressure and heart rate measurements, routine blood tests (including lipids and cardiac biomarkers), and complete validated patient-reported outcome measures: quality of life (World Health Organization Quality of Life-BREF (WHOQOL-BREF)), anxiety (Generalized Anxiety Disorder 7-item scale (GAD-7)), depression (Patient Health Questionnaire-9 (PHQ-9)) and relevant symptom questionnaires.

The HIIT intervention consists of supervised sessions delivered by trained physiotherapists, typically using treadmill walking or running with individualized speed and incline. Each session includes a warm-up period at low-to-moderate intensity, followed by repeated 4-minute high-intensity intervals targeting approximately 85-95% of peak heart rate or Borg scale ratings of 15-18, interspersed with active recovery periods at about 60-70% of peak heart rate (Borg 11-13). Heart rate is monitored continuously using portable devices to document training intensity and adherence. Participants and physiotherapists are instructed to stop exercise immediately if chest pain, dizziness, palpitations or other symptoms suggestive of cardiovascular intolerance occur, and prespecified rules guide modification or termination of sessions.

Participants allocated to usual care do not receive a structured supervised exercise program during the 12-week intervention period. They are advised to continue their usual physical activity patterns but to avoid high-intensity exercise, defined as sustained effort above 85% of maximum heart rate. To characterize real-world exercise behavior in the control group, participants are provided with heart rate monitors and simple training diaries to record type, duration, and perceived intensity of physical activity. This allows detailed comparison of physical activity patterns between groups and assessment of potential contamination (high-intensity training) in the usual care arm.

Safety is a central focus of the study. Eligibility criteria include exclusion of conditions with strict exercise restrictions (such as major heritable aortic diseases), exercise-induced severe hypertension (e.g. systolic blood pressure > 220 mmHg) or complex ventricular arrhythmias during baseline CPET (e.g. non-sustained ventricular tachycardia >3 beats), and current pregnancy. Safety is monitored throughout the 12-week intervention and an additional 25-week follow-up period (total study duration per participant: 37 weeks). Major adverse cardiovascular events (MACE) including death, recurrent myocardial infarction (SCAD or non-SCAD), heart failure, stroke or transient ischemic attack, extracoronary artery dissection, cardioversion, and implantable cardioverter-defibrillator therapy, as well as serious adverse events and clinically significant arrhythmias, are systematically recorded and adjudicated. A Data Monitoring Committee (DMC) regularly reviews unblinded safety data and applies predefined stopping rules, including a Bayesian-based safety stopping rule, to ensure that the trial can be modified or terminated if unacceptable risk emerges.

Beyond the primary focus on VO2peak and MACE, the trial incorporates exploratory evaluation of blood pressure responses to exercise, including hypertensive response to exercise (HRE), and their potential sex-specific implications. HRE, quantified using systolic blood pressure relative to workload, may unmask latent hypertension and has been associated with future cardiovascular events independent of resting blood pressure. Because SCAD is a female-dominated, non-atherosclerotic coronary disease with reported overlaps with pregnancy complications and other vascular disorders, HRE may help identify subgroups with increased vascular risk who could benefit from targeted follow-up. The study also uses digital tools (such as the MIA activity-tracking app and portable heart rate monitors) to characterize physical activity patterns and heart rate responses in everyday life, providing additional insight into how SCAD survivors engage in exercise under different recommendations.

The overarching hypothesis is that a carefully supervised HIIT program will produce clinically meaningful improvements in cardiorespiratory fitness (a between-group difference in VO2peak of at least 2.5 ml/kg/min) compared with usual care, without an unacceptable increase in MACE. Secondary and exploratory hypotheses include that HIIT will improve quality of life and reduce symptoms of anxiety and depression, that supervised exercise training will favorably modify HRE and other cardiovascular risk markers, and that structured rehabilitation can reduce fear of exertion and support a safe return to physical activity in this vulnerable, predominantly female patient population. By integrating objective measures of fitness, blood pressure, and activity with patient-reported outcomes and rigorous safety monitoring, NOR-SCAD-Ex aims to provide the first randomized evidence on the efficacy and safety of HIIT after SCAD in Norway and to inform future, SCAD-specific exercise and rehabilitation recommendations.