Exercise Therapy for Women With ANOCA

There is a gap in knowledge on evidence-based therapy for ANOCA. Stratified medicine is a population-level diagnostic approach for identifying endotypes in a heterogenous population of all-comers. An endotype is defined as a subtype of a condition, which must be characterised by a distinct functional or pathophysiological mechanism.

Use of quantitative noninvasive and invasive diagnostic methods, such as magnetic resonance imaging and coronary function tests involving acetylcholine testing, enables more accurate identification and discrimination of causal endotypes of ANOCA. This is especially relevant for women with ANOCA who have historically been under-recognised.

Quantitative diagnostic methods should bring an end to empirical therapy, therapeutic nihilism and sex disparities in ANOCA.

Precision medicine is different. Precision medicine targets the individual (and their endotype) with a mechanism informed therapy. Accordingly, in this Wellcome Leap Visible project, we will employ a stratified medicine diagnostic approach in women with suspected ANOCA undergoing invasive CFTs in multiple hospitals and then employ a precision medicine strategy by offering each woman an endotype-informed therapy option.

Resistance exercise has not been previously investigated in ANOCA and it therefore represents a novel therapeutic option. This lifestyle intervention will increase the range of trial options, maximize patient choice for participation, and facilitate timely delivery of this project. The beneficial effects of resistance exercise on cardiovascular function have recently been endorsed in a Scientific Statement from the American Heart Association and further supported by a systematic review and favourable experience in our recent randomized trial in Long COVID.

In 2023, a Scientific Statement from the American Heart Association affirmed that resistance exercise training can improve or maintain muscle mass and strength and confer favourable physiological and clinical effects on cardiovascular disease and risk factors. In 19 men with coronary artery disease and endothelial dysfunction, indicated by abnormal acetylcholine-induced coronary vasoconstriction, a randomized controlled trial of aerobic exercise training demonstrated improvements in endothelium-dependent vasodilatation both in epicardial coronary vessels and in resistance vessels. The intervention involved an exercise program six times per day for at least 10 minutes. These results were promising but came with major limitations: no women were included in the study and the exercise program is both burdensome and impractical.

Resistance exercise has not been assessed in ANOCA. Inclusion of a non-CTIMP (lifestyle intervention) brings strategic advantages to our ANOCA platform. A non-medicinal intervention provides an accessible therapy option for women of child-bearing age and for those who may prefer not to participate in an investigational drug trial. This non-CTIMP may also become an option for women who withdraw from a CTIMP, or who complete a CTIMP and are willing to continue into a second trial. The basket trial of resistance exercise may include participants who have completed a precision medicine CTIMP who then wish to participate in the resistance exercise trial or vice versa.

• Myocardial perfusion reserve (MPR) [Time frame: Change from baseline to week 9]
• Handgrip strength using hand dynamometer [Time frame: Change from baseline to week 9]
• Short Physical Performance Battery (SPPB) [Time frame: Change from baseline to week 9]
• Brief Illness perception Questionnaire (Brief IPQ) [Time frame: Change from baseline to week 9]
• Patient Health Questionnaire-4 of (PHQ4) [Time frame: Change from Baseline to Week 9]
• Duke Activity Status Index (DASI) [Time frame: From Baseline to Week 9]
• EQ-5D (EQ-5D-5L) [Time frame: Change from Baseline to Week 9]
• International Physical Activity Questionnaire (IPAQ) [Time frame: Change from Baseline to Week 9]
• Fatigue severity scale questionnaire [Time frame: Change from Baseline to Week 9]
• Short Form Post-Exercise Malaise Questionnaire [Time frame: Change from Baseline to Week 9]
• Episodes of care (primary, secondary, physiotherapy, rehabilitation) [Time frame: Week 9]
• Hospitalisation for any reason by electronic health record review (where available) up to 4 months (Visit 3) [Time frame: Week 17]