Clinical and Genetic Determinants of Disease Progression and Response to Sacubitril/Valsartan vs Lifestyle (Physical Activity and Dietary Nitrate) in Patients With Hypertrophic Cardiomyopathy
Phase: PHASE2
Conditions: Hypertrophic Cardiomyopathy
Sponsor: Newcastle University

 
                                                                                  
 
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Research Study Protocol  
 
 
 
Full Title: Clinical and genetic determinants of disease progression and response to lifestyle 
and pharmacological interventions in patients with hypertrophic cardiomyopathy   
 
Short Tittle: Lifestyle and Pharmacological Interventions in Hypertrophic Cardiomyopathy   
  
 
Research Protocol: Version 2.0      14th September 2018 
 
 
Research Team / Investigators: 
Novi Sad (RS): Lazar Velicki et al. 
Paris (FRA): Philippe Charron et al. 
Florence (IT): Iacopo Olivotto et al. 
Regensburg (DE): Lars Maier et al. 
Newcastle (UK): Djordje Jakovljevic et al. 
 
 
 
 
 

 
                                                                                  
 
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Abstract  
The overall aim of this project is to establish potential benefits of a novel lifestyle (physical 
activity and dietary nitrate) and pharmacological (angiotensin receptor neprilysin inhibitor) 
intervention in patients with hypertrophic cardiomyopathy (HCM). HCM is the most common 
genetic cardiovascular disease with a broad spectrum of disease severity. Exercise training is 
associated with a significant increase in exercise tolerance, but appear to have limited effect 
on measures of cardiac morphology or function in patients with hypertrophic cardiomyopathy. 
Dietary supplementation with inorganic nitrate (i.e. concentrated nitrate-rich beetroot juice) 
improves exercise capacity, vasodilatation and cardiac output reserves while reduces arterial 
wave reflections, which are linked to left ventricular diastolic dysfunction and remodelling. 
Angiotensin receptor neprilysin inhibitor reduces death, hospitalisation, and may improve 
cardiac function and exercise tolerance in heart failure. Using a five-centre, open label, three-
arm, pilot design, the present study will evaluate the effect of lifestyle intervention (physical 
activity and dietary supplementation with inorganic nitrate) and pharmacological (angiotensin 
receptor neprilysin inhibitor sacubitril / valsartan) in patients with hypertrophic cardiomyopathy. 
The Aim is to examine whether these interventions improve functional capacity, clinical 
phenotypic characteristics, and quality of life in patients with HCM.   
Background and Rationale for the Study 
Hypertrophic cardiomyopathy (HCM) is the most common hereditary cardiac disease, 
affecting one in 500 individuals.[1] The predominant cause is mutation of genes that encode 
protein components of the cardiac sarcomere.[2] The mechanisms that lead from a sarcomere 
gene mutation to phenotypic expression of HCM are poorly understood, which impedes the 
search for a treatment that can disrupt the pathophysiological process.[3] 
The clinical diagnosis of HCM is based on hypertrophy of the left ventricle that cannot be 
explained by extrinsic factors such as increased afterload.[4] The course of the disease is 
highly variable, ranging from an asymptomatic, benign course with a normal life expectancy 
to a progressive disease characterised by angina, heart failure, atrial fibrillation, stroke, 
malignant arrhythmia, syncope, or sudden cardiac death. Disease progression can relate to 
increasing left ventricular hypertrophy and fibrosis leading to worsening of diastolic (and  
 

 
                                                                                  
 
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occasionally  systolic) function, increased left ventricular end-diastolic pressure, and left atrial 
enlargement.[5] 
No medical treatment has been reliably shown to halt or reverse disease progression.[6] 
Clinical trials demonstrated limited or no effect of angiotensin receptor blockers or late sodium 
current inhibitor on disease progression, cardiac structure and function, exercise tolerance 
and quality of life in patients with HCM.[7 8] Accordingly, treatment recommendations are 
focused on the alleviation of symptoms, prevention of thromboembolic events, and 
implantation of prophylactic implantable cardioverter defibrillators in patients at high risk of 
sudden cardiac death.[4] 
Lifestyle interventions including physical activity and dietary nitrate supplementation are safe 
and can improve symptoms and signs in patients with heart hear failure. Exercise training is 
associated with a significant increase in exercise tolerance, but appear to have limited effect 
on measures of cardiac morphology or function in patients with HCM.[15] Dietary 
supplementation with inorganic nitrate (i.e. concentrated nitrate-rich beetroot juice) improves 
exercise capacity, vasodilatation and cardiac output reserves while reduces arterial wave 
reflections, which are linked to a left ventricular diastolic dysfunction and remodelling.[16-18]  
Angiotensin receptor neprilysin inhibitor (ARNI) is a novel treatment shown to reduce mortality 
and hospitalisation in heart failure with reduced ejection fraction, [9] while there is an ongoing 
trial to evaluate its effect on heart failure with preserved ejection fraction.[10] Recent 
preliminary data suggest that ARNI improves left ventricular wall motion and exercise 
tolerance, while reduces markers of left ventricular wall stress.[11-13] The impact of ARNI on 
parameters of cardiac function and remodeling has not been previously described  in heart 
failure. Several trials are ongoing aiming provide mechanistic insight on the effect of ARNI in 
heart failure.[14] The effect of ARNI has not been evaluated in patients with HCM.   
Despite both lifestyle and ARNI interventions may have potential positive effect, no study so 
far has evaluated their effect on exercise tolerance, cardiac remodelling and quality of life in 
patients with HCM.  
 
 
 
  

 
                                                                                  
 
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Aim and Objectives: 
 
The aim of the project is to identify clinical and genetic markers of disease progression and 
response to lifestyle and pharmacological interventions in patients with hypertrophic 
cardiomyopathy. Specifically, the project will examine whether i) Lifestyle intervention 
incorporating physical activity and dietary supplementation with inorganic nitrate, and ii) 
Angiotensin receptor neprilysin inhibitor will improve functional capacity, clinical phenotypic 
characteristics, and quality of life in patients with HCM. This aim will be achieved through the 
following objectives:  
(1) Review of the genetic testing and medical history of eligible patients. 
(2) Perform detailed clinical assessments and phenotyping before and after four months of 
pharmacological and lifestyle interventions i.e.: 
- 
Compare peak oxygen consumption by cardiopulmonary exercise testing before and 
after the interventions; 
- 
Quantitatively determine effects of the interventions on hypertrophy, left ventricular 
obstruction, left ventricular mass and fibrosis using echocardiography and cardiac 
magnetic resonance imaging. 
- 
Administer quality of life questionnaires before and after exercise intervention.  
 
Main Hypotheses:  
1. Lifestyle intervention incorporating physical activity and dietary supplementation will 
significantly improve exercise tolerance, clinical phenotype and quality of life in HCM patients.  
2. Angiotensin receptor neprilysin inhibitor will significantly improve exercise tolerance, clinical 
phenotype and quality of life in HCM patients. 
 
Primary outcome:  
Change in exercise tolerance i.e. peak oxygen consumption and anaerobic threshold. 
 
Secondary outcomes will include changes in: 
1. Magnitude or distribution of cardiac hypertrophy or left ventricular chamber dimensions.  
2. Degree of left ventricular outflow obstruction.  
3. Systolic or diastolic function.  
4. Cardiac energetic and left ventricular wall motion.  
5. Injury and stretch activation markers.  

 
                                                                                  
 
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6. Quality of life indicators. 
Research Design and Methods 
Overall study design 
We propose to study at least 225 patients across five centres using an open label, three-arm 
pilot trial designed to evaluate the effect of lifestyle intervention (physical activity and dietary 
supplementation with inorganic nitrate) and pharmacological (angiotensin receptor neprilysin 
inhibitor sacubitril / valsartan) in patients with HCM, who are currently not participating in any 
drug trial or a regular exercise regimen (i.e. ≤ minutes of exercise, ≤ 1 day per week for the 
previous 3 months). All patients will be administered a pre-screening questionnaire in order to 
determine eligibility and will be randomized into a intervention or a standard (control) care 
group in the 2:1 ratio. This will be a collaborative effort with investigators from University 
Hospital Regensburg, Assistance Publique - Hôpitaux de Paris (France), Azienda Ospedaliero 
Universitaria Careggi Florence (Italy), Institute of Cardiovascular Diseases of Vojvodina 
(Serbia), and University of Newcastle (United Kingdom) who will secure their own Institutional 
Review Board approvals. Target number is at least 45 patients at each centre. The study will 
be performed at the Clinical Research Facilities, Cardiac Genetics Departments, and Magnetic 
Resonance Centres in participating institutions, three of which will evaluate the effect of 
pharmacological intervention, and two will evaluate lifestyle intervention.  
Eligibility criteria 
In accordance with clinical guidelines, patients diagnosed with hypertrophic cardiomyopathy 
are eligible for inclusion if they had a history of unexplained left ventricular hypertrophy with 
either a maximum wall thickness of 15 mm or more on echocardiography or borderline 
hypertrophy (maximum wall thickness 13–14 mm) on echocardiography and at least one first-
degree relative with hypertrophic cardiomyopathy.[4] 
Inclusion criteria:   
1. Adults (≥18 years of age) with confirmed diagnosis of obstructive and/or non-obstructive 
hypertrophic cardiomyopathy.    
2. Confirmed diagnosis of hypertrophic cardiomyopathy. 
3. Agreement to be a participant in the study protocol and willing/able to return for follow-up. 
4. Able to provide written informed consent. 

 
                                                                                  
 
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Exclusion criteria: 
1. Less than 3 months post septal reduction therapy (surgery or catheter based intervention) 
2. Clinical decompensation in the previous 3 months, defined as New York Heart Association 
class IV congestive heart failure symptoms.  
3. Resting blood pressure greater than 180/100 mm Hg. 
4. Systolic blood pressure lower than 100 mmHg 
5. Hypotensive response to exercise testing (≥20 mmHg decrease of systolic blood pressure 
from baseline blood pressure or an initial increase in systolic blood pressure followed by a 
decrease of systolic blood pressure  ≥20 mmHg).  
6. Use of angiotensin converting inhibitors or angiotensin receptor blockers. 
7. Resting left ventricular outflow tract gradient > 50 mm Hg. 
8. Left ventricular ejection fraction of less than 50% by echocardiography. 
9. Implanted pacemaker or cardiodefibrilator in the last 3 months or scheduled. 
10. Renal insufficiency with an glomerular filtration rate of less than 30 mL/min per 1.73m2. 
11. Present or planned pregnancy. 
12. Life expectancy less than 12 months.  
13. Body mass index >40 kg/m2. 
14. A history of exercise induced syncope or ventricular arrhythmias. 
15. Inability to exercise due to orthopaedic or other non-cardiovascular limitations. 
16. Use of other investigational drugs at the time of enrolment.  
17. Any surgical or medical condition that in the opinion of the investigator may place the 
patient at higher risk from his/her participation in the study or is likely to prevent the patient 
from complying with the requirements of the study or completing the study. 
18. History or presence of any other disease with a life expectancy of <3 years 
19. History of noncompliance to medical regimens and patients who are considered potentially 
unreliable. 
20. History or evidence of drug or alcohol abuse within the past 12 months. 
21. History of malignancy of any organ system (other than localized basal or squamous cell 
carcinoma of the skin or localized prostate cancer), treated or untreated, within the past 2 
years, regardless of whether there is evidence of local recurrence or metastases. 
22. Life-threatening or uncontrolled dysrhythmia, including symptomatic or sustained 
ventricular tachycardia and AF or atrial flutter with a resting ventricular rate >110 beats per 
minute. 

 
                                                                                  
 
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23. Participation in competitive or organized sport activities (such as football, basketball, rugby, 
hockey, etc), burst activity (such as sprinting, racket sports, etc) or heavy isometric exercise 
(such as body building or bench-pressing) or opposition of refraining from the same for the 
duration of the study. 
Recruitment procedures 
Potentially eligible patients will be identified through the Cardiology clinics of the participating 
centres. Patients will be identified and contacted by the member of the study research team. 
An information sheet will be mailed out upon request. Consent forms will be signed by the 
participant and countersigned by a member of the study team during the first research visit. 
 
Interventions 
Duration of lifestyle and pharmacological interventions is proposed to be 4 months.  
Lifestyle Intervention  
The lifestyle intervention will consist of two integrated components i.e. physical activity and 
dietary supplementation with inorganic nitrate. 
The first component of the lifestyle intervention is physical activity component which is a 
validated home-based exercise intervention aiming to increase daily physical activity level by 
at least 2000 steps/day from baseline (e.g. walking for approximately 30 minutes), at least 5-
7 days per week, as this increment in daily physical activity was associated with a 10% lower 
risk of a cardiovascular events in high risk patients.[19]  
The previous study confirmed the feasibility and acceptability of such physical activity 
intervention in patients with chronic heart failure.[20] This increase can be divided into several 
bouts of shorter activity duration throughout the day (e.g. 3 x 10 min or similar). To control for 
exercise intensity patients will be instructed to use standardised Borg Scale (0-20) to rate 
perceived exertion aiming for achieving the levels between 11 – 13 (easy-light-to somewhat 
hard). The exercise prescription will be progressed individually as conditioning takes place, 
with the emphasis placed on volume of activity i.e. duration before intensity. Targets will be 
set by participants, but we will present potential health benefits of increasing physical activity 
by 2000 steps per day at least five days per week (≥150 minutes per week). No strength 
training or burst activity will be prescribed and all activities will fall well within the recommended 
national guidelines for recreational exercise. Participants will be counselled to hydrate 
adequately during exercise, and to be alert to warning signs and symptoms that should prompt 
them to stop exercising and contact the research team. All patients will be provided with 

 
                                                                                  
 
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pedometers and asked to complete a daily physical activity diary which will be reviewed and 
discussed on a weekly basis (telephone call) with the member of the research team. All study 
participants will keep an exercise log and be provided with pedometers. 
The second component of the lifestyle intervention is a dietary supplementation with 
inorganic nitrate. A single dose of inorganic nitrate given in the form of concentrated nitrate-
rich beetroot juice (NO3−, BEET IT Sport, James White Drinks Ltd., Ipswich, UK) containing 
6 mmol of NO3− in 70 ml bottle versus an otherwise identical nitrate-depleted placebo (James 
White Drinks, LTD., Ipswich, UK). Instructions will be provided for self-administration of the 
nutritional intervention and patients will be asked to consume beetroot juice each morning with 
the breakfast for 4 months. 
The EPIC Food Frequency Questionnaire (FFQ) will be administered at baseline and the 
FETA software used to extract dietary (energy and nutrient) information.[21] Adherence to the 
intervention will be tracked by completion of activity logs, weekly telephone follow-ups, 
pedometers, and self-reported diaries.   
Pharmacological Intervention 
(Angiotensin receptor neprilysin inhibitor sacubitril / valsartan) 
Patients who meet the study inclusion/exclusion criteria, after signing the informed consent, 
will be invited to the screening visit. Patients previously receiving angiotensin-converting 
enzyme inhibitor or angiotensin receptor blocker therapy will require a 36-hour washout period 
before initiation of sacubitril/valsartan to reduce the risk of angioedema.[14]  
The treatment period begins on day 1 with initial dosing of sacubitril/valsartan, followed by 
uptitration every 2 to 4 weeks, according to the prescribing information, to the target dose of 
97/103 mg twice daily. The 3 doses of sacubitril/valsartan available throughout the study are  
24/26 mg (dose level 1), 49/51 mg (dose Level 2), and 97/103 mg (dose Level 3), each taken 
by mouth twice daily. 
Doses may be adjusted based on overall safety and tolerability. If necessary, dose 
adjustments or elimination of concomitant medications is made to alleviate adverse effects. If 
adverse effects are not alleviated or it is not possible to adjust concomitant medications, the 
study treatment may be down-titrated by 1 dose level—or, at the lowest dose, temporarily 
withdrawn—for 1 to 4 weeks. The patient may then be reassessed and the study treatment 
further down-titrated every 1 to 4 weeks until the patient is deemed stable. Once stability is 

 
                                                                                  
 
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achieved, the patient is re-challenged with up-titration to the target dose. If the patient 
discontinues the study medication, the patient is advised to return to the clinic for an end-of-
study visit. Patients undergo treatment for four months. 
 
Control group / Usual Care  
Patients with HCM typically do not receive exercise and/or nutritional therapies. The choice of 
a usual care (no intervention) comparator in this pilot study is therefore reflective of the 
situation for the vast majority of patients with HCM. In this study, the intervention and control 
group will receive usual medical management for HCM according to national and local 
guidelines. Participants in the control group will also be provided with activity logs, weekly 
telephone follow-ups, pedometers, and self-reported diaries but will be asked not to change 
their physical activity and dietary habits during the study. 
 
Research Visits  
Eligible participants will attend the Clinical Research Facilities of five participating centres for 
the total of 5 visits i.e. two at baseline (Visit 1 and Visit 2), and two at 4-month (Visit 3 and Visit 
4) when the assessments performed during Visits 1 and 2 (detailed below) will be repeated. 
Patients will be given new activity logs at the end of 4-month protocol period and these logs 
will be reviewed 3 months later (7 months after study initiation) during the follow-up visit (Visit 
5). During this visit, patients will be asked to complete quality of life questionnaires. 
Additionally, physical activity will be reviewed and patients will be asked to repeat 
cardiopulmonary exercise test.  
Participants will be contacted via email, telephone or spoken to in person to discuss the project 
and will be taken through the information sheet to ensure they understand the nature of the 
study.  
The following testing will be performed at study initiation and termination, as detailed below:  
1. Bloods, body composition, electrocardiography, cardiac autonomic function, arterial 
stiffness.  
2. Cardiopulmonary exercise testing in combination with echocardiography. 
3. Cardiac magnetic resonance imaging in patients without implantable devices. 
4. Quality of life, Anxiety and Depression, and Food Frequency questionnaires.   

 
                                                                                  
 
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Mandatory procedures: Medical history review; Physical examination and anthropometry; 
Fasting bloods; Resting ECG; Echocardiography (rest and Valsava); Cardiopulmonary 
exercise stress testing; Magnetic Resonance Imaging (standard cine imaging + LGE, 
spectroscopy, tagging as available) for 20 randomly selected patients (at each centre) i.e. 10 
intervention and 10 control; 24hr Holter monitoring; Questionnaires (2 x Quality of Life and 1 
x Anxiety and Depression); and 5-7 days physical activity (pedometer). Genetic testing only in 
patients without existing genetic testing.  
Optional procedures: Body composition (% body fat, lean body mass etc) by airdisplacement 
plethysmography, bioimpedance, or DEXA; Stress echocardiography; Arterial stiffness; Heart 
Rate and Blood Pressure Variability. 
Research Visit 1: will be performed at the Clinical Research Facility and will last 3.5-4 hours. 
It will include one-hour break for breakfast. The following clinical investigations will be 
performed during the Visit 1: 
i) Consent and Screening Questionnaires (20 minutes). 
- Patients will be provided with the opportunity to ask further questions and requested to 
provide written informed consent. Review of the medical history will be performed.  
 
ii) Physical examination, anthropometric and body composition (30 min). 
- Body weight and height will be measured using hospital based scale and stadiometer. The 
amount of fat and muscle in the body will be assessed using non-invasive air displacement 
plethesmography (BodPod), or bioimpedance methods, as appropriate. In case of 
contraindications only anthropometrics (weight, height, and waist circumference) will be 
measured. 
 
iii) Blood Sample and Genetic Testing (15 min). 
- After an overnight fast, the blood sample will be taken from the antecubital vein. The blood 
sample will be assessed for brain natriuretic peptides (NTproBNP), lipid profile (total 
cholesterol, HDL-cholesterol, LDL-cholesterol), triglycerides, glucose, HbA1c, markers of 
renal function (urea, creatinine, eGFR), markers of inflammation (TNFα, CRP), endothelial 
progenitor cells, and circulating endothelial cells. Blood sample (25 ml) will be collected before 
and after the intervention. In patients who did not have genetic testing performed earlier, it will  

 
                                                                                  
 
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the genetic analyses will include the following genes: MYH7, MYBPC3, TNNT2, TNNI3, 
ACTC1, ACTN2, ANKRD1, CSRP3, FHL1, GLA, LAMP2, MYL2, MYL3, PLN, PRKAG2 and 
TPM1. 
 
iv) Breakfast (60 min) 
- As participants are coming following an overnight fast, they will be provided with a light 
breakfast consisting of a toast and orange juice. Following breakfast patients will be asked to 
complete validated questionnaires: Quality of Life (Minnesota Living with Heart Failure and 
SF36), Hospital Anxiety and Depression Scale, and Food Frequency Questionnaires. 
 
v) Electrocardiography (ECG) (10 min). 
- The ECG will be performed using a standard 12-lead electrocardiogram in supine position.  
 
vi) Arterial stiffness assessment (10 min). 
- Arterial stiffness, as a measure of arterial function, will be assessed using non-invasive 
SphygmoCor device which allows for both pulse wave analysis and pulse wave velocity to be 
performed non-invasively using the gold standard techniques. The measurement is simple 
and painless, taking only a few minutes to perform. While the participant is in a comfortable 
supine position, the researcher will place a tonometer (pencil-like sensor) gently against the 
wrist and will record blood pressure signal from the pulse.  
 
vii) Cardiac autonomic function (20 min). 
- Cardiac autonomic function i.e. heart rate and blood pressure variability will be assessed 
using non-invasive methods integrated into the TaskForce device. Using electrocardiogram 
and continuous blood pressure monitoring with a finger cuff under resting supine condition 
computer will assess heart rate variability and blood pressure variability. 
 
viii) Transthoracic Echocardiography (ultrasound of the heart) (30 min).  
- An echocardiogram is an ultrasound scan of the heart which details structure and function of 
the heart. Participant will be undressed to the waist. A probe (e.g. thick blunt pen) is placed 
on the chest. Lubricating jelly is put on the chest to form good contact between the probe and 
skin. The probe is connected by a wire to the ultrasound machine and monitor. Pulses of 
ultrasound are sent from the probe through the skin towards the heart. The ultrasound waves 
then echo ('bounce back') from the heart and various structures in the heart. Transthoracic  

 
                                                                                  
 
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echocardiography including color and tissue Doppler will be performed at rest, in response to 
Valsalva manoeuvre, and at the end of cardiopulmonary exercise test, detailed below. Real-
time images acquired in the standard parasternal (long-axis) and apical (apical 4, apical 2, 
and apical long) views, and 3 cardiac cycles recorded. Parasternal short-axis views acquired 
at 3 levels: basal (at mitral valve level), midpapillary, and apical (minimum cavity distal to 
papillary muscle level). Parasternal long axis of the right ventricular and right ventricular 
outflow tract will be monitored. Peak velocity of the left ventricular outflow tract will be recorded 
from the apical 5 chamber view by pulse Doppler, used to calculate pressure gradient. Apical 
4-chamber view will be used for right ventricular evaluation. 
 
ix) Cardiopulmonary exercise test (30 min). 
- A progressive exercise test using cycle ergometer will be undertaken to assess oxygen 
consumption and ventilation. Patients will be asked to wear facemask to collect and analyse 
expired gasses. An ECG, blood pressure, and cardiac output (using non-invasive  
bioreactance method that utilise 4 dual electrodes placed on the back side of the thorax) will 
also be performed at resting and during the exercise. Additionally heart rate will be monitored 
using wireless smart cardia device at rest and during exercise. In brief, using a cycle 
ergometer the progressive exercise test involves maintaining a pedal frequency of 60-70 
revolutions per minutes with work increasing at 1 minute intervals. The test will be terminated 
when the patient is unable to maintain pedal frequency above 60 rpm or the patient voluntary 
terminates the test.   
 
x) Holter monitoring  
A type of portable heart monitor that is a small electrocardiogram (ECG) device worn in a 
pouch around the neck or waist. A Holter monitor keeps a record of the heart rhythm, typically 
over a 24-hour period, and the patient keeps a diary of activities and symptoms. The ECG 
recording is then correlated with the person's activities and symptoms. This type of test is 
useful for identifying heart disturbances that are sporadic and not readily identified with a 
resting ECG. 
 
xi) Physical activity monitoring (explanation 10 min). 
- At the end of all investigations the patient will be provided with the small, unobtrusive 
accelerometery monitor (i.e. wrist-watch and/or pedometer for counting daily number of steps) 

 
                                                                                  
 
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to assess physical activity level over a 7-day period. The monitor will be returned to the 
research team through the post in provided pre-paid envelope. 
- Lunch will also be offered at the end of research Visit 1 to study participants. 
 
Research Visit 2: will be performed at the Magnetic Resonance Centre on different day but 
during the same week as Research Visit 1 depending on availability of the scanner, and will 
last up to 2 hours. It is expected that some people will not be eligible for the scan, particularly 
if they have implanted a metal device, or if they feel claustrophobic (fear of being enclosed in 
a small space). Cardiac magnetic resonance imaging assessment will be include the following: 
i) Magnetic Resonance Imaging (MRI) Screening Questionnaire (15 min).  
The subject is taken through a MRI screening questionnaire (Version 1-1 April 2008) to 
ascertain that they have no contraindications to MRI studies by an experienced MR 
radiographer. They have the opportunity to ask questions about the MR studies. 
ii) Cardiac MRI Examination (90 min):  
Selected participants (20 per centre) without MRI examination over the previous 6 months will 
undergo a standard cardiac cine imaging, to evaluate cardiac morphology, systolic and 
diastolic function, (ii) cardiac tagging to evaluate wall motion and torsion. These 
measurements will be taken with the participants laying supine within a Philips 3T MRI scanner. 
After a short break, participants will lie in the scanner prone for phosphorus magnetic 
resonance spectroscopy, to measure the ratio of PCr/ATP, a measure of steady state 
metabolite use. Perfusion imaging performed to assess first pass perfusion during bolus 
injection of 0.1 mmol/kg of gadolinium contrast agent. Phase sensitive 2D inversion recovery 
prepared Gradient Echo imaging will be performed 15-20 minutes post injection to evaluate 
for delayed enhancement of the myocardium. 
Research Visit 3: will be performed within 3 days after the intervention i.e. 4 months after 
Research Visit 1 and will include assessments undertaken during Research Visit 1. 
Research Visit 4: will be performed within 7 days after the intervention i.e. 4 months after 
Research Visit 2 and will include assessments of the cardiac MRI undertaken during Research 
Visit 2. 
Research Visit 5 (3-month follow-up): will be performed 7 months after study initiation when 
quality of life questionnaires and cardiopulmonary exercise testing will be completed, and 
physical activity reviewed.  
End of the Study 
At the end of the study all participants will be provided with information about study’s major 
findings. This will be communicated by letter mailed to the participants home address and will 

 
                                                                                  
 
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also include an invitation to attend a volunteer feedback evening at the Clinical Research  
Facility where the overall results of the study will be presented. The study will be completed 
when study participants completed the proposed research visit. 
Statistical Analyses  
Clinical data will be collected, coded and entered into database generated and managed by 
the research team. Descriptive statistics will be reported as mean ± SD. All major treatment 
comparisons between the randomized groups will be performed according to the intention-to-
treat principle: that is, patients will be analysed – and end points will be attributed – according 
to the treatment arm to which patients are randomized regardless of non-adherence. 
Comparisons between groups will be performed by unpaired t tests for continuous variables 
and χ2 or Fisher’s exact test for categorical variables. Changes in continuous variables over 
time within each group, and between groups, will be assessed by paired t-tests. The bivariate 
correlations procedure will be used to compute Pearson’s correlation coefficients with the 
significance levels. For all subjects, multiple linear regression analysis will be performed for 
changes in primary and secondary outcome measures at month 6 from baseline as the 
dependent variable, with baseline demographic and clinical characteristics (age, sex, and 
genetic status) as independent variables. Results will be reported as means with 95% 
confidence intervals. Two-sided P values will be calculated for all statistical analyses. 
Significance will be defined as P less than 0.05. 
Funding 
This project has received funding from the European Union’s Horizon 2020 Research and 
Innovation Programme under Grant Agreement no. 777204. 
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