This study aims to develop, implement, and determines the effectiveness of a personalized medicine approach to each individual's phenotype, based on an innovative physical exercise program to promote the treatment of pain and functional limitation resulting from knee osteoarthritis (KOA) in patients recovering after acute myocardial infarction (AMI) and cardiovascular risk (CVR).

This randomized clinical study is important due to the lack of evidence according to the effectiveness of a personalized physical exercise intervention in people after MI or CVR with simultaneous KOA.

Some studies have shown the existence of a relationship between OA and cardiovascular diseases (CVD), including coronary artery disease, stroke, congestive heart failure, peripheral arterial disease, cardiac procedures, or death related to CVD, since individuals with OA have a higher prevalence of CVD than individuals without OA.

Sedentary behaviour is a risk factor for AMI, CVR and KOA, and, at the same time, physical exercise is a common non-pharmacological treatment for people suffering from these conditions, namely in the control of joint pain, gains in functional capacity, and the improvement of cardiorespiratory functional capacity, whose impact can be felt in level of quality of life.

Chronic diseases have a significant impact on the global burden of disease, particularly CVD and OA, with the added presence of obesity also contributing to a high rate of all-cause morbidity and mortality, representing a substantial health burden and with growing implications for individuals, health systems and socioeconomic costs.

The presence of OA seems to lead to an increased risk of developing CVD. Several mechanisms have been proposed to explain this relationship. Chronic inflammation associated with OA is one of the hypotheses suggested to explain the increased risk of CVD in these individuals. Furthermore, the pain and disability associated with OA may also limit participation in exercise/physical activity, influencing other risk factors associated with both chronic diseases, such as weight gain.

The lack of studies about physical exercise intervention on people that suffered acute myocardial infarction or is in cardiovascular risk with simultaneous knee osteoarthritis and the lack of offer of phase III cardiac rehabilitation in Algarve motivated the development of this study, with the assumption of adopting a healthier lifestyle.

A new exercise protocol (A3-COR Protocol) for patients with knee osteoarthritis (OA) recovering after acute myocardial infarction (AMI) or with cardiovascular risk (CVR) was developed and implemented. The purpose of the A3-COR protocol is to improve quality of life, functionality, and pain, through regular physical exercise facilitating an active and healthy lifestyle.

This clinical trial includes 2 parallel intervention groups with a pre- and post-test analysis. In the exercise group (EG), the participants will receive a twelve weeks of a supervised personalised exercise program and in the control group (CG) there will be no intervention. Both groups will have a behavioral change session with a psychologist to promote changes in lifestyle and a session with a nutritionist to promote healthy eating habits.

Both groups will be assessed two times, the pre-test in the beginning of the study (T0-Baseline) before starting the intervention or control and the post-test taking place at the end of 12 weeks (T1-Post-test).

The sample includes subjects from the community who met the defined eligibility criteria. Participation in the study is voluntary and sample recruitment will be carried out through publicity materials, such as flyers posted at senior universities, institutions/associations, municipalities, parish councils, sports complexes, health centres, among other public spaces of interest.

To calculate the sample size, the software G*Power was used. The primary outcome for this clinical trial was the knee-related pain, measured by the Knee Injury and Osteoarthritis Outcome Score (KOOS) with is a self-reported outcome with five subscales: 1) Symptoms+Stiffness; 2) Pain; 3) Function, daily living; 4) Function, sports and recreational activities and 5) Quality of Life, all score 0-100. According to the literature, an important clinical difference in the KOOS subscales has been suggested to be 8 to 10 points. Based on the expected difference of 10 points between the intervention and control groups and a standard deviation of 20 in Pain, 64 patients were required in each group with a significance level of 0.05 and power of 80%. With an estimated dropout rate of 10%, a total number of 142 subjects will be randomized to the EG (n = 71) and to the CG (n = 71).

The screening for acute myocardial infarction will be done with the presence of myocardial lesion detected by abnormal cardiac biomarkers evidencing acute myocardial ischemia. The screening of cardiovascular risk will consider the presence of any of the following cardiovascular risk factors: hypertension, dyslipidemia, or smoking habits, according to the SCORE2 or SCORE2 O.P. The screening of knee osteoarthritis will be done according to the National Institute for Health and Excellence (NICE) (2022)(NG226), EULAR evidence-based recommendations for the diagnosis of knee osteoarthritis (2009) and American College of Rheumatology (ACR)(1986) clinical criteria. To identify participants with cognitive impairment, the Montreal Cognitive Assessment (MoCA) instrument was applied and cutoff points for the Portuguese population considering age and educational level were used.

The training sessions combine cardiorespiratory exercises for the development of aerobic capacity and strength exercises, particularly resistant strength, in tasks that include open and closed chain exercises, using your own body weight and equipment for this purpose. The training zones are defined according to the performance of each individual in the test of cardiorespiratory fitness in effort and test of maximum isokinetic strength, carried out in the baseline.

Inclusion Criteria:

• Age 50 or older; Knee pain, Morning stiffness that lasts no longer than 30 minutes and one of the following: crepitus, restricted function, bony enlargement. Acute Myocardial Infarction with myocardial lesion detected by abnormal cardiac biomarkers evidencing acute myocardial ischemia; High risk level in the Systematic Coronary Risk Evaluation (SCORE2) or the Systematic Coronary Risk Evaluation Older Person (SCORE2 O.P.) cardiovascular risk algorithm or prior cardiovascular disease; Independent gait

Exclusion Criteria:

• Occurrence of acute myocardial infarction with less than 12 months; Cognitive impairment- Montreal Cognitive Assessment (MoCA); Type 1 diabetes or insulin dependence; Pacemaker device; Knee prosthesis; Currently doing formal exercise session for more that 30 minutes per week; Class III or IV angina according to Canadian Cardiovascular Society criteria; Class III or IV symptoms according to New York Heart Association criteria; Type 2 Myocardial Infarction; Uncontrolled and symptomatic cardiac arrythmia with hemodynamic impact; Severe and symptomatic aortic valve stenosis; Uncontrolled and symptomatic heart failure; Active myocarditis, pericarditis or endocarditis; Acute aortic syndrome; Known or suspected desiccant aneurism; Acute systemic infection.