Cardiac rehabilitation influences serum myokine levels in patients after acute coronary syndrome: the randomised CARDIO-REH study – Nature

Report on Cardiac Rehabilitation, Myokine Modulation, and Sustainable Development Goal 3

1.0 Executive Summary

• This report details a study investigating the effects of a 2-week cardiac rehabilitation (CR) programme on circulating myokine levels in patients recovering from acute coronary syndrome (ACS).
• The study aligns with the United Nations Sustainable Development Goal 3 (SDG 3), specifically Target 3.4, which aims to reduce premature mortality from non-communicable diseases (NCDs) like ischaemic heart disease (IHD).
• A randomised trial compared 110 patients undergoing CR (Group S) with 110 patients not undergoing CR (Group K). Key measurements included serum levels of myokines (apelin, myostatin, follistatin, FSTL1), blood pressure, and body composition.
• Key findings indicate that CR significantly increased serum levels of apelin, myostatin, and FSTL1. These changes were associated with improved cardiovascular parameters, such as reduced blood pressure.
• The study concludes that myokines are independent factors linking CR to cardiovascular benefits, offering a deeper understanding of treatment mechanisms. This knowledge can enhance CR protocols, contributing to more effective management of IHD and the achievement of global health targets under SDG 3.

2.0 Introduction: The Global Health Burden of Ischaemic Heart Disease and SDG 3

2.1 The Challenge to SDG Target 3.4

Ischaemic heart disease (IHD) represents a significant obstacle to achieving SDG 3 (Good Health and Well-being), particularly Target 3.4, which focuses on reducing premature mortality from NCDs. The global impact of IHD is substantial:

• Mortality: IHD was responsible for approximately 9.96 million deaths in 2021, establishing it as the leading cause of cardiovascular mortality.
• Disability-Adjusted Life Years (DALYs): The burden of IHD translated into 196 million DALYs in 2021, with projections approaching 200 million.
• Prevalence: An estimated 1.72% of the global population, or 126 million people, currently suffer from IHD, with this figure projected to rise.
• Economic Cost: The annual cost of therapy following ACS ranges from $34,087 to $86,914, placing a heavy financial burden on health systems and individuals, thereby challenging progress towards universal health coverage (SDG Target 3.8).

2.2 The Role of Cardiac Rehabilitation and Myokines in Promoting Well-being

Physical inactivity is a major modifiable risk factor for cardiovascular disease. Cardiac rehabilitation (CR), an intervention centred on structured physical activity, is a critical tool for secondary prevention and therapy, directly supporting the objectives of SDG 3. CR has been proven to:

• Reduce major adverse cardiac events (MACE) (relative risk [RR] 0.49).
• Lower the risk of ACS recurrence (RR 0.63).
• Decrease the cardiac death rate (RR 0.40).

Myokines—peptides secreted by muscle tissue—are believed to be a key mechanistic link between physical exercise and its systemic health benefits. This study investigates four myokines relevant to the cardiovascular system to better understand how CR improves patient outcomes:

1. Apelin: Exerts cardioprotective effects, lowers blood pressure, and counteracts hypoxia.
2. Myostatin: A negative regulator of muscle growth, its role in cardiac pathology is complex, potentially regulating energy homeostasis in the heart.
3. Follistatin: An antagonist to myostatin with cardioprotective properties, including counteracting cardiac fibrosis.
4. Follistatin-Related Protein 1 (FSTL1): A cardioprotective glycoprotein that promotes cardiomyocyte proliferation and reduces apoptosis.

Elucidating the role of these myokines is essential for optimising CR programmes and developing novel therapeutic strategies to combat the global burden of IHD, thereby accelerating progress towards SDG 3.

3.0 Methodology

3.1 Study Design and Population

• The investigation was a randomised, interventional, prospective, and comparative study.
• A total of 220 patients who had experienced ACS were allocated into two groups of 110.
  • Group S (Study): Underwent a 2-week inpatient CR programme.
  • Group K (Control): Did not undergo the CR programme.
• After exclusions, final analysis was conducted on 99 patients from Group S and 100 from Group K.
• The study received ethical approval (Bioethics Committee, Poznan University of Medical Sciences, no. 476/19) and was registered at ClinicalTrials.gov (NCT03935438).

3.2 Intervention and Measurements

• The intervention for Group S consisted of a comprehensive 2-week CR programme.
• Data were collected at baseline and post-intervention for Group S, and once for Group K.
• The following parameters were measured:
  1. Biochemical Analysis: Serum concentrations of apelin, myostatin, follistatin, and FSTL1.
  2. Cardiovascular Parameters: Resting systolic and diastolic blood pressure and heart rate.
  3. Anthropometrics and Body Composition: Body mass, BMI, fat tissue content, and muscle mass.

4.0 Key Findings: Linking Cardiac Rehabilitation to Physiological Outcomes

4.1 Impact on Myokine Levels

• Apelin: Serum levels increased significantly in Group S after CR and were higher compared to Group K post-intervention.
• Myostatin: Serum levels increased in Group S after CR and were higher compared to Group K post-intervention.
• FSTL1: Serum levels increased in Group S after CR. Levels were initially higher in Group K compared to Group S at baseline.
• Follistatin: No significant change was observed in Group S after CR. Levels remained consistently higher in Group K.

4.2 Cardiovascular and Anthropometric Improvements

• Blood Pressure: Both systolic and diastolic blood pressure were significantly lower in Group S after the CR intervention compared to baseline and compared to Group K.
• Body Composition: In Group S, body mass, BMI, and fat-free mass (FFM) increased post-CR, while muscle mass (MM) and basal metabolic rate (BMR) decreased. Post-CR, FSTL1 levels were related to fat tissue, muscle mass, and BMI.

4.3 Differentiated Response in ACS Subtypes

Analysis within Group S revealed different myokine responses based on the type of ACS, suggesting that tailored interventions could further improve health outcomes and contribute more effectively to SDG 3.

• STEMI (ST-segment elevation myocardial infarction) Patients: Showed significant increases in serum apelin and FSTL1 levels post-CR.
• NSTEMI (non-ST-segment elevation myocardial infarction) Patients: Showed a significant increase in serum myostatin levels post-CR.

5.0 Discussion: Implications for Achieving Good Health and Well-being (SDG 3)

5.1 Myokines as Independent Mediators of Health

The study demonstrates that a short-term, 2-week CR programme effectively modulates key myokines. Regression analysis indicated that the favourable effects of these myokines are largely independent of classical cardiovascular risk factors (e.g., blood pressure, BMI). This suggests that myokines represent a distinct pathway through which physical activity confers health benefits, a finding that is critical for advancing NCD treatment strategies as outlined in SDG 3.

• The significant increase in apelin likely contributes to the observed reduction in blood pressure, directly addressing a primary risk factor for IHD.
• The rise in FSTL1, a known cardioprotective factor, following CR suggests an enhancement of the body’s self-repair mechanisms post-ACS.
• The increase in myostatin, while counterintuitive, may reflect an acute adaptive response to maintain cardiac homeostasis and proper circulation under the stress of rehabilitation.

5.2 Advancing SDG Target 3.4 through Enhanced Treatment

By identifying the specific biochemical changes induced by CR, this research provides a foundation for enhancing therapeutic effectiveness. A deeper understanding of myokine responses can lead to the refinement of CR protocols to maximise physiological benefits. This optimisation is a direct contribution to SDG Target 3.4, as more effective rehabilitation reduces the likelihood of recurrent cardiac events and premature mortality from IHD.

5.3 Towards Personalized Medicine and Universal Health Coverage (SDG Target 3.8)

The differentiated myokine response between STEMI and NSTEMI patients underscores the need for personalised rehabilitation strategies. Tailoring CR programmes to a patient’s specific ACS pathophysiology could maximise clinical benefits and improve resource allocation within healthcare systems. Such precision medicine approaches enhance the quality and efficiency of care, which is a core component of achieving universal health coverage (SDG Target 3.8). By proving the efficacy and understanding the mechanisms of a relatively short and cost-effective intervention, this study strengthens the case for the widespread implementation of CR in health systems globally.

6.0 Conclusion and Recommendations

6.1 Summary of Findings

• A 2-week CR programme in post-ACS patients successfully increases serum levels of the myokines apelin, myostatin, and FSTL1.
• These myokines appear to be independent factors that link the physical activity of CR to its cardiovascular benefits, contributing to the goals of SDG 3.
• Patients with STEMI and NSTEMI exhibit different myokine responses to CR, highlighting an opportunity for personalised therapeutic approaches.

6.2 Recommendations for Policy and Practice

To leverage these findings for the advancement of SDG 3, the following actions are recommended:

1. Enhance Clinical Monitoring: Consider incorporating the determination of serum myokine levels in clinical practice to assess the efficacy of CR and stratify patient risk.
2. Develop Personalised Protocols: Future CR guidelines should consider tailoring training modality and duration based on ACS type (STEMI vs. NSTEMI) to maximise beneficial myokine responses.
3. Strengthen Health Systems: Promote the integration of CR as a standard, essential service for post-ACS care within national health policies to reduce the burden of NCDs and support universal health coverage.
4. Foster Further Research: Encourage further investigation into myokine pathways, including the potential for myokine-based supplementation or therapies for patients unable to perform physical exercise.

Analysis of Sustainable Development Goals (SDGs) in the Article

1. Which SDGs are addressed or connected to the issues highlighted in the article?

The primary Sustainable Development Goal (SDG) addressed in the article is:

• SDG 3: Good Health and Well-being

Explanation:

The entire article is centered on health, specifically cardiovascular health, which is a core component of SDG 3. The analysis is justified by the following points from the text:

• Focus on a Major Health Issue: The introduction immediately establishes the scale of the health problem by stating, “In 2021, ischaemic heart disease (IHD) led to as many as 9,960,000 deaths” and that “IHD remains the top cause of cardiovascular deaths.” This directly relates to the SDG 3 aim of ensuring healthy lives.
• Addressing Non-Communicable Diseases (NCDs): Ischaemic heart disease is a leading NCD. The article’s investigation into cardiac rehabilitation (CR) as a “crucial role… in the prevention and therapy of cardiovascular diseases” is a direct effort to combat NCDs.
• Promoting Well-being through Physical Activity: The article identifies that “Low physical activity was responsible for 684,000 deaths” and highlights physical activity during CR as an “essential intervention.” This aligns with the promotion of well-being and healthy lifestyles under SDG 3.
• Improving Health Outcomes: The study’s objective is to better understand the mechanisms (myokines) behind the benefits of CR to develop “new therapeutic approaches and improvement of those already used,” including “personalised rehabilitation strategies.” This contributes to the broader goal of improving health outcomes for all.

2. What specific targets under those SDGs can be identified based on the article’s content?

Based on the article’s focus, the following specific targets under SDG 3 can be identified:

1. Target 3.4: By 2030, reduce by one third premature mortality from non-communicable diseases through prevention and treatment and promote mental health and well-being.
2. Target 3.8: Achieve universal health coverage, including financial risk protection, access to quality essential health-care services and access to safe, effective, quality and affordable essential medicines and vaccines for all.

Explanation:

• Connection to Target 3.4: The article directly addresses the reduction of premature mortality from NCDs. It provides evidence that cardiac rehabilitation is an effective treatment, stating that it “diminishes… the cardiac death rate (RR 0.40)” and that the “mortality hazard ratio is 0.47 in patients after cardiac rehabilitation compared with patients who do not receive such intervention.” The research aims to enhance these treatments, further contributing to the reduction of mortality from cardiovascular diseases.
• Connection to Target 3.8: While the primary focus is on the clinical aspects, the article implicitly connects to the economic burden of healthcare. It mentions that the “annual cost of therapy after acute coronary syndrome (ACS)… ranges from $34,087 to $86,914.” By investigating ways to improve the effectiveness of cardiac rehabilitation, the study contributes to providing more effective and potentially more cost-efficient healthcare services. Effective rehabilitation can reduce recurrence and re-hospitalization, thus lowering long-term costs and protecting individuals from financial hardship associated with chronic illness.

3. Are there any indicators mentioned or implied in the article that can be used to measure progress towards the identified targets?

Yes, the article mentions and implies several indicators that can be used to measure progress towards the identified targets.

Explanation:

For Target 3.4 (Reduce premature mortality from NCDs), the following indicators are relevant:

• Official Indicator 3.4.1: Mortality rate attributed to cardiovascular disease, cancer, diabetes or chronic respiratory disease.
  • The article provides direct data related to this indicator. It states that “ischaemic heart disease (IHD) led to as many as 9,960,000 deaths” in 2021. It also quantifies the impact of an intervention (cardiac rehabilitation) on this mortality by citing a reduction in the “cardiac death rate (RR 0.40)” and a lower “mortality hazard ratio is 0.47.” These statistics are direct measures of mortality from cardiovascular disease.
• Implied Indicators for Morbidity and Disease Burden:
  • Disability-Adjusted Life Years (DALYs): The article mentions that IHD resulted in “196 × 10⁶ disability-adjusted life years (DALYs).” DALYs are a key measure of the overall burden of disease, combining years of life lost due to premature mortality and years lived with disability. Reducing DALYs is a core component of achieving Target 3.4.
  • Recurrence and Adverse Events Rates: The article notes that cardiac rehabilitation diminishes “the frequency of major adverse cardiac events (MACE; relative risk [RR] 0.49)” and “the risk of ACS recurrence (RR 0.63).” These are crucial clinical endpoints that measure the effectiveness of treatment in preventing the progression and recurrence of NCDs, thereby reducing both morbidity and premature mortality.
  • Cardiovascular Risk Factors: The study measures parameters like “blood pressure, heart rate, anthropometrics, body composition,” which are well-established risk factors for cardiovascular disease. The finding that CR led to lower “systolic and diastolic blood pressure” is an indicator of successful secondary prevention.

4. Table of SDGs, Targets, and Indicators

Source: nature.com