Background: Muscle mass loss and metabolic dysfunction, exacerbated by inactivity and nutritional inadequacies, underpin both cardiovascular disease and frailty in ageing. The investigators' proposal seeks to develop interventions in exercise and diet that are targeted for older adults with cardiac frailty.

Methods:

The investigators' proposal is a five-year study comprising of first phase (first 2-2.5 years) and second phase (next 2-2.5 years). In the first phase cardiac frail participants (up to N=500) from each healthcare transition (inpatient hospital, step-down community hospital, outpatient clinic/community) will be randomized to receive Intervention Sets or usual care. The second phase will scale up these programs. Three Intervention Sets A, B, and C will be implemented in the outpatient, step-down community hospital, and acute hospital settings. Diet intervention comprises meal sets prepared with nutrients involved in energy metabolism. Exercise training is facilitated by hospital gyms and hospital physiotherapists. Diet and exercise behavior will be monitored using questionnaires, video conferencing and meal photos.

Significance: Clinical studies are urgently needed using consistent frailty tools to evaluate the efficacy and promise of frailty interventions, targeted to achieve reversal/retardation of frailty. When scaled up, these approaches will provide high-quality science needed to manage cardiac frailty towards healthier population ageing.

BACKGROUND Cardiovascular disease is a formidable disruptor of interventions related to exercise intervention. Patients and physicians face uncertainty about dispensing safe and effective exercise programs to frail patients with concomitant cardiovascular disease. This hesitancy permeates across transitions from acute to step-down care to community settings. Uncertainties include fear of exacerbating heart conditions, individual variability in exercise response and what exercise targets to reach that is rational for each patient. Often, little or no exercise intervention is applied in the acute to step-down phases, which are the periods most critical for frailty reversal. Current dietary interventions do not address the special nutritional needs of acute cardiovascular conditions like heart failure, and may paradoxically induce a syndrome of cardiac cachexia that contributes to the downward spiral of frailty.

STUDY DESIGN:

This will be a prospective randomized clinical trial.

The investigators' proposal is a five-year study comprising of first phase (first 2-2.5 years) and second phase (next 2-2.5 years). In the first phase cardiac frail participants (up to N=500) from each healthcare transition (inpatient hospital, step-down community hospital, outpatient clinic/community) will be randomized to receive Intervention Sets or usual care. The second phase will scale up these programs. At enrolment, pre-defined study time points and end of study, participants will undergo assessments of clinical status, frailty status, cardiovascular function, nutrition, quality of life (QOL), diet/exercise behaviour, and biospecimen sampling. Three Intervention Sets will be implemented in the outpatient, step-down community hospital, and acute hospital settings. Diet intervention comprises meal sets prepared with nutrients involved in energy metabolism. During the trial, exercise intervention is performed in hospitals and community hospitals by physiotherapists. Associated factors such as dietary, comorbidities and other related habits will be tracked simultaneously during the trial

Intervention Set A: exercise sessions and meals over approximately 12 weeks. Intervention Set B : exercise sessions and meals over approximately 3 weeks. Intervention Set C: meals over approximately 3 weeks.

PROCEDURES

1. Baseline Procedures i. Cardiovascular measurements

   • Non-invasive brachial blood pressure machine
   • Echocardiography
   • Electrocardiography ii. Biospecimen collection iii. Six-minute walk test iv. Musculoskeletal Analysis v. Cardiopulmonary exercise test (CPET)/ Treadmill vi. Questionnaires vii. Timed up and go (TUG) test

2. Post-intervention procedures i. Cardiovascular measurements

   • Non-invasive brachial blood pressure machine
   • Echocardiography
   • Electrocardiography ii. Biospecimen collection iii. Six-minute walk test iv. Musculoskeletal Analysis v. Questionnaires vi. Timed up and go (TUG) test

3. Closing questionnaires

Inclusion Criteria:

• Age ≥ 21 years old
• Outdoor ambulant

Exclusion Criteria:

1. Bed-bound
2. Dementia (Stage 6 onwards)
3. Residing in sheltered or nursing home
4. Cancer (to avoid confounding with cardiac disease sequelae from cancer)
5. Participation in ongoing clinical trials that involve interventional drugs or devices
6. Uncontrolled hypertension (systolic blood pressure ≥160mmHg and/or diastolic blood pressure ≥90mmHg) despite being on treatment for hypertension
7. Low blood pressure (systolic blood pressure <90mmHg or diastolic blood pressure <40mmHg)
8. Uncontrolled atrial fibrillation (controlled atrial fibrillation is allowed)
9. Ventricular arrhythmias (such as ventricular tachycardia)
10. Renal failure on dialysis
11. Chronic kidney disease Stage 4 and above
12. Nephrotic syndrome
13. Liver cirrhosis Child's B and above
14. Inflammatory Bowel Disease
15. Severe uncontrolled gout
16. Poorly controlled Diabetes Hba1c ≥9%
17. On warfarin
18. Presence of food allergies (such as shell-fish, prawn)
19. Patient's life expectancy is expected to be less than one year at the time of potential enrolment as assessed by the investigator
20. Nasogastric or parenteral nutrition
21. Hypertrophic cardiomyopathy
22. Cardiac amyloidosis
23. Cardiac sarcoidosis