Redirecting immune, lipid, and metabolic drivers of early cardiovascular disease: the RESET cohort study and randomized trial

Project RESET is a Singapore National Medical Research Council Large Collaborative Grant funded programme that brings together a nationwide community of cardiovascular (CVD), metabolic, and digital health researchers, as well as clinicians across primary and tertiary care to study the immune, lipid and metabolic drivers of early CV disease. RESET incorporates a nested randomized controlled trial (RCT) to test the use of a combined digital wearable and artificial intelligence (AI)-human symbiotic lifestyle intervention to halt or reverse the progression of early disease (Figure 1).

Figure 1

Project RESET overview

The case for a new well-phenotyped Asian multi-ethnic preventive cardiology cohort

Holistic assessment for CVD prevention relies on demographic and medium-term modifiable risk factors in quantitative, multivariate Atherosclerotic Cardiovascular Disease (ASCVD) risk scores. The Multi-ethnic study in atherosclerosis (MESA) and Progression of early atherosclerosis (PESA) studies have paved the way for the characterization and assessment of subclinical atherosclerosis progression. Yet, many patients with CVD have ‘normal’ cholesterol, and many with elevated cholesterol do not develop CVD,¹ underlining an example of why improved risk assessment is still much needed. The need for better risk assessment is even more acute in the under-studied 3 billion population of South-east Asia (Malay, Indian and Chinese).

Adding value to the management of cardiovascular disease prevention

First, current risk algorithms do not include dynamic lifestyle and physiological variables, representing a promising but unexploited dimension of personalizable modifiable risk factors. Second, a cost-effective selection of new molecular markers comprising metabolites, cytokines, RNA and DNA either free in plasma or packaged within exosomes is not yet systematically characterized for subclinical disease, particularly heart failure (HF). More pertinently, big data and AI may break the paradigm so that prediction tools rely on personal billion-point databases rather than conventional singular predictive assays. Furthermore, assessing subclinical markers in the myocardium, such as left ventricular (LV) fibrosis, could lend a new actionable dimension to HF disease trajectories and prevention, fundamental to Asia where HF frequently progresses independently of ASCVD, and where up to 60% of HF patients do not have a history of ischaemia.^2,3 Our data, collected from extensive phenotyping, digital wearables, and high dimensional omics in the Project RESET cohort, aims to represent one of the world’s largest digital biobanks that could inform future CVD risk.

Digital biomarkers and personalized risk management: the future of smart cardiovascular health

Despite their potential, the clinical application of digital biomarkers to healthcare remains hampered by challenges.

1. Longitudinal studies of wearables so far have small sample sizes, and had participants wear them for a limited time, leaving gaps in the long-term assessment of complex lifestyle factors, including diet, physical activity, sleep, psychological resilience and physiological measures (Heart rate, VO₂ max, Electrocardiogram) that fluctuate beyond daily/weekly intervals.

2. Current application of mainly conventional epidemiology data analysis methods still has much to benefit from modern machine learning/AI applications.

Meanwhile, a lack of coaching and training on using feedback from digital biomarkers also presents a challenge to users. In an optimal human-AI interaction, humans provide data feeds, and AI reinforces human behaviour, building the opportunity for a feedback loop. A successful version of this forms a human-AI symbiosis.^4,5 Human coaches with digital interventions offer a smart CVD health ecosystem for human-AI symbiosis.^6,7 Moreover, multi-omics big data with individualized genomics info can be leveraged by digital health tools and AI, to deliver precise yet cost-effective clinical care superior to current guideline-based care.

In RESET, studies on economic feasibility, behaviour, and implementation will be assessed for scale and application to early CVD prevention.

RESET trial design

This will be the cohort assembled to study early CVD in Singapore (N = 3000) (Theme 1), providing the platform to map clinical associations and trajectories (Theme 2), novel biomarker and target discovery (Theme 3), and a human digital health coaching lifestyle intervention RCT (Theme 4) (Table 1).

Table 1

Project RESET themes and study cohort

Theme 1. To assemble a cohort for (a) cardiovascular, (b) liver, (c) metabolic, (d) molecular and (e) digital lifestyle characterization (N = 3000)

Theme 2. To map the clinical, molecular, and digital lifestyle associations, trajectories and outcomes in RESET

Theme 3. To discover new targets in early CVD and validate mechanistic causality with mouse and human cell platforms (‘reverse translation’)

Theme 4. To carry out a nested RCT of a digitally supported lifestyle intervention, incorporating behavioural, implementation, and economic evaluations

Study Cohort:

Inclusion criteria: 40–70 years old. No history of CV events. 10-year ASCVD > 5% (e.g. hypertension, hyperlipidaemia, smoker). Central obesity (waist-to-height ratio >0.5).

Exclusion: Contraindications to imaging tests. Limited life expectancy from other ongoing unstable medical conditions.

Additional considerations: We will enrich the cohort to optimize for CV events by including individuals with fatty liver disease, diastolic dysfunction and asymptomatic CAD. Recruitment will also pay close attention to the Singaporean multi-ethnicity, aiming for the 75:15:10 mix of Chinese:Malay:Indian.

Project RESET: specific aims (themes).

In RESET, we will carry out ‘CVLMLM” phenotyping, comprising a panel of Cardio-Vascular tests (myocardial strain, fibrosis, vascular function, coronary artery calcium), Liver (novel cardio-liver ¹³C Magnetic Resonance spectroscopy, liver fibrosis), Metabolic (Intravenous glucose tolerance testing (IVGTT), Homeostatic model assessment (HOMA), calorimetry, magnetic resonance body composition), Molecular (genomics, metabolites, proteomics, immune cytokines, RNA, exosomes, bile acids) and wearable digital Lifestyle biomarkers (psychological resilience, sleep, circadian rhythm, electrocardiogram, heart rate, and physical activity), for association and trajectory analyses, as well as new biomarker and target discovery. A sub-cohort of 200 participants with LV fibrosis on cardiac magnetic resonance imaging will be invited to participate in a nested RCT to test the concept of AI-human symbiosis, in a 1-year long digitally supported lifestyle intervention, incorporating behavioural, implementation, and economic evaluations.

The RESET cohort will be followed longitudinally for at least 5 years with annual interval assessments. Longitudinal analyses will investigate determinants of non-fatal stroke, non-fatal myocardial infarction, admission for HF or CVD death (major adverse cardiac event) outcomes in the observational cohort and changes in cardiometabolic states such as lipids, immune and metabolic profiles, and clinical phenotypes. For the RCT, the primary outcome will be LV myocardial fibrosis, and secondary outcomes will be (i) vascular (i.e. including carotid and femoral arterial assessment, not only CAD), (ii) metabolic, and (iii) molecular phenotypes. Myocardial fibrosis will be assessed by cardiac magnetic resonance using a combination of non-ischemic late gadolinium enhancement (LGE), native myocardial T1, post-contrast myocardial T1, extracellular volume fraction including/excluding LGE regions, interstitial volume (extracellular volume × myocardial volume), and interstitial/myocyte ratio.⁸

National and international collaboration

RESET brings together the two heart centres in Singapore, the National University Heart Centre (NUHC) and the National Heart Centre Singapore (NHCS), along with two universities, the National University of Singapore (NUS) and Nanyang Technological University (NTU) as well as scientists across four A*STAR (Agency of Science, Technology and Research) research institutes, Bioinformatics Institute (BII), Singapore Institute of Clinical Science (SICS), Singapore Institute of Food and Biotechnology Innovation (SIFBI) and the Genome Institute of Singapore (GIS). In addition, we have invited leading international cardiometabolic disease and CVD digital health key opinion leaders to form a RESET advisory panel. Finally, reflecting the timeliness of increasing attention on cardiometabolic disease, early disease detection, and global prevention, plans are also underway for parallel RESET cohort studies in the United Kingdom and South-East Asia.

Supplementary data

Supplementary data are available at European Heart Journal online.

Declarations

Disclosure of Interest

All authors declare no conflict of interest for this contribution.

Funding

This study is funded by The National Medical Research Council Large Collaborative Grant (NMRC LCG), Singapore.

Author notes

Refer to Supplementary data for RESET Consortium.