Heart disease is a modern epidemic. Thrombosis of the coronary arteries (aptly named for the ‘crown’ they resemble at the top of the heart), was first described by James Herrick at the meeting of the Association of American Physicians in 19122. Just a decade later, the diagnosis of coronary thrombosis had become widespread and by the post-war years, accounted for nearly half of deaths in America.
The impact of this apparently novel disease in the United Kingdom was so great that Sir Maurice Cassidy, at that time a physician to King George VI, wrote a discourse in 1946 expressing that, “We cannot be said to know a thing of which we do not know the cause”3. We now know a great deal more about the pathogenesis of coronary arterial atherosclerosis, a key predisposing feature to the development of coronary thrombosis. The exact ‘how’ and predisposing factors (‘why’), however, remain a work in progress to date.
Our current understanding of coronary atherosclerosis begins from the cradle. What was initially thought to be a disease caused by ‘bacon and eggs’ (Ancel Keys’ ‘diet-heart’ theory)4, has now evolved into a multifactorial one.
The disease encompasses our genetic programming, epigenetics, lifestyle (inclusive of fitness, physical activity and diet) and the final clinical ‘phenotype’: a positive electrocardiogram (ECG) test, a ‘non-dipping’ blood pressure, a structurally abnormal cardiac magnetic resonance imaging (MRI), a positive calcium score, etc.
Derived focus on a narrow caucasian population segment Our ‘traditional’ knowledge of risk factors predisposing to CVD is owed to large, prospective, populationbased studies in Western cohorts. The most famous of these was the Framingham Heart Study5, from which total cholesterol (TC), ‘bad’ cholesterol (also known as low-density lipoprotein cholesterol (LDL-C)) ‘good cholesterol’ (high-density lipoprotein cholesterol (HDL-C)), blood pressure, smoking, diabetes and age were identified as risk factors in a population free from overt coronary heart disease. Other study groups validating these traditional risk factors include QRISK and EUROScore: British and European groups, respectively.
Criticisms of the Framingham Heart Study have been levelled, citing the predominantly middle-class, middleaged Caucasian population that was recruited, limiting accuracy in younger or elderly individuals, and other ethnic cohorts.
Moreover, other risk factors such as family history or physical activity were not incorporated, nor were novel biomarkers, such as C-reactive protein, which was thought to reflect the inflammatory nature of atherosclerosis. It is readily apparent that these large cohort studies do not shed light into the multifactorial nature of CVD progression.
What of genetics and our molecular ‘signatures’ (proteomics, lipidomics)?
What of the ethnic differences between CVD patients?
Ethnicity, with its accompanying cultural and dietary differences, has long been known to play a role in disease.
Take, for instance, Ancel Keys’ historical account ‘From Naples to Seven Countries’:
i) A Sentimental Journey’6, published in Biochemical Pharmacology, whereupon travelling through the city of Fukuoka in Japan, he noticed a dramatic reduction in serum cholesterol in Japanese clerks, farmers and miners, with an apparent reduction in CVD incidence, which was diminished in Japanese migrant offspring in Los Angeles – an example of ethnicity being of influence in CVD development.
ii) Note also the incidence of clopidogrel ‘resistance’ – in the context of the CYP2C19*2 allele, an issue prevalent in Asian populations7.
iii) Consider the penchant of heart failure with preserved ejection fraction for younger Asians with multiple comorbidities 8. The presence of the ‘lean diabetes’ clinical phenotype9 particular to Asian woman with chronic kidney disease and heart failure.
These point to a unique Asian disease profile which warrants further study.
In the West, attempts have been made to improve upon our traditional understanding of cardiovascular risk factors and include a wider array of patients.
The Pooled Cohort is the most contemporary study group out of the United States, out of which the 2013 American College of Cardiology/ American Heart Association (ACC/ AHA) Atherosclerotic Cardiovascular Disease (ASCVD) risk calculator was derived. This incorporates the Cardiovascular Health Study (featuring patients above the age of 65), Atherosclerosis Risk in Communities Study (featuring African-American populations), in addition to more contemporary Framingham Heart Study cohorts.
Despite these attempts, the ACC/AHA 2013 Prevention Guideline highlighted two apparent areas of need:
Firstly, there was insufficient study data on non-white or non-African American ethnic groups. The document highlighted a “specific call for further research to develop similar equations applicable to other ethnic groups”.
Secondly, regarding alternative risk factors and novel biomarkers, there remains a degree of uncertainty as to their clinical utility, due to the current ‘limited’ evidence available.
In recent years, Western study groups have embarked on collaborative efforts involving data analytics (Project Baseline, Verily Life Sciences) and integrated molecular biosignatures, i.e. proteomics and genomics (MURDOCK Horizon I).
A unique Asian study
SingHEART enters this space as a unique Asian study – the first of its kind in Asia. It is the first contemporary population-based study in Asia involving a multiethnic, healthy Asian population coupled with the use of the latest technologies, including genomics, lipidomics, advanced imaging, wearable data and data analytics.
The study seeks to further our understanding of CVD in the contemporary sense:
SingHEART, led by Associate Professor Yeo Khung Keong, Senior Consultant with the Department of Cardiology at the
National Heart Centre Singapore (NHCS), is one of the multiple projects which uses the NHCS Biobank (led by Professor Stuart Cook from the NHCS, and the Director of the National Heart Research Institute Singapore, and Tanoto Foundation Professor of Cardiovascular Medicine). The Biobank allows patients to share their medical information and provide their blood samples for genetic research.
SingHEART also partners with SingHealth Duke-NUS Institute of Precision Medicine (PRISM), to perform the complex genetic and metabolomic analyses in the study. PRISM, led by Professor Patrick Tan, is a joint institute between SingHealth and Duke-NUS Medical School, whose goal is to develop precise medical therapy for each individual patient using a combination of genetics and other advanced technologies.
Broadly speaking, the study has a threefold objective:
1. Firstly, SingHEART aims to characterise cardiovascular health specifically in Asians, addressing the areas of need mentioned in the ACC/ AHA 2013 Prevention Guideline.
It answers the call for further research on non-Black, non-Caucasian ethnic groups, thanks to Singapore’s diverse ethnic representation of Chinese (East- Asian), Malay and Indian (South-Asian) people. Moreover, it includes the study of elderly Asian populations, due to Singapore’s status as a developed city state with a high average lifeexpectancy and sizeable proportion of elderly citizens, 65 years of age and above (12.4%).
2. Secondly, SingHEART aims to assess and validate pre-existing biomarkers (lipid markers, family history), measurements of cardiorespiratory fitness, and imaging studies identifying subclinical cardiovascular disease, all in Asian populations.
It also seeks to identify new markers influencing the development of cardiovascular disease, involving information derived from wearable devices, sleep trackers, ambulatory blood pressure, continuous ECG monitoring, genomics and lipidomics. Validation of Calcium Score, and cardiovascular phenotyping with Cardiac MRI, will also be performed.
Below is a list of investigations which will be included in SingHEART:
3. Thirdly, SingHEART aims to use both traditional statistical analysis and newer data analytics (machine learning).
Patients enrolled in the study have agreed to a follow-up of up to 20 years, with permission to track their outcomes via national disease registries and databases. Unique to SingHEART is the pre-hoc intention to pool data gathered across multiple domains into larger datasets suitable for analysis by machine learning algorithms (deep learning systems and neural networks; and classification techniques involving decision trees and probabilistic prediction). This will likely provide insights into CVD development and prevention, previously unattainable by traditional methods.
As of February 2018, more than 800 patients have been recruited, with an initial target of 5000 patients based on feasibility and initially funding availability.
The SingHEART Steering Committee is responsible for the overall conduct of the study, with close attention paid to patient confidentiality and data anonymisation. The study protocol involves the obtaining of written informed consent from all subjects.
Already, the study has yielded fruit.
Historians of science refer to ‘paradigm shifts’, where the scientific preoccupations particular to one epoch, give way or are displaced by those of another13. Recent advances in data analytics – artificial intelligence and deep learning, coupled with genomics, metabolomics, and proteomics, represent a ‘quantum leap’ in technology and a subsequent revolution in healthcare. Singapore, and our SingHealth institutions, are well poised to take the lead in this worldwide healthcare revolution through studies such as SingHEART.
In a recent interview with Singapore Health on SingHEART,
Associate Professor Yeo stated that “We need to promote a culture of participation in our own destiny.” How apt it is that less than a century after Sir Cassidy’s lamentation of his failure to solve the mystery of coronary disease in postwar London, Singaporeans in the 21st century Singapore now have the opportunity to take matters into their own hands. To validate, study, and advance the boundaries of clinical science pertaining to cardiovascular disease prevention.
Therefore, we encourage the public to participate in SingHEART programme as volunteers to contribute towards the health of future generations. We also encourage giving to SingHEART, to help with the funding of the study. Your contributions will help your children and your grandchildren to have a better and healthier life in the future.
For queries and/or to volunteer, please contact:
NHCS Biobank Coordinators Tel:
9159 7029 (Mondays to Fridays, 8.30am to 5.30pm)
firstname.lastname@example.orgTo donate, please contact: Tel:
6704 2384 (Mondays to Fridays, 8.30am to 5.30pm)
Associate Professor Yeo Khung Keong is a Senior Consultant with the
Department of Cardiology at the National Heart Centre Singapore (NHCS). He is the Academic Vice-Chair of Training and Education, and the Research EXCO in the Cardiovascular Sciences Academic Clinical Programme. Associate Professor Yeo is also the Deputy Group Chief Medical Informatics Officer (Research) of SingHealth. His sub-specialty interests are in interventional cardiology, structural heart disease, vascular medicine and peripheral arterial interventions.
Dr Kenneth Chew is a Senior Resident with the Department of Cardiology at the National Heart Centre Singapore (NHCS). He is a study team member of SingHEART. Apart from this, he is actively engaged in research and education, serving on the Singapore General Hospital (SGH) Senior Residents' committee and chairing the Division of Medicine Education Sub-Committee. He is also a participant in welfare and tutoring of Junior Residents within the SGH Division of Medicine.
GPs can call for appointments through the GP Appointment Hotline at 6704 2222 for more information.
1. Principle Causes of Death. Ministry of Health, Singapore. www.moh.gov.sg. 2017.
2. Means JH. The Association of American Physicians: its first seventy-five years. New York: McGrawHill, 1961:108. [https://www.ncbi.nlm.nih.gov/ pubmed/1020125] [https://www.ncbi.nlm.nih.gov/books/NBK714/#A382
3. M. Cassidy, ‘Coronary Disease: The Harveian Oration’, The Lancet, 1946, Vol 2. Pp.587-90
4. Ancel keys et al., ‘Mortality and Coronary Heart Disease Among Men Studies for Twenty three Years’, Archives of Internal Medicine, 1971, Vol. 128, pp. 201-14
5. Wilson PWF et al. Prediction of coronary heart disease using risk factor categories. Circulation 1998; 97:1837-47.
6. Ancel keys, ‘From Naples to Seven Countries: A Sentimental Journey’, Progress in Biochemical Pharmacology, 1983, Vol. 19, p. 130.
7. Mega J.L., Simon T., Collet J.P., Anderson J.L., et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010 Oct 27;304(16):1821–30. 8. Tromp J et al; ASIAN-HF Investigators. Heart failure with preserved ejection fraction in Asia. European Journal of Heart Failure (2019) 21, 2336
9. Chandramouli et al. ASIAN-HF Investigators. Impact of diabetes and sex in heart failure with reduced ejection fraction patients from the ASIAN-HF registry. European Journal of Heart Failure (2018).
10. Goff et al. 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk. Circulation (2014)
11. Bylstra Y et al. Population genomics in South East Asia captures unexpectedly high carrier frequency for treatable inherited disorders. Genet Med. 2018.
12. Lim WK et al. Beyond fitness tracking: The use of consumer-grade wearable data from normal volunteers in cardiovascular and lipidomics research. PLoS Biol. 2018;16:e2004285.
13. James Le Fanu. The Rise and Fall of Modern Medicine. Hachette Digital, 2011.
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