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Predicting heart disease risks

February 6, 2012


Making sense of less conventional risk markers in your blood test results.

DR Deepak Chopra, the famous health, spirituality and wellbeing guru, once said in a TV show: “We are all on death row. The only uncertainty is the length of reprieve and the method of execution. Death makes life possible.”

Over the past 20-30 years, the “method of execution” inMalaysia, as in the rest of the world, has principally been cardiovascular diseases. This includes heart attacks and strokes.

Statistics in 2009 from the Health Ministry estimated that about one in four deaths in government hospitals are attributed to either heart or strokes.

Such grim statistics are not likely to improve in the coming years. Instead, the numbers are poised to worsen given the rising trend of risk factors that contribute to cardiovascular diseases. The recently completed fourth National Health and Morbidity Survey revealed an increasing incidence of non-communicable diseases. Approximately 15% of adult Malaysians are obese and nearly one in every two Malaysians are either overweight or obese. About 20% of us are diabetics, and more than one in three have high blood pressure.

Related to these embarrassing statistics are our poor lifestyle habits, eg low intake of adequate servings of vegetable and inadequate exercise (only 65% claim to exercise regularly).

A large international trial involving nearly 30,000 subjects, the INTERHEART study, showed very clearly that 90-95% of the risks attributable to the causation of heart attacks can be explained by nine potentially modifiable risk factors (smoking, apoprotein B/apoprotein A1 ratio, hypertension, diabetes, abdominal obesity, psychosocial factors, daily consumption of fruits and vegetables, regular alcohol intake, and regular physical activity).

This association is generic as it applies to men and women, old and young, and in all regions of the world.

Atherosclerosis: basis of cardiovascular diseases

The term atherosclerosis refers to the build-up of plaque – a predominantly cholesterol deposit with an overlying cap of fibrous tissue – in the wall of the arteries in the body. It is now clear that the development of the plaque is a chronic process that often begins in childhood and adolescence. This is an active inflammatory process involving the body’s immune cells and mechanisms, but remains silent for decades until a late stage of advanced plaque accumulation or plaque rupture.

The manifestation of disease may be the development of chest pain on effort (angina pectoris) or the more risky situation of threatened or established heart attack.

All too often, we hear stories of apparently healthy and even fit young persons collapsing suddenly in the midst of their regular activities. In fact, statistics reveal that 40-60% of persons with heart disease first manifest in the form of a heart attack or sudden death.

Detecting early disease

The prospect for such an outcome is scary, and this has led to intense efforts by clinicians and scientists to develop methods and tests to detect heart disease in asymptomatic individuals. The potential to prevent such catastrophic events through early detection and treatment is enticing.

The detection of early disease or increased risk entails more aggressive treatment of risk factors, and sometimes, initiation of cardioprotective medications.

In general, there are a number of ways that your doctor employs to estimate an asymptomatic person’s cardiovascular risk. The simplest, inexpensive and rather useful way is to identify the presence of established traditional risk factors. These include high cholesterol levels, high blood pressure, diabetes, smoking, age and gender.

Through various validated risk prediction models, estimated risk – expressed as percentage risk of a cardiovascular event over a number of years, may be obtained.

One of the most popular models is the Framingham Risk Score. A low risk is conventionally defined as having a 5% or less chance of cardiovascular event in the next 10 years. Intermediate risk is between 6-20%, and a high risk individual has more than 20% risk projection of a cardiovascular event in the next 10 years.

However, no single risk prediction model is perfect. Hence, the search for better ways to improve the stratification of risks in asymptomatic individuals.

This may be in the form of imaging tools, blood markers or ankle-brachial index (ABI) test. The former are methods to directly identify the presence of plaque, and include cardiac CT (computed tomography) angiography scans, heart MRI (magnetic resonance imaging), carotid intimal medial thickness (CIMT) measurements with ultrasound and invasive tests (eg intravascular ultrasound), and optical coherence tomography (OCT).

Investigators have identified new and novel markers in the blood that appear to predict cardiovascular risks. The detection of peripheral arterial disease – narrowing of arteries of the lower limb via conducting an ABI test has also been shown to predict risks.

These new tests are available to the Malaysian public and are often recommended in enterprising ways. Confronted by the confusion and anxiety that often arises from such tests, this writer hopes to briefly put into perspective the indications and current scientific opinion for some of these novel blood tests.

The use of ABI and imaging modalities, is by large, a sometimes controversial topic and will not be covered in this article.

Current paradigm and use of new blood markers

We need to understand that no single test is definitive in risk estimation. The approach that most clinicians use combines the global clinical evaluation of an individual based on the traditional risk scores and refining the risk estimates with additional selected tests.

Importantly, a test should not be conducted just for the sake of testing. For example, a person already deemed to be at high risk for a cardiovascular event based on global risk estimates will have little to gain from doing further tests as his/her risk profile remains elevated, regardless of the test results.

Requesting a whole battery of tests would hence be a waste of funds, with little additional information to gain.

Similarly, a person with very low risk may not benefit from additional testing as his/her risk category is not likely to change. However, a physician may, in selected cases, recommend additional tests based on professional knowledge of limitations of certain risk models.

An example would be an often underestimation of risks with theFraminghammodel for women with a family history of premature coronary heart disease.

The best category of persons to gain from these additional tests are those in the intermediate risk group. Selecting appropriate tests may reclassify the prevailing risk estimate either upwards or downgrade the risk projection.

Another misconception that needs to be addressed is the understanding that certain blood markers are good only to predict risk. The relationship between marker and risk does not necessarily mean a causative link. This means that although an elevated blood marker predicts greater cardiovascular risk, the logic that reducing the level of such a marker will reduce risk may not necessarily apply.

Highly sensitive C-reactive protein (hs-CRP)

C-reactive protein is a circulating protein involved in immunity, and elevated levels are indicative of inflammation, including that of the vessel wall. It has been implicated in the development of atherosclerotic plaques and also in the conversion of the quiescent plaque to an unstable ruptured one that is liable to cause a heart attack.

Multiple large scale studies have shown elevated hs-CRP to independently predict risk of a heart attack, stroke, or death from cardiovascular disease.

The incorporation of hs-CRP in theFraminghamcalculation of cardiovascular risk (ie Reynold’s Risk Score) has further improved its risk-predictive ability.

The general categories of hs-CRP levels are 1mg/l (low); 1-3 mg/l (intermediate) and 3 mg/l (high). However, these cut-off levels are arbitrary, and even lower levels have been shown to correlate with further lowered risks.

The best value of this test, however, comes from the potential for some medications, especially cholesterol-lowering medications (statins), to lower hs-CRP.

A study called the JUPITER trial investigated the use of statins in asymptomatic patients with fairly normal cholesterol levels but elevated hs-CRP levels. This trial was prematurely stopped owing to resounding benefits seen in individuals actively treated with a statin, as the study safety committee found it unethical to withhold such benefits from the placebo-treated study group.

However, there are many caveats to the use of this test. There are many factors that may increase hs-CRP levels, eg smoking, any infection, inflammatory conditions, etc.

Apo-lipoprotein A and B

The conventional lipid profile measures the total cholesterol level, HDL-cholesterol level (good cholesterol), triglyceride level and the mathematical calculation-derived LDL-cholesterol level (bad cholesterol).

LDL-cholesterol is recognised as the major culprit in the development of cholesterol plaques.

The cholesterol particles are, however, not a simple lump of cholesterol travelling in the blood stream to be deposited in the arterial walls. Cholesterol is packaged as a lipoprotein particle that has a protein component called apo-lipoprotein (Apo-A or Apo-B), and the cholesterol/lipid component.

Apo-A1 is the major apo-lipoprotein in HDL-cholesterol and apo-B in LDL-cholesterol. HDL-C cholesterol, we know, are the “reverse-transporters”. It collects cholesterol from the vessel walls and brings them back to the liver for excretion.

In certain situations like diabetes mellitus or metabolic syndrome (combined presence of obesity, abnormal blood sugars, hypertension, abnormal lipid profile), the LDL-cholesterol particles are predominantly small and dense. These LDL particles are more pro-atherogenic. The increased numbers of these small dense-LDLs are not reflected in the conventional calculation of LDL-C cholesterol.

Hence, one may get a false impression of normal LDL-C cholesterol levels in these subjects. By measuring apo-B level, we are able to directly assess the number of LDL-C cholesterol particles and give a better assessment of risk associated with LDL-C cholesterol.

Therefore, conceptually, apo-B reflects the total amount of pro-atherosclerotic lipid particles and apo-A reflects the total protective lipid fraction. The ratio of apo-B/apo-A1 tells us the balance of cholesterol transport – the lower the value, the better the risk.


This lipoprotein basically has an apolipoprotein (a) of unknown significance attached to the lipid particle. This apolipoprotein (a) may have properties that enhance oxidation of LDL-cholesterol, which encourages deposition of cholesterol in vessel walls and also promotes clot formation.

This test is not recommended for routine screening but may be most useful for individuals with high cholesterol and a family history of premature coronary artery disease.


The homocysteine story is an interesting one. The correlation between elevated homocysteine level and cardiovascular risk is well established. It has also been shown to increase risk prediction capability of theFraminghamrisk score.

We also know that supplementation with folic acid and vitamin B6 or B12 can lower homocysteine level. It was based on this observation that some have recommended this therapy as a means to prevent cardiovascular events.

Despite lowering homocysteine by 25%, folic acid supplementation did not result in less cardiovascular events. A recent large study (compilation of eight trials involving 37,485 individuals in 2010) reaffirms the lack of benefit from lowering homocysteine with vitamin B therapy.

Homocysteine seems to be a marker for cardiovascular disease, but may not be involved in disease development. Hence, an individual with intermediate risk may choose to perform this test for better classification of his/her risk, but there is no further treatment advocated to lower the level even if it is elevated. There has been much progress in our understanding of the causation of heart disease. The number of persons with known cases of heart disease are only the tip of the iceberg. There is a large pool of individuals with silent, “smouldering” coronary heart disease, waiting for a cardiac event to occur.

Not uncommonly, the outcome is catastrophic, with sudden death or major heart attack as the first presentation of cardiac disease.

Medical science has achieved much success in treating heart disease. However, success will be greater if we can prevent heart disease, or at least detect disease earlier to allow preventive treatment.

The conventional global risk scoring methods based on traditional risk factors stratify individuals to different categories of risk. Intermediate risk patients, however, will benefit from refinement of their risk using selected blood tests or imaging methods.

Beyond conventional blood tests that identify the presence of risk factors that contribute to heart disease like cholesterol levels, sugar levels, etc, there are many new emerging markers that help to improve risk prediction.

However, not all tests are necessary nor useful. Though some of these tests are easily available at your disposal, performing unnecessary tests may create undue distress without incremental useful information. You are encouraged to consult your personal physician on the appropriate tests.

In This article is contributed by The Star Health Ageing Panel, which comprises a group of panellists who are not just opinion leaders in their respective fields of medical expertise, but have wide experience in medical health education for the public. The members of the panel include: Datuk Prof Dr Tan Hui Meng, consultant urologist; Dr Yap Piang Kian, consultant endocrinologist; Datuk Dr Azhari Rosman, consultant cardiologist; A/Prof Dr Philip Poi, consultant geriatrician; Dr Hew Fen Lee, consultant endocrinologist; Prof Dr Low Wah Yun, psychologist; Datuk Dr Nor Ashikin Mokhtar, consultant obstetrician and gynaecologist; Dr Lee Moon Keen, consultant neurologist; Dr Ting Hoon Chin, consultant dermatologist; Prof Khoo Ee Ming, primary care physician; Dr Ng Soo Chin, consultant haematologist. For more information, e-mail starhealth@thestar.com.my. The Star Health Ageing Advisory Panel provides this information for educational and communication purposes only and it should not be construed as personal medical advice. Information published in this article is not intended to replace, supplant or augment a consultation with a health professional regarding the reader’s own medical care. The Star Health Ageing Advisory Panel disclaims any and all liability for injury or other damages that could result from use of the information obtained from this article.


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