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Fulltext Hereditary hyperlipidemia in Malaysia: A historical perspective of six decade of research and treatment

Khoo KL

Med J Malaysia, 2014 Apr;69(2):57-9.
PMID: 25241812

No abstract available.
Acute myocardial infarction in systemic lupus erythematosus

Khoo KL, Pillay RP

Med J Malaysia, 1975 Mar;30(3):206-8.
PMID: 1160680
Serum lipid levels and the prevalence of hyperlipidaemia in Malaysia

Chong YH, Khoo KL

Clin Chim Acta, 1975 Nov 15;65(1):143-8.
PMID: 172262 DOI: 10.1016/0009-8981(75)90346-0
Fulltext Genetic causes of familial hypercholesterolaemia in a Malaysian population

Khoo KL, Van Acker P, Tan H, Deslypere JP

Med J Malaysia, 2000 Dec;55(4):409-18.
PMID: 11221151

A total of 86 unrelated Malaysian patients with familial hypercholesterolaemia (FH) were studied for mutations in their low-density lipoprotein receptor (LDL-R) gene. Amongst them, 23 had a LDL-R gene mutation, while none having an Apolipoprotein B-3500 (Apo B-3500) mutation. Patients with the LDL-R gene defect appeared to have a higher level of low-density lipoprotein cholesterol (LDL-C), an increased incidence of xanthomas and coronary heart disease (CHD), but no relationships were found between the type of LDL-R gene mutations and their lipid levels or clinical signs of CHD. In contrast to Western data, our findings seemed to indicate a predominance of mutations in the ligand binding domain and an absence of Apo B-3500 gene mutation. The latter finding may offer a genetic basis as to why Asian patients with familial hypercholesterolaemia have lower LDL-C levels and less premature CHD than their Western counterparts.
Fulltext Familial hyperlipidaemia in Malaysian children

Khoo KL, Tan H, Liew YM

Med J Malaysia, 2000 Jun;55(2):249-58.
PMID: 19839155

This paper highlights two cases of paediatric familial hyperlipidaemia (hypercholesterolaemia and hypertriglyceridaemia). The first case was an 11 year old Chinese boy, a "homozygous" (Type II) hypercholesterolaemic patient. He had extremely high blood cholesterol level (19.4 mmol/l), severe multiple xanthoma and abnormal resting electrocardiogram. He had repeated heart attacks and died at the age of 15 in spite of early intervention, treatment and follow up. The second case was a 2 1/2 years old girl who had severe hypertriglyceridaemia. She had raised cholesterol (6.2 mmol/l) and extremely high triglycerides (14.8 mmol/l). The patient did not resemble Type I lipoproteinaemia which is classically seen in childhood. On the contrary, the patient exhibited clinical and biochemical manifestations of a Type V lipoproteinaemia which often occurs in adults. Apart from a Type V lipoprotein pattern, the patient had low post hepatic lipase activity (PHLA), Apo C II and Apo E2/E3 phenotype. In addition, the lipid profile of her family members (both the parents and brothers) had raised triglycerides and thus ruled out the Type I lipoprotein inheritance pattern, which is an autosomal recessive condition. The issue of paediatric hyperlipidaemia, their management and treatments are discussed.
Fulltext Serum lipids and their relationship with other coronary risk factors in healthy subjects in a city clinic

Khoo KL, Tan H, Liew YM

Med J Malaysia, 1997 Mar;52(1):38-52.
PMID: 10968052

Over a thousand subjects who visited a city private medical clinic for health screening and advice were examined for their lipid profile and other cardiovascular risk factors. The mean TC, TG, LDL-C and HDL-C were 5.43, 1.45, 3.61 and 1.15 mmol/l. Their derived ratios viz, TC:HDL-C and LDL:HDL-C were 5.11 and 3.43 respectively. The prevalence of hyperlipidaemia was moderately high. Of the subjects studied 58.5% had elevated serum cholesterol, 14.8% had raised triglycerides, 64.9% had raised LDL-C and 20.8% had low HDL-C. Male subjects generally showed higher mean values and abnormality frequency in TC, TG, LDL-C, TC:HDL-C and LDL:HDL-C as compared to female subjects. Although significant ethnic differences were not detected for certain lipid parameters (e.g. TC, TG and HDL-C), the Indians appeared to have higher mean lipid values (except HDL-C), and higher percentage abnormality for all the lipid parameters as compared to the Chinese and the Malays. In correlation studies, the following lipid parameters:- TC versus TG, LDL-C, TC:HDL-C; TG versus TC:HDL-C and LDL:HDL-C; LDL-C versus TC:HDL-C and LDL:HDL-C; were positively correlated. On the other hand, TC versus HDL-C, TG versus HDL-C, LDL-C and HDL-C, and HDL-C versus TC:HDL-C and LDL:HDL-C were negatively correlated. The coronary risk factors which generally showed positive correlations with lipid parameters were BMI and blood pressure. Positive correlations were also recorded between fasting blood glucose and TG; uric acid with TG, TC:HDL-C and LDL:HDL-C. In contrast, risk factors of negative correlations were observed between HDL-C and the coronary risk factors of BMI, diastolic blood pressure and uric acid. Smoking showed raised per cent lipid abnormality for TG, HDL-C, TC:HDL-C and LDL:HDL-C. Alcohol consumption also increased the mean level and abnormality frequency for TG. The implication of this investigation is discussed.
Fulltext Cardiovascular mortality in Peninsular Malaysia: 1950-1989

Khoo KL, Tan H, Khoo TH

Med J Malaysia, 1991 Mar;46(1):7-20.
PMID: 1836041

Mortality statistics of Peninsular Malaysia for the period 1950-1989 have been studied in relation to cardiovascular diseases, with particular emphasis on coronary heart disease as an important cause of death. It was observed that among six major disease groups reviewed, cardiovascular diseases which occupied third place as a cause of death in 1950 emerged as the number one killer during the 1970s and has remained so since (with exception in 1980). In contrast, infectious diseases which ranked first in 1950 dropped to fourth position in 1980. Between 1960 and 1980, mortality due to cardiovascular diseases was higher in males than in females. This tendency became less apparent during 1985-1989. With reference to race, the incidence of cardiovascular deaths was highest in Indians followed by Chinese and Malays. Among the specific cardiovascular diseases, coronary heart and cerebrovascular diseases accounted for the main causes of mortality. Mortality due to coronary heart disease has increased by more than three fold over the last 40 years and is still rising. However, mortality incidence due to rheumatic heart disease and hypertension decreased during the same period. In 1965, mortality due to coronary heart disease was highest in the 55-59 age group. In recent years (1985 to 1989), it shifted to the older age group (i.e. 65-69). There was a tendency for higher mortality due to coronary heart disease in males compared to females. Indians had a higher mortality due to coronary heart disease than Chinese and Malays.
Familial type II hyperlipoproteinaemia in a Chinese family

Khoo KL, Chong YH, Pillay RP

Med J Aust, 1973 May 26;1(21):1048-50.
PMID: 4718497
Fulltext Health status of senior civil servants in Kuala Lumpur

Liew YM, Zulkifli A, Tan H, Ho YN, Khoo KL

Med J Malaysia, 1997 Dec;52(4):348-66.
PMID: 10968112

733 senior civil servants comprising 520 males and 213 females with a mean age of 44 years (range 25-56 years) were screened for their health status. The sample population comprised of 67.9% Malays, 22.5% Chinese, 9.1% Indians and 0.4% other ethnic origins. The subjects' medical histories were recorded and a full medical examination including anthropometric measurements (weight, height, waist and hip circumference), blood biochemistry and urine analysis, chest X-ray and electrocardiograms were done. The results obtained showed that 36.0% of the study population were overweight with 6.5% being obese. Of this 32.0% had central obesity. 15.2% of the subjects had systolic hypertension (systolic BP > or = 140 mmHg) whilst 27.6% had diastolic hypertension (diastolic BP > or = 90 mmHg). Hyperlipidaemia was common, with 75.2% subjects having raised cholesterol, 19.9% raised triglycerides, 50.2% raised LDL-C, 74.6% raised TC:HDL-C and 26.6% raised LDL:HDL-C. An elevated blood glucose was found in 8.4% subjects, whilst urine sugar was detected in only 2.6%, and a raised uric acid was found in 2.8% subjects. The prevalence of hypertension, raised blood glucose and hyperlipidaemia increased with age with more males affected than females. Although hypercholesterolaemia appeared more frequently amongst the Malays, the Indians, by comparison had the highest prevalence for a raised LDL:HDL-C ratio, a reflection of the increase in LDL-C and a concomitant decrease in HDL-C. The latter findings indicate that the Indians are at greater risk for the development of coronary heart disease than the Chinese and Malays. In addition, the mean levels of serum cholesterol found in this study seemed to have exceeded the levels found in populations in the industrialised countries such as the USA. There is thus an urgent need for more public health campaigns aimed at the reduction and control of such coronary risk factors.
Lipids and coronary heart disease in Asia

Khoo KL, Tan H, Liew YM, Deslypere JP, Janus E

Atherosclerosis, 2003 Jul;169(1):1-10.
PMID: 12860245

In Western countries, it has been shown that coronary heart disease (CHD) is related to high serum total cholesterol (TC) levels. In less developed continents such as Asia and Africa, serum lipid levels are low and CHD incidence is much lower as compared with Western countries. With growing urbanization and industrialization in Asia, it has been shown that there is a concomitant rise in the level of serum TC and with it a rise in CHD. In all the Asian countries, serum TC levels are also higher in the urban compared with the rural population. Singapore, the only Asian country which is 100% urbanized since 1980, showed a rise of serum TC similar to that seen in the US and UK from the 1950s to the 1980s followed thereafter by a fall. This is reflected in the trend (rise followed by a fall) of CHD morbidity and mortality as well. In spite of a declining trend in serum TC level, CHD morbidity and mortality are still high in Singapore and comparable to the Western countries. The rest of the Asian countries show a different pattern from Singapore. In general, there is still a rising trend in serum TC level and in CHD mortality in most Asian countries. However, Japan is considered an exception in having a decreasing CHD mortality in spite of an increasing trend in serum TC. This may be attributed to a better control of other CHD risk factors such as hypertension and smoking. The rising trend in serum TC level remains a cause for concern, as this will emerge as a major problem for CHD morbidity and mortality in the future.
Fulltext Patients' knowledge and attitude towards treatment and control of hypertension: a nation-wide telephone survey conducted in Malaysia

Khoo KL, Liew YM, Tan H, Sambhi JS, Hatijah BA

Med J Malaysia, 1999 Mar;54(1):37-46.
PMID: 10972003

The telephone survey of 2,526 hypertensive subjects showed 94% of the respondents were aware of the importance in controlling hypertension. Among these 504 were not on anti-hypertensive medication while the majority of 2,022 were currently on anti-hypertensive medication. Of those who were not on medication, 80% (n = 403) were found non-hypertensive on follow-up. The remaining 20% (n = 101) were confirmed hypertensive and were offered medication. However, 38 subjects refused to take medication and 63 subjects complied with medication but subsequently gave up. The main reasons for giving up medication included lack of motivation (38%), doctors' advice (20%), side effects (19%) and concern of side effects (10%). Of 2,022 hypertensive respondents who were currently on medication, almost half (44%, n = 890) required a change of medication due to side effects (40%, n = 356) or the blood pressure not controlled with the previous medication (33%, n = 294). Despite the change in medication, 42% (n = 150) still continued to suffer from some form of side effects. The information obtained from this survey suggested it is important to recommend some strategies to improve patient compliance. These strategies comprise of motivating the patient, improving medication with less side effects, improving potency and efficiency of medication, and reduction of cost in medication. In addition, convenient blood pressure monitoring such as home blood pressure monitoring is also encouraged.
Fulltext Blood pressure, body mass index, heart rate and levels of blood cholesterol and glucose of volunteers during National Heart Weeks, 1995-1997

Khoo KL, Tan H, Liew YM, Sambhi JS, Aljafri AM, Hatijah A

Med J Malaysia, 2000 Dec;55(4):439-50.
PMID: 11221155

The paper presents the results of a health screening programme conducted in 10 major centers in Malaysia--Kuala Lumpur, Penang, Ipoh, Johor Bahru, Alor Star, Kuala Terengganu, Malacca, Kota Bahru, Kuching and Kota Kinabalu during the National Heart Weeks, 1995-1997. There were 6,858 participants of both sexes aged between 6 years to 81 years old. The parameters involved in the screening programme were body mass index, blood pressure, heart rate, cholesterol and glucose. The following are the results of the study:- 1. The mean and standard deviation for the body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), total cholesterol (TC) and non fasting (random) blood glucose (GL) of the volunteers studied were 24.3 +/- 4.0 kg/m2, 128.3 +/- 21.1 mmHg, 79.6 +/- 11.9 mmHg, 77.2 +/- 12.1 bpm, 5.33 +/- 1.37 mmol/l and 5.11 +/- 1.97 mmol/l respectively. 2. There was a rising trend for BMI, SBP, DBP, TC and GL with age. The HR was higher in the younger age group of those below 20 years. Males tended to have higher mean values than females except for HR which was similar in both sexes. 3. The Malays, Chinese and Indians seemed to have closely similar mean values for SBP, DBP and HR but the Indians possessed the highest BMI (25.62 +/- 3.90 kg/m2), TC (5.61 +/- 1.48 mmol/l) and GL (5.41 +/- 2.43 mmol/l) among the three major ethnic groups. While the Ibans had highest TC (6.07 + 1.09 mmol/l), their GL level was the lowest (4.76 +/- 1.15 mmol/l). The Kadazans had the lowest TC level (4.94 +/- 1.39 mmol/l) among all the ethnic groups. 4. Among the participants screened, 31.9% were overweight (BMI > or = 25), 7.6% were obese (BMI > or = 30); 26.8% had raised SBP (> or = 140 mmHg) and 19.3% had raised DBP (> or = 90 mmHg); 13.6% of the participants had increased HR (> or = 90 bpm), 22% had raised TC (> or = 6.20 mmol/l) and 2% had raised GL (> or = 11.00 mmol/l). There was a higher prevalence for abnormal values with increasing age until between the ages of 60 or 70 years, when the values began to fall. 5. Age was positively correlated with SBP (r = 0.41***, df = 4351), DBP (r = 0.27***, df = 4351), TC (r = 0.22***, df = 3303) and GL (r = 0.16***, df = 2442) but negatively correlated with HR (r = -0.13***, df = 4351). The BMI was positively correlated with SBP (r = 0.29***, df = 2769), DBP (r = 0.31***, df = 2769), TC (r = 0.16***, df = 2137) and GL (r = 0.11**, df = 1637) but there was no correlation with HR (r = 0.03NS, df = 2771). The SBP and DBP were highly correlated with each other (r = 0.75***, df = 4351) and they also showed highly significant positive correlation (r = 0.08***-0.13***, df = 2441-3301) with TC and GL. TC was positively correlated with GL (r = 0.05* df = 2319) but only at the 5% probability level.
Fulltext Denaturing gradient-gel electrophoresis screening of familial defective apolipoprotein B-100 in a mixed Asian cohort: two cases of arginine3500-->tryptophan mutation associated with a unique haplotype

Choong ML, Koay ES, Khoo KL, Khaw MC, Sethi SK

Clin Chem, 1997 Jun;43(6 Pt 1):916-23.
PMID: 9191540

The Arg-to-Trp substitution at codon 3500 in the apolipoprotein (apo) B-100 gene is established as a cause of familial defective apo B-100 (FDB), a functional mutation, resulting in reduced LDL receptor binding and manifest hypercholesterolemia. In a search for similar mutations in 163 Malaysians, we screened the putative receptor-binding region (codons 3456-3553) of the apo B-100 gene by PCR amplification and denaturing gradient-gel electrophoresis. Four single-base mutations were detected and confirmed by DNA sequencing. Two females, a Chinese and a Malay, had the same CGG3500-->TGG mutation, resulting in an Arg3500-to-Trp substitution. This is the second published report of such an independent mutation involving the same codon as the established Arg3500-to-Gln mutation. The two other mutations detected, CTT3517-->CTG and GCC3527-->GCT, resulted in degenerate codons with no amino acid substitutions. All four mutations were associated with a unique apo B haplotype, different from those found in Caucasian FDB patients but concurring with that previously reported for two other Asians with FDB.
Ten years of lipoprotein apheresis for familial hypercholesterolemia in Malaysia: A creative approach by a cardiologist in a developing country

Khoo KL, Page MM, Liew YM, Defesche JC, Watts GF

J Clin Lipidol, 2016 05 13;10(5):1188-94.
PMID: 27678436 DOI: 10.1016/j.jacl.2016.05.006

BACKGROUND: Familial hypercholesterolemia (FH) leads to premature coronary artery disease and aortic stenosis, with undertreated severe forms causing death at a young age. Lipoprotein apheresis (LA) is often required for lowering low-density lipoprotein cholesterol levels in severe FH.
OBJECTIVES: The objective of this study was to present the first experiences with LA in Malaysia, between 2004 and 2014.
METHODS: We retrospectively collected data from patient records to assess the effectiveness, adverse effects, patient quality of life, and costs associated with an LA service for genetically confirmed homozygous and heterozygous FH.
RESULTS: We treated 13 women and 2 men aged 6 to 59 years, 10 with homozygous and 5 with heterozygous FH, all on maximally tolerated cholesterol-lowering drug therapy, for a total of 65 patient-years. Acute lowering of low-density lipoprotein cholesterol post apheresis was 56.3 ± 7.2%, with time-averaged mean lowering of 34.9 ± 13.9%. No patients experienced any cardiovascular events during the period of receiving LA. Patients receiving LA experienced few side effects and enjoyed reasonable quality of life, but inability to continue treatment was frequent because of cost.
CONCLUSION: LA for severe FH can be delivered effectively in the short term in developing nations, but costs are a major barrier to sustaining this mode of treatment for this high-risk group of patients. New drug therapies for FH, such as the proprotein convertase subtilisin/kexin type 9 inhibitors, microsomal triglyceride transfer protein inhibitors, and apolipoprotein-B100 antisense oligonucleotides may allow improved care for these patients, but costs and long-term safety remain as issues to be addressed.
Low-density lipoprotein receptor gene mutations in a Southeast Asian population with familial hypercholesterolemia

Khoo KL, van Acker P, Defesche JC, Tan H, van de Kerkhof L, Heijnen-van Eijk SJ, et al.

Clin Genet, 2000 Aug;58(2):98-105.
PMID: 11005141 DOI: 10.1034/j.1399-0004.2000.580202.x

The aim of this study was to detect mutations in the genes coding for the low-density lipoprotein receptor and apolipoprotein B in patients of Southeast Asian origin with clinically diagnosed familial hypercholesterolemia (FH) and to relate these findings with the observed lower incidence of coronary heart disease in this part of the world. A total of 86 unrelated patients with FH were selected on clinical grounds, and complete DNA analysis of the low-density lipoprotein (LDL)-receptor and apolipoprotein B (apoB) genes by DGGE and DNA-sequencing was performed. In the majority (73%) of the cohort studied, no mutations could be detected, even after extensive analysis of the LDL-receptor and apoB genes. However, the 22 patients with a mutation had significantly more xanthomas and a higher incidence of coronary heart disease and levels of low-density lipoproteins were also significantly different. There was no correlation between the type of the mutation and lipoprotein levels or clinical signs of atherosclerosis. The fact that the majority of the FH patients studied had no detectable mutation and that this group had a significant milder phenotype, suggests the presence of a third gene in the Southeast Asian population, predominantly leading to a disorder resembling a milder form of FH. A similar, but less frequent, trait has recently been described in a number of European families.
Lipid-lowering treatment in hypercholesterolaemic patients: the CEPHEUS Pan-Asian survey

Park JE, Chiang CE, Munawar M, Pham GK, Sukonthasarn A, Aquino AR, et al.

Eur J Prev Cardiol, 2012 Aug;19(4):781-94.
PMID: 21450606 DOI: 10.1177/1741826710397100

BACKGROUND: Treatment of hypercholesterolaemia in Asia is rarely evaluated on a large scale, and data on treatment outcome are scarce. The Pan-Asian CEPHEUS study aimed to assess low-density lipoprotein cholesterol (LDL-C) goal attainment among patients on lipid-lowering therapy.
METHODS: This survey was conducted in eight Asian countries. Hypercholesterolaemic patients aged ≥18 years who had been on lipid-lowering treatment for ≥3 months (stable medication for ≥6 weeks) were recruited, and lipid concentrations were measured. Demographic and other clinically relevant information were collected, and the cardiovascular risk of each patient was determined. Definitions and criteria set by the updated 2004 National Cholesterol Education Program guidelines were applied.
RESULTS: In this survey, 501 physicians enrolled 8064 patients, of whom 7281 were included in the final analysis. The mean age was 61.0 years, 44.4% were female, and 85.1% were on statin monotherapy. LDL-C goal attainment was reported in 49.1% of patients overall, including 51.2% of primary and 48.7% of secondary prevention patients, and 36.6% of patients with familial hypercholesterolaemia. The LDL-C goal was attained in 75.4% of moderate risk, 55.4% of high risk, and only 34.9% of very high-risk patients. Goal attainment was directly related to age and inversely related to cardiovascular risk and baseline LDL-C.
CONCLUSION: A large proportion of Asian hypercholesterolaemic patients on lipid-lowering drugs are not at recommended LDL-C levels and remain at risk for cardiovascular disease. Given the proven efficacy of lipid-lowering drugs in the reduction of LDL-C, there is room for further optimization of treatments to maximize benefits and improve outcomes.
Ethnicity, obstructive sleep apnoea and ischaemic heart disease

Tan YK, Khoo KL, Low JA, Wong ZW, Theng CT, Ong TH, et al.

Ann Acad Med Singap, 1999 Mar;28(2):214-6.
PMID: 10497669

We studied the relationship between different ethnic groups, obstructive sleep apnoea (OSA) and ischaemic heart disease. Four hundred and thirty-two inpatients from the medical wards were interviewed. Limited overnight sleep studies were done in 129 of those who had habitual snoring, daytime sleepiness based on an Epworth sleepiness scale of 8 or more, or a large neck size of 40 cm or more. There were 315 Chinese (72.9%), 67 Malays (15.5%), 43 Indians (10%) and 3 from other races (1.4%). The prevalence of OSA was 19.7%, 30% and 12% among the Chinese, Malays and Indians, respectively. The prevalence ratio for OSA was 1.52 in Malays using Chinese patients as the baseline (P = 0.07). The median neck circumference was 37 cm in both racial groups. The median body mass index was 22.7 kg/m2 in Chinese compared to 23.6 kg/m2 in Malays. The median apnoea-hypopnoea index was 22.7, 19.0 and 26.9 events/hour among the Chinese, Malays and Indians, respectively. OSA was independently associated with the prevalence of IHD (adjusted prevalence ratio 1.68; 95% CI: 1.15, 2.46; P = 0.009). The prevalence of ischaemic heart disease (IHD) was 31%, 24% and 28% in Chinese, Malays and Indians, respectively. The prevalence ratio for IHD in Malays compared to Chinese was 0.77. After adjusting for OSA, there was an even greater reduction in the risk of IHD (adjusted prevalence ratio 0.70). This suggests that OSA is a confounder in the relationship between race and ischaemic heart disease.

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