Q J Med 2001; 94: 327-332
© 2001 Association of Physicians
Dyslipidaemia in patients with malignant-phase hypertension
1 From the University of Birmingham Division of Medical Sciences, City Hospital and 2 Queen Elizabeth Hospital, Birmingham, UK
Received 27 February 2001 and in revised form 6 April 2001
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Summary |
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Low-density lipoprotein (LDL) consists of a heterogeneous group of particles of differing size, density and electrophoretic mobility, smaller particles being more atherogenic. A high proportion of small LDL particles is an independent risk factor for cardiovascular disease. We hypothesized that patients with malignant phase hypertension (MHT), the most severe form of hypertension, would demonstrate a more atherogenic LDL subfraction profile than either non-malignant hypertension (NMHT) or normotensive controls. We compared 16 patients with MHT to 41 patients with untreated NMHT and 45 normotensive controls. LDL subfraction profile was measured by disc polyacrylamide gel electrophoresis using a validated scoring system to calculate the mean size (locus) and heterogeneity (spread) of LDL subfraction mobilities. A higher LDL locus indicates a greater proportion of small LDL subfractions. LDL cholesterol levels were similar in all three groups (p=0.23). High-density lipoprotein cholesterol (HDL-C) levels were significantly lower (p<0.001) and serum triglyceride concentrations significantly higher (p=0.02) in the MHT group, compared to normotensive controls. LDL locus was greater in the NMHT group than in the normotensive controls and intermediate in the MHT group (p=0.008). There was no significant difference in LDL spread (p=0.26). Serum triglyceride concentrations were not significantly higher after adjusting for confounding variables. MHT is associated with an abnormal lipid profile, characterized by low HDL-cholesterol concentration. This dyslipidaemia may be partly responsible for the vascular complications and the poor prognosis of these patients.
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Introduction |
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Malignant hypertension is a rare condition characterized by the presence of marked hypertension in association with bilateral retinal haemorrhages and/or exudates, with or without papilloedema.1 While effective blood pressure control has significantly improved prognosis, these patients still have a substantially higher morbidity and mortality when compared to non-malignant hypertensive controls matched for age and level of blood pressure. This excess mortality and morbidity is largely due to atherosclerotic complications and renal failure.2 For example, in the West Birmingham malignant hypertension series, 40% of the 126 deaths after 33 months were due to renal failure, while 35% were due to stroke or myocardial infarction.3
It is now accepted that elevated low-density lipoprotein (LDL) cholesterol is an independent, modifiable risk factor for atherosclerotic cardiovascular disease.4,5 However, a number of authors have described an ‘atherogenic lipid profile’ consisting of reduced HDL-cholesterol and increased serum triglyceride concentrations. In this phenotype, the concentration of LDL-cholesterol may be normal or only slightly raised. However, LDL is not a single entity but consists of a heterogeneous group of particles of differing sizes, and there is a preponderance of smaller particles. These smaller particles are more atherogenic: they have reduced affinity for LDL receptors and are less readily removed from the circulation by the liver,6 are better able to penetrate the arterial intima, and are more easily oxidized by free radicals, resulting in rapid uptake by macrophage scavenger receptors and enhanced foam cell formation. Indeed, a preponderance of small LDL particles has been shown to be associated with both coronary and carotid artery disease.7,8
Interest in the ‘atherogenic lipid profile’ has been raised by the presence of prospective observational studies showing increased risk of vascular events in individuals with raised triglycerides, low HDL-cholesterol or abnormal LDL subfraction profile.9,10 Additionally, there is some evidence that fibrates, which improve this dyslipidaemia through their action on lipoprotein lipase activity, may reduce the risk of vascular events in patients exhibiting this phenotype.11
We have previously investigated lipid profiles, including LDL subfractions, in patients with untreated, essential hypertension, and found that LDL particles are significantly more mobile (smaller) in patients with essential hypertension.12 We now present a study of the lipid profile, including LDL subfraction profile, in patients admitted to our hospital with MHT. The results are compared with those in patients with untreated non-malignant, essential hypertension (NMHT), and with normotensive controls (NC).
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Methods |
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Consecutive patients admitted to our city centre teaching hospital with a diagnosis of malignant hypertension (MHT) were recruited into the study and compared with patients with non-malignant, essential hypertension (NMHT) and normotensive controls.
MHT was defined as the presence of severe hypertension in association with bilateral retinal linear or flame-shaped haemorrhages and/or cotton-wool exudates, with or without papilloedema on fundoscopy.3 This definition fulfils the existing clinical criteria for MHT, which includes both Grades III and IV of the Keith, Wagener and Barker classification.3,13
Consecutive patients with untreated, essential, non-malignant hypertension (NHMT) were recruited from new referrals to a hypertension out-patient clinic at a city-centre teaching hospital. Hypertension was defined as systolic blood pressure >160 mmHg and/or diastolic blood pressure >90 mmHg, measured by the patient's primary care physician and confirmed at the hypertension clinic on at least two separate occasions. Patients in this group had either no hypertensive retinal changes, or grade I or II hypertensive retinopathy. Those receiving antihypertensive medication were excluded.
Normotensive controls (NC) free from overt vascular disease (as above) were recruited from two local primary care centres. Those with a history of hypertension, those receiving antihypertensive drugs and those with blood pressure >160/90 mmHg were excluded.
In all three groups, patients with diabetes mellitus, overt vascular disease (angina, previous myocardial infarction, coronary revascularization procedures, transient ischaemic attack, stroke, intermittent claudication, peripheral revascularization procedure or amputation for vascular disease) and liver impairment were excluded, as were those on lipid-lowering drugs or hormone replacement therapy.
Informed, written consent was obtained and the study was approved by the West Birmingham Local Research Ethics Committee. Blood pressure was measured in the sitting position using a standard mercury sphygmomanometer according to the recommendations of the British Hypertension Society.14 Diastolic blood pressure was recorded at the disappearance of sounds. The mean of two measurements taken 5 min apart was recorded. Venous blood was taken into Vacutainer tubes and allowed to clot. Samples from patients with MHT were taken within 24 h of admission to hospital.
Laboratory methods
Venous blood samples were centrifuged at 3000 g for 15 min at 4 °C, within 3 h of venesection. Serum samples were stored at -80 °C for analysis of LDL subfraction profile. Total serum cholesterol and serum triglyceride concentrations were measured by standard enzymic techniques in the Department of Biochemistry, City Hospital Birmingham. HDL-cholesterol concentration was measured directly using the N-geneous method (Biostat Diagnostics).15 LDL-cholesterol concentration was calculated using the Friedewald formula.16
LDL subfraction profile was analysed by disc polyacrylamide gel electrophoresis (DPAGE) using the Lipoprint system (Quantimetrix). Thawed serum (25 µl) was added to each gel tube (pre-cast polyacrylamide 3%). To this, 200 µl loading gel (2.4 g/dl acrylamide, 0.2 g/dl N,N methlyenebisacrylamide, 3.6 mg/dl Sudan Black B) was added. Following repeated inversion of the tubes to allow thorough mixing, the gels were allowed to photopolymerize for 30 min in front of a fluorescent light source. Electrophoresis was then carried out at a constant current of 3 mA per tube for 60 to 70 min, until the HDL fraction had migrated approximately 40 mm. The electrophoresis buffer contained 66.1% Tris (hydroxymethyl) aminomethane and 33.9% boric acid (pH 8.2–8.6). Gel tubes were allowed to stand for at least 30 min and then scanned directly at a wavelength of 610 nm (ImageMater Software, Pharmacia). The resultant digitized images were exported to a bespoke computer programme. This programme uses the observation that the LDL concentration profile approximates to a normal distribution curve and can thus be described in terms of the mean (‘locus’) and standard deviation (‘spread’) of LDL mobility. The peaks of VLDL and HDL serve as reference points to which the mobility of LDL can be compared (Figure 1
). DPAGE of lipoproteins was originally described by Naito in 197317 and has been used to describe abnormalities of LDL subfraction profile in a number of disease states.7,8,18 The use of dedicated computer software allows more precise reporting of the electrophoresis results. A high LDL locus indicates smaller average size of LDL particles, while increased LDL spread indicates greater heterogeneity of the LDL particles. Within-batch coefficients of variation were 2.4% for LDL locus and 8.2% for LDL spread. Between-batch coefficients of variation were 3.3% for LDL locus and 8.1% for LDL spread.
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Statistical methods
Continuous variables are reported as mean (95%CIs) and compared with one-way ANOVA, with Tukey's test for post hoc comparisons. Serum triglyceride, creatinine and glucose concentrations, LDL locus and LDL spread results were positively skewed, and were therefore log-transformed before statistical comparison. Results were then expressed in natural units for ease of interpretation. Discrete variables are reported as percentages and compared with 
2 tests.
Logistic regression analysis was used to identify factors independently associated with MHT. A probability of p<0.05 was taken as statistically significant.
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Results |
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Sixteen patients with MHT were compared with 41 patients with untreated, essential NMHT and 45 normotensive controls (NC) (Table 1
). Although the age and sex distribution in the NMHT and NC groups were similar, there were significantly more men in the MHT group. Antihypertensive treatment was used by only three individuals in the MHT group: metoprolol, nifedipine, valsartan, moxonidine and minoxidil (1 patient); amlodipine (1 patient); and lacidipine (1 patient). By design, no patient in the NC or NMHT groups was receiving antihypertensive drugs. In addition to the anticipated differences in blood pressure, serum creatinine concentration was greater in the MHT group than in either of the other two groups.
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Total and LDL-cholesterol concentrations were similar in all three groups (Table 2
). The most notable finding, however, was of markedly lower HDL-cholesterol concentrations in the MHT group (p<0.001). The total:HDL-cholesterol ratio was therefore significantly higher in the MHT group than either of the other two groups. Serum triglycerides were greater in the MHT group than in the NC group (p=0.02).
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LDL locus was highest (indicating smaller average LDL particle size) in the NHMT group and intermediate in the MHT group (p=0.008) (Table 2
). However, the confidence interval for LDL locus in the MHT group was large.
A series of multivariate logistic regression analyses were performed to identify whether differences in lipid profile were independent of the effects of age, sex or renal function (serum creatinine concentration) (Tables 3 and 4). These analyses show that whilst the differences in HDL-cholesterol concentration between the MHT group and the other two groups remained, there were no differences in serum triglycerides or measures of LDL subfraction profile. Results for total and LDL-cholesterol concentration remained unchanged.
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Discussion |
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In this study, we have attempted to compare patients presenting with MHT to normotensive controls and patients with untreated essential hypertension. Patients with diabetes mellitus or overt vascular disease were excluded. It is not possible to be certain that subclinical atherosclerosis was not present in any of the study participants. However, the use of pre-defined criteria for the definition of vascular disease applied to all three study groups minimizes the likelihood of confounding by vascular disease.
Other potential confounders include drug therapy and an acute-phase response. The effects of drug treatment have largely been avoided, although a small proportion (3/16) of the MHT group had received antihypertensive medication prior to admission. An acute-phase response may be responsible for reductions in both LDL- and HDL-cholesterol concentrations and an increase in serum triglycerides, for example after acute myocardial infarction.19 This takes some time to develop (about 18 h in the case of acute myocardial infarction), and may persist for several weeks. It is difficult to estimate the extent to which the results in the MHT group may have been affected by an acute-phase response, as it is not possible to be certain of the time at which the illness developed. However, all samples were taken within 18 h of hospital admission. It is also reassuring to note that LDL-cholesterol concentrations were similar in all three groups.
Despite MHT being reported to be an increasingly rare disease, we have not noted a decline in our clinical practice, and have previously reported on the West Birmingham MHT register, which probably represents one of the largest series in the literature.3 The cohort in the present analysis was prospectively recruited over approximately 2 years and apart from being one of the first investigations into dyslipidaemia in MHT per se, probably represents one of the largest prospective cohorts of MHT investigated in this way. Dyslipidaemia in MHT is relevant, as in spite of improved overall survival in patients with MHT, due to the advent of new antihypertensive drugs, there remains a significant excess mortality and morbidity in these patients,2 much of which is due to atherosclerotic vascular diseases such as stroke and myocardial infarction.3 However, we recognize that in the present paper, our findings are based on only 16 cases of MHT, and that they will need confirmation in further studies.
In conclusion, this study demonstrates that MHT may be associated with an abnormal lipid profile, characterized by low HDL-cholesterol concentrations. The study was underpowered to convincingly demonstrate any differences in LDL subfraction size, and the observed difference in serum triglyceride concentrations did not remain after adjustment for age, sex and renal function. More work is therefore needed to better define the dyslipidaemia of malignant hypertension, which may be at least in part responsible for the poor prognosis of these patients.
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Acknowledgments |
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We acknowledge the support of the City Hospital NHS Trust Research and Development programme for the Haemostasis, Thrombosis and Vascular Biology Unit. We also wish to thank the patients, doctors and staff of Lawrie Pike Health Centre, Handsworth, Lordswood Road Surgery, Harborne, and City Hospital, Birmingham.
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Notes |
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Address correspondence to Dr G.Y.H. Lip, Haemostasis, Thrombosis and Vascular Biology Unit, City Hospital NHS Trust, Dudley Road, Birmingham B18 7QH. e–mail: g.y.h.lip{at}bham.ac.uk
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References |
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