Saudi Journal of Kidney Diseases and Transplantation

ORIGINAL ARTICLE
Year
: 2008  |  Volume : 19  |  Issue : 3  |  Page : 420--427

Association of Serum Lipoprotein (a) with Hypertension in Diabetic Patients


Hamid Nasri 
 Hemodialysis Section, Department of Medicine, Hajar Medical Educational and Therapeutic Center, Shahrekord University of Medical Sciences, Shahrekord, Iran

Correspondence Address:
Hamid Nasri
Hemodialysis Section, Hajar Medical Educational and Therapeutic Center, Shahrekord University of Medical Sciences, P.O. Box:88155-468, Shahrekord
Iran

Abstract

To evaluate the influence of serum Lp(a) concentration on hypertension in patients with diabetes mellitus (DM) and under treatment with oral hypoglycemic agents or insulin injections, we studied 122 patients, 82 females and 40 males with a mean age of 63 ± 10 years and duration of DM and HTN of 7.4 ± 5.8 and 3.2 ± 4.6 years, respectively. The mean systolic and diastolic blood pressure (BP) were 138 ±23 mmHg and 83 ± 12 mmHg, respectively. In this cross-sectional study, we measured serum lipoprotein(a) (Lp(a), glycosilated hemoglobine (HbA1c) and other lipids while the patients were receiving either oral hypogycemic agents or insulin. In addition, body mass index (BMI) and creatinine clearance (CrCL) were asessed. The mean serum Lp(a) was 22.2 ± 24.7 mg/dl (median: 18.3 mg/dl), and serum Lp(a) levels > 30 mg/dl was found in 29 (23.8%) patients. There were significant positive correlations of duration of DM and duration of hypertension, and serum Lp(a) levels with of systoli and diastolic levels of BP. However, a significant inverse correlation of serum Lp(a) with CrCL were observed. This study suggests that kidney function is an independent determinant of Lp(a) and HTN in diabetic patients. Furthermore, Lp(a) in diabetic patients may have important implications for the increased susceptibility to vascular disease in these patients.



How to cite this article:
Nasri H. Association of Serum Lipoprotein (a) with Hypertension in Diabetic Patients.Saudi J Kidney Dis Transpl 2008;19:420-427


How to cite this URL:
Nasri H. Association of Serum Lipoprotein (a) with Hypertension in Diabetic Patients. Saudi J Kidney Dis Transpl [serial online] 2008 [cited 2021 Sep 23 ];19:420-427
Available from: https://www.sjkdt.org/text.asp?2008/19/3/420/40503


Full Text

 Introduction



Hypertension (HTN) is an extremely com­mon comorbid condition in diabetes, affec­ting 20%-60% of patients with diabetes, depending on obesity, ethnicity and age. [1]

In type 2 diabetes, hypertension is often present as a component of the metabolic syn­drome of insulin resistance, which includes central obesity and dyslipidemia, while in type 1 diabetes, hypertension may reflect the onset of diabetic nephropathy. [2] Hyper­tension substantially increases the risk of both macrovascular and microvascular com­plications, including stroke, coronary artery disease, and peripheral vascular disease, reti­nopathy, nephropathy, and possibly neuropathy. [2],[3]

Lipoprotein(a) (Lp(a) is a heterogeneous macromolecule that consists of a glyco­protein apolipoprotein(a), which is disulfide­linked to apolipoprotein B-100 on an LDL core. [4],[5],[6],[7] Apolipoprotein(a) exhibits size poly­morphism, which is closely linked to Lp(a) density and concentrations. [8] The limited dis­tribution of Lp(a) in a few animal species implies that it is not essential in lipoprotein metabolism. [9] However, it is clinically impor­tant because its concentrations are primarily genetically determined, associated with athe­rosclerotic disease, and less affected by lifestyle or medication. [6],[7],[8],[9],[10] Lp(a) concentra­tions are quite constant in an individual. [11],[12],[13],[14] Moreover, Lp(a) is an independent risk factor for cardiovascular disease. [12],[13],[14],[15],[16],[17],[18]

Several studies have reported high con­centrations of Lp(a) in diabetic patients, which has led to speculation that Lp(a) may contribute to the greatly increased inci­dence of vascular disease associated with diabetes. [19],[20] Considerable debate remains, however, regarding the precise cause of supranormal Lp(a) levels in diabetics. [19],[20],[21]

In nondiabetic patients, renal disease co­rrelates with elevated levels of Lp(a) that are normalized by kidney transplantation. [16] Recent studies have also demonstrated uri­nary excretion of Lp(a) degradation products, [11],[17],[18] but evidence for active role of the kidney in Lp(a) catabolism is not established yet. Renal disease is a frequent complication of diabetes that has prompted speculation that kidney dysfunction is the principal cause of raised Lp(a) in type 1 and type 2 diabetic patients. [19],[20],[21],[22],[23]

Observational and clinical studies have demonstrated that elevated systolic blood pressure (SBP) confers significantly higher risk of all cause and coronary heart disease mortality than elevated diastolic blood pre­ssure (DBP) or combined systolic/diastolic hypertension, especially in those with diabetis mellitus. [24],[25] More recent studies revealed an association between Lp(a) and hypertension. In vitro experiments have illustrated that oxidized Lp(a) is able to impair the arterial endothelium-dependent dilation, and suggested a possible role of Lp(a) in the genesis of essential hypertension. [26],[27],[28],[29],[30]

Hence, although dyslipidemia and hyper­tension occur together more often than can be explained by chance, few studies have carefully explored the nature of the rela­tionship between plasma Lp(a) levels and hypertension in diabetic patients.

The aim of this study is to evaluate the influence of serum Lp(a) concentration on hypertension in diabetic patients with va­rious kidney functions and not yet on dialysis.

 Patients and Methods



This cross-sectional study was conducted on diabetic mellitus patients who admitted in the hospital for controlling the diabetes with either oral hypoglycemic agents or insulin. We included in the study patients who developed hypertension and received antihypertensive therapy. Exclusion criteria included acute or chronic infections and use of lipid-lowering medications. The study was performed at Hajar Medical Educational and Therapeutic Center of Shahrekord University of Iran from July to August of 2005. All patients signed con­sent forms for participation in this study.

After admission to hospital, detailed me­dical history was obtained, and careful physical exam was performed. A trained physician measured all baseline BP using a random-zero manometer. Two BP and heart rate measurements were averaged to esta­blish the baseline BP and heart rate varia­bles. Follow-up BP included two measures on a single day after at least 30 minutes of rest. Hypertension was diagnosed accor­ding to WHO guidelines [31] and the seventh report of the joint national committee on prevention, detection, evaluation and treat­ment of high blood pressure. [32]

Blood samples were collected after 12 hour overnight fasting and centrifuged within 15 min of venopuncture. Serum Lp(a) were measured by enzyme-linked immunosor­bent assay kit (Macra® Lp(a) manufactured by Strategic Diagnostics Inc. for Trinity Biotech USA, Jamestown, NY, USA). The test is a sandwich assay which utilizes both a monoclonal and polyclonal antibodies, which specifically bind to the apolipo­protein (a) moiety of Lp(a). All samples were run in duplicate and the results were expressed in mg/dl; the intra- and inter­assay coefficients of variation for this me­thod were 2 ). Serum LDL-C was calculated by friedewald's formula. [33] Crea­tinine clearance(CrCL) was evaluated from serum creatinine, age and body weight. [34]

 Statistical analysis



Results are expressed as the mean ± SD and median values. Statistical correlations were assessed using a partial correlation test. Comparison between female and male genders data was assessed using students't test. For normalization of the serum Lp(a) data, the cube root of Lp(a) was used. All analyses were performed with the SPSS sta­tistical package (version 11.0 for Windows; SPSS, Chicago). Statistical significance was determined at value of p 30 mg/dl was found in 29 patients (23.8%).

[Figure 1] shows a significant positive cor­relation of duration of DM and HTN (r= 0.45, p [35]

Wildman et al, studied the relationship between baseline measures of serum lipo­proteins and incident hypertension in older adults in 187 patients with systolic blood pressure (SBP) [29]

In 1992, Sesso et al, conducted a pros­pective study on 16,130 middle-aged and older female health professionals who had no history of high cholesterol level or hypertension. During 10.8 years of follow­up, incident hypertension developed in 4593 (28%) women. They illustrated with follow-up of lipid levels that atherogenic dyslipidemias were associated with the subsequent development of hypertension among healthy women. [36]

Recent studies suggest that Lp(a) can act as a marker for determining vascular or tissue injury. [6],[30] In a study conducted by Bhavani et al, on a total of 37 essential hypertensive patients, it was observed that the hypertensive patients had higher plasma concentrations of Lp(a) (more than 30 mg/dl), total cholesterol (TC), low-Density lipoprotein-cholesterol, and triglycerides than controls. Lp(a) values correlated signi­ficantly with SBP and DBP. [30] In a similar study, Catalano et al, reported significantly elevated levels of plasma Lp(a) in 123 Caucasian essential arterial hypertensive patients. [37] Recent report from Fytili et al, suggested that arterial hypertension is asso­ciated with elevated Lp(a) levels in patients of end-stage renal disease. In their study, it was observed that Lp(a) levels were signi­ficantly higher in the hypertensive patients, but that difference was not significant from the non-renal failure patients. [38]

There are no adequate studies conducted on the influence of Lp(a) on HTN in dia­betic patients, however, there is a strong epidemiological connection between hyper­tension in diabetes and adverse outcomes of diabetes. Recent studies demonstrated that Lp(a) is an independent risk factor for the progression of diabetic nephropathy in type 2 diabetic patients with overt proteinuria. [39],[40] Macroalbuminuria was uniformly associated with significantly raised plasma concentra­tions of Lp(a) regardless of the marker used to identify kidney dysfunction. Moreover, altered kidney function, measured by creati­nine clearance or creatinine levels, is a major determinant of raised Lp(a) levels in micro­albuminuric and normoalbuminuric diabetics patients. [12],[16] Studies in nondiabetic patients have firmly established renal disease as a cause of increased plasma Lp(a) levels. [16]

Increased levels of Lp(a) are an inde­pendent risk factor for vascular disease in the general population [9],[10],[13] and in diabetic patients. [41],[42],[43],[44],[45],[46] In view of these considerations, defining the relationship between renal com­plications and Lp(a) in diabetic patients is important. Studies that have considered renal disease, usually expressed as albuminuria or the emerege of hypertension and increased plasma levels of Lp(a) in patients with renal disease who have either type 2 [32],[33],[34] or type 1 [6],[32],[35],[36],[37] diabetes were reported.

In conclusion, our results suggest that serum Lp(a) concentration aggravate hyper­tension and identify kidney failure as a primary determinant of raised Lp(a) in dia­betic patients. This has important impli­cations for the increased susceptibility to vascular disease associated with Lp(a) in diabetic patients.

 Acknowledgment



We would like to thank Dr. M. Khaksar M.D. for gathering the data, also thanking from laboratory technicians of our hospital for performing the laboratory tests.

References

1Kannel WB. Elevated systolic blood pressure as a cardiovascular risk factor. Am J Cardiol 2000;85(2):251-5.
2Cushman WC. The clinical significance of systolic hypertension. Am J Hypertens 1998;11(11.2):182S-5S.
3Lackland DT, Egan BM. The dominant role of systolic hypertension as a vascular risk factor: Evidence from the southeastern United States. Am J Med Sci 1999;318 (6):365-8.
4Black HR. The paradigm has shifted, to systolic blood pressure. Hypertension 1999; 34(3):386-7.
5Antonicelli R, Testa R, Bonfigli AR, Sirrolla C, Marra M, Marcovina SM. Blood pressure levels in patients with essential hyper­tension. Clin Exp Med 2001;1(3):145-50.
6Baradaran A, Nasri H, Ganji F. Association of serum lipoprotein(a) with intimae-media thickness as a target-organ damage in essential hypertensive patients. Iran Heart J 2004;5:55-63..
7Nasri H, Baradaran A. Relationship of early atherosclerotic vascular changes with serum Lipoprotein(a) in predialysis chronic renal failure and maintenance hemodialysis patients. Turk J Endocrinol Metabol 2003;7(4):169-74.
8Armstrong VW, Cremer P, Eberle E, et al. The association between serum Lp(a) concentrations and angiogiraphically assessed coronary atherosclerosis: Depen­dence on serum LDL levels. Athero­sclerosis 1986;62(3):249-57.
9Rhoads GG, Dahlen G, Berg K, Morton NE, Dannenberg AL. Lp(a) lipoprotein as a risk factor for myocardial infarction. JAMA 1986;256(18):2540-4.
10Schaefer EJ, Lamon-Fava S, Jenner JL, et al. Lipoprotein(a) levels and risk of coronary heart disease in men: The Lipid Research Clinics Coronary Primary Prevention Trial. JAMA 1994;271(13): 999-1003.
11Baradaran A, Nasri H, Ganji F. Close relationship of serum lipoprotein(a) with ultrasonographically determined early atherosclerotic changes in the carotid and femoral artery in end-stage renal failure patients undergoing hemo­dialysis. Timok Med J (Journal of Regional Section of Serbian Medical Association in Zajecar) 2004;29(1):8­13.
12Bolibar I, Thompson SG, von Eckardstein A, Sandkamp M, Assmann G. Dose-response relationship of serum lipid measurements with the extent of coronary stenosis: Strong, independent and comprehensive. Arterioscler Thromb Vasc Biol 1995;15(8):1035-42.
13Bostom AG, Gagnon DR, Cupples LA, et al. A prospective investigation of elevated lipoprotein(a) detected by electrophoresis and cardio-vascular disease in women: The Framingham Heart Study. Circulation 1994;90(4):1688-95.
14Jenkins AJ, Best JD. The role of lipo­protein(a) in the vascular complications of diabetes. J Intern Med 1995;237(4):359­65.
15Kronenberg F, Utermann G, Dieplinger H. Lipoprotein(a) in renal disease. Am J Kidney Dis 1996;27(1):1-25.
16Mooser V, Seabra MC, Abedin M, et al. Apolipoprotein(a) kringle 4-containing fragments in human urine: Relationship to plasma levels of lipoprotein(a). J Clin Invest 1996;97(3):858-64.
17Clodi M, Oberbauer R, Waldhausl W, Maurer G, Kostner GM, Kostner K. Urinary excretion of apo(a) fragments in NIDDM patients. Diabetologia 1997;40 (12):1455-60.
18Jenkins AJ, Steele JS, Janus ED, Best JD. Increased plasma apolipoprotein(a) levels in IDDM patients with microalbuminuria. Diabetes 1991;40(6):787-90.
19Winocour PH, Bhatnagar D, Ishola M, Arrol S, Durrington PN. Lipoprotein(a) and microvascular disease in type 1 (insulin-dependent) diabetes. Diabet Med 1991;8(10):922-7.
20Csaszar A, Dieplinger H, Sandholzer C, et al. Plasma lipoprotein(a) concentration and phenotypes in diabetes mellitus. Diabe­tologia 1993;36(1):47-51.
21Haffner SM. Lipoprotein(a) and diabetes. Diabetes Care 1993;16(5):835-40.
22Mooser V, Seabra MC, Abedin M, Land­schulz KT, Marcovina S, Hobbs HH. Apolipoprotein(a) kringle 4-containing fragments in human urine: Relationship to plasma levels of lipoprotein(a). J Clin Invest 1996;97(3):858-64.
23Arauz-Pacheco C, Parrott MA, Paskin P; American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care 2003;26(Suppl 1):S80-2.
24Tomlinson JW, Owen KR, Close CF. Treating hypertension in diabetic nephropathy. Diabetes Care 2003;26(6): 1802-5.
25Scanu AM. Lipoprotein(a) and the atherothrombotic process: Mechanistic insights and clinical implications. Curr Atheroscler Rep 2003;5(2):106-13.
26Rainwater DL, Kammerer CM. Lipoprotein Lp(a): Effects of allelic variation at the LPA locus. J Exp Zool 1998;282(1-2):54- 61.
27Utermann G. The mysteries of lipoprotein(a). Science 1989;246(4932):904-10.
28Wildman RP, Sutton-Tyreell K, Newman AB, Bostom A, Brockwell S, Kuller LH. Lipoprotein levels are associated with incident hypertension in older adults. J Am Geriatr Soc 2004;52(6):916-21.
29Bhavani BA, Padma T, Sastry BK, Krishna Reddy N. Plasma Lipoprotein (a) levels in patients with untreated essential hyper­tension. Indian J Hum Genet 2003;9(2):65­8.
30WHO Technical report series on Hyper­tension, Geneva; 1996.
31Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. JAMA 2003;289(19):2560-72.
32Friedewald WT, Levy R, Fredrickson DS. Estimation of the concentration of Low­density lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge. Clin Chem 1972;18(6): 499-502.
33Cockcroft DW, Gault MH. Prediction of creatinin clearance from serum creatinine. Nephron 1976;16(1):31-41.
34Schaars CF, Denig P, Kasje WN, Stewart RE, Wolffenbuttel BH, Haaijer-Ruskamp FM. Physician, organizational and patient factors associated with suboptimal blood pressure management in type 2 diabetic patients in primary care. Diabetes Care 2004;27(1):123-8.
35Sesso HD, Buring JE, Chown MJ, Ridker PM, Gaziono JM. A prospective study of plasma lipid levels and hypertension in women. Arch Intern Med 2005;165 (20):2420-7.
36Catalano M, Perilli E, Carzaniga G, Colombo F, Carotla M, Andreoni S. Lp (a) hypertensive patients. J Hum Hypertens 1998;12(2):83-9.
37Fytili CI, Passadakis PS, Progia EG, et al. Arterial hypertension is associated with serum lipoproteins (a) levels in end stage renal disease patients. Hemodial Int 2001;5:66-9.
38Song KH, Ko SH, Kim HW, et al. Prospective study of lipoprotein(a) as a risk factor for deteriorating renal function in type 2 diabetic patients with overt proteinuria. Diabetes Care 2005;28(7): 1718-23.
39Boemi M, Sirolla C, Fumelli P, James RW. Renal disease as a determinant of increased lipoprotein concentrations in diabetic patients. Diabetes Care 1999;22 (12):2033-6.
40Heesen BJ, Wolfenbuttel BH, Leurs PB, et al. Lipoprotein(a) levels in relation to diabetic complications in patients with non-insulin dependent diabetes. Eur J Clin Invest 1993;23(9):580-4.
41Ruiz J, Thillet J, Huby T, et al. Association of elevated lipoprotein(a) levels and coronary heart disease in NIDDM patients: Relationship with apoli­poprotein(a) phenotypes. Diabetologia 1994;37(6):585-91.
42James RW, Boemi M, Sirolla C, Amadio L, Fumelli P, Pometta D. Lipoprotein(a) and vascular disease in diabetic patients. Diabetologia 1995;38(6):711-4.
43Hirata K, Saku K, Jimi S, Kikuchi S, Hamaguchi H, Arakawa K. Serum lipo­protein(a) concentrations and apolipo­protein(a) phenotypes in the families of NIDDM patients. Diabetologia 1995;38 (12):1434-42.
44Heller FR, Jamart J, Honore P, et al. Serum lipoprotein(a) in patients with diabetes mellitus. Diabetes Care 1993;16(5):819-23.
45Durlach V, Gillery P, Bertin E, et al. Serum lipoprotein(a) concentrations in a population of 819 non-insulin-dependent diabetic patients. Diabet Metab 1996; 22(5):319-23.
46Appel GB, Blum CB, Chien S, Kunis CL, Appel AS. The hyperlipidemia of the nephrotic syndrome: Relation to plasma albumin concentration, oncotic pressure and viscosity. N Engl J Med 1985; 312(24):1544-8.