Andrejs Kalvelis 1, MD, PhD, Inga Stukena 2, MD, Guntis Bahs 3 MD, PhD & Aivars Lejnieks 4, MD, PhD ABSTRACT INTRODUCTION. Riga Stradins University

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1 CARDIOVASCULAR RISK FACTORS ORIGINAL ARTICLE Do We Correctly Assess the Risk of Cardiovascular Disease? Characteristics of Risk Factors for Cardiovascular Disease Depending on the Sex and Age of Patients in Latvia Andrejs Kalvelis 1, MD, PhD, Inga Stukena 2, MD, Guntis Bahs 3 MD, PhD & Aivars Lejnieks 4, MD, PhD Riga Stradins University Received 10/1/2011, Reviewed 18/1/2011, Accepted 25/1/2011 Key words: risk factors, serum lipids DOI: /ejcm ABSTRACT Objective: The objective of this study was to characterise the main risk factors (RFs) for cardiovascular disease and their correlation with sex and age in the Latvian population. Background: The significance of the data regarding the variation of different RFs for cardiovascular disease according to sex and age is controversial. Methods: Various RFs were analysed in 1400 outpatients (mean age, years, 27.1% were men) depending on age and sex. Results: Male individuals had a larger waist circumference (WC) than did female patients ( vs cm, p<0.001), higher diastolic blood pressure (DBP) ( vs mmHg, p=0.002), and higher levels of blood glucose ( vs mmol/l, p=0.006) and triglycerides ( vs mmol/l, p<0.001), but lower levels of total cholesterol ( vs mmol/l, p<0.001) and high-density lipoprotein-cholesterol (HDL-C) ( vs mmol/l, p<0.001). Compared with the younger age (i.e., males, <45 years; females, <55 years), patients in the older age had a significant (p<0.001 in all cases) larger WC, higher systolic blood pressure, higher DBP, higher blood glucose level, and a higher level low-density lipoprotein-cholesterol, but lower HDL-C level. Age significantly correlated with all RFs in the younger-patient sub as well as in the female sub. Conclusions: Analyses of cardiovascular RFs in different age subs of both sexes clearly showed the individual features of the risk profile. The new approach requires individual attention based on sex and age as well as in the management of risk. These data suggest that activities for reducing cardiovascular risk are needed in s which are at relatively lower risk of cardiovascular disease: younger persons and in female subs. 1. Professor, Department of Internal Medicine 2. Department of Internal Medicine 3. Associate Professor, Head of Department of Family Medicine and 4. Professor, Head of Department of Internal Medicine Riga Stradins University CORRESPONDENCE Inga Stukena, Lokomotives street , Riga, Latvia, LV 1057 Phone: inga.stukena@rsu.lv ACKNOWLEDGMENTS: This work was supported by the Latvian National Research Programme in Medicine INTRODUCTION The development of cardiovascular disease is mainly dependent upon the presence of risk factors (RFs). More than 200 RFs for cardiovascular disease have been described (1). The most important RFs are age, sex, smoking habit, diabetes mellitus, elevated blood pressure (BP), high level of low-density lipoprotein-cholesterol (LDL-C), low level of high-density lipoprotein-cholesterol (HDL-C), and unfavourable family history (1, 2, 3 ). Obesity and a sedentary lifestyle are additional and supporting RFs (1, 2). Recently demonstrated RFs include elevated levels of triglycerides (TG) and various inflammatory markers (e.g., C-reactive protein (CRP)) (2). The significance of the data regarding the variation of different RFs for cardiovascular disease according to sex is controversial. For example, higher CRP levels have been reported in females (4), and studies have debated the prevalence of obesity in females compared with males (5, 6). It has also been suggested that arterial hypertension (AH) and diabetes mellitus have a greater impact in females than males (7). In the presence of several RFs, the risk of coronary heart disease (CHD) is sevenfold greater in males and fivefold greater in females than the risk in persons without cardiovascular RFs (8). Examination of the correlation of other RFs with age revealed that only the correlation with TG levels should be considered. No significant correlation was found between age and obesity, HDL-C, systolic blood pressure (SBP) or diastolic blood pressure (DBP) (9). ISSN

2 HEALTHCARE BULLETIN CARDIOVASCULAR RISK FACTORS Significantly higher levels of LDL-C, CRP, and oxidised LDL-C were found in females aged >56 years. In contrast, levels of TG and HDL-C do not vary with age. A direct correlation between age and levels of CRP and oxidised LDL-C has been reported in females. A large international study (7) showed that traditional RFs (e.g., dyslipidaemia, smoking, AH and abdominal obesity) promote the development of myocardial infarction. Thus, prevention of cardiovascular disease should be based on a simple principle: elimination of RFs. That large international study (7) also showed that the prevalence of RFs and their correlation with myocardial infarction were different in different countries and ethnic s. The marked variation in the prevalence of atherosclerosis and mortality from cardiovascular diseases in different countries may be explained by the variability in the prevalence of specific RFs. It would be ideal to elaborate individual risk-reduction models for each patient or patient (10). The differential access to various patient s, based on the levels of RFs and their correlation, is important in reducing the risk of cardiovascular disease. The situation is very unfavourable in Latvia because the prevalence of cardiovascular mortality is one of the highest in Europe. The prevalence of RFs and their mutual correlations (particularly regarding sex and age) are poorly studied in Latvia. The aim of the present study was to characterise the main cardiovascular RFs and their correlation with sex and age in a Latvian population. PATIENTS AND METHODS All patients provided written informed consent to be included in the study. The study protocol was approved by the local Medical Ethics Committee. Subjects The prevalence of cardiovascular RFs and health status was examined in 1400 patients who attended the clinic of their family doctor (general practitioner (GP)) for a planned visit to deal with any health-related problem. All persons were included by voluntary consent throughout all regions of Latvia. The exclusion criteria were as follows: age<18 years and >75 years; renal disease with glomerular filtration rate (GFR)<30 ml/min; thyroid-gland disorders; liver disease with liver-cell insufficiency; oncologic disease with dissemination and signs of acute inflammatory process (CRP>10 mg/ml). Methods The following parameters and cardiovascular RFs were evaluated separately in males and females, as well in the younger age (males, <45 years; females, <55 years) and older (males, >45 years; females >55 years): waist circumference (WC), body mass index (BMI), SBP, DBP, as well as levels of blood glucose, total cholesterol (TC), LDL-C, HDL-C, triglyceride (TG), and CRP. Fasting concentrations of lipids, glucose, and CRP were analysed using standard methods. Two most important RFs (levels of LDL-C and SBP) were analysed in different age subs (years): <30, 31 50, and >70. Statistical analyses After testing the normality of data distribution, statistical differences between two s were analysed by the two-sided unpaired Student s t-test (if data were distributed normally) or by the Mann Whitney test (if data did not meet the criteria for normal distribution). Data were recorded as the mean ± standard deviation (SD) if data were normally distributed or median (I; III quartiles) if the data did not meet the criteria for normal distribution; two-tailed values of p<0.05 were considered significant. Correlation analyses were undertaken using Spearman s rank correlation coefficient. All analyses were carried out using SPSS for Windows 18.0 version (SPSS, Chicago, IL, USA). RESULTS Among the patients questioned, 27.1% were men, 19.7% were smokers, 52.6% had pre-existing AH, and 9.2% had previously diagnosed diabetes. The patient was characterised by the following parameters mean + SD or median (I; III quartiles): mean age, years; BMI, kg/m2; WC, cm; SBP, mmhg; DBP, mmhg; blood glucose, mmol/l; TC, mmol/l; LDL-C, mmol/l; HDL-C, mmol/l; TG, 1.52 (1.24; 2.37) mmol/l; CRP, 1.50 (0.71; 3.32) mg/l. Table 1 lists the main differences and level of significance (p) of patient characteristics and cardiovascular RFs in subs organised according to sex and age. The results listed in Table 1 reveal higher values of WC and DBP, higher levels of blood glucose, TG and CRP, and lower levels of TC, LDL-C, and HDL-C in males. We observed no significant difference in the BMI and SBP between sexes. Compared with the younger age, the older had higher values of BMI, WC, SBP and DBP, higher levels of blood glucose, TC, LDL-C, TG and CRP, and a lower level of HDL-C. Differences in mean levels of LDL-C and SBP in different age and sex subs are shown in Figures 1 and 2. The mean level of LDL-C in the general increased until the age of 70 years, but it started to decrease after that age (Figure 1A). The same changes were observed in female subs, whereas the observed changes in LDL-C levels dependent upon age were not significant in the male subs (Figure 1B). The mean level of SBP increased with age in the general (Figure 2A) and in the female sub (Figure 2B). However, in the male sub, the increase in mean SBP with age was less pronounced (Figure 2B). Correlation of age with studied RFs dependent upon sex and in two age subs is shown in Table 2. Age correlated with unfavourable changes in all studied parameters in the general and in the female sub. We observed an increase in WC, BMI, SBP and DBP, as well as in blood levels of glucose, TC, LDL-C and TG, and a decrease in the blood level of HDL-C, with age. Only five of the observed parameters (WC, SBP, DBP; levels of glucose and CRP) correlated with age in the male sub, whereas the BMI and all lipid parameters did not correlate significantly. In the younger-patient sub, age correlated with unfavourable changes in all studied parameters except HDL-C levels. In the older-patient sub, age correlated only with SBP and levels of TC and LDL-C. 20

3 DO WE CORRECTLY ASSESS THE RISK OF CARDIOVASCULAR DISEASE? Table 1: Variability in risk factors for cardiovascular disease according to sex and age (mean + SD or median (I; III quartiles) Index Male Female p Younger age Older age p BMI 28.53± ± ± ±5.03 <0.001 WC 99.13± ±14.7 < ± ±13.8 <0.001 SBP 137.0± ± ± ±19.3 <0.001 DBP 82.6± ± ± ±8.8 <0.001 Glucose 5.81± ± ± ±1.34 <0.001 TC 5.42± ±1.20 < ± ±1.25 <0.001 LDL-C 3.36± ± ± ±1.07 <0.001 HDL-C 1.23± ±0.37 < ± ±0.38 <0.001 TG 1.85 (1.53; 2.32) 1.56 (1.21; 2.08) < (1.23; 2.10) 1.75 (1.63; 2.35) <0.001 CRP 1.70 (0.90; 3.40) 1.50 (0.70; 3.10) (0.50; 2.71) 1.80 (0.91; 3.42) <0.001 BMI, body mass index (kg/m2); CRP, C-reactive protein (mg/l); glucose (mmol/l); HDL-C, high-density lipoprotein-cholesterol (mmol/l); LDL-C, low-density lipoprotein-cholesterol (mmol/l); older age, males >45 years and females, >55 years; p, level of significance; SBP, systolic blood pressure (mmhg); DBP, diastolic blood pressure (mmhg); TG, triglycerides (mmol/l); TC, total cholesterol (mmol/l); WC, waist circumference (cm); younger age, males, <45 years and females, <55 years. Figure 1: Mean low density lipoprotein cholesterol level in the general study and different age subs (A) and in different age subs depending on sex (B) 21

4 HEALTHCARE BULLETIN CARDIOVASCULAR RISK FACTORS Figure 2: Mean systolic blood pressure in different age subs (A) and in different age subs depending on sex (B) Table 2: Spearman rank correlation coefficient (SCC) between age and other parameters in the general study, in males and females, and in the both age subs Index GG Male Female Younger age Older age BMI SCC p < <0.001 < WC SCC p < <0.001 < SBP SCC p <0.001 <0.001 <0.001 <0.001 <0.001 DBP SCC p < <0.001 < Glucose SCC p <0.001 <0.001 <0.001 < TC SCC p < <0.001 < LDL-C SCC p < <0.001 < HDL-C SCC p TG SCC p < <0.001 < CRP SCC p <0.001 <0.001 <0.001 < BMI, body mass index (kg/m2); CRP, C-reactive protein (mg/l); glucose (mmol/l); HDL-C, high-density lipoprotein-cholesterol (mmol/l); LDL-C, low-density lipoprotein-cholesterol (mmol/l); older age, males >45 years and females, >55 years; p, level of significance; SBP, systolic blood pressure (mmhg); DBP, diastolic blood pressure (mmhg); TG, triglycerides (mmol/l); TC, total cholesterol (mmol/l); WC, waist circumference (cm); younger age, males, <45 years and females, <55 years. 22

5 DO WE CORRECTLY ASSESS THE RISK OF CARDIOVASCULAR DISEASE? DISCUSSION The present study revealed great differences in the characteristics of cardiovascular RFs in subs based on sex and age. Higher values of WC, DBP, blood glucose level and TG level were found in males than in females, whereas levels of TC, LDL-C and HDL-C were lower in males. More pronounced changes in lipid levels (with the exception of HDL-C) have been reported in females (9). The literature reports (9) that TG is the only lipid that correlates with age. However, we found correlations between age and levels of TC, LDL-C, TG and CRP, and an inverse correlation between age and HDL-C levels in the general study. Increased values of BMI, WC, SBP, DBP, and levels of blood glucose, TC, LDL-C and TG were found in older age sub, as well as a decreased level of HDL-C. A stronger correlation among RFs has been observed in females (11). Correlation analyses showed an increase in the BMI, WC, SBP, DBP, and levels of blood glucose, TC, LDL-C and TG, as well as a decrease in HDL-C level, with age. Correction of dyslipidaemia is of relatively lower importance but control of SBP is of greater importance in the older-patient sub (particularly after the age of 70 years). Prevention of CVD risk in patient s with a lower risk could provide more effective CVD prophylaxis than reduction of CVD risk in persons with a higher CVD risk. It may be necessary to have different guidelines for CVD prevention based on sex and age s. REFERENCES Gotto A, Pownal H. Manual of Lipid Disorders. 3-rd ed. Lippincott Williams and Wilkins, 2003:17. Smith SC, Jackson R, Pearson TA, et al. Principles for National and Regional Guidelines on Cardiovascular Disease Prevention. Circulation 2004; 109: Smith SC, Milani RV. Atherosclerotic Vascular Disease Conference. Writing II: Risk Factors. Circulation 2004; 109: Correlation analyses showed an increase in unfavourable changes in all studied parameters except HDL-C with age in the youngerpatient. In the older-patient, only SBP increased with age, whereas levels of TC and LDL-C decreased. Age correlated with unfavourable changes in all studied RFs in the female sub. Age correlated only with unfavourable changes in WC, SBP, DBP, and levels of CRP and glucose in the male sub. Males had higher levels of TG and HDL-C, and these levels did not change (correlate) with age. Unfavourable changes in the profiles of these lipids with age were detected in women only. These data suggested that effective prevention of the increase in cardiovascular risk is more likely in younger age s and in females. In general, young females have a lower cardiovascular risk, but primary and secondary prevention measures would be most effective in this population. The most promising (and possibly most effective) RF corrections would pertain to WC, the BMI, SBP, and DBP in younger age s of both sexes, as well as correction of lipid levels in younger females. Relatively high risks of dyslipidaemia and AH have been reported in younger patients (7). The correlation of age with the BMI, WC, SBP, DBP and blood glucose level exclusively in the younger patient may indicate the necessity of more active correction in younger patients. A higher RF for diabetes mellitus has been reported in younger individuals (particularly females) (7) Arena R., Arrowood JA, Fei OY, Helm S, Kraft KA. The relationship between C-reactive protein and other cardiovascular risk factors in men and women. J Cardiopulm Rehabil. 2006;26(5): De Lusignan S, Hague N, van Vlymen Dhoul N, Chan T, Kumarapeli P. A study of cardiovascular risk in overweight and obese people in England. Eur J Gen Pract 2006; 12(1): Rezende FA, Rosado LE, Ribeiro RC, et al. Body mass index and waist circumference: association with cardiovascular risk factors. Arq Bras Cardiol 2006;87(6): Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case control study. Lancet 2004;364: Gotto AM, Amarenco P, Assman G, et al. The ILIB Lipid Handbook for clinical Practice. New York 2003;31. Aghaeishahsavari M, Noroozianavval M, Veisi P, Parizad R, Samadikhah J. Cardiovascular disease risk factors in patient with confirmed cardiovascular disease. Saudi med J 2006;27(9): Vinereanu D. Risk factors for atherosclerotic disease: present and future. Herz 2006;31. Suppl.3:5-24. Oda E, Abe M, Kato K, Watanabe K, Veeraveedu PT, Aizawa Y. Gender differences in correlations among cardiovascular risk factors. Gend Med 2006;3(3): CONCLUSIONS Analyses of cardiovascular RFs in different age subs of both sexes clearly showed the individual features of risk profiles. Age-related changes in adverse RFs were more pronounced in women and younger patients (i.e. patient subs not typically associated with high risk of cardiovascular disease (CVD)). Hence, more intensive prevention measures are required in these s. These recommendations might be particularly useful in the situation of insufficient compliance or limited healthcare funding, when the priorities of healthcare must be determined. 23

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