LEFT ventricular mass (LVM), as measured by M-mode

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1 Journal of Gerontology: MEDICAL SCIENCES 2007, Vol. 62A, No. 10, Copyright 2007 by The Gerontological Society of America Association Between Functional Polymorphisms of Renin-Angiotensin System, Left Ventricular Mass, and Geometry Over 4 Years in a Healthy Chinese Population Aged 60 Years and Older Tsung-Hsien Lin, 1,4,5 Herng-Chia Chiu, 6 Ya-Ting Lee, 2 Ho-Ming Su, 1 Wen-Chol Voon, 1,4 Hong-Wen Liu, 3,4 Wen-Ter Lai, 1,4 and Sheng-Hsiung Sheu 1,4,5 1 Division of Cardiology, Department of Internal Medicine, 2 Division of Nephrology, Department of Pediatrics, and 3 Department of Family Medicine, Kaohsiung Medical University Hospital, Taiwan. 4 Department of Internal Medicine, Faculty of Medicine, Graduate Institute of 5 Medicine and 6 Public Health, Kaohsiung Medical University, Kaohsiung, Taiwan. Background. Cross-sectional studies investigated the impact of renin-angiotensin system (RAS) gene polymorphism on left ventricular mass index (LVMI) with conflicting results. We conducted a longitudinal study to investigate the influence of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) and angiotensinogen (AGT) M235T and angiotensin II type 1 receptor (AT1R) A1166C gene polymorphisms on the LVMI and geometry. Methods. Of 1500 people screened, 110 nondiabetic normotensive elderly Chinese persons were recruited and received echocardiography at baseline and at the 2nd and 4th year follow-up. No participants had a history of organic heart disease or chronic medication. The gene polymorphisms were analyzed by using polymerase chain reaction. Results. Participant age was years (range years). The prevalence of concentric remodeling, eccentric hypertrophy, and concentric hypertrophy was significantly increased as well as LVMI after 4 years (all p,.05). These changes and the magnitude of LVMI increase were significantly higher in participants carrying the ACE D allele than non- D-allele carriers (all p,.05). This association was still significant in multivariate analyses ( p.02). A similar analysis showed a borderline significance in the AT1R but not in the AGT gene polymorphism. Conclusions. This longitudinal study showed that the aging process was associated with an increase of LVMI and changes of geometry. The RAS gene polymorphism, especially the ACE D allele, might modulate these changes in the Chinese population. This provides further knowledge that is essential in the assessment of cardiac disease and the determination of the left ventricular structure in older persons. LEFT ventricular mass (LVM), as measured by M-mode echocardiography, is a major independent risk factor for cardiovascular morbidity and mortality (1). Aging is accompanied by cardiovascular modifications, both structural and functional. It was reported that age was associated with LVM in previous cross-sectional studies (2). Therefore, it is mandatory to seek risk factors that may predispose to LVM increase in elderly persons. The renin-angiotensin system (RAS) has been shown to be involved in many cardiovascular diseases. Carriers of the D allele of angiotensin-converting enzyme (ACE) insertion/ deletion (I/D) polymorphism display elevated serum and cardiac ACE activity and thus may have higher RAS activation (3). Compelling studies reported that the ACE D allele was associated with many cardiovascular diseases, such as myocardial infarction (4). However, cross-sectional studies investigated the impact of ACE I/D polymorphism on LVM with conflicting results (5,6). The angiotensinogen (AGT) M235T polymorphism is associated with plasma AGT levels and cardiovascular disease (7). The T allele has very different distributions between Asian (70% 73%) and Caucasian (10% 24%) persons (8,9). Earlier findings associating this potentially functional variant with LVM are inconsistent and contradictory (10,11). The A1166C polymorphism of the angiotensin II type 1 receptor (AT1R) gene is associated with myocardial collagen type I synthesis (12). However, previous studies showed the equivocal association between the AT1R A1166C polymorphism and left ventricular structures (12 14). We have conducted a prospective study to investigate several physiological parameters in an elderly Chinese population living in Taiwan. We found that the aging process was associated with prolongation in the corrected QT interval (QTc), QT dispersion (QTd), and QTc dispersion (QTcd), which are influenced by ACE gene polymorphism (15,16). To our knowledge, the influence of RAS gene polymorphisms on the changes in LVM and geometry has not been reported in prospective cohorts. In the present study, we proposed to test for the relationship between changes of left ventricular structures and three genetic polymorphisms: the ACE I/D, AGT M235T, and AT1R A1166C polymorphisms. METHODS Participants The participants were from a community-based longitudinal cohort study, which was designed to discover the 1157

2 1158 LIN ET AL. Figure 1. Trial profile. change of several physiological functions and structures with the aging process in healthy elderly persons. The detail was described as in the previous article (16). Each participant needed to be free of disease at baseline to be recruited into the aging group. Baseline examinations were performed from October 1, 2000 through March 31, Figure 1 demonstrates the numbers of participants at three stages of screening or examination. There were 1500 potential candidates at the beginning. Inclusion criteria for healthy elderly participants were: (i) age 60 years; (ii) active lifestyle, with no limitations in daily life; (iii) no history of previously diagnosed diabetes, hypertension, ischemic heart disease, or cerebrovascular accident; (iv) no significant electrocardiographic or echocardiographic abnormality, including atrial fibrillation and myocardial infarction; and (v) no chronic medications. All of the measurements were repeated every 2 years. The examinations were usually scheduled in the same month as the first visit to assure the same interval of follow-up. As part of the whole study, we included participants who had no diabetes (fasting glucose, 126 mg/dl) and no hypertension (blood pressure no more than 140 mmhg in

3 ACE GENE POLYMORPHISM AND LVM 1159 systole and 90 mmhg in diastole) at the beginning of the study. This study was approved by the Institutional Review Board, Kaohsiung Medical University Hospital. All enrolled participants gave written informed consent. Echocardiographic Methods A single experienced cardiologist (WV) blinded to the clinical data performed the two-dimensional echocardiography with quantitative LV analysis. Echocardiographic examinations were performed using commercially available instruments (HP Sonos 5500; Hewlett-Packard, Andover, MA) equipped with a 2 4 MHz imaging transducer. The LVM was calculated according to the formula of Devereux and Reichek (17). The ratio of LVM to body surface area (BSA) was used as LVM index (LVMI) to adjust for body size. Increased LVMI was defined as having LVMI g/m 2 (i.e., 2 standard deviations above the mean of LVM value in the normotensive Chinese group) (18). Relative wall thickness (RWT) was calculated as (2 3 left ventricular posterior wall [LVPW])/LV end-diastolic dimension (LVEDD). Increased RWT was noted when RWT measured more than From these calculations, the participants were categorized into four groups: (i) normal (normal LVMI and RWT); (ii) concentric remodeling (normal LVMI and increased RWT); (iii) eccentric hypertrophy (increased LVMI and normal RWT); and (iv) concentric hypertrophy (increased LVMI and increased RWT). The LVM intraobserver error, calculated by dividing the difference between two measurements by the mean of two measurements from 10 random selected cases, was % in this study. Extraction and Amplification of Genomic DNA In accordance with standard methodology, genomic DNA was extracted from peripheral blood with a blood DNA kit (Puregene; Gentra Systems, Minneapolis, MN). Genomic DNA was suspended in Tris HCl at 10 mmol/l, EDTA at 1 mmol/l (ph 8.0), and concentrations of DNA were measured by spectrophotometry. The ACE I/D, AGT M235, and AT1R A1166C gene polymorphisms were analyzed by polymerase chain reaction as previously described in detail (11,12,19). Statistical Analysis All data were expressed as mean 6 standard deviation. The genotypic distribution was tested by Hardy Weinberg equilibrium. The paired t test and McNemar test were used to evaluate the change of continuous variables and changes of different geometry during 4-year follow-up. Univariate correlation was analyzed using Pearson correlation tests. The independent t test was used for analysis between continuous variables. We used one-way analysis of variance (ANOVA) to test for the overall significant differences of baseline characteristics among the different genotypes. Afterward, a statistical adjustment using multiple linear regression analysis was performed to test for the association between significant variables, three different RAS genotypes, and LVM parameters. Our independent variables included sex (female ¼ 0, male ¼ l), age, body mass index (BMI), systolic and diastolic blood pressure, LV dimensions, and LVMI at baseline. All tests were two-sided, and the level of significance was established as p,.05. The Statistical Package for the Social Sciences (SPSS) 11.0 for Windows (SPSS Inc., Chicago, IL) was used for statistical analysis. RESULTS Clinical Characteristics One hundred ninety-three participants were enrolled initially. As shown in Figure 1, 132 completed 4 years of examinations of electrocardiography and echocardiography. One hundred fifteen participants provided blood for genetic analysis; five had fasting glucose. 126 mg/dl, blood pressure. 140 in systole or 90 in diastole at baseline. Finally, 110 participants were included in the study. Table 1 summarizes the demographic information at the baseline and at the 2nd and 4th year. The participants included 83 men and 27 women. Age at enrollment ranged from 60 to 81 years (mean years). At the end of the 4-year follow-up, weight, height and BMI were significantly reduced as well as total cholesterol. There were no significant changes in systolic and blood pressure after 2 and 4 years. Echocardiographic Data There was an increase in the LVMI ( to g/m 2, p¼.012) at the third examination (Table 1). The prevalence of three geometries increased with age (p ¼.044 at the 4th year). Univariate analysis showed significant correlation between the 4th year LVMI and six baseline variables. These were baseline BMI (r ¼ 0.197, p ¼.039), LV interventricular septum dimension (LVIVS) (r ¼ 0.313, p ¼.001), LVEDD (r ¼ 0.401, p,.001), LVPW (r ¼ 0.411, p,.001), LV end-systolic dimension (LVESD) (r ¼ 0.353, p,.001), and LVMI (r ¼ 0.592, p,.001). The magnitude of LVMI increase after 4 years was correlated with LVIVS (r ¼ 0.367, p,.001), LVPW (r ¼ 0.311, p ¼.001), and LVMI at baseline (r ¼ 0.390, p,.001). ACE I/D, AGT M235T, and AT1R A1166C Gene Polymorphism Among 110 study participants, 6 (5.5%) were DD, 48 (43.6%) DI, and 56 (50.9%) II genotype of the ACE gene. Twelve (10.9%) were AGT MM, 30 (27.3%) had MT, and 68 (61.8%) had TT genotype. One (0.9%) was AT1R AA, 13 (11.8%) had CA, and 96 (87.3%) had CC genotype. The genotypic distribution was in Hardy Weinberg equilibrium in three genes. The ACE genotypes were correlated with LVMI at the 4th year (p ¼.027). The ACE genotypes were correlated with change of 4-year LVMI (p ¼.037). The ACE genotypes were not correlated with LVMI at baseline. The increase of LVMI at year 4 is proportional to the number of the D allele, which possibly suggests a potential dose effect (Table 2). The LVMI and magnitude of LVMI increase were significantly higher in participants with ACE D allele than in non D-allele carriers at year 4. The AT1R genotypes (CC vs CCþAA) were correlated with a change of 4-year LVMI ( p ¼.046) but not with LVMI at baseline, the 4th year. The

4 1160 LIN ET AL. Table 1. Patients Characteristics and Left Ventricular Parameters Characteristics Baseline Year 2 Year 4 No. 110 p Value Men, No. (%) 83 (75.5) Year 2 Baseline Year 4 Baseline Age, y Weight, kg ,.001 Height, cm ,.001,.001 BMI, kg/m Cholesterol, mg/dl Fasting sugar, mg/dl ,.001 SBP, mmhg DBP, mmhg LVIVS, mm LVPW, mm LVEDD, mm LVESD, mm , LVMI, g/m RWT, % LV geometry, % Normal Concentric remodeling Eccentric hypertrophy Concentric hypertrophy Notes: Values are mean 6 standard deviation (SD). BMI ¼ body mass index; SBP ¼ systolic blood pressure; DBP ¼ diastolic blood pressure; LVIVS ¼ left ventricular interventricular septum dimension; LVPW ¼ left ventricular posterior wall dimension; LVEDD ¼ left ventricular end-diastolic dimension; LVESD ¼ left ventricular end-systolic dimension; LVFS ¼ left ventricular fractional shortening; LVMI ¼ left ventricular mass index; RWT ¼ relative wall thickness. AGT genotypes were not correlated with all echocardiographic parameters at baseline or year 4. Because the frequency of the DD genotype was very low, the DD and DI genotypes were categorized into one group in analysis of changes of left ventricular geometry (Table 3). The left ventricular geometric pattern after 4 year follow-up had a significant change in participants carrying the ACE D allele ( p ¼.043), a trend to change in participants with AGT Table 2. Different RAS DNA Genotype and Left Ventricular Mass Index (g/m 2 ) Gene Genotype p Value ACE II ID DD No Baseline Year Year Year Year AGT MM TM TT No Baseline Year Year Year Year AT1R CC CA þ AA No þ 1 Baseline Year Year Year Year Notes: Values are mean 6 standard deviation. RAS¼ renin angiotensin system; ACE ¼ angiotensin-converting enzyme; AGT ¼ angiotensinogen; AT1R ¼ angiotensin II type 1 receptor; LVMI ¼left ventricular mass index; Year 2 0 ¼ LVMI increase at Year 2 minus baseline; Year 4 0 ¼ LVMI increase at Year 4 minus baseline.

5 ACE GENE POLYMORPHISM AND LVM 1161 TT (p ¼.061) or AT1R CC carrier (p ¼.088), but no change in participants carrying ACE II, AGT M allele, or AT1R A allele (Table 3). Predictors of LVMI and Magnitude of LVMI Increase Multivariate linear regression analysis showed that baseline LVMI was a significant determinant of year 4 LVMI ( p ¼.029). The ACE I/D gene polymorphism could significantly predict the LVMI at year 4 ( p ¼.020) and magnitude of LVMI increase at year 4 ( p ¼.010). There was a trend for AT1R gene polymorphism to predict the LVMI at year 4 ( p ¼.063) and magnitude of LVMI increase at year 4(p ¼.055) (Table 4). DISCUSSION There are four findings in this 4-year longitudinal study. First, we found that the aging process was associated with LMVI increase and changes of left ventricular geometry in elderly persons. Second, we demonstrated that the ACE I/D polymorphism was associated with the magnitude of LVMI increase as well as left ventricular geometric changes. The participants carrying the ACE D allele had a higher increase of LVMI in our population. Third, our data indicated that the D allele may have a dose effect on the magnitude of LVMI increase. Fourth, there was a trend for AT1R A1166C gene polymorphism to predict the LVMI and magnitude of LVMI increase at year 4. Some observations in humans have indicated that myocytes retain the capacity to hypertrophy and proliferate in the senescent heart (20). Previous cross-sectional studies have not reached a conclusion regarding whether aging is associated with LVM (2,21). Our prospective study may be less subject to ascertainment bias than are cross-sectional studies. In addition, we investigated elderly persons who may be more likely to predispose to LVM alternation. Left ventricle geometry is considered a better indicator of cardiovascular prognosis than LVM (22). In the Framingham Heart Study, Krumholz and colleagues (23) found that the healthy participants with concentric hypertrophy in their study had the worst prognosis for incident cardiovascular disease (23). Previously, age has also been positively related to the LVPW thickness and RWT (24). In this prospective study, we found that aging is associated with an increases in LVM. Both of these findings possibly explained the relationship between aging and increased prevalence of concentric remodeling, eccentric hypertrophy, and concentric hypertrophy. Table 3. Different RAS DNA Genotype and Change of Prevalence of Geometry Genotype (No.) Baseline Year 4 p Value ACE DD þ DI (54)*.043 Normal Concentric remodeling Eccentric hypertrophy Concentric hypertrophy II (56)*.541 Normal Concentric remodeling Eccentric hypertrophy Concentric hypertrophy AGT TMþMM (42)*.503 Normal Concentric remodeling Eccentric hypertrophy Concentric hypertrophy TT (68)*.061 Normal Concentric remodeling Eccentric hypertrophy Concentric hypertrophy AT1R CAþAA (14)*.233 Normal Concentric remodeling Eccentric hypertrophy Concentric hypertrophy CC (96)*.088 Normal Concentric remodeling Eccentric hypertrophy Concentric hypertrophy Notes: *Left ventricular geometry (%). RAS ¼ renin angiotensin system; ACE ¼ angiotensin-converting enzyme; AGT¼ angiotensinogen; AT1R ¼ angiotensin II type 1 receptor. Age, medications, hypertension, and diabetes have been demonstrated to be associated with change in LVM (25,26). Aging and hypertension were associated with increased stiffness in large arteries. This increases afterload, and therefore contributes to an increase in LVMI (27). In addition, noninsulin-dependent diabetes is known to be associated with hyperinsulinemia, a trophic hormone-simulating Table 4. Independent Predictors for LVMI and Change of LVMI in Multiple Regression Analysis in Year 4 Predictors Coefficient SE t p Value LVMI at Year 4 (Intercept ¼ , R 2 ¼ 0.452) ACE polymorphism AT1R polymorphism Baseline LVMI Magnitude of LVMI Increase at Year 4 (Intercept ¼ , R 2 ¼ 0.260) ACE polymorphism AT1R polymorphism Note: SE ¼ standard error; LVMI ¼ left ventricular mass index; ACE ¼ angiotensin-converting enzyme; AT1R ¼ angiotensin II type 1 receptor.

6 1162 LIN ET AL. myocyte proliferation (28). In our study, participants had no organic heart disease, chronic medications, hypertension, or diabetes to influence LVM. There must be something else contributing to LVM change. Data have suggested that the direct trophic effects of angiotensin II may lead to increased LVM (29). A study by Harrap and colleagues (30) of healthy adults also showed that angiotensin II directly affects myocardial size. Plasma angiotensin II was significantly correlated with LVM independent of systolic blood pressure and body size (30). Because carriers of the D allele of ACE I/D polymorphism display elevated serum and cardiac ACE activity, they are exposed to a higher angiotensin II level than are non-dallele carriers (3). However, cross-sectional studies investigated the impact of ACE I/D polymorphism on LVM with conflicting results (5,6). These inconsistent findings may be due to the limitations of cross-sectional studies. In our prospective study, the LMVI and magnitude of LVMI increase were significantly higher in participants carrying the ACE D allele than in non-d-allele carriers at the 4th year. In addition, this association was still significant in multivariate analyses. The AGT M235T polymorphism was associated with plasma AGT levels which is the direct precursor of angiotensin II and is the rate-limiting factor in the renin reaction (7,31). However, earlier findings with inconsistent data reported AGT M235T polymorphism to be associated with cardiac hypertrophy (7,11,12). We did not find a link between LVM and AGT M235T polymorphism. The possible explanation for this difference is that the studies had different enrolled populations. The dialysis patients reported by Wang and colleagues had different underlying diseases and were subjected to more volume and pressure overload, which may predispose to significant LVM change (11). The AT1R A1166C polymorphism is associated with myocardial collagen type I synthesis (12). Although studies investigated the association between AT1R A1166C polymorphism and hypertension with conflicting results, carriers of the AT1R C allele were reported to have higher vascular stiffness than were the AA homozygotes (32,33). Therefore, people carrying the AT1R A1166C C allele may be subjected to LVM increase during follow-up. The possible explanation for only borderline significance between AT1R genotypes and left ventricular parameter is small sample size in this study. There are two limitations to this study. First, we had a relatively small sample size and only studied three genes, which may not provide enough power to investigate genes with minor effects and also restricted us to explore a Gene 3 Gene interaction. Second, we did not measure RAS activity that can be linked to the genetic polymorphisms in our population. Although our findings are potentially intriguing, the result needs to be replicated for confirmation. Conclusion This longitudinal study demonstrated that aging significantly alters left ventricular structure and geometry. Furthermore, we disclosed an association between the RAS gene polymorphism, especially ACE I/D genotype, and LVM change and geometry in an elderly Chinese cohort. However, AT1R A1166C showed borderline significance, and the AGT M235T polymorphism did not demonstrate a significant association with the phenotypes of interest. Investigations of larger participant cohorts over longer follow-up periods to replicate our results are mandatory. ACKNOWLEDGMENTS This work was supported by the National Health Research Institutes (NHRI-EX PL) from the Department of Health, Executive Yuan, Taiwan, ROC. CORRESPONDENCE Address correspondence to Sheng-Hsiung Sheu, MD, Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University, Chung-Ho Memorial Hospital, 100 Shi-Chuan 1st Road, Kaohsiung , Taiwan, ROC. sheush@kmu.edu.tw REFERENCES 1. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. 1990;322: Gardin JM, Siscovick D, Anton-Culver H, et al. Sex, age and disease affect echocardiographic left ventricular mass and systolic function in the free-living elderly. The Cardiovascular Health Study. Circulation. 1995;91: Danser AH, Schalekamp MA, Bax WA, et al. Angiotensin-converting enzyme in the human heart. Effect of the deletion/insertion polymorphism. Circulation. 1995;92: Samani NJ, Thompson JR, O Toole L, Channer K, Woods KL. 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