Clustering of silent cardiovascular risk factors in apparently healthy ...

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IS Hoffmann1 and LX Cubeddu2. 1Center for the Detection and Treatment of Silent Cardiovascular and Metabolic Risk Factors, Central. University of Venezuela ...
Journal of Human Hypertension (2002) 16 (Suppl 1), S137–S141  2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh

Clustering of silent cardiovascular risk factors in apparently healthy Hispanics IS Hoffmann1 and LX Cubeddu2 1

Center for the Detection and Treatment of Silent Cardiovascular and Metabolic Risk Factors, Central University of Venezuela, Caracas, Venezuela; 2Nova Southeastern University, HPD, Ft Lauderdale, FL 33308, USA

Ischaemic heart disease is one of the leading causes of cardiovascular morbidity and mortality. Because most factors leading to cardiovascular disease have a silent course, early screening is needed for prevention and for halting disease progression. In our centre, a programme was implemented in apparently healthy subjects for the early diagnosis and treatment of factors known to increment the risk of developing cardiovascular and metabolic disease. We present data from the first 153 individuals evaluated. The incidence of modifiable risk factors in our healthy population was as follows: overweight 33% (BMI: 25–30 kg/m2), obesity 45% (BMI >30 kg/m2), sedentarism 84%, arterial hypertension 15% (> 140/90 mm Hg), hyperinsulinaemia 50%, glucose intolerance 14% (>160 mg/dl 120 min after 75 g glucose load), type 2 diabetes mellitus 5%, hypercholesterolaemia 50%, hypertriglyceridaemia 28%, and salt sensitivity

25%. Clustering of three or more cardiovascular risk factors was observed in 59% of the apparently healthy subjects. Obesity was associated with greater clustering of risk factors. The cardiovascular dysmetabolic syndrome was present in 72% of the obese individuals. These findings revealed a very high prevalence of cardiovascular risk factors in apparently healthy Hispanics. Even though these individuals were clinically asymptomatic, they are at increased risk for developing cardiovascular disease and type 2 diabetes mellitus. Mechanisms for the early detection and correction of modifiable risk factors in the healthy population must be implemented. Only through prevention will a reduction in the incidence of cardiovascular atherosclerotic disease and of type 2 diabetes mellitus be achieved. Journal of Human Hypertension (2002) 16 (Suppl 1), S137– S141. DOI: 10.1038/sj/jhh/1001360

Keywords: cardiovascular risk factors; obesity; dyslipidaemia; insulin; glucose; salt sensitivity

Introduction Cardiovascular diseases, particularly ischaemic heart disease, are one of the main causes of morbidity and mortality in western countries. Most predisposing factors for atherosclerotic vascular disease have a silent course (produce no symptoms) and commonly coexist in one individual, producing synergistic deleterious effects.1,2 Early detection and treatment of modifiable risk factors prevents irreversible damage to the vasculature and the heart. Obesity, in particular abdominal obesity, smoking, type 2 diabetes mellitus, hypertension and dyslipidaemia are known to increase the risk for developing ischaemic heart disease.1,3–7 However, insulin resistance, hyperinsulinaemia, glucose intolerance, fasting glucose levels in the upper normal limit, high normal blood pressures (BP), sedentarism, and salt sensitivity have been associated either

Correspondence: I Hoffman, Center for the Detection and Treatment of Silent Cardiovascular and Metabolic Risk Factors, Central University of Venezuela, Caracas, Venezuela E-mail: hoffmani얀camelot.rect.ucv.ve Support: Conicit S1–96001890, CDCH F.06.30.4362.99 y CDCH 06.10.4214.98.

directly or indirectly with increased cardiovascular events.8–14 Recently, a Centre for the Detection and Treatment of Silent Cardiovascular and Metabolic Risk Factors was founded at the Central University of Venezuela. One of the Centre’s objectives is to evaluate the prevalence of risk factors for cardiovascular disease and for type 2 diabetes mellitus, in apparently healthy individuals. It is envisaged that this small-scale study will provide the ground for a larger scale investigation and to institute appropriate public health measures for disease prevention. In this study, the following modifiable risk factors were evaluated: obesity, central obesity, sedentarism, hypertension and high upper normal BP, salt sensitivity, type 2 diabetes mellitus, glucose intolerance, high normal fasting glucose levels, fasting and postload hyperinsulinaemia and dyslipidaemia. In addition of being of interest to the international scientific community, information about coexistence of these risk factors is not available for the apparently healthy Venezuelan population.

Materials and methods Written informed consent was obtained for all participants. A total of 153 apparently healthy subjects

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attending our centre were studied. A complete medical history, physical examination and laboratory work-up was performed in all subjects. Detailed family and personal medical history was obtained. Subjects with evidence of active cardiovascular, cerebral, renal, hepatic, pulmonary, haematologic, oncologic or autoimmune disease were excluded. Physical activity was assessed as: sendentary (0), active, but no regular physical activity (1), regular physical activity at low level (2), regular physical activity of moderate intensity (3) and athlete (4). Body mass index (BMI) was calculated as the ratio: weight in kg/(height in cm)2. The waist and hip circumferences were measured in cm and expressed as the ratio: waist/hip (WHR). Fasting blood samples were obtained for serum lipids, glucose and insulin. An oral glucose tolerance test (75 g of glucose) was performed in all subjects. Blood samples for glucose and insulin levels were obtained at 0, 30, 60, 90, 120 and 180 min. Glucose was measured by the glucose oxidase technique in a glucose analyzer (Beckman Instruments, Palo Alto, CA, USA), and insulin by solid phase radio-immunoassay (Diagnostic Products Corporation, Los Angeles, CA, USA). Plasma lipids were quantitated by spectrophotometry (Express 550). Complete haematology, blood chemistry, liver function tests, urinalysis, 24-h urinary excretion of creatinine and electrolytes, were also obtained. After these baseline determinations patients were tested for salt sensitivity. Patients were placed a liberal sodium intake diet, prescribing in addition a total of 12 tablets a day, each containing 1 g of sodium chloride. Subsequently, patients received a low-salt diet (20– 40 mEq/day) for 7 days. On days 6 or 7 of both sodium diets, patients returned to the centre for the following procedures: systolic BP (SBP), diastolic BP (DBP), and pulse rate (HR), 24h sodium and potassium excretion, and serum and urinary creatinine levels. BP was measured with a standard mercury sphygmomanometer. Korotkoff sounds 1 and 5 were used to record SBP and DBP, respectively. The BP measurements were done with the patient in the supine position after the patient had rested for at least 30 min. The average of at least three determinations was used. The mean BP was calculated as one-third of the pulse pressure added to the diastolic pressure. Patients were classified as salt sensitive, salt resistant and of intermediate salt sensitivity. If the difference in mean BP between low and high sodium weeks was equal to or more than 10 mm Hg, the patient was deemed salt sensitive. Salt resistance was defined as increases of less than 3 mm Hg, no change or decreases in mean BP. Subjects with intermediate values were classified as of intermediate salt sensitivity.15 The following criteria were employed for patient classification and cardiovascular risk assessment: (1) lean/overweight/obesity was determined based on BMI. Lean ⬍25 kg/m2, overweight 25–30 kg/m2 and obese ⬎30 kg/m2;16 (2) central fat accumulation

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based on WHR, women ⬎0.85 and males ⬎1;16 (3) hyperlipidaemia: total cholesterol ⬎200 mg/dl, HDL-cholesterol ⬍40 mg/dl, LDL-cholesterol ⬎160 mg/dl and triglycerides ⬎140 mg/dl; (4) hyperinsulinaemia: ⬎15 ␮UI/ml fasting and ⬎100 ␮UI/ml during the oral glucose tolerance test;17,18 (5) fasting glucose: ⬍110 mg/dl normal, 110–126 mg/dl intolerant, and ⬎126 mg/dl diabetes mellitus. Two hours after 75 g of oral glucose ⬍140 mg/dl normal, 140– 199 mg/dl glucose intolerance, and ⭓200 mg/dl diabetes mellitus.

Results Of the 153 subjects, 78% had BMI ⬎25 kg/m2, and 45% were considered obese with BMI above 30 kg/m2 16 (Figure 1). WHR greater than 1 for males and greater than 0.85 for females were observed in 43% of the subjects. Interestingly, 84% of the subjects studied classified themselves as sedentary or as ‘active’ but not engaged in regular physical activity. Physical activity was inversely related to the BMI of the subjects studied. Nearly 95% of the obese subjects were sedentary; whereas, the prevalence of obesity and overweight was only 11% in the physically active group (Figure 2). Asymptomatic, previously undiagnosed type 2 diabetes mellitus was encountered in 5% of the ‘healthy’ subjects screened for cardiovascular risk factors. Furthermore, 14% of the subjects screened were glucose intolerant. These findings revealed that nearly 20% of the apparently healthy subjects had marked glucose abnormalities. A very high incidence of hyperinsulinemia was found in the apparently healthy subjects studied. Hyperinsulinaemia either fasting or after a 75 g glucose load was found in 50% of the subjects. A higher

Figure 1 BMI distribution in apparently healthy subjects screened for modifiable cardiovascular risk factors. Subjects were divided in three groups according to their BMI (kg/m2): ⬍25 lean, ⬎25 to ⬍30 overweight and ⭓30 obese.

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Figure 2 Physical activity in apparently healthy lean, overweight and obese subjects screened for modifiable cardiovascular risk factors. Physical activity was assessed as: sendentary (0), active, but no regular physical activity (1), regular physical activity at low level (2), regular physical activity of moderate intensity (3) and athlete (4).

incidence of hyperinsulinaemia was found in the obese individuals (Figure 3). High total cholesterol was found in 62%, low HDL-cholesterol in 57%, high LDL-cholesterol in 29% and high triglycerides in 43% of the subjects. Low-HDL cholesterol and hypertriglyceridemia were found in 58% and 51%, respectively of the obese individuals. BP values above 140/90 mm Hg were found in 15% of the subjects studied and high normal BP in 10% of the subjects screened. Most lean subjects had BP within normotensive range. On the other hand, obese subjects had a higher prevalence of high upper normal BPs and of hypertension (Figure 4). Salt sensitivity was detected in 25% and salt resistance in 44% of the subjects. The remaining 31% showed intermediate sensitivity to salt (increases ⭓3 and ⭐10 mm Hg).

Figure 4 Blood pressure levels in apparently healthy lean and obese subjects screened for cardiovascular risk factors. Normal BP (NT); ⬍130/85 mmHg; high normal (HN); 131–139/86–89 mm Hg; hypertension (HT); ⭓140/90 mm Hg.

lipidaemia was found in obese than in lean subjects. In the obese group, 30% were hypertensive (BP ⬎140/90 mm Hg), 64% hyperinsulinaemic, 24% glucose intolerant, 58% had low HDL-cholesterol and 51% had serum triglyceride levels above 140 mg/dl (Figures 5). Clustering of risk factors (cardiovascular dysmetabolic syndrome) was evaluated as follows: presence of at least three of the following abnormalities: obesity, hypertension, dyslipidaemia (low HDL and/or high triglycerides) and alterations in glucose metabolism (hyperinsulinaemia, glucose intolerance or type 2 diabetes mellitus). The cardiovascular dysmetabolic syndrome was present in 72% of the obese individuals. Dyslipidaemia and hyperinsulinaemia were the commonest abnormalities associated to obesity.

Clustering of cardiovascular risk factors A much greater prevalence of central obesity, high BP, hyperinsulinaemia, glucose intolerance, dys-

Figure 3 Insulin levels after 12-h fast and 2-h post 75-g. oral glucose in apparently healthy lean and obese subjects screened for cardiovascular risk factors. Normal levels: fasting ⬍15 ␮UI/ml, and post glucose ⬍100 ␮UI/ml.

Figure 5 Clustering of modifiable cardiovascular risk factors in apparently healthy lean and obese subjects. Abscissa: number of risk factors coexisting in each subject. The following risk factors were taken into account: hypertension, obesity, central obesity, hyperinsulinaemia, glucose intolerance, type 2 diabetes mellitus, dyslipidaemia (low HDL, high LDL or high triglycerides) and salt sensitivity. Journal of Human Hypertension

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Discussion The present study demonstrates a very high prevalence of modifiable cardiovascular risk factors in apparently healthy Hispanic (Venezuelan) subjects. It is important to emphasise that subjects with evidence of cardiovascular, renal, hepatic, pulmonary, metabolic, haematologic, oncologic, autoimmune, or cerebral (neurologic) disease were excluded form the study. Therefore, the population studied was considered as healthy. The high prevalence of untreated risk factors for cardiovascular and metabolic disease in healthy subjects may reflect poor primary care. However, many of these factors give no symptoms until disease has been fully established. Its early detection resulted in prompt management. Asymptomatic type 2 diabetes mellitus was found in 5% of the subjects and an additional 14% of subjects had biochemical evidence of glucose intolerance. Consequently, nearly 20% of the healthy subjects screened had marked abnormalities of glucose metabolism, which are known to be associated with increased cardiovascular morbidity and mortality.5,9 Even glucose levels on the upper normal range are associated with increased cardiovascular mortality and increase conversion to type 2 diabetes mellitus.19 Our results clearly demonstrate the need for systematic screening of the apparently healthy population for early abnormalities in glucose metabolism. In our programme, subjects with glucose intolerance were managed with diet, exercise and pharmacological treatment to avoid progression to type 2 diabetes mellitus and to reduce associated cardiovascular risk. A very high incidence of overweight and obesity was found in our ‘healthy’ subjects. This high prevalence (78%) is consistent with an increased worldwide prevalence of obesity through age, race and race-ethnic groups, as shown in a successive crosssectional analysis.7,20 In our subjects, overweight and obesity were inversely associated with physical activity. Genetic, cultural (dietary habits, sedentarism, self-esteem) and socio-economic factors determine the high prevalence observed of overweight and obesity. In fact, 84% of our obese subjects were basically sedentary, whereas the prevalence of overweight and obesity was only 11% in the physically active group. The beneficial effects of exercise on cardiovascular morbidity and mortality are wellestablished.10,12 These findings further stress the need of implementing educational programmes to impact negative alimentary and exercise habits. The prevalence of obesity-related comorbidities emphasises the need for concerted efforts to prevent and treat obesity. A striking finding was the observed coexistence of several risk factors in a ‘healthy’ subject. Approximately 80% of the apparently healthy subjects had three or more concomitant risk factors for cardiovascular disease. As previously shown, the coexistence of cardiovascular risk factors was increased in

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obese individuals.7,14,21–25 In our study, 30% of the obese subjects were hypertensive, 64% hyperinsulinaemic, 24% glucose intolerant, 58% had low HDLcholesterol and 51% had hypertriglyceridaemia. The clustering of at least two of the cardiovascular risk factors characteristic of cardiovascular dysmetabolic syndrome (obesity, hypertension, glucose intolerance/type 2 diabetes mellitus, dyslipidaemia) was present in 72% of the obese individuals. Cardiovascular disease is the main cause of death in most developed and underdeveloped countries, and has been considered as the epidemic of the XXI century. Substantial physical and emotional incapacity results from these conditions. Further, cardiovascular diseases account for large part of the increase in health care. There is no doubt that effective preventive strategies are required. A better understanding of modifiable cardiovascular risk factors, together with early recognition and aggressive correction is needed. Increase general public education in health matters, improvement of socioeconomic status and a demand for better primary care are needed in the war against the XXI century epidemic. In our Centre for the Detection and Prevention of Silent Cardiovascular and Metabolic Risk Factors an effort is being made for the early detection and prompt management of these factors. Reports from these efforts are forthcoming. From these data it is clear that absence of symptoms is not the sole indicator of cardiovascular health. A detailed assessment of cardiovascular and metabolic risk factors is required to detect and halt silent disease.

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