- Email: [email protected]
Gender, obesity, alcohol use, hyperlipidemia, hypertension and decline of renal endothelial barriers
Original article
Gender, obesity, alcohol use, hyperlipidemia, hypertension and decline of renal endothelial barriers Keywords Obesity Alcohol misuse Dyslipidemia Hypertension Albumin Proteinuria Hematuria Men’s health
Ruth-Maria Korth Abstract Background: Raised body weight and hypertension are locally relevant risk factors. Patients were examined in a Bavarian General Medicine Practice to investigate the relationship between raised body weight, hypertriglyceridemia and alcohol misuse with raised blood pressure or abnormal morning urines. Methods: The risk factors evaluated in this study of primary care patients were obesity, overweight, hypertriglyceridemia, self-reported alcohol misuse, raised blood pressure and proteinuria and/or hematuria in men (n = 86, 31 12 years) and women (n = 160, 30 10 years). Results: Men or women with obesity (BMI2) or alcohol misuse (AHA1) had significantly higher systolic or diastolic blood pressure and significantly lower HDL levels (p < 0.05) compared with men or women of normal weight or without alcohol problems and the ratio of serum albumin to triglycerides was significantly lower with obesity or alcohol misuse (p = 0.001, p = 0.001, respectively). Men with hypertriglyceridemia tended to be overweight and showed significantly higher blood pressure than men with normal triglyceride levels (p < 0.05). Obese men showed significantly higher diastolic blood pressure compared to obese women (p = 0.049). An increase in systolic (p = 0.0026) or diastolic (p = 0.0002) blood pressure was significantly associated with raised body weight (BMI1 + BMI2), while a rise in diastolic blood pressure was linked with alcohol misuse (p = 0.0005) using multivariate modelling. Proteinuria and/or hematuria in men’s morning urine samples were significantly associated with misuse of alcohol or nicotine (p = 0.041, p = 0.045, respectively). Conclusion: The data showed significant associations between raised systolic or diastolic blood pressure and raised body weight. Raised diastolic blood pressure or proteinuria and/or hematuria were associated with misuse of alcohol and indicated a decline in renal endothelial barriers. ß 2006 WPMH GmbH. Published by Elsevier Ireland Ltd.
Ruth-Maria Korth, MD Research in General Medicine F.I.D.A., Munich, Germany E-mail: Ruth-Maria.Korth@ i-dial.de
Online 7 September 2006
Introduction Patients were examined in a Bavarian General Medicine practice to gain knowledge about the relationship between obesity, overweight, hypertriglyceridemia, alcohol misuse and/or hypertension. Proteinuria and/or hematuria in men’s morning urine samples were related to misuse of alcohol or nicotine
ß 2006 WPMH GmbH. Published by Elsevier Ireland Ltd.
while infections or chronic renal disorders were excluded. Hypertension has been associated with proteinuria, albuminuria, impaired renal function and higher mortality in a 24 year follow-up of 1462 women in Sweden [1]. Hypertension and age were the strongest determinants of proteinuria in a Dutch study of 335 type 2 diabetes patients at risk for renal disease
Vol. 3, No. 3, pp. 279–289, September 2006
279
Original article [2]. The third National Health and Nutrition Examination Survey called upon the medical community to improve the control of hypertension, defined as blood pressure of at least 140/90 mmHg [3]. Cohorts of obese children and adolescents in the USA have shown that an increase in systolic blood pressure and a decrease in high-density lipoprotein (HDL)cholesterols are closely correlated to elevated blood insulin levels (insulin resistance) [4]. Microalbuminuria was a predictor for cardiovascular disease in a Dutch Prevent study of non-diabetic patients [5]. Genetic polymorphism in the gap junctional proteins of endothelial cells (connexin 37) partly explains the thickened carotid artery intima found in a Swedish study and the prevalence of myocardial infarction in Japanese men (but not women) [6,7]. The carotid intima-media thickness has been associated with hyperinsulinemia, borderline hypertension and elevated antibodies against ether phospholipids (LApaf) [8–10]. However, the clinical study from Karolinska University [9] did not investigate the dysfunction of renal endothelial barriers. Genetic variations in alcohol dehydrogenases decrease the alcohol-related aldehydes resulting in light alcohol consumption having a beneficial effect against myocardial infarction [11]. Subjects with moderate alcohol consumption in France and Ireland showed good HDL-parameters (HDL-cholesterol, apoA-1) [12]. Genetically impaired hepatic lipase deficiency causes an increase in unhealthy intermediate lipoproteins and an unhealthy amount of alcohol combined with a high-fat diet leads to steatosis, hepatitis, fibrosis and cirrhosis of the liver [13,14]. The metabolites of alcohol are aldehydes and ether phospholipids such as the inflammatory platelet activating factor (PAF-Acether, Paf) [10,14–18]. Antagonists against Paf are present [19–22]. Lecithin, found for example in soya, prevents the oxidation of fatty acids [23]. Alcohol mediates hepatitis probably because free radicals initiate liver necrosis, fibrosis and the synthesis of PAF-Acether, as has been shown in the liver cells of rats after intoxication [24]. Men and women were examined in a Bavarian General Medicine practice and gender risk groups were selected on the basis of overweight, obesity, hypertriglyceridemia or alcohol misuse. Hypertension or proteinuria and microhematuria (hematuria) were evaluated here as
280
Vol. 3, No. 3, pp. 279–289, September 2006
independent risk factors because those men had a higher risk for developing renal disorders.
Methods Objectives Primary care patients (n = 1068) were examined in a Bavarian General Medicine practice. The initial risk factors for men (86 out of 313 (27%) aged 31 12 years) were compared with the biomarkers from an appropriate female study group (160 out of 636 (25%) aged 30 10 years). The local ethical authority approved this study as an epidemiological study with anonymous and confidentially documented data (Bayerische Landesa¨rztekammer, EthikKommission Nr 02088). Men (n = 56) and women (n = 127) with urological infections were treated but were initially excluded from the study. A further 171 men and 476 women were excluded because they had only attended the Practice for counseling, vaccinations or drug therapy, including antihypertensive or lipid lowering therapy, or they had at least one of the disorders mentioned below. Patients with known diabetes mellitus or kidney disorders (HbA1c 6%, plasma creatinine >1.2 mg/dl) were excluded. Those with infections or fever (C-reactive protein 6 mg/ dl, temperature 37 8C) were treated but not included. Viral hepatitis was excluded for patients with elevated liver values. Patients with neoplastic and hematological disorders, cancer, cardiovascular, cerebral or inflammatory disorders were also excluded. Self-reported alcohol consumption was scored. A consumption of 60 g beer/day was taken as an unhealthy amount. This was based on previous local studies of both early alcohol syndromes in primary care patients, who reported the consumption of at least 60 g beer/day for at least 5 years (AHA1), and late alcohol abusers, who reported an intake of 125 71 g alcohol/ day as determined in the social care unit of St. Bonifaz in Munich (AHA2) [16,17].
Study program Baseline measures of age, body mass index (BMI), blood pressure, morning urine samples and clinical chemistry were documented, as were personal and family disorders and the
Original article self-reported consumption of alcohol and/or nicotine. Blood pressure was determined after 5 min of rest. Body mass index (BMI) was calculated and subjects were divided into subgroups: normal weight (BMIn: <25 kg/m2), overweight (BMI1: 25–29 kg/m2) or obesity (BMI2: >29 kg/m2). Venous blood was taken after 12 h fasting and fasting blood glucose, triglyceride levels, total cholesterol, cholesterol in low-density lipoproteins (LDL) or in high density lipoproteins (HDL) were measured using standard procedures in a clinical laboratory. Serum albumin level was determined using an Elephanscan/Fractoscan to be calculated with 1.5% variation (Merck, Laborgemeinschaft ¨ nchen-Innenstadt). Four men were at risk Mu of having a Chlamydia infection. Polymerase chain reaction (PCR) of first morning urines excluded an infection and these men were included in the study. Hematuria was confirmed using urine microscopy and no pathological casts were found. Renal diseases were also excluded with urine profile confirming microalbuminuria without pathological proteins (or casts). These urine tests were per¨ nchenformed in the ‘‘Laborgemeinschaft Mu Innenstadt’’.
Practice diagnostics Capillary glucose was measured in the Practice. Tolerance to glucose (GTT) was determined either 1 h or 2 h after intake of 100 g oral glucose (Reflotron, Roche, Switzerland). Only morning urine samples were tested in the Practice to assess proteinuria and hematuria with parallel exclusion of urological infections (Combur 9, Roche, Switzerland). Albuminuria (Microbumin from Roche or Microalbustix, Bayer) confirmed proteinuria and was determined when more than 20 mg/l albumin was found in the first morning urine sample from two out of three different samples given within 1 week once a year: these patients were re-examined after 3 months. Patients with normal urine samples and without relevant risk factors were re-examined after 12 months.
Medical care A full medical examination was provided and self control documentation was offered (www.fida-aha.com). The biomarkers were confidentially discussed and documented in
the Medical Practice with informed consent. Medical counseling included aspects of food quality and lifestyle. Hypertension was successfully treated by preference with verapamile as the Paf antagonist potency of this calcium antagonist has been shown [22].
Statistical methods Results were caclulated as means standard deviations (1S.D.). The patient data were confidentially collected in a General Medicine practice between 1990 and 1999. The observed risk factors for this study group were estimated elsewhere using numbered data for analysis without identification of patients (estimatedR, Augsburg, Germany). Least square estimates for means and standard deviations were calculated there from a generalized linear model (GLM) using SAS-V8.2, PROC GLM. Tukey’s tests were used for all pairwise comparisons, controlling for type I error rate. The data for the male study group were reanalyzed to evaluate the relationship between the risk factors. The putative independent risk factors were increasing systolic or diastolic blood pressure, abnormal morning urine samples and the LDL/HDL ratio. Their relationship with obesity, raised body weight, age, drinking and smoking as well as smoking with drinking, high cholesterol, triglycerides or gammaglutamyl transferase (gamma-GT) levels was assessed by means of a multiple logistic regression (SAS V8.2, PROC LOGIST).
Results Characteristics of men or women The selected biomarkers of men or women are characterized in Table 1, which shows that a rather large proportion of the subjects in the obesity (BMI2) and overweight (BMI1) groups reported misuse of alcohol (AHA1) or nicotine. Men and women with obesity or selfreported alcohol misuse had elevated blood pressure, borderline cholesterol profiles and increased levels of triglycerides that lowered the ratio of serum albumin to triglycerides (Fig. 1). Intolerance to glucose increased with obesity or alcohol misuse and liver values showed high variance (GTT, Gamma-GT: Table 1).
Vol. 3, No. 3, pp. 279–289, September 2006
281
Original article Table 1 Gender characteristics of primary care patients with normal weight (BMIn), overweight (BMI1), obesity (BMI2) or selfreported alcohol misuse (AHA1) BMI2
AHA1
BMI1
BMIn
Men
Women
Men
Women
Men
Women
Men
Women
Cases: BMI (kg/m2): Age (years): Reported alcohol abuse, cases: Reported nicotine abuse, cases:
19 35 2 37 13 10 2
17 32 3 37 15 4 6
19 29 4 37 12 19 8
22 28 5 37 13 22 12
17 27 2 35 10 9 6
20 27 1 33 4 6 7
50 22 2 31 12 5 11
123 21 5 30 10 5 22
Systolic RR (mmHg): Diastolic RR (mmHg):
148 24* 104 8*
139 20* 97 13*
146 15* 103 10
135 24* 94 14*
139 18 93 9*
134 20 88 12
114 19 85 8
119 14 81 9
Abnormal morning urines, cases:
4
6
8
10
3
5
5
8
Clinical chemistry: Triglycerides (mg/dl): Cholesterol (mg/dl): LDL (mg/dl): HDL (mg/dl): LDL/HDL: GTT (mg/dl): Glucose (mg/dl): GGT (U/l): Plasma albumin (g/dl):
181 77 208 4 174 56 36 12* 3.4 0.6 181 41 97 5 28 17 5.4 0.3
206 100 206 10 155 30 46 11* 3.3. 0.9 175 53 93 12 28 27 4.8 0.4
178 82 203 40 161 45 36 5* 3.6 1.5 189 57 92 9 48 57 5.1 4.9
170 96 218 31 168 36 47 14* 3.7 1.7 155 47 92 11 35 19 4.9 0.4
145 81 190 29 141 49 50 19 2.6 1.4 147 15 90 8 20 8 5.2 0.3
166 95 203 62 139 35 50 9 3.4 0.5 158 17 88 10 11 5 4.8 0.4
106 42 179 30 126 35 57 16 2.2 0.6 130 26 88 7 11 4 5.2 0.3
104 45 198 47 135 42 64 18 2.3 0.9 128 12 85 5 10 12 5.0 0.4
Men or women with obesity or overweight and alcohol misuse had significantly elevated blood pressure (RR, resting rate, *p < 0.05)) and significantly lower HDL (*p < 0.05) compared with those who had normal weight. Those who abused alcohol (AHA1) often had proteinuria and/or hematuria. Data showed abnormal lipid profiles, borderline albumin, intolerance to glucose (GTT: 1 h, 100 g), normal fasting blood glucose and a raised Gamma-Gt (GGT) in men and women at risk. Values are means 1 standard deviation (SD).
Figure 1
282
Men with obesity (BMI2, n = 19), alcohol misuse (AHA1, n = 19) or normal weight (BMIn, n = 50) were examined. Men with obesity or alcohol misuse showed elevated systolic (A) or diastolic (B) blood pressure compared with men of normal weight or those without alcohol problems (p < 0.05 in Table 2). Capillary glucose increased 1 h after intake of 100 g glucose and the rise in triglyceride levels lowered the ratio of serum albumin to triglycerides in men with obesity and/or alcohol misuse with an indicated high prevalence of proteinuria and/or hematuria.
Vol. 3, No. 3, pp. 279–289, September 2006
Original article Men with indicated risk factors showed an elevated rate of proteinuria and/or hematuria after exclusion of urological infections (Fig. 1).
Observed biomarkers in men Men with obesity showed hypertension, moderate intolerance to glucose and dyslipidemia (Fig. 1). Obese men had elevated blood pressure with or without self-reported alcohol misuse (154 22/107 8 mmHg or 150 25/95 3 mmHg, respectively). Men who reported an unhealthy consumption of alcohol (AHA1: 83 30 g per day) tended to be overweight and had elevated blood pressure. More overweight men reported an unhealthy consumption of alcohol compared with men of normal weight (7 of the BMI1 group (37%) versus 11 of the BMIn group (22%)). Men reporting alcohol misuse had elevated triglycerides and a low albumin to triglycerides ratio (Fig. 1). Men with hypertriglyceridemia (n = 20) were overweight and tended to have elevated blood pressure (see Fig. 4). Men with hypertriglycidemia often reported misuse of alcohol (12 out of 20 (60%)). They had either normal morning urine samples (11 out of 20 (55%)), hematuria (5 out 20 (25%)) and/or proteinuria (4 out of 20 (20%)). Only a rather small number of men had intolerance to glucose, limiting further analysis. These men had normal fasting blood glucose (7 out of 86 (8%); 0 h = 95 8 mg/dl, 1 h = 185 40 mg/dl, 2 h = 116 26 mg/dl). Glucose intolerant men tended to be overweight and have elevated blood pressure (BMI = 27 6 kg/ m2; blood pressure = 143 13/97 11 mmHg; age = 26 9 years). An elevated rate of albuminuria and/or hematuria was confirmed using protein profiles while pathological casts were excluded with urine microscopy (not shown). The first morning urine samples from those men with proteinuria and/or hematuria (16 out of 86) showed levels of 58 38 mg/l for proteins and/or 17 10 erythrocytes/ml (Fig. 1). It was found that those men with pure hematuria (8 out of 86 (9%)) had elevated blood pressure (141 21/95 16 mmHg) and normal weight (24 4 kg/m2). They had normal fasting blood glucose and normal plasma creatinine levels (glucose = 86 5 mg/dl; creatinine = 0.9 0.17 mg/dl; age = 38 14 years). Four out of these 8 men with hematuria
reported an alcohol consumption of 83 48 g/day and five were smokers reporting an intake of 20 0 cigarettes per day. It was also found that those men with pure proteinuria (4 out of 86 (5%)) had elevated blood pressure (130 12/101 5 mmHg), were overweight (27 4 kg/m2) and reported an alcohol consumption of 70 12 g per day. Their fasting blood glucose and plasma creatinine remained normal (glucose = 79 9 mg/dl; creatinine = 0.9 0.2 mg/dl; age = 38 13 years). Pure microalbuminuria (20 10 mg/l) was confirmed using urine profiles (not shown). Men with both hematuria and proteinuria (4 out of 86 (5%)) had hypertension (148 19/ 100 5 mmHg), were overweight (27 4 kg/ m2) and had borderline triglyceride levels (194 146 mg/dl). Fasting blood glucose and plasma creatinine showed normal values (glucose = 90 11 mg/dl; creatinine = 0.8 0.17 mg/dl; age = 37 15 years). Of these four men with proteinuria/hematuria, those with alcohol problems reported an alcohol consumption of 111 47 g/day and those who smoked consumed 18 5 cigarettes per day. Their urine erythrocyte levels and albuminuria (69 31 mg/l, n = 4) were confirmed using urine microscopy and protein profiles and pathological casts or proteins were excluded (not shown). Men who reported smoking also showed more proteinuria and/or hematuria (7 out of 19 (37%)) than male non-smokers (12 out of 53 (22%)). Smokers reported more alcohol misuse (9 out of 19 (47%)) and more men with selfreported alcohol misuse smoked (42% smoked 15 7 cigarettes per day: Table 1). Cigarette consumption by male smokers varied with BMI subgroup (normal weight: 23%, 19 18 cigarettes; overweight: 35%, 18 4 cigarettes; obesity:11%, 15 7 cigarettes).
Estimated biomarkers for men and women Subjects were assigned to subgroups characterized by one of the risk factors for comparison with the appropriate controls (Fig. 2). Men or women characterized by obesity or alcohol misuse showed a significant increase in systolic and/or diastolic blood pressure compared with men or women with normal weight or without alcohol problems (Fig. 2, Table 2A: p < 0.05).
Vol. 3, No. 3, pp. 279–289, September 2006
283
Original article
Figure 2
Systolic (A) and diastolic (B) blood pressure in men and women with normal weight was compared with that in men and women with obesity (C: BMI2), alcohol misuse (D: AHA1) or who were overweight (E: BMI1). Systolic (A versus *CA or *DA) or diastolic (B versus *CB or *DB) blood pressure was significantly increased in the obese and alcohol misuse groups. There was a significant gender difference between obese men and women (*CB-male versus CB-female, *p < 0.05. See Table 1 for further details).
Men or women characterized by obesity or alcohol misuse had significantly lower HDL levels compared with men or women with normal weight or without alcohol problems
Figure 3
284
(Fig. 3, Table 2B: p < 0.05). A significantly lower ratio of serum albumin to triglycerides (Fig. 1) was found for those in the obese (p = 0.001) or alcohol misuse groups (p = 0.001) when
The cholesterol profile of men (n = 19) and women (n = 19) with alcohol misuse (AHA1) was compared with that in men (n = 45) and women (n = 109) without alcohol problems (Normal). HDL levels were significantly decreased in men and women who misused alcohol (p = 0.049 see Table 1 for further details). (Values are means 1 SD).
Vol. 3, No. 3, pp. 279–289, September 2006
Original article Table 2 Estimated characteristics for men with overweight (BMI1), obesity (BMI2) or self-reported alcohol misuse (AHA1) compared with men who had normal weight (BMIn) or with those without alcohol problems (N) A: p-Values for increasing blood pressure in men: Risk factors: BMIn Number of cases: 50 Blood presssure (RR) (mmHg): 114 19/85 8 BMIn Systolic blood pressure (RR): Diastolic blood pressure (RR):
BMI1 17 139 18/93 9
BMI2 19 148 24/104 8
AHA1 19 146 15/103 10
n.s. p < 0.05*
p < 0.05* p < 0.05*
see N see N
n.s. p < 0.05*
see N see N
BMI1 Systolic blood pressure (RR): Diastolic blood presure (RR): Without alcohol problems, N (n = 45): Systolic blood pressure (RR): Diastolic blood pressure (RR):
p < 0.05* p < 0.05*
B: p-Values for decreasing HDL levels in men: Risk factors: BMIn HDL-values (mean SD) (mg/dl): 57 16
BMI1 50 19
BMI2 36 12
AHA1 36 5
n.s.
p < 0.05* n.s.
see N see N p = 0.004*
Urine pathology 0.59/0.31 (n.s.)
Smoking 0.32/0.28 (n.s.)
BMI1 + BMI2 0.0026*/0.0002*
AHA1 0.32/0.0005*
Triglycerides 0.78 (n.s.)
Smoking 0.0445*
BMI2 0.12 (n.s.)
AHA1 0.0410*
BMIn: BMI1: Without alcohol problems, N (n = 45): C: Multivariate modelling of men’s data: Rising RR systolic/diastolic: p-Values: Urine pathology: p-Values:
Raised blood pressure or urine pathology were significantly associated with raised body weight or with alcohol misuse (*p < 0.05).RR, resting rate; HDL, high density lipoproteins; SD, standard deviation; n.s., not significant.
compared with normal weight subjects or those without alcohol problems, respectively. Men characterized as being overweight versus those of normal weight or men with obesity versus those who were overweight both showed a significant increase in diastolic blood pressure (Table 2A: p < 0.05). Men characterized as having hypertriglyceridemia tended to be overweight and showed a significantly higher systolic and diastolic blood pressure compared to men with normal triglyceride levels. Women with hypertriglyceridemia had significantly higher diastolic blood pressure (p < 0.05, Fig. 4).
Gender differences In this study, obese men showed significantly higher diastolic blood pressure than obese women (p = 0.049: CB-male versus CB-female, Fig. 2) but no difference was found between
men and women reporting alcohol misuse. Men reporting alcohol misuse showed significantly lower HDL levels compared with women reporting alcohol misuse (p = 0.049: Fig. 3).
Multivariate analysis of men’s risk factors A multivariate analysis of the men’s biomarkers showed a significant association between either increased systolic or diastolic blood pressure and raised body weight (p = 0.003, p = 0.0002, respectively), and between either increased systolic or diastolic blood pressure and obesity (p = 0.001, p < 0.0001, respectively). Raised diastolic blood pressure was significantly associated here with alcohol misuse (p = 0.0005). The multivariate analysis provided evidence for a significant risk of hypertension in men with obesity or overweight and alcohol misuse (Table 2).
Vol. 3, No. 3, pp. 279–289, September 2006
285
Original article
Figure 4
Men (n = 20) and women (n = 28) with high triglyceride levels (175 mg/dl) were compared with men (n = 58) and women (n = 110) with normal triglyceride levels (means 1 SD). Men and women with high triglycerides were overweight and showed a significant rise in blood pressure (p < 0.05).
The multivariate analysis did not confirm a significant (direct) association between hypertension and hypertriglyceridemia, indicating that being overweight and misusing alcohol were the relevant risk factors for high blood pressure in men with hypertriglyceridemia (Fig. 4). There was no significant association between increasing blood pressure and age perhaps because the male study group was relatively young. There was also no association with total cholesterol level or with abnormal morning urine samples (Table 2). Proteinuria and/or hematuria in men’s morning urine samples were significantly associated, for the first time, with self-reported misuse of alcohol (Table 2: p = 0.041). The multivariate analysis provided evidence that proteinuria and/or hematuria was directly related to alcohol misuse in men from a Bavarian General Medicine practice. Proteinuria and/or hematuria in men’s morning urine samples were significantly associated in this study with self-reported smoking (p = 0.045). However, the multivariate analysis did not confirm an association between raised systolic or diastolic blood pressure and smoking (p = 0.32, p = 0.28, respectively). Proteinuria and/or hematuria did not show significant associations (p > 0.1) with overweight, obesity, age, high triglyceride level,
286
Vol. 3, No. 3, pp. 279–289, September 2006
cholesterol or LDL/HDL ratio. Furthermore, proteinuria and/or hematuria could not be associated with gamma-GT level, perhaps because gamma-GT increased with high variance (Table 1). There was no significant relationship between men’s increasing LDL/HDL ratio and obesity, smoking, smoking and drinking, triglycerides, gamma-GT or urine pathology. Quite surprisingly there was no significant association of LDL/HDL with age or total cholesterol, probably because the male study group was relatively young (31 21 years). Raised blood pressure was associated with obesity or overweight and alcohol misuse. The multivariate analysis showed significant associations between raised blood pressure and raised body weight but did not confirm a direct relationship between hypertension and abnormal morning urine samples in the male study group. Raised diastolic blood pressure, as well as proteinuria and/or hematuria, were significantly associated with misuse of alcohol and/ or nicotine.
Discussion The aim of the study was to determine the early risk factors for raised blood pressure and
Original article proteinuria and/or hematuria in primary care patients. This study found significant associations between raised blood pressure and raised body weight in men and between abnormal morning urine samples and the misuse of alcohol and/or nicotine. Men and women who were obese or overweight and misused alcohol showed a significant increase in systolic or diastolic blood pressures. Multivariate modelling of men’s data confirmed a significant association between either raised systolic or diastolic blood pressure and raised body weight, while diastolic blood pressure was significantly associated with alcohol misuse in this male study group. Proteinuria and/or hematuria were significantly associated in the male study group, for the first time, with misuse of alcohol or nicotine, whereas obesity, age, cholesterol, triglycerides and gamma-GT did not show any relevant associations. Proteinuria and/or hematuria are clinical predictors for microvascular disorders of the kidney and heart and the pathological morning urine samples from the male study group showed that there was a decline in renal endothelial barriers, since other renal disorders had been excluded using, by preference, urine microscopy. Men with hematuria and proteinuria were at risk for chronic renal diseases, impaired renal function and a higher mortality in male US cohorts [1,2,25]. Proteinuria and/or hematuria were significantly associated here with nicotine misuse in men and 47% of smokers reported an unhealthy consumption of alcohol, whereas hypertension was not significantly associated here with smoking. It has been shown that nicotine misuse aggravates mortality risks in obese men and women in the US [26]. The male study group and the gender differences found were representative for patients from a Bavarian General Medicine practice. The data were confidentially collected and only numbered samples were statistically analyzed by an independent statistician using two statistical models. The values used for ‘‘unhealthy alcohol consumption’’ had been previously determined in two mixed study groups suffering from either early or late alcohol syndromes (AHA1 or AHA2) [16,17]. It has been shown that antagonists against ether phospholipids (LA-paf), especially those sharing the regression line with the
Ginkgolides, have a protective effect on endothelial cells in the presence of insulin or LDL [19,20,27–29]. A previous report has shown dysfunctional endothelial relaxation in patients suffering from hypertension with proteinuria and hematuria when the ratio of nighttime to daytime blood pressure rises from 0.88 0.1 to 0.93 0.02 [18]. Hypertension or proteinuria/hematuria indicate dysfunction in renal endothelial cells and the significant association with alcohol misuse indicates a role for stable alcohol metabolites. The oxygen from stable ether phospholipids such as LA-paf is derived from long chain fatty alcohols [10,15–22,27–29,30]. Other alcohol-related ether phospholipids, such as ethanolamine-plasmalogen could modulate the cholesterol transport as has been proposed in transgenic animal models [31]. Men with moderate intolerance to glucose tended to be overweight and hypertensive, in agreement with previous work which showed a relationship between hyperinsulinemia, borderline hypertension, intima thickening and/ or raised levels of antibodies against the ether phospholipid LA-paf [9,10]. Recent clinical reports support the prevalence of metabolic syndromes with obesity, hypertension, hyperinsulinemia and dyslipidemia all being found in elderly patients with late atherosclerosis [32]. Experimental data have shown that lysophospholipids with ester compounds in lipoproteins are sensitive to oxidation and induce the proliferation of vascular smooth muscle cells from cultured rabbit aortas and the synergistic benefit of antioxidant therapy with angiotensin receptor antagonists has been shown in vitro [33]. Albumin restores vasodilatation in rats, probably because it can incorporate ether phospholipids, lysophospholipids and/or fatty acids [15,34]. Other reports have shown the reduced capacity of serum samples from men with hypertriglyceridemia to promote cholesterol efflux from hepatoma cell lines to HDL [35]. Serum from patients with type IV hypertriglyceridemia does not impair the cholesterol efflux capacity of macrophages in culture, perhaps because phospholipids in serum HDL could enhance cholesterol efflux [36]. Hepatic lipases mediate hydrolysis of triglycerides in very low density lipoproteins and are positively related to HDL2 [37]. The significantly lower HDL levels and high triglyceride levels found in this male
Vol. 3, No. 3, pp. 279–289, September 2006
287
Original article study group, suggested that hepatic lipases could be impaired in those who were obese or overweight and misused alcohol. Men who were obese or overweight with high triglyceride levels showed significantly higher systolic and/or diastolic blood pressures. Hormonal lipases on endothelial cells are sensitive to epinephrine (or insulin) with the release of free fatty acids from triglycerides in muscles, macrophages and adipose tissue [38] probably explaining why obese men showed a high sensitivity to hypertension in this Bavarian study group. Taken together, raised blood pressure and raised body weight in men were significantly associated, in this Bavarian study, using two statistical models.
Raised diastolic blood pressure and proteinuria and/or hematuria were significantly associated, for the first time, with alcohol misuse in this young male study group as independent indicators of a decline in renal endothelial barriers.
Summary In this study, obese men and those who were overweight and misused alcohol had significantly higher blood pressure, significantly lower HDL levels and a significantly lower ratio of serum albumin to triglycerides. Proteinuria and/or hematuria was significantly associated with alcohol misuse in the male study group.
References [1] Kristjansson K, Ljungmann S, Bengtsson C, Bjo¨rkelund C, Sigurdsson JA. Microproteinuria and long-term prognosis with respect to renal function and survival in normotensive and hypertensive women. Scand J Urol Nephrol 2001;35:63–70. [2] Pijls LTJ, de Vries H, Kriegsman DMW, Donker AJM, van Eijk JTM. Determinants of albuminuria in people with Type 2 diabetes mellitus. Diab Res and Clin Practice 2001; 52:133–43. [3] Hyman DJ, Pavlik VN. Characteristics of patients with uncontrolled hypertension in the United States. New Engl J Med 2001; 345:479–96. [4] Weiss R, Dziura J, Burgert TS, Tamborlane WV, Taksali SE, Yeckel CW, et al. Obesity and the Metabolic Syndrome in children and adolescents. New Engl J Med 2004;350: 2362–74. [5] Stuveling EM, Hillege HL, Bakker SJL, Asselbergs FW, de Jong RO, Fans A, et al. Urine protein and microalbuminuria differ in their associations with various domains of vascular disease. Atherosclerosis 2004;172: 107–14. [6] Boerma M, Forsberg L, Van Zeijl L, Morgenstern R, De Faire U, Lemne C, et al. A genetic polymorphism in connexin 37 as a prognostic marker for atherosclerotic plaques development. J Int Medicine 1999;246:211–8. [7] Yamada Y, Izawa H, Ichihara S, Takatsu F, Ishihara H, Hirayama H, et al. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. New Engl J Med 2002;347:1916–23. [8] Frostegard J, Huang YH, Ro¨nnelid J, Scha¨fer-Elinder L. PAF and oxidized LDL induce immune activation by a common
288
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
Vol. 3, No. 3, pp. 279–289, September 2006
mechanism. Arterioscler Thromb Vasc Biol 1997;17:963–8. Wu R, Lemne C, De Faire U, Frostegard J. Antibodies to platelet-activating factor are associated with borderline hypertension, early atherosclerosis and the metabolic syndrome. J Int Med 1999;246:389–97. Korth R, Zimmermann K, Richter W. Lipoprotein-associated paf (LA-paf) was found in washed human platelets and monocytemacrophage-like U937 cells. Chem Phys Lipids 1994;70:109–19. Hines LM, Stampfer MJ, Ma J, Gaziano JM, Ridker PM, Hankinson SE, et al. Genetic variation in alcohol dehydrogenase and the beneficial effect of moderate alcohol consumption on myocardial infarction. New Engl J Med 2001;344:549–55. Marques-Vidal P, Montaye M, Haas B, Bingham A, Evans A, Juhan-Vague I, et al. Relationships between alcoholic beverages and cardiovascular risk factor levels in middleaged men, the PRIME study. Atherosclerosis 2001;157:431–40. Inazu A, Brown ML, Hesler CB, Agellon LB, Koizumi J, Takata K, et al. Increased highdensity lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. New Engl J Med 1990;323: 12343–8. Lands WEM. Cellular signals in alcoholinduced liver injury: a review. Alcohol Clin Exp Res 1995;19:928–38. Korth R-M. Comparison of phosphocholines in human plasma and cerebrospinal fluid (CSF). Faseb J 2000;14:A72. Korth R-M. Ether-linked phospholipids and hyperlipidemia. In: Pandalai SG, editor. Recent Research Developments in Lipids,
[17] [18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
5. Trivandium India: Transworld Research Network; 2001. p. 61–70. Korth R-M. AHA-Syndromes. Chem Phys Lipids 2002;118:96–7. Korth R-M. Alcohol, obesity, hypertension and endothelial irritation. Faseb J 2003;17: A1140. Korth R, Nunez D, Bidault J, Benveniste J. Comparison of three paf-acether receptor antagonists ginkgolides. Eur J Pharmacol 1988;152:101–10. Korth R, Hirafuji M, Benveniste J, RussoMarie F. Human umbilical vein endothelial cells: Specific binding of platelet-activating factor and cytosolic calcium flux. Biochem Pharmacology 1995;49:1793–9. Korth R-M. Specific binding sites for 1-Oalkyl-sn-glyceryl-3-phosphorylcholine on intact human blood neutrophils. Int Arch Allergy Immunol 1997;113:460–4. Korth R, Riess H, Brehm G, Hiller E. Unsaturated platelet-activating factor: influence on aggregation, serotonin release and thromboxane synthesis of human thrombocytes. Thrombosis Res 1986;41:699–706. Li J, Kim C, Leo M, Mak K, Rojkind M, Lieber C. Polyunsaturated lecithin prevents acetaldehyde-mediated hepatic collagen accumulation by stimulating collagenase activity in cultured lipocytes. Hepatology 1992; 15:373–81. Marathe GK, Harrison KA, Roberts JL, Morrow JD, Murphy RC, Tjoelker LW, et al. Identification of platelet-activating factor as the inflammatory lipid mediator in CCL4-metabolizing rat liver. J Lipid Res 2001;42:587–96. Anavekar NS, McMurray JJV, Velazquez EJ, Solomon SD, Kober L, Rouleau J-L, et al. Relation between renal dysfunction and
Original article
[26]
[27]
[28]
[29]
cardiovascular outcomes after myocardial infarction. New Engl J Med 2004;351: 1285–95. Berenson GS, Srinivasan SR, Bao W, Newmann WP, Tracy RE, Wattigney WA. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. New Engl J Med 1998;338: 1650–6. Korth R.-M. Verwendung von paf-AcetherAntagonisten zur Herstellung eines Arzneimittels und Verfahren zu deren Wirksamkeitsbestimmung. Europa¨ische Patentschrift, Publication No. 0312913, 1989. Korth R, Middeke M. Long time incubation of monocytic U 937 cells with LDL increase specific PAF-acether binding and the cellular acetylhydrolase activity. Chem Phys Lipids 1991;59:207–13. Ihida K, Predescu D, Czekay RP, Palade GE. Platelet activating factor receptor (PAF-R) is found in a large endosomal compartment in human umbilical vein endothelial cells. J Cell Science 1999;112:285–95.
[30] Snyder F. Metabolism of platelet activating factor and related ether lipids: enzymatic pathways, subcellular sites, regulation and membrane processing. In: Alan R, editor. Biological membranes: Aberrations in Membrane Structure and Function.. Liss Inc.; 1988. p. 57–72. [31] Munn NJ, Arnio E, Liu D, Zoeller RA, Liscum L. Deficiency in ethanolamine plasmalogen leads to altered cholesterol transport. J Lipid Res 2003;44:182–92. [32] Calle E, Thun MJ, Petrelli JM, Rodriguez C, Heath C. Body mass index and mortality in a prospective Cohort of U.S. Adults. New Engl J Med 1999;341:1097–105. [33] Watanabe T, Pakala R, Katagiri T, Benedict CR. Mildly oxidized low-density lipoprotein acts synergistically with angiotensin II in inducing vascular smooth muscle cell proliferation. J Hypertension 2001;19:1065– 73. [34] Vuong D, de Kimpe S, de Roos R, Rabelink TJ, Koomans HA, Joles JA. Albumin restores lysophosphatidylcholine-induced inhibition
[35]
[36]
[37]
[38]
of vasodilation in rat aorta. Kidney Int 2001;60:1088–96. Brites FD, Bonavita CD, de Geitere C, Cloes M, Delfly B, Yael MJ, et al. Alterations in the main steps of reverse cholesterol transport in male patients with primary hypertriglyceridemia and low HDL-cholesterol levels. Atherosclerosis 2000;152:181–92. Fournier N, Francone O, Rothblat G, Goudouneche D, Cambillau M, Kellner-Weibel G, et al. Enhanced efflux from ABCA1expressing macrophages to serum from type IV hypertriglyceridemic subjects. Atherosclerosis 2003;171:287–93. Ramsamy TA, Boucher J, Brown RJ, Yao Z, Sparks DL. HDL regulates the displacement of hepatic lipase from cell surface proteoglycans and the hydrolysis of VLDL triacylglycerol. J Lipid Res 2003;44: 733–41. Kraemer FB, Shen W-J. Hormone-sensitive lipase: control of intracellular tri-(di)acylgylcerol and cholesteryl ester hydrolysis. J Lipid Res 2002;43:1585–94.
Vol. 3, No. 3, pp. 279–289, September 2006
289
Gender, obesity, alcohol use, hyperlipidemia, hypertension and decline of renal endothelial barriers Keywords Obesity Alcohol misuse Dyslipidemia Hypertension Albumin Proteinuria Hematuria Men’s health
Ruth-Maria Korth Abstract Background: Raised body weight and hypertension are locally relevant risk factors. Patients were examined in a Bavarian General Medicine Practice to investigate the relationship between raised body weight, hypertriglyceridemia and alcohol misuse with raised blood pressure or abnormal morning urines. Methods: The risk factors evaluated in this study of primary care patients were obesity, overweight, hypertriglyceridemia, self-reported alcohol misuse, raised blood pressure and proteinuria and/or hematuria in men (n = 86, 31 12 years) and women (n = 160, 30 10 years). Results: Men or women with obesity (BMI2) or alcohol misuse (AHA1) had significantly higher systolic or diastolic blood pressure and significantly lower HDL levels (p < 0.05) compared with men or women of normal weight or without alcohol problems and the ratio of serum albumin to triglycerides was significantly lower with obesity or alcohol misuse (p = 0.001, p = 0.001, respectively). Men with hypertriglyceridemia tended to be overweight and showed significantly higher blood pressure than men with normal triglyceride levels (p < 0.05). Obese men showed significantly higher diastolic blood pressure compared to obese women (p = 0.049). An increase in systolic (p = 0.0026) or diastolic (p = 0.0002) blood pressure was significantly associated with raised body weight (BMI1 + BMI2), while a rise in diastolic blood pressure was linked with alcohol misuse (p = 0.0005) using multivariate modelling. Proteinuria and/or hematuria in men’s morning urine samples were significantly associated with misuse of alcohol or nicotine (p = 0.041, p = 0.045, respectively). Conclusion: The data showed significant associations between raised systolic or diastolic blood pressure and raised body weight. Raised diastolic blood pressure or proteinuria and/or hematuria were associated with misuse of alcohol and indicated a decline in renal endothelial barriers. ß 2006 WPMH GmbH. Published by Elsevier Ireland Ltd.
Ruth-Maria Korth, MD Research in General Medicine F.I.D.A., Munich, Germany E-mail: Ruth-Maria.Korth@ i-dial.de
Online 7 September 2006
Introduction Patients were examined in a Bavarian General Medicine practice to gain knowledge about the relationship between obesity, overweight, hypertriglyceridemia, alcohol misuse and/or hypertension. Proteinuria and/or hematuria in men’s morning urine samples were related to misuse of alcohol or nicotine
ß 2006 WPMH GmbH. Published by Elsevier Ireland Ltd.
while infections or chronic renal disorders were excluded. Hypertension has been associated with proteinuria, albuminuria, impaired renal function and higher mortality in a 24 year follow-up of 1462 women in Sweden [1]. Hypertension and age were the strongest determinants of proteinuria in a Dutch study of 335 type 2 diabetes patients at risk for renal disease
Vol. 3, No. 3, pp. 279–289, September 2006
279
Original article [2]. The third National Health and Nutrition Examination Survey called upon the medical community to improve the control of hypertension, defined as blood pressure of at least 140/90 mmHg [3]. Cohorts of obese children and adolescents in the USA have shown that an increase in systolic blood pressure and a decrease in high-density lipoprotein (HDL)cholesterols are closely correlated to elevated blood insulin levels (insulin resistance) [4]. Microalbuminuria was a predictor for cardiovascular disease in a Dutch Prevent study of non-diabetic patients [5]. Genetic polymorphism in the gap junctional proteins of endothelial cells (connexin 37) partly explains the thickened carotid artery intima found in a Swedish study and the prevalence of myocardial infarction in Japanese men (but not women) [6,7]. The carotid intima-media thickness has been associated with hyperinsulinemia, borderline hypertension and elevated antibodies against ether phospholipids (LApaf) [8–10]. However, the clinical study from Karolinska University [9] did not investigate the dysfunction of renal endothelial barriers. Genetic variations in alcohol dehydrogenases decrease the alcohol-related aldehydes resulting in light alcohol consumption having a beneficial effect against myocardial infarction [11]. Subjects with moderate alcohol consumption in France and Ireland showed good HDL-parameters (HDL-cholesterol, apoA-1) [12]. Genetically impaired hepatic lipase deficiency causes an increase in unhealthy intermediate lipoproteins and an unhealthy amount of alcohol combined with a high-fat diet leads to steatosis, hepatitis, fibrosis and cirrhosis of the liver [13,14]. The metabolites of alcohol are aldehydes and ether phospholipids such as the inflammatory platelet activating factor (PAF-Acether, Paf) [10,14–18]. Antagonists against Paf are present [19–22]. Lecithin, found for example in soya, prevents the oxidation of fatty acids [23]. Alcohol mediates hepatitis probably because free radicals initiate liver necrosis, fibrosis and the synthesis of PAF-Acether, as has been shown in the liver cells of rats after intoxication [24]. Men and women were examined in a Bavarian General Medicine practice and gender risk groups were selected on the basis of overweight, obesity, hypertriglyceridemia or alcohol misuse. Hypertension or proteinuria and microhematuria (hematuria) were evaluated here as
280
Vol. 3, No. 3, pp. 279–289, September 2006
independent risk factors because those men had a higher risk for developing renal disorders.
Methods Objectives Primary care patients (n = 1068) were examined in a Bavarian General Medicine practice. The initial risk factors for men (86 out of 313 (27%) aged 31 12 years) were compared with the biomarkers from an appropriate female study group (160 out of 636 (25%) aged 30 10 years). The local ethical authority approved this study as an epidemiological study with anonymous and confidentially documented data (Bayerische Landesa¨rztekammer, EthikKommission Nr 02088). Men (n = 56) and women (n = 127) with urological infections were treated but were initially excluded from the study. A further 171 men and 476 women were excluded because they had only attended the Practice for counseling, vaccinations or drug therapy, including antihypertensive or lipid lowering therapy, or they had at least one of the disorders mentioned below. Patients with known diabetes mellitus or kidney disorders (HbA1c 6%, plasma creatinine >1.2 mg/dl) were excluded. Those with infections or fever (C-reactive protein 6 mg/ dl, temperature 37 8C) were treated but not included. Viral hepatitis was excluded for patients with elevated liver values. Patients with neoplastic and hematological disorders, cancer, cardiovascular, cerebral or inflammatory disorders were also excluded. Self-reported alcohol consumption was scored. A consumption of 60 g beer/day was taken as an unhealthy amount. This was based on previous local studies of both early alcohol syndromes in primary care patients, who reported the consumption of at least 60 g beer/day for at least 5 years (AHA1), and late alcohol abusers, who reported an intake of 125 71 g alcohol/ day as determined in the social care unit of St. Bonifaz in Munich (AHA2) [16,17].
Study program Baseline measures of age, body mass index (BMI), blood pressure, morning urine samples and clinical chemistry were documented, as were personal and family disorders and the
Original article self-reported consumption of alcohol and/or nicotine. Blood pressure was determined after 5 min of rest. Body mass index (BMI) was calculated and subjects were divided into subgroups: normal weight (BMIn: <25 kg/m2), overweight (BMI1: 25–29 kg/m2) or obesity (BMI2: >29 kg/m2). Venous blood was taken after 12 h fasting and fasting blood glucose, triglyceride levels, total cholesterol, cholesterol in low-density lipoproteins (LDL) or in high density lipoproteins (HDL) were measured using standard procedures in a clinical laboratory. Serum albumin level was determined using an Elephanscan/Fractoscan to be calculated with 1.5% variation (Merck, Laborgemeinschaft ¨ nchen-Innenstadt). Four men were at risk Mu of having a Chlamydia infection. Polymerase chain reaction (PCR) of first morning urines excluded an infection and these men were included in the study. Hematuria was confirmed using urine microscopy and no pathological casts were found. Renal diseases were also excluded with urine profile confirming microalbuminuria without pathological proteins (or casts). These urine tests were per¨ nchenformed in the ‘‘Laborgemeinschaft Mu Innenstadt’’.
Practice diagnostics Capillary glucose was measured in the Practice. Tolerance to glucose (GTT) was determined either 1 h or 2 h after intake of 100 g oral glucose (Reflotron, Roche, Switzerland). Only morning urine samples were tested in the Practice to assess proteinuria and hematuria with parallel exclusion of urological infections (Combur 9, Roche, Switzerland). Albuminuria (Microbumin from Roche or Microalbustix, Bayer) confirmed proteinuria and was determined when more than 20 mg/l albumin was found in the first morning urine sample from two out of three different samples given within 1 week once a year: these patients were re-examined after 3 months. Patients with normal urine samples and without relevant risk factors were re-examined after 12 months.
Medical care A full medical examination was provided and self control documentation was offered (www.fida-aha.com). The biomarkers were confidentially discussed and documented in
the Medical Practice with informed consent. Medical counseling included aspects of food quality and lifestyle. Hypertension was successfully treated by preference with verapamile as the Paf antagonist potency of this calcium antagonist has been shown [22].
Statistical methods Results were caclulated as means standard deviations (1S.D.). The patient data were confidentially collected in a General Medicine practice between 1990 and 1999. The observed risk factors for this study group were estimated elsewhere using numbered data for analysis without identification of patients (estimatedR, Augsburg, Germany). Least square estimates for means and standard deviations were calculated there from a generalized linear model (GLM) using SAS-V8.2, PROC GLM. Tukey’s tests were used for all pairwise comparisons, controlling for type I error rate. The data for the male study group were reanalyzed to evaluate the relationship between the risk factors. The putative independent risk factors were increasing systolic or diastolic blood pressure, abnormal morning urine samples and the LDL/HDL ratio. Their relationship with obesity, raised body weight, age, drinking and smoking as well as smoking with drinking, high cholesterol, triglycerides or gammaglutamyl transferase (gamma-GT) levels was assessed by means of a multiple logistic regression (SAS V8.2, PROC LOGIST).
Results Characteristics of men or women The selected biomarkers of men or women are characterized in Table 1, which shows that a rather large proportion of the subjects in the obesity (BMI2) and overweight (BMI1) groups reported misuse of alcohol (AHA1) or nicotine. Men and women with obesity or selfreported alcohol misuse had elevated blood pressure, borderline cholesterol profiles and increased levels of triglycerides that lowered the ratio of serum albumin to triglycerides (Fig. 1). Intolerance to glucose increased with obesity or alcohol misuse and liver values showed high variance (GTT, Gamma-GT: Table 1).
Vol. 3, No. 3, pp. 279–289, September 2006
281
Original article Table 1 Gender characteristics of primary care patients with normal weight (BMIn), overweight (BMI1), obesity (BMI2) or selfreported alcohol misuse (AHA1) BMI2
AHA1
BMI1
BMIn
Men
Women
Men
Women
Men
Women
Men
Women
Cases: BMI (kg/m2): Age (years): Reported alcohol abuse, cases: Reported nicotine abuse, cases:
19 35 2 37 13 10 2
17 32 3 37 15 4 6
19 29 4 37 12 19 8
22 28 5 37 13 22 12
17 27 2 35 10 9 6
20 27 1 33 4 6 7
50 22 2 31 12 5 11
123 21 5 30 10 5 22
Systolic RR (mmHg): Diastolic RR (mmHg):
148 24* 104 8*
139 20* 97 13*
146 15* 103 10
135 24* 94 14*
139 18 93 9*
134 20 88 12
114 19 85 8
119 14 81 9
Abnormal morning urines, cases:
4
6
8
10
3
5
5
8
Clinical chemistry: Triglycerides (mg/dl): Cholesterol (mg/dl): LDL (mg/dl): HDL (mg/dl): LDL/HDL: GTT (mg/dl): Glucose (mg/dl): GGT (U/l): Plasma albumin (g/dl):
181 77 208 4 174 56 36 12* 3.4 0.6 181 41 97 5 28 17 5.4 0.3
206 100 206 10 155 30 46 11* 3.3. 0.9 175 53 93 12 28 27 4.8 0.4
178 82 203 40 161 45 36 5* 3.6 1.5 189 57 92 9 48 57 5.1 4.9
170 96 218 31 168 36 47 14* 3.7 1.7 155 47 92 11 35 19 4.9 0.4
145 81 190 29 141 49 50 19 2.6 1.4 147 15 90 8 20 8 5.2 0.3
166 95 203 62 139 35 50 9 3.4 0.5 158 17 88 10 11 5 4.8 0.4
106 42 179 30 126 35 57 16 2.2 0.6 130 26 88 7 11 4 5.2 0.3
104 45 198 47 135 42 64 18 2.3 0.9 128 12 85 5 10 12 5.0 0.4
Men or women with obesity or overweight and alcohol misuse had significantly elevated blood pressure (RR, resting rate, *p < 0.05)) and significantly lower HDL (*p < 0.05) compared with those who had normal weight. Those who abused alcohol (AHA1) often had proteinuria and/or hematuria. Data showed abnormal lipid profiles, borderline albumin, intolerance to glucose (GTT: 1 h, 100 g), normal fasting blood glucose and a raised Gamma-Gt (GGT) in men and women at risk. Values are means 1 standard deviation (SD).
Figure 1
282
Men with obesity (BMI2, n = 19), alcohol misuse (AHA1, n = 19) or normal weight (BMIn, n = 50) were examined. Men with obesity or alcohol misuse showed elevated systolic (A) or diastolic (B) blood pressure compared with men of normal weight or those without alcohol problems (p < 0.05 in Table 2). Capillary glucose increased 1 h after intake of 100 g glucose and the rise in triglyceride levels lowered the ratio of serum albumin to triglycerides in men with obesity and/or alcohol misuse with an indicated high prevalence of proteinuria and/or hematuria.
Vol. 3, No. 3, pp. 279–289, September 2006
Original article Men with indicated risk factors showed an elevated rate of proteinuria and/or hematuria after exclusion of urological infections (Fig. 1).
Observed biomarkers in men Men with obesity showed hypertension, moderate intolerance to glucose and dyslipidemia (Fig. 1). Obese men had elevated blood pressure with or without self-reported alcohol misuse (154 22/107 8 mmHg or 150 25/95 3 mmHg, respectively). Men who reported an unhealthy consumption of alcohol (AHA1: 83 30 g per day) tended to be overweight and had elevated blood pressure. More overweight men reported an unhealthy consumption of alcohol compared with men of normal weight (7 of the BMI1 group (37%) versus 11 of the BMIn group (22%)). Men reporting alcohol misuse had elevated triglycerides and a low albumin to triglycerides ratio (Fig. 1). Men with hypertriglyceridemia (n = 20) were overweight and tended to have elevated blood pressure (see Fig. 4). Men with hypertriglycidemia often reported misuse of alcohol (12 out of 20 (60%)). They had either normal morning urine samples (11 out of 20 (55%)), hematuria (5 out 20 (25%)) and/or proteinuria (4 out of 20 (20%)). Only a rather small number of men had intolerance to glucose, limiting further analysis. These men had normal fasting blood glucose (7 out of 86 (8%); 0 h = 95 8 mg/dl, 1 h = 185 40 mg/dl, 2 h = 116 26 mg/dl). Glucose intolerant men tended to be overweight and have elevated blood pressure (BMI = 27 6 kg/ m2; blood pressure = 143 13/97 11 mmHg; age = 26 9 years). An elevated rate of albuminuria and/or hematuria was confirmed using protein profiles while pathological casts were excluded with urine microscopy (not shown). The first morning urine samples from those men with proteinuria and/or hematuria (16 out of 86) showed levels of 58 38 mg/l for proteins and/or 17 10 erythrocytes/ml (Fig. 1). It was found that those men with pure hematuria (8 out of 86 (9%)) had elevated blood pressure (141 21/95 16 mmHg) and normal weight (24 4 kg/m2). They had normal fasting blood glucose and normal plasma creatinine levels (glucose = 86 5 mg/dl; creatinine = 0.9 0.17 mg/dl; age = 38 14 years). Four out of these 8 men with hematuria
reported an alcohol consumption of 83 48 g/day and five were smokers reporting an intake of 20 0 cigarettes per day. It was also found that those men with pure proteinuria (4 out of 86 (5%)) had elevated blood pressure (130 12/101 5 mmHg), were overweight (27 4 kg/m2) and reported an alcohol consumption of 70 12 g per day. Their fasting blood glucose and plasma creatinine remained normal (glucose = 79 9 mg/dl; creatinine = 0.9 0.2 mg/dl; age = 38 13 years). Pure microalbuminuria (20 10 mg/l) was confirmed using urine profiles (not shown). Men with both hematuria and proteinuria (4 out of 86 (5%)) had hypertension (148 19/ 100 5 mmHg), were overweight (27 4 kg/ m2) and had borderline triglyceride levels (194 146 mg/dl). Fasting blood glucose and plasma creatinine showed normal values (glucose = 90 11 mg/dl; creatinine = 0.8 0.17 mg/dl; age = 37 15 years). Of these four men with proteinuria/hematuria, those with alcohol problems reported an alcohol consumption of 111 47 g/day and those who smoked consumed 18 5 cigarettes per day. Their urine erythrocyte levels and albuminuria (69 31 mg/l, n = 4) were confirmed using urine microscopy and protein profiles and pathological casts or proteins were excluded (not shown). Men who reported smoking also showed more proteinuria and/or hematuria (7 out of 19 (37%)) than male non-smokers (12 out of 53 (22%)). Smokers reported more alcohol misuse (9 out of 19 (47%)) and more men with selfreported alcohol misuse smoked (42% smoked 15 7 cigarettes per day: Table 1). Cigarette consumption by male smokers varied with BMI subgroup (normal weight: 23%, 19 18 cigarettes; overweight: 35%, 18 4 cigarettes; obesity:11%, 15 7 cigarettes).
Estimated biomarkers for men and women Subjects were assigned to subgroups characterized by one of the risk factors for comparison with the appropriate controls (Fig. 2). Men or women characterized by obesity or alcohol misuse showed a significant increase in systolic and/or diastolic blood pressure compared with men or women with normal weight or without alcohol problems (Fig. 2, Table 2A: p < 0.05).
Vol. 3, No. 3, pp. 279–289, September 2006
283
Original article
Figure 2
Systolic (A) and diastolic (B) blood pressure in men and women with normal weight was compared with that in men and women with obesity (C: BMI2), alcohol misuse (D: AHA1) or who were overweight (E: BMI1). Systolic (A versus *CA or *DA) or diastolic (B versus *CB or *DB) blood pressure was significantly increased in the obese and alcohol misuse groups. There was a significant gender difference between obese men and women (*CB-male versus CB-female, *p < 0.05. See Table 1 for further details).
Men or women characterized by obesity or alcohol misuse had significantly lower HDL levels compared with men or women with normal weight or without alcohol problems
Figure 3
284
(Fig. 3, Table 2B: p < 0.05). A significantly lower ratio of serum albumin to triglycerides (Fig. 1) was found for those in the obese (p = 0.001) or alcohol misuse groups (p = 0.001) when
The cholesterol profile of men (n = 19) and women (n = 19) with alcohol misuse (AHA1) was compared with that in men (n = 45) and women (n = 109) without alcohol problems (Normal). HDL levels were significantly decreased in men and women who misused alcohol (p = 0.049 see Table 1 for further details). (Values are means 1 SD).
Vol. 3, No. 3, pp. 279–289, September 2006
Original article Table 2 Estimated characteristics for men with overweight (BMI1), obesity (BMI2) or self-reported alcohol misuse (AHA1) compared with men who had normal weight (BMIn) or with those without alcohol problems (N) A: p-Values for increasing blood pressure in men: Risk factors: BMIn Number of cases: 50 Blood presssure (RR) (mmHg): 114 19/85 8 BMIn Systolic blood pressure (RR): Diastolic blood pressure (RR):
BMI1 17 139 18/93 9
BMI2 19 148 24/104 8
AHA1 19 146 15/103 10
n.s. p < 0.05*
p < 0.05* p < 0.05*
see N see N
n.s. p < 0.05*
see N see N
BMI1 Systolic blood pressure (RR): Diastolic blood presure (RR): Without alcohol problems, N (n = 45): Systolic blood pressure (RR): Diastolic blood pressure (RR):
p < 0.05* p < 0.05*
B: p-Values for decreasing HDL levels in men: Risk factors: BMIn HDL-values (mean SD) (mg/dl): 57 16
BMI1 50 19
BMI2 36 12
AHA1 36 5
n.s.
p < 0.05* n.s.
see N see N p = 0.004*
Urine pathology 0.59/0.31 (n.s.)
Smoking 0.32/0.28 (n.s.)
BMI1 + BMI2 0.0026*/0.0002*
AHA1 0.32/0.0005*
Triglycerides 0.78 (n.s.)
Smoking 0.0445*
BMI2 0.12 (n.s.)
AHA1 0.0410*
BMIn: BMI1: Without alcohol problems, N (n = 45): C: Multivariate modelling of men’s data: Rising RR systolic/diastolic: p-Values: Urine pathology: p-Values:
Raised blood pressure or urine pathology were significantly associated with raised body weight or with alcohol misuse (*p < 0.05).RR, resting rate; HDL, high density lipoproteins; SD, standard deviation; n.s., not significant.
compared with normal weight subjects or those without alcohol problems, respectively. Men characterized as being overweight versus those of normal weight or men with obesity versus those who were overweight both showed a significant increase in diastolic blood pressure (Table 2A: p < 0.05). Men characterized as having hypertriglyceridemia tended to be overweight and showed a significantly higher systolic and diastolic blood pressure compared to men with normal triglyceride levels. Women with hypertriglyceridemia had significantly higher diastolic blood pressure (p < 0.05, Fig. 4).
Gender differences In this study, obese men showed significantly higher diastolic blood pressure than obese women (p = 0.049: CB-male versus CB-female, Fig. 2) but no difference was found between
men and women reporting alcohol misuse. Men reporting alcohol misuse showed significantly lower HDL levels compared with women reporting alcohol misuse (p = 0.049: Fig. 3).
Multivariate analysis of men’s risk factors A multivariate analysis of the men’s biomarkers showed a significant association between either increased systolic or diastolic blood pressure and raised body weight (p = 0.003, p = 0.0002, respectively), and between either increased systolic or diastolic blood pressure and obesity (p = 0.001, p < 0.0001, respectively). Raised diastolic blood pressure was significantly associated here with alcohol misuse (p = 0.0005). The multivariate analysis provided evidence for a significant risk of hypertension in men with obesity or overweight and alcohol misuse (Table 2).
Vol. 3, No. 3, pp. 279–289, September 2006
285
Original article
Figure 4
Men (n = 20) and women (n = 28) with high triglyceride levels (175 mg/dl) were compared with men (n = 58) and women (n = 110) with normal triglyceride levels (means 1 SD). Men and women with high triglycerides were overweight and showed a significant rise in blood pressure (p < 0.05).
The multivariate analysis did not confirm a significant (direct) association between hypertension and hypertriglyceridemia, indicating that being overweight and misusing alcohol were the relevant risk factors for high blood pressure in men with hypertriglyceridemia (Fig. 4). There was no significant association between increasing blood pressure and age perhaps because the male study group was relatively young. There was also no association with total cholesterol level or with abnormal morning urine samples (Table 2). Proteinuria and/or hematuria in men’s morning urine samples were significantly associated, for the first time, with self-reported misuse of alcohol (Table 2: p = 0.041). The multivariate analysis provided evidence that proteinuria and/or hematuria was directly related to alcohol misuse in men from a Bavarian General Medicine practice. Proteinuria and/or hematuria in men’s morning urine samples were significantly associated in this study with self-reported smoking (p = 0.045). However, the multivariate analysis did not confirm an association between raised systolic or diastolic blood pressure and smoking (p = 0.32, p = 0.28, respectively). Proteinuria and/or hematuria did not show significant associations (p > 0.1) with overweight, obesity, age, high triglyceride level,
286
Vol. 3, No. 3, pp. 279–289, September 2006
cholesterol or LDL/HDL ratio. Furthermore, proteinuria and/or hematuria could not be associated with gamma-GT level, perhaps because gamma-GT increased with high variance (Table 1). There was no significant relationship between men’s increasing LDL/HDL ratio and obesity, smoking, smoking and drinking, triglycerides, gamma-GT or urine pathology. Quite surprisingly there was no significant association of LDL/HDL with age or total cholesterol, probably because the male study group was relatively young (31 21 years). Raised blood pressure was associated with obesity or overweight and alcohol misuse. The multivariate analysis showed significant associations between raised blood pressure and raised body weight but did not confirm a direct relationship between hypertension and abnormal morning urine samples in the male study group. Raised diastolic blood pressure, as well as proteinuria and/or hematuria, were significantly associated with misuse of alcohol and/ or nicotine.
Discussion The aim of the study was to determine the early risk factors for raised blood pressure and
Original article proteinuria and/or hematuria in primary care patients. This study found significant associations between raised blood pressure and raised body weight in men and between abnormal morning urine samples and the misuse of alcohol and/or nicotine. Men and women who were obese or overweight and misused alcohol showed a significant increase in systolic or diastolic blood pressures. Multivariate modelling of men’s data confirmed a significant association between either raised systolic or diastolic blood pressure and raised body weight, while diastolic blood pressure was significantly associated with alcohol misuse in this male study group. Proteinuria and/or hematuria were significantly associated in the male study group, for the first time, with misuse of alcohol or nicotine, whereas obesity, age, cholesterol, triglycerides and gamma-GT did not show any relevant associations. Proteinuria and/or hematuria are clinical predictors for microvascular disorders of the kidney and heart and the pathological morning urine samples from the male study group showed that there was a decline in renal endothelial barriers, since other renal disorders had been excluded using, by preference, urine microscopy. Men with hematuria and proteinuria were at risk for chronic renal diseases, impaired renal function and a higher mortality in male US cohorts [1,2,25]. Proteinuria and/or hematuria were significantly associated here with nicotine misuse in men and 47% of smokers reported an unhealthy consumption of alcohol, whereas hypertension was not significantly associated here with smoking. It has been shown that nicotine misuse aggravates mortality risks in obese men and women in the US [26]. The male study group and the gender differences found were representative for patients from a Bavarian General Medicine practice. The data were confidentially collected and only numbered samples were statistically analyzed by an independent statistician using two statistical models. The values used for ‘‘unhealthy alcohol consumption’’ had been previously determined in two mixed study groups suffering from either early or late alcohol syndromes (AHA1 or AHA2) [16,17]. It has been shown that antagonists against ether phospholipids (LA-paf), especially those sharing the regression line with the
Ginkgolides, have a protective effect on endothelial cells in the presence of insulin or LDL [19,20,27–29]. A previous report has shown dysfunctional endothelial relaxation in patients suffering from hypertension with proteinuria and hematuria when the ratio of nighttime to daytime blood pressure rises from 0.88 0.1 to 0.93 0.02 [18]. Hypertension or proteinuria/hematuria indicate dysfunction in renal endothelial cells and the significant association with alcohol misuse indicates a role for stable alcohol metabolites. The oxygen from stable ether phospholipids such as LA-paf is derived from long chain fatty alcohols [10,15–22,27–29,30]. Other alcohol-related ether phospholipids, such as ethanolamine-plasmalogen could modulate the cholesterol transport as has been proposed in transgenic animal models [31]. Men with moderate intolerance to glucose tended to be overweight and hypertensive, in agreement with previous work which showed a relationship between hyperinsulinemia, borderline hypertension, intima thickening and/ or raised levels of antibodies against the ether phospholipid LA-paf [9,10]. Recent clinical reports support the prevalence of metabolic syndromes with obesity, hypertension, hyperinsulinemia and dyslipidemia all being found in elderly patients with late atherosclerosis [32]. Experimental data have shown that lysophospholipids with ester compounds in lipoproteins are sensitive to oxidation and induce the proliferation of vascular smooth muscle cells from cultured rabbit aortas and the synergistic benefit of antioxidant therapy with angiotensin receptor antagonists has been shown in vitro [33]. Albumin restores vasodilatation in rats, probably because it can incorporate ether phospholipids, lysophospholipids and/or fatty acids [15,34]. Other reports have shown the reduced capacity of serum samples from men with hypertriglyceridemia to promote cholesterol efflux from hepatoma cell lines to HDL [35]. Serum from patients with type IV hypertriglyceridemia does not impair the cholesterol efflux capacity of macrophages in culture, perhaps because phospholipids in serum HDL could enhance cholesterol efflux [36]. Hepatic lipases mediate hydrolysis of triglycerides in very low density lipoproteins and are positively related to HDL2 [37]. The significantly lower HDL levels and high triglyceride levels found in this male
Vol. 3, No. 3, pp. 279–289, September 2006
287
Original article study group, suggested that hepatic lipases could be impaired in those who were obese or overweight and misused alcohol. Men who were obese or overweight with high triglyceride levels showed significantly higher systolic and/or diastolic blood pressures. Hormonal lipases on endothelial cells are sensitive to epinephrine (or insulin) with the release of free fatty acids from triglycerides in muscles, macrophages and adipose tissue [38] probably explaining why obese men showed a high sensitivity to hypertension in this Bavarian study group. Taken together, raised blood pressure and raised body weight in men were significantly associated, in this Bavarian study, using two statistical models.
Raised diastolic blood pressure and proteinuria and/or hematuria were significantly associated, for the first time, with alcohol misuse in this young male study group as independent indicators of a decline in renal endothelial barriers.
Summary In this study, obese men and those who were overweight and misused alcohol had significantly higher blood pressure, significantly lower HDL levels and a significantly lower ratio of serum albumin to triglycerides. Proteinuria and/or hematuria was significantly associated with alcohol misuse in the male study group.
References [1] Kristjansson K, Ljungmann S, Bengtsson C, Bjo¨rkelund C, Sigurdsson JA. Microproteinuria and long-term prognosis with respect to renal function and survival in normotensive and hypertensive women. Scand J Urol Nephrol 2001;35:63–70. [2] Pijls LTJ, de Vries H, Kriegsman DMW, Donker AJM, van Eijk JTM. Determinants of albuminuria in people with Type 2 diabetes mellitus. Diab Res and Clin Practice 2001; 52:133–43. [3] Hyman DJ, Pavlik VN. Characteristics of patients with uncontrolled hypertension in the United States. New Engl J Med 2001; 345:479–96. [4] Weiss R, Dziura J, Burgert TS, Tamborlane WV, Taksali SE, Yeckel CW, et al. Obesity and the Metabolic Syndrome in children and adolescents. New Engl J Med 2004;350: 2362–74. [5] Stuveling EM, Hillege HL, Bakker SJL, Asselbergs FW, de Jong RO, Fans A, et al. Urine protein and microalbuminuria differ in their associations with various domains of vascular disease. Atherosclerosis 2004;172: 107–14. [6] Boerma M, Forsberg L, Van Zeijl L, Morgenstern R, De Faire U, Lemne C, et al. A genetic polymorphism in connexin 37 as a prognostic marker for atherosclerotic plaques development. J Int Medicine 1999;246:211–8. [7] Yamada Y, Izawa H, Ichihara S, Takatsu F, Ishihara H, Hirayama H, et al. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. New Engl J Med 2002;347:1916–23. [8] Frostegard J, Huang YH, Ro¨nnelid J, Scha¨fer-Elinder L. PAF and oxidized LDL induce immune activation by a common
288
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
Vol. 3, No. 3, pp. 279–289, September 2006
mechanism. Arterioscler Thromb Vasc Biol 1997;17:963–8. Wu R, Lemne C, De Faire U, Frostegard J. Antibodies to platelet-activating factor are associated with borderline hypertension, early atherosclerosis and the metabolic syndrome. J Int Med 1999;246:389–97. Korth R, Zimmermann K, Richter W. Lipoprotein-associated paf (LA-paf) was found in washed human platelets and monocytemacrophage-like U937 cells. Chem Phys Lipids 1994;70:109–19. Hines LM, Stampfer MJ, Ma J, Gaziano JM, Ridker PM, Hankinson SE, et al. Genetic variation in alcohol dehydrogenase and the beneficial effect of moderate alcohol consumption on myocardial infarction. New Engl J Med 2001;344:549–55. Marques-Vidal P, Montaye M, Haas B, Bingham A, Evans A, Juhan-Vague I, et al. Relationships between alcoholic beverages and cardiovascular risk factor levels in middleaged men, the PRIME study. Atherosclerosis 2001;157:431–40. Inazu A, Brown ML, Hesler CB, Agellon LB, Koizumi J, Takata K, et al. Increased highdensity lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. New Engl J Med 1990;323: 12343–8. Lands WEM. Cellular signals in alcoholinduced liver injury: a review. Alcohol Clin Exp Res 1995;19:928–38. Korth R-M. Comparison of phosphocholines in human plasma and cerebrospinal fluid (CSF). Faseb J 2000;14:A72. Korth R-M. Ether-linked phospholipids and hyperlipidemia. In: Pandalai SG, editor. Recent Research Developments in Lipids,
[17] [18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
5. Trivandium India: Transworld Research Network; 2001. p. 61–70. Korth R-M. AHA-Syndromes. Chem Phys Lipids 2002;118:96–7. Korth R-M. Alcohol, obesity, hypertension and endothelial irritation. Faseb J 2003;17: A1140. Korth R, Nunez D, Bidault J, Benveniste J. Comparison of three paf-acether receptor antagonists ginkgolides. Eur J Pharmacol 1988;152:101–10. Korth R, Hirafuji M, Benveniste J, RussoMarie F. Human umbilical vein endothelial cells: Specific binding of platelet-activating factor and cytosolic calcium flux. Biochem Pharmacology 1995;49:1793–9. Korth R-M. Specific binding sites for 1-Oalkyl-sn-glyceryl-3-phosphorylcholine on intact human blood neutrophils. Int Arch Allergy Immunol 1997;113:460–4. Korth R, Riess H, Brehm G, Hiller E. Unsaturated platelet-activating factor: influence on aggregation, serotonin release and thromboxane synthesis of human thrombocytes. Thrombosis Res 1986;41:699–706. Li J, Kim C, Leo M, Mak K, Rojkind M, Lieber C. Polyunsaturated lecithin prevents acetaldehyde-mediated hepatic collagen accumulation by stimulating collagenase activity in cultured lipocytes. Hepatology 1992; 15:373–81. Marathe GK, Harrison KA, Roberts JL, Morrow JD, Murphy RC, Tjoelker LW, et al. Identification of platelet-activating factor as the inflammatory lipid mediator in CCL4-metabolizing rat liver. J Lipid Res 2001;42:587–96. Anavekar NS, McMurray JJV, Velazquez EJ, Solomon SD, Kober L, Rouleau J-L, et al. Relation between renal dysfunction and
Original article
[26]
[27]
[28]
[29]
cardiovascular outcomes after myocardial infarction. New Engl J Med 2004;351: 1285–95. Berenson GS, Srinivasan SR, Bao W, Newmann WP, Tracy RE, Wattigney WA. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. New Engl J Med 1998;338: 1650–6. Korth R.-M. Verwendung von paf-AcetherAntagonisten zur Herstellung eines Arzneimittels und Verfahren zu deren Wirksamkeitsbestimmung. Europa¨ische Patentschrift, Publication No. 0312913, 1989. Korth R, Middeke M. Long time incubation of monocytic U 937 cells with LDL increase specific PAF-acether binding and the cellular acetylhydrolase activity. Chem Phys Lipids 1991;59:207–13. Ihida K, Predescu D, Czekay RP, Palade GE. Platelet activating factor receptor (PAF-R) is found in a large endosomal compartment in human umbilical vein endothelial cells. J Cell Science 1999;112:285–95.
[30] Snyder F. Metabolism of platelet activating factor and related ether lipids: enzymatic pathways, subcellular sites, regulation and membrane processing. In: Alan R, editor. Biological membranes: Aberrations in Membrane Structure and Function.. Liss Inc.; 1988. p. 57–72. [31] Munn NJ, Arnio E, Liu D, Zoeller RA, Liscum L. Deficiency in ethanolamine plasmalogen leads to altered cholesterol transport. J Lipid Res 2003;44:182–92. [32] Calle E, Thun MJ, Petrelli JM, Rodriguez C, Heath C. Body mass index and mortality in a prospective Cohort of U.S. Adults. New Engl J Med 1999;341:1097–105. [33] Watanabe T, Pakala R, Katagiri T, Benedict CR. Mildly oxidized low-density lipoprotein acts synergistically with angiotensin II in inducing vascular smooth muscle cell proliferation. J Hypertension 2001;19:1065– 73. [34] Vuong D, de Kimpe S, de Roos R, Rabelink TJ, Koomans HA, Joles JA. Albumin restores lysophosphatidylcholine-induced inhibition
[35]
[36]
[37]
[38]
of vasodilation in rat aorta. Kidney Int 2001;60:1088–96. Brites FD, Bonavita CD, de Geitere C, Cloes M, Delfly B, Yael MJ, et al. Alterations in the main steps of reverse cholesterol transport in male patients with primary hypertriglyceridemia and low HDL-cholesterol levels. Atherosclerosis 2000;152:181–92. Fournier N, Francone O, Rothblat G, Goudouneche D, Cambillau M, Kellner-Weibel G, et al. Enhanced efflux from ABCA1expressing macrophages to serum from type IV hypertriglyceridemic subjects. Atherosclerosis 2003;171:287–93. Ramsamy TA, Boucher J, Brown RJ, Yao Z, Sparks DL. HDL regulates the displacement of hepatic lipase from cell surface proteoglycans and the hydrolysis of VLDL triacylglycerol. J Lipid Res 2003;44: 733–41. Kraemer FB, Shen W-J. Hormone-sensitive lipase: control of intracellular tri-(di)acylgylcerol and cholesteryl ester hydrolysis. J Lipid Res 2002;43:1585–94.
Vol. 3, No. 3, pp. 279–289, September 2006
289