- Email: [email protected]
Essential hypertension is associated with Chlamydia pneumoniae but not Epstein-Barr antibodies
AJH
2002; 15:924 –926
Letters to the Editor Deficient Oxygen Transport: An Alternative Mechanism for the Development of Hypertension? I would like to suggest an alternative mechanism for the development of hypertension. The function of the heart is to transport blood and a primary function of blood is to transport oxygen. Is it possible that hypertension is the result of a deficiency in oxygen transport? Please allow me to explain. In electrical engineering there is an equation that describes the relationship between power (P), current (I), and voltage (V), ie, P ⫽ I ⫻ V. The analogy to oxygen transport works as follows. Power (energy per unit time) is related to the rate of oxygen delivered to the body’s tissues. The amount of oxygen used to burn fuel in the tissues is directly proportional to energy consumed by the tissues. Current (charge per unit time) is related to the rate of blood flow, that is, the number of red blood cells that pass through the tissues per unit time. In the electrical analogy electrons (the carriers of charge) are related to red blood cells (the carriers of oxygen). Finally, voltage (energy per unit charge) is related to the amount of oxygen carried by each red blood cell. One can relate this amount to the differential oxygen concentration before and after the lungs. One can now see a possible explanation for hypertension in conditions where the amount of oxygen carried by each red blood cell diminishes. The heart must work harder to increase the flow rate so that the power delivered remains constant. An increased flow rate is directly related to an increase in blood pressure (BP) (Pressure ⫽ Flow rate times Flow resistance). As we age the efficiency of oxygen uptake declines, therefore a natural linkage between age and hypertension would be apparent (as long as the tissues’ requirements and flow resistance remain relatively undiminished). In the pathologic condition of sleep apnea oxygen uptake is seriously impaired and high BP is a known accompanying symptom. It is also interesting to note the body’s normal response to various conditions. In exercise physiology the tissue requirements increase so the body responds by increasing the flow rate and the uptake of oxygen. In high altitude physiology the immediate response is increased flow rate with an attempt at increased oxygen uptake. The acclimated response is increased flow rate, not by increased heart output, but by increased red blood cell count. It is also well known that deep breathing has a significant ability to lower BP in normal and hypertensive individuals. In the past, the medical community has focused its attention on flow resistance (increased by arteriosclerosis) and static pressure (increased by fluid retention) as the 0895-7061/02/$22.00
major causes of hypertension. Given the limited success of hypertension treatments, perhaps it is time for a radical change in the thinking of its cause. GREGORY MARLOW 486 Kalmia Street Warminster, PA PII S0895-7061(02)03024-8 Address correspondence and reprint requests to Dr. Gregory Marlow, 486 Kalmia Street, Warminster, PA 18974; e-mail: [email protected]
Essential Hypertension Is Associated With Chlamydia pneumoniae But Not Epstein-Barr Antibodies Conflicting data exist regarding the relationship between Chlamydia pneunoniae (C. pneumoniae) antibodies and essential hypertension. A positive association between C. pneumoniae immunoglobulin G (IgG) antibodies and severe essential hypertension has been first reported by Cook et al,1 whereas, Nishimura et al2 previously supported an inverse association between C. pneumoniae and high blood pressure (BP) in Japanese adults. We designed this study to investigate whether both IgA and IgG antibodies against this microorganism are elevated in patients with mild-to-severe hypertension defined by 24-h ambulatory BP monitoring. We also measured the following antibodies against Epstein-Barr virus (EPV), EPV IgM, EPV IgG, Epstein-Barr nuclear antigen (EBNA) IgG, EPV EA IgG to examine whether a possible association between essential hypertension and C. pneumoniae antibodies is specific. Three hundred forty-eight hypertensives (taking antihypertensive medication or not) were recruited from outpatients attending the University Hypertension Clinic of the Department of Clinical Therapeutics at Alexandra Hospital of Athens. They were enrolled if all of the following criteria were met: clinical BP reading ⱖ140/90 mm Hg during their first and second (the next day) examination in the outpatient department or mean 24-h systolic/diastolic BP ⱖ125/80 mm Hg; no clinical or laboratory evidence of secondary hypertension; no clinical or laboratory evidence of other coexisting cardiovascular disease except for possible cardiovascular complications of the elevated BP; normal results of serum urea, electrolytes, creatinine, plasma renin activity at rest and after exercise, and urinary excretion of catecholamines; and normal renal imaging studies (radionuclide renogram, intravenous pyelography, or ultrasound scan). Fifty-four healthy subjects with no clinical or laboratory evidence of pulmonary or cardiovascular disease volunteered and were included as a control © 2002 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.
AJH–October 2002–VOL. 15, NO. 10, PART 1
LETTER TO THE EDITOR
925
Table 1. Characteristics of hypertensives and normotensives
Sex (M/F) Age (y ⫾ SD) Weight (kg) Height (cm) Body surface area (m2) Smoking habit (no/yes) Serum glucose (mg/dL) Serum cholesterol (mg/dL) Serum triglycerides (mg/dL) Serum HDL (mg/dL) Serum LDL (mg/dL) Clinic SBP (mm Hg) Clinic DBP (mm Hg) Mean SBP 24h (mm Hg) Mean DBP 24h (mm Hg) CRP (mg/L) EPV EBNA IgG (AcU/mL) EPV IgG (AcU/mL) C. pneumoniae IgA titer ⱖ40, n (%) C. pneumoniae IgG titer ⱖ80, n (%)
Normotensives (n ⴝ 54) (mean ⴞ SD)
Hypertensives (n ⴝ 348) (mean ⴞ SD)
P
26/28 46.46 ⫾ 13.18 69.3 ⫾ 13.52 166.4 ⫾ 8.6 1.76 ⫾ 0.18 32/22 93.7 ⫾ 15.94 214 ⫾ 36.8 112 ⫾ 44.17 55 ⫾ 11.16 138.31 ⫾ 34.4 118 ⫾ 12.12 79.07 ⫾ 8.95 113.31 ⫾ 8.3 70.33 ⫾ 6.4 0.54 ⫾ 0.52 126 ⫾ 91.8 37.01 ⫾ 28.12 18.5% 27.8%
175/173 49.13 ⫾ 9.41 76.5 ⫾ 15.3 166.38 ⫾ 11 1.8 ⫾ 0.2 229/119 99.10 ⫾ 22.38 224 ⫾ 46.9 119.34 ⫾ 69.7 51.1 ⫾ 13.68 141.08 ⫾ 42.5 149.26 ⫾ 18.07 93.22 ⫾ 11.61 131.63 ⫾ 13.6 78.91 ⫾ 11.05 0.58 ⫾ 0.56 143.53 ⫾ 110.19 37.51 ⫾ 31.2 58.3% 53.4%
NS NS NS NS NS NS NS NS NS NS NS .05 .05 .05 .05 NS NS NS .05 .05
NS ⫽ not significant; SBP ⫽ systolic blood pressure; DBP ⫽ diastolic blood pressure; CRP ⫽ C-reactive-protein; EBNA ⫽ Epstein-Barr nuclear antigen; AcU ⫽ activity unit; IgG ⫽ immunoglobulin G; IgA ⫽ immunoglobulin A.
group. They were enrolled only if they had 1) no history of hypertension, based on previous and past BP measurements (subjects who reported even once in their life clinic BP values ⱖ140/90 mm Hg were excluded); and 2) clinic BP measurements ⬍140/90 mm Hg on the first and second visit (on the next day) at the outpatient unit and mean 24-h systolic/diastolic BP ⬍125/80 mm Hg. Smoking habit, hyperlipidemia, obesity, diabetes mellitus were recorded in each subject and serum glucose, HDL- and LDLcholesterol, triglycerides, and C-reactive-protein (CRP) were determined. C. pneumoniae antibody titers were measured by indirect microimmunofluorescence test. The enzyme-linked immunosorbent assay (ELISA) was used to detect EPV IgM, EPV IgG, EBNA IgG, and EPV EA IgG antibodies of Epstein-Barr virus in human serum. The two groups did not significantly differ regarding age, male/female ratio, body surface area (BSA), lipid profile, blood glucose level, CRP, and smoking habit (Table 1). Of the total participants, 203 (58.3%) hypertensives and 10 (18.5%) normotensives had IgA titers ⱖ40 (P ⬍ .001 2). One hundred eighty-six hypertensives (53.4%) and 15 normotensives (27.8%) had IgG titers ⱖ80 (P ⬍ .001 2). The EPV IgM and EPV EA (early) antibodies were not detected in any of the hypertensive and normotensive subjects examined. No statistically significant differences were found in EPV IgG and EPV EBNA antibody levels between hypertensives and the control group. C. pneumoniae IgG seropositivity was 63.7% in nonsmokers and 76% in smokers (P ⬍ .011 2). No statistically significant difference was found in IgA serum titers between the two groups. No difference in age between IgA/IgG
seropositive and IgA/IgG seronegative individuals was found. C. pneumoniae IgG and IgA elevated titers were more frequently found in men than in women (P ⬍ .008 and P ⬍ .012, respectively, 2). Our results are in agreement with the findings of Cook et al1. However, in their study, C. pneumoniae IgA antibodies were not examined. Serologic evidence of IgA immunoglobulin indicates chronic chlamydial infection, which most probably contributed to the development of hypertension by triggering a chronic inflammatory process.3 In the study by Nishimura et al2, C. pneumoniae antibodies were determined by ELISA and clinic but not 24-h ambulatory BP measurements were provided in the 229 participants. We have used ambulatory BP monitoring in 402 subjects and controls to correctly identify and classify hypertensives and especially normotensives and we have also used the microimmunofluorescence test, which remains the most widely used laboratory technique for C. pneumoniae antibody measurements. We presume that the inverse association found by Nishimura et al may exist because of the different genetic characteristics of the Japanese population (different ethnic origin). In contrast, we found no association between Epstein-Barr infection and hypertension. Antibodies against this virus were measured to elucidate whether our data indicate a specific association between essential hypertension and C. pneumoniae antibodies, as the Epstein-Barr virus is also an intracellular agent that has been implicated in atherosclerosis in the past,4 and it is widespread in the Greek community. Furthermore, the C. pneumoniae organism is viruslike in that it is an obligate intracellular organism that
926
LETTER TO THE EDITOR
diverts the host cell’s energy production mechanisms and lyses the host cell at the end of the replication cycle.5 If elevated antibody levels of the Epstein-Barr virus were more frequently found in hypertensives, it would lead us to speculate that these individuals are more susceptible to infections. Thus, no specific association would have been established between C. pneumoniae infection and hypertension. Furthermore, the presence of infections in general, suggesting low immunoresistance, is may be an important risk factor, together with age, sex, and smoking, that leads to a chronic form of C. pneumoniae infection,6 thus the association between chronic C. pneumoniae infection and hypertension would have been less specific. The mechanisms underlying this positive association between C. pneumoniae infection and essential hypertension are not clear. C. pneumoniae could either be an innocent bystander in atheromatous plaques resulting for high BP or play a pathogenic role in the progression of established plaques. We can hypothesize that chronic C. pneumoniae infection may induce a chronic immune response orchestrated by cytokines, which may result in increased vascular resistance, leading to increased BP. The presence of vasoconstrictive molecules in this inflammatory progress might further be considered as a possible agent contributing to the pathogenesis of hypertension. VASSILIKI CH. PITIRIGA VASILIOS TH. KOTSIS MARIA-ELENI K. ALEXANDROU VASSILIKY D. PETROCHEILOU-PASCHOU ROUBINI N. ZAKOPOULOU NIKOS A. ZAKOPOULOS
AJH–October 2002–VOL. 15, NO. 10, PART 1
Department of Clinical Therapeutics Alexandra Hospital, University of Athens National and Kapodistrial University Athens, Greece PII S0895-7061(02)03025-X Address correspondence and reprint requests to Dr. Nikos Zakopoulos, Department of Clinical Therapeutics, Alexandra Hospital, Vas. Sofias and Lourou str.11528, Athens, Greece; e-mail: [email protected]
References 1.
2.
3.
4.
5.
6.
Cook PJ, Lip GYH, Davies P, Beevers DG, Wise R, Honeybourne D: Chlamydia pneumoniae antibodies in severe essential hypertension. Hypertension 1998;31:589 –594. Nishimura M, Ushiyama M, Nanbu A, Mashida C, Kawagoe K, Yoshimura M: Inverse association of Chlamydia pneumoniae infection with high blood pressure in Japanese adults. Am J Hypertens 2001;14:20 –26. Saikku P, Leinonen M, Tenkanen L, Linnanmaki E, Ekman MR, Manninen V, Manttari M, Frick MH, Huttunen JK: Chronic Chlamydia pneumoniae infection as a risk factor for coronary heart disease in the Helsinki Heart Study. Ann Intern Med 1992;116:273– 277. Musiani M, Zerbini ML, Muscari A, Puddu GM, Gentilomi G, Gibellini D, Gallinella G, Puddu P, La Placa M: Antibody patterns against Cytomegalovirus and Epstein-Barr virus in human atherosclerosis. Microbiologica 1990;13:35– 41. Alexander ER, Harrison HR: Chlamydial infections, In: Evans AS, Brachman PS (eds): Bacterial Infections of Humans: Epidemiology and Control, 2nd ed. New York, Plenum Medical Book, 1991, pp 179 –206. Leinonen M, Saikku P: Interaction of Chlamydia pneumoniae infection with other risk factors of atherosclerosis. Am Heart J 1999; 138(Suppl I):S504.
2002; 15:924 –926
Letters to the Editor Deficient Oxygen Transport: An Alternative Mechanism for the Development of Hypertension? I would like to suggest an alternative mechanism for the development of hypertension. The function of the heart is to transport blood and a primary function of blood is to transport oxygen. Is it possible that hypertension is the result of a deficiency in oxygen transport? Please allow me to explain. In electrical engineering there is an equation that describes the relationship between power (P), current (I), and voltage (V), ie, P ⫽ I ⫻ V. The analogy to oxygen transport works as follows. Power (energy per unit time) is related to the rate of oxygen delivered to the body’s tissues. The amount of oxygen used to burn fuel in the tissues is directly proportional to energy consumed by the tissues. Current (charge per unit time) is related to the rate of blood flow, that is, the number of red blood cells that pass through the tissues per unit time. In the electrical analogy electrons (the carriers of charge) are related to red blood cells (the carriers of oxygen). Finally, voltage (energy per unit charge) is related to the amount of oxygen carried by each red blood cell. One can relate this amount to the differential oxygen concentration before and after the lungs. One can now see a possible explanation for hypertension in conditions where the amount of oxygen carried by each red blood cell diminishes. The heart must work harder to increase the flow rate so that the power delivered remains constant. An increased flow rate is directly related to an increase in blood pressure (BP) (Pressure ⫽ Flow rate times Flow resistance). As we age the efficiency of oxygen uptake declines, therefore a natural linkage between age and hypertension would be apparent (as long as the tissues’ requirements and flow resistance remain relatively undiminished). In the pathologic condition of sleep apnea oxygen uptake is seriously impaired and high BP is a known accompanying symptom. It is also interesting to note the body’s normal response to various conditions. In exercise physiology the tissue requirements increase so the body responds by increasing the flow rate and the uptake of oxygen. In high altitude physiology the immediate response is increased flow rate with an attempt at increased oxygen uptake. The acclimated response is increased flow rate, not by increased heart output, but by increased red blood cell count. It is also well known that deep breathing has a significant ability to lower BP in normal and hypertensive individuals. In the past, the medical community has focused its attention on flow resistance (increased by arteriosclerosis) and static pressure (increased by fluid retention) as the 0895-7061/02/$22.00
major causes of hypertension. Given the limited success of hypertension treatments, perhaps it is time for a radical change in the thinking of its cause. GREGORY MARLOW 486 Kalmia Street Warminster, PA PII S0895-7061(02)03024-8 Address correspondence and reprint requests to Dr. Gregory Marlow, 486 Kalmia Street, Warminster, PA 18974; e-mail: [email protected]
Essential Hypertension Is Associated With Chlamydia pneumoniae But Not Epstein-Barr Antibodies Conflicting data exist regarding the relationship between Chlamydia pneunoniae (C. pneumoniae) antibodies and essential hypertension. A positive association between C. pneumoniae immunoglobulin G (IgG) antibodies and severe essential hypertension has been first reported by Cook et al,1 whereas, Nishimura et al2 previously supported an inverse association between C. pneumoniae and high blood pressure (BP) in Japanese adults. We designed this study to investigate whether both IgA and IgG antibodies against this microorganism are elevated in patients with mild-to-severe hypertension defined by 24-h ambulatory BP monitoring. We also measured the following antibodies against Epstein-Barr virus (EPV), EPV IgM, EPV IgG, Epstein-Barr nuclear antigen (EBNA) IgG, EPV EA IgG to examine whether a possible association between essential hypertension and C. pneumoniae antibodies is specific. Three hundred forty-eight hypertensives (taking antihypertensive medication or not) were recruited from outpatients attending the University Hypertension Clinic of the Department of Clinical Therapeutics at Alexandra Hospital of Athens. They were enrolled if all of the following criteria were met: clinical BP reading ⱖ140/90 mm Hg during their first and second (the next day) examination in the outpatient department or mean 24-h systolic/diastolic BP ⱖ125/80 mm Hg; no clinical or laboratory evidence of secondary hypertension; no clinical or laboratory evidence of other coexisting cardiovascular disease except for possible cardiovascular complications of the elevated BP; normal results of serum urea, electrolytes, creatinine, plasma renin activity at rest and after exercise, and urinary excretion of catecholamines; and normal renal imaging studies (radionuclide renogram, intravenous pyelography, or ultrasound scan). Fifty-four healthy subjects with no clinical or laboratory evidence of pulmonary or cardiovascular disease volunteered and were included as a control © 2002 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.
AJH–October 2002–VOL. 15, NO. 10, PART 1
LETTER TO THE EDITOR
925
Table 1. Characteristics of hypertensives and normotensives
Sex (M/F) Age (y ⫾ SD) Weight (kg) Height (cm) Body surface area (m2) Smoking habit (no/yes) Serum glucose (mg/dL) Serum cholesterol (mg/dL) Serum triglycerides (mg/dL) Serum HDL (mg/dL) Serum LDL (mg/dL) Clinic SBP (mm Hg) Clinic DBP (mm Hg) Mean SBP 24h (mm Hg) Mean DBP 24h (mm Hg) CRP (mg/L) EPV EBNA IgG (AcU/mL) EPV IgG (AcU/mL) C. pneumoniae IgA titer ⱖ40, n (%) C. pneumoniae IgG titer ⱖ80, n (%)
Normotensives (n ⴝ 54) (mean ⴞ SD)
Hypertensives (n ⴝ 348) (mean ⴞ SD)
P
26/28 46.46 ⫾ 13.18 69.3 ⫾ 13.52 166.4 ⫾ 8.6 1.76 ⫾ 0.18 32/22 93.7 ⫾ 15.94 214 ⫾ 36.8 112 ⫾ 44.17 55 ⫾ 11.16 138.31 ⫾ 34.4 118 ⫾ 12.12 79.07 ⫾ 8.95 113.31 ⫾ 8.3 70.33 ⫾ 6.4 0.54 ⫾ 0.52 126 ⫾ 91.8 37.01 ⫾ 28.12 18.5% 27.8%
175/173 49.13 ⫾ 9.41 76.5 ⫾ 15.3 166.38 ⫾ 11 1.8 ⫾ 0.2 229/119 99.10 ⫾ 22.38 224 ⫾ 46.9 119.34 ⫾ 69.7 51.1 ⫾ 13.68 141.08 ⫾ 42.5 149.26 ⫾ 18.07 93.22 ⫾ 11.61 131.63 ⫾ 13.6 78.91 ⫾ 11.05 0.58 ⫾ 0.56 143.53 ⫾ 110.19 37.51 ⫾ 31.2 58.3% 53.4%
NS NS NS NS NS NS NS NS NS NS NS .05 .05 .05 .05 NS NS NS .05 .05
NS ⫽ not significant; SBP ⫽ systolic blood pressure; DBP ⫽ diastolic blood pressure; CRP ⫽ C-reactive-protein; EBNA ⫽ Epstein-Barr nuclear antigen; AcU ⫽ activity unit; IgG ⫽ immunoglobulin G; IgA ⫽ immunoglobulin A.
group. They were enrolled only if they had 1) no history of hypertension, based on previous and past BP measurements (subjects who reported even once in their life clinic BP values ⱖ140/90 mm Hg were excluded); and 2) clinic BP measurements ⬍140/90 mm Hg on the first and second visit (on the next day) at the outpatient unit and mean 24-h systolic/diastolic BP ⬍125/80 mm Hg. Smoking habit, hyperlipidemia, obesity, diabetes mellitus were recorded in each subject and serum glucose, HDL- and LDLcholesterol, triglycerides, and C-reactive-protein (CRP) were determined. C. pneumoniae antibody titers were measured by indirect microimmunofluorescence test. The enzyme-linked immunosorbent assay (ELISA) was used to detect EPV IgM, EPV IgG, EBNA IgG, and EPV EA IgG antibodies of Epstein-Barr virus in human serum. The two groups did not significantly differ regarding age, male/female ratio, body surface area (BSA), lipid profile, blood glucose level, CRP, and smoking habit (Table 1). Of the total participants, 203 (58.3%) hypertensives and 10 (18.5%) normotensives had IgA titers ⱖ40 (P ⬍ .001 2). One hundred eighty-six hypertensives (53.4%) and 15 normotensives (27.8%) had IgG titers ⱖ80 (P ⬍ .001 2). The EPV IgM and EPV EA (early) antibodies were not detected in any of the hypertensive and normotensive subjects examined. No statistically significant differences were found in EPV IgG and EPV EBNA antibody levels between hypertensives and the control group. C. pneumoniae IgG seropositivity was 63.7% in nonsmokers and 76% in smokers (P ⬍ .011 2). No statistically significant difference was found in IgA serum titers between the two groups. No difference in age between IgA/IgG
seropositive and IgA/IgG seronegative individuals was found. C. pneumoniae IgG and IgA elevated titers were more frequently found in men than in women (P ⬍ .008 and P ⬍ .012, respectively, 2). Our results are in agreement with the findings of Cook et al1. However, in their study, C. pneumoniae IgA antibodies were not examined. Serologic evidence of IgA immunoglobulin indicates chronic chlamydial infection, which most probably contributed to the development of hypertension by triggering a chronic inflammatory process.3 In the study by Nishimura et al2, C. pneumoniae antibodies were determined by ELISA and clinic but not 24-h ambulatory BP measurements were provided in the 229 participants. We have used ambulatory BP monitoring in 402 subjects and controls to correctly identify and classify hypertensives and especially normotensives and we have also used the microimmunofluorescence test, which remains the most widely used laboratory technique for C. pneumoniae antibody measurements. We presume that the inverse association found by Nishimura et al may exist because of the different genetic characteristics of the Japanese population (different ethnic origin). In contrast, we found no association between Epstein-Barr infection and hypertension. Antibodies against this virus were measured to elucidate whether our data indicate a specific association between essential hypertension and C. pneumoniae antibodies, as the Epstein-Barr virus is also an intracellular agent that has been implicated in atherosclerosis in the past,4 and it is widespread in the Greek community. Furthermore, the C. pneumoniae organism is viruslike in that it is an obligate intracellular organism that
926
LETTER TO THE EDITOR
diverts the host cell’s energy production mechanisms and lyses the host cell at the end of the replication cycle.5 If elevated antibody levels of the Epstein-Barr virus were more frequently found in hypertensives, it would lead us to speculate that these individuals are more susceptible to infections. Thus, no specific association would have been established between C. pneumoniae infection and hypertension. Furthermore, the presence of infections in general, suggesting low immunoresistance, is may be an important risk factor, together with age, sex, and smoking, that leads to a chronic form of C. pneumoniae infection,6 thus the association between chronic C. pneumoniae infection and hypertension would have been less specific. The mechanisms underlying this positive association between C. pneumoniae infection and essential hypertension are not clear. C. pneumoniae could either be an innocent bystander in atheromatous plaques resulting for high BP or play a pathogenic role in the progression of established plaques. We can hypothesize that chronic C. pneumoniae infection may induce a chronic immune response orchestrated by cytokines, which may result in increased vascular resistance, leading to increased BP. The presence of vasoconstrictive molecules in this inflammatory progress might further be considered as a possible agent contributing to the pathogenesis of hypertension. VASSILIKI CH. PITIRIGA VASILIOS TH. KOTSIS MARIA-ELENI K. ALEXANDROU VASSILIKY D. PETROCHEILOU-PASCHOU ROUBINI N. ZAKOPOULOU NIKOS A. ZAKOPOULOS
AJH–October 2002–VOL. 15, NO. 10, PART 1
Department of Clinical Therapeutics Alexandra Hospital, University of Athens National and Kapodistrial University Athens, Greece PII S0895-7061(02)03025-X Address correspondence and reprint requests to Dr. Nikos Zakopoulos, Department of Clinical Therapeutics, Alexandra Hospital, Vas. Sofias and Lourou str.11528, Athens, Greece; e-mail: [email protected]
References 1.
2.
3.
4.
5.
6.
Cook PJ, Lip GYH, Davies P, Beevers DG, Wise R, Honeybourne D: Chlamydia pneumoniae antibodies in severe essential hypertension. Hypertension 1998;31:589 –594. Nishimura M, Ushiyama M, Nanbu A, Mashida C, Kawagoe K, Yoshimura M: Inverse association of Chlamydia pneumoniae infection with high blood pressure in Japanese adults. Am J Hypertens 2001;14:20 –26. Saikku P, Leinonen M, Tenkanen L, Linnanmaki E, Ekman MR, Manninen V, Manttari M, Frick MH, Huttunen JK: Chronic Chlamydia pneumoniae infection as a risk factor for coronary heart disease in the Helsinki Heart Study. Ann Intern Med 1992;116:273– 277. Musiani M, Zerbini ML, Muscari A, Puddu GM, Gentilomi G, Gibellini D, Gallinella G, Puddu P, La Placa M: Antibody patterns against Cytomegalovirus and Epstein-Barr virus in human atherosclerosis. Microbiologica 1990;13:35– 41. Alexander ER, Harrison HR: Chlamydial infections, In: Evans AS, Brachman PS (eds): Bacterial Infections of Humans: Epidemiology and Control, 2nd ed. New York, Plenum Medical Book, 1991, pp 179 –206. Leinonen M, Saikku P: Interaction of Chlamydia pneumoniae infection with other risk factors of atherosclerosis. Am Heart J 1999; 138(Suppl I):S504.