Persistence is a key factor for long-term blood pressure control, which is of high prognostic importance for patients at increased cardiovascular risk. Here we present the results of a post-marketing survey including 4769 hypertensive patients treated with irbesartan in 886 general practices in Switzerland. The goal of this survey was to evaluate the tolerance and the blood pressure lowering effect of irbesartan as well as the factors affecting persistence in a large unselected population.Prospective observational survey conducted in general practices in all regions of Switzerland. Previously untreated and uncontrolled pre-treated patients were started with a daily dose of 150 mg irbesartan and followed up to 6 months.After an observation time slightly exceeding 4 months, the average reduction in systolic and diastolic blood pressure was 20  -19.6 to -20.7 mmHg) and 12 mmHg (95% CI -11.4 to -12.1 mmHg), respectively. At this time, 26% of patients had a blood pressure < 140/90 mmHg and 60% had a diastolic blood pressure < 90 mmHg. The drug was well tolerated with an incidence of adverse events  of 8.0%. In this survey more than 80% of patients were still on irbesartan at 4 month. The most important factors predictive of persistence were the tolerability profile and the ability to achieve a blood pressure target ≤ 140/90 mmHg before visit 2. Patients who switched from a fixed combination treatment tended to discontinue irbesartan more often whereas those who abandoned the previous treatment because of cough (a class side effect of ACE-Inhibitors) were more persistent with irbesartan.The results of this survey confirm that irbesartan is effective, well tolerated and well accepted by patients, as indicated by the good persistence. This post-marketing survey also emphasizes the importance of the tolerability profile and of achieving an early control of blood pressure as positive predictors of persistence. Angiotensin II receptor antagonists (AIIRA) have demonstrated excellent efficacy in patients with hypertension ,2, heartHowever, the main message of the published guidelines remains that a normalization of arterial blood pressure in hypertensive patients is the key objective to the prevention of cardiovascular events, especially in high-risk categories, where stricter therapeutic targets and aggressive strategies to reach them have been proposed. Yet, achieving normalization of blood pressure (BP) remains a difficult task, or, in the words of the JNC-7 report : "The moThe inadequate persistence with therapy, i.e. the frequent switch or discontinuation of the prescribed therapy has been recognized as a frequent cause of treatment failure . PersistThe aim of this open prospective observational survey with 4769 hypertensive patients treated in general practices in Switzerland, was to evaluate the persistence with irbesartan in real-life settings over a period of about one year and to investigate factors affecting either positively or negatively the persistence. In addition, the tolerability profile and the effect of irbesartan on BP control were assessed.This prospective observational survey was conducted in general practices in all regions of Switzerland from October 1997 to March 1999 i.e. shortly after the launch of irbesartan in the country. The general practitioners (GPs) were asked to document their daily routine in the treatment of hypertensive patients with irbesartan; 1390 physicians were contacted, 1045 included patients and 886 documented the treatment. They were recruited by the field forces of the sponsors of the study i.e. BMS and Sanofi-Synthelabo Switzerland. GPs filled in a baseline visit (Visit 1) form for every treated patient, and could report up to five follow up visits in the following 3–6 months (End Form). They were asked to document two arterial blood pressure measurements at every visit and to report concomitant antihypertensive medication and adverse events, as well as changes or discontinuation of treatment. At the end of the observation period, GPs reported if their patients were continuing the treatment with irbesartan, alone or in combination with other antihypertensive drugs. About 1 year after baseline, patients with ongoing treatment with irbesartan received a Compliance Form Patient, where they were asked how irbesartan was tolerated  and how many times weekly they took irbesartan in the preceding 3–4 weeks; a further question was how many tablets  were taken daily. Their GPs received a Compliance Form MD, to report the last blood pressure measurement and if and when the patient had discontinued the treatment. The various forms were designed by external consultants. The data were collected by mail using self-addressed envelopes and processed by the consultants. Queries for incomplete forms were done by the sponsor representatives. No standard validated questionnaire was used. In Switzerland, this type of survey does not need to be submitted to an ethical committee.All patients with newly diagnosed hypertension, or with treated hypertension requiring a change in medication according to the GP, were considered for the survey. No standardized definition was used but physicians considered a BP >140/90 mmHg as hypertension. There were neither demographic nor clinical exclusion criteria. The only condition to participate was that patients should not have been pre-treated with irbesartan. Treatment was started with irbesartan 150 qd. Thereafter, physicians were free to change the antihypertensive therapy at any time during the follow-up based on their individual therapeutic goals .Values are presented as mean +/- sd. The statistical significance of between-group differences was computed using the 2-sided Chi-square test, the Mann-Whitney-U test or ANOVA methods as appropriate. For multivariate correlations, a logistic regression analysis with a dichotomous dependent variable was used . To support the results of the logistic regression models, Cox regression models with cumulative survival functions were further computed.As shown in Figure Table More that 90% of the Efficacy Sample patients received irbesartan 150 mg qd, as a monotherapy or in combination with other antihypertensives. 69% of the Efficacy Sample patients received a constant monotherapy and 5.6% a constant polytherapy. In the Efficacy Sample, the mean reduction of systolic blood pressure (SBP) from baseline to the last visit was 20.2 ± 19.5 mmHg (p < 0.001). For the diastolic blood pressure (DBP), the mean reduction was 11.7 ± 11.3 mmHg (p < 0.001). Figure Since GPs did not receive specific instructions about therapeutic goals in this survey, various therapeutic targets were used to evaluate the success in controlling blood pressure Figure . As showAdverse events were reported for 383 patients (8.0% of the AE-Sample), more often by older patients  and by pre-treated patients . Yet, in the majority of patients (90.7%), irbesartan was well tolerated according to GPs. Tolerance was reported as poor only for 131 patients (2.7%). Adverse events led to discontinuation of irbesartan in 343 cases (7.4%). The most frequent side effects are listed in Table 3829 patients out of 4639 continued the treatment with irbesartan after the last visit . The main reasons for discontinuation of the remaining 810 patients were the occurrence of adverse events and an insufficient efficacy  who returned the Compliance Form Patient reported an irbesartan intake of 6–7 times per week, i.e. more than 80% of the prescribed doses. All subgroups scored around 90%  entered the trial after a failed experience with other antihypertensive drugs. Irbesartan proved to be the drug inducing more persistence in a comparative study with newly-diagnosed patients ; therefoIn this survey, an attempt was made to obtain information on drug adherence using simplified questionnaires addressed to the patients and physicians. Unfortunately, only a small proportion of these questionnaires were filled by the participants. There is therefore a high probability of bias towards highly compliant patients. Moreover, questionnaires are known to overestimate drug adherence. Hence it is not surprising that good compliance with the dosing schedule was reported by more than 90% of the patients after about one year treatment, meaning that this fraction of the patients reported to have taken irbesartan at least 6 times a week in the preceding 3–4 weeks. Yet, the results of more than 1000 questionnaires confirm previous observations such as the lower compliance in men and the absence of effect of age. Indeed, Degoulet at al have also reported thatmale sex is a variable significantly associated with an increased dropout rate in hypertensive patients attending a hypertension clinic . Of inteIn conclusion, this survey confirms that irbesartan is a safe and effective antihypertensive drug in clinical practice. A high persistence with irbesartan was found in this program which is likely related to the consistent reductions in blood pressure and the good tolerability profile. This post-marketing survey has also tend to confirm in a large population of patients that achieving an early control of blood pressure may be a positive predictor of persistence. Based on this observation one could encourage physicians to start the antihypertensive therapy more aggressively using higher doses of well tolerated drugs such as angiotensin II receptor antagonists or fixed low-dose combinations in order to improve blood pressure control as well as long-term persistence.All authors had a consultant agreement with both Bristol Myers Squibb and Sanofi-Synthelabo. These companies supported the study financially and monitored the study.MB has written the paper, BH, PG and BW have contributed to the conception of the study, to the analysis of the data and to the redaction of the paper.The pre-publication history for this paper can be accessed here:


The coexistence of type 2 diabetes mellitus and hypertension increases the risk of cardiovascular diseases. The U.K. Prospective Diabetes Study has shown that blood pressure control as well as blood glucose control is efficient for prevention of complications in hypertensive patients with diabetes mellitus. However, some reports have shown that it is difficult to control the blood pressure and the concomitant use of a plurality of drugs is needed in hypertensive patients with diabetes mellitus. In recent years renin-angiotensin system depressants are increasingly used for the blood pressure control in diabetic patients. Particularly in Japan, angiotensin II (A II) antagonists are increasingly used. However, there is no definite evidence of the point of which is efficient for the control, the increase in dose of A II antagonist or the concomitant use of another drug, in hypertensive patients whose blood pressure levels are inadequately controlled with A II antagonist.Hypertensive patients of age 20 years or over with type 2 diabetes mellitus who have been treated by the single use of AII antagonist at usual doses for at least 8 weeks or patients who have been treated by the concomitant use of AII antagonist and an antihypertensive drug other than calcium channel blockers and ACE inhibitors at usual doses for at least 8 weeks are included.ADVANCED-J, to compare the increases in dose of A II antagonist and the concomitant use of a Ca-channel blocker (amlodipine) and A II antagonist in hypertensive patients with diabetes mellitus, whose blood pressure levels were inadequately controlled with A II antagonist. This study is different from the usual previous studies in that home blood pressures are assessed as indicators of evaluation of blood pressure. The ADVANCED-J study may have much influence on selection of antihypertensive drugs for treatment in hypertensive patients with diabetes mellitus. It is expected to give an important hint for considering the validity of selection of antihypertensive drugs from the aspects not only of the antihypertensive effect but medical cost-effectiveness.We designed a multi-center, prospective, randomized, open label, blinded-endpoint trial,  It has been revealed by many epidemiological studies including the Framingham study that diabetes mellitus (DM) and hypertension (HT) are respectively risk factors of cardiovascular diseases and that the coexistence of DM with HT considerably increases the risk of cardiovascular diseases -4. The rOn the basis of these knowledge, observations, and findings, optimum target blood pressure levels for HT patients with DM (DM+HT patients) are set at 130/80 mm Hg lower than those for general HT patients in various guidelines -10. WhilThe types of antihypertensive drugs that are recommended to the treatment of DM+HT patients vary with guidelines, but in many cases renin-angiotensin (RA) system depressants and calcium channel blockers (Ca blockers) are recommended, taking into consideration the influence on glucose metabolism.Angiotensin II (A II) is a peptide hormone closely involved with the Na excretion control via the RA system. A II is widely recognized from the action mechanism to influence the onset and exacerbation of HT. ACE inhibitors suppressing A II production and A II receptor antagonists (A II antagonists) have been developed as antihypertensive drugs suppressing the RA system, and used all over the world ,11,12. IOn the other hand, Ca antagonists exert the antihypertensive action to wide-ranging patients, and are commonly used as antihypertensive drugs through the mechanism of inhibiting calcium entry, which triggers constriction in vascular smooth muscle cells. Ca antagonists are recommended as a therapeutic medicine for DM+HT patients, because they have no adverse influence on lipid metabolism or glucose metabolism -28.In recent years, the use of A II antagonists as antihypertensive drugs for DM+HT patients is being increased in Japan. The increase in dose of antihypertensive drug, the combined use of antihypertensive drugs with different mechanisms, and so on, are considered as methods to respond to the inadequate control of blood pressure in HT patients. However, there is no distinct evidence of the measure that will make better control of blood pressure to become a reality in DM+HT patients, whose blood pressure is inadequately controlled with A II antagonist.In hypertensive patients whose blood pressure levels were inadequately controlled by single therapy with an A II antagonist, we designed the ADVANCED-J study to compare different methods for antihypertensive therapy, i.e., the increase in dose of A II antagonist and the combined use of a Ca blocker amlodipine, which is most frequently used in Japan, in terms of the usefulness.Subjects are recruited in outpatient offices of university hospitals or general hospitals from the entire apectrum of patients with coexistent hypertension and type 2 diabetes mellitus.all of the following conditions by investigators, are included in the study.The patients, who are judged as meeting 1) Patients with type 2 diabetes mellitus2) Patients who have been treated by the single use of AII antagonist  at usual doses for at least 8 weeks (including the observation period of 2 weeks or more for the study) or patients who have been treated by the concomitant use of AII antagonist and an antihypertensive drug other than calcium channel blockers and ACE inhibitors at usual doses for at least 8 weeks (including the observation period of 2 weeks or more for the study).3) Patients who show > 135 mm Hg systolic or > 85 mm Hg diastolic of the ambulatory blood pressure levels measured (in the sitting position) at the time of start of the observation period, and show > 130 mm Hg systolic or > 80 mm Hg diastolic of the mean (home blood pressure level measured after getting up before the start of study) of the home blood pressure levels after getting up for the last 5 days during the last 2-week observation period.4) Patients whose consent is obtained at age 20 years or over.5) Patients whose consent is obtained from themselves in written form.With regard to 2) and 3), however, the case, which shows > 180 mm Hg systolic or > 110 mm Hg diastolic of the mean of the home blood pressure levels measured after getting up for the last 5 days during the first 1-week observation period, is included in the study.one of the following conditions by investigators.This study excludes the patients who are judged as being conformed to 1) Patients with secondary hypertension.2) Patients who show > 180 mm Hg systolic or > 110 mm Hg diastolic of the ambulatory blood pressure levels measured (in the sitting position) at the time of start of the observation period.3) Patients with severe hepatic dysfunction.4) Patients with severe renal dysfunction.5) Patients with a past history of hypersensitiveness to study drugs.6) Pregnant, lactating, and probably pregnant patients, and patients who want to become pregnant during the study period.7) Patients who have attended other trials within 3 months before the start of the observation period or who attend other trials simultaneously with the present study.8) Other patients judged as being inappropriate for the subjects of the study by investigators.Investigators confirm that the subjects are consistent with the inclusion criteria and are not contrary to the exclusion criteria and input necessary matters on the Web before the start of the study (before the start of the period when the dose is increased or other concomitant drug is used). The results of the dynamic allocation to two groups according to the eligibility of the relevant patient to the study and background factors (Increased AII antagonist dose group and combined amlodipine group) are indicated on the Web by E-mail.The urinary albumin levels during the observation period  and systolic blood pressure levels  of the home blood pressure levels after getting up before the start of the study are taken into consideration on allocation of the patients (into the increased AII antagonist dose group and the combined amlodipine group).The following commercially-available drugs are used as study drugs in the study , the study drug is taken after breakfast or after getting up once a day.The dose of AII antagonist in the increased AII antagonist dose group is the maximum dose approved. However, in the cases in which the antihypertensive effect is excessive (< 110 mm Hg systolic or < 65 mm Hg diastolic of the home blood pressure after getting up), and in which the dose is required to be reduced, the dose of AII antagonist may be reduced.The dose of AII antagonist in the combined amlodipine group is the same as that  during the observation period, and the dose of amlodipine is 5 mg/day. However, in the cases in which the antihypertensive effect is excessive (< 110 mm Hg systolic or < 65 mm Hg diastolic of the home blood pressure* after getting up) and in which the dose is required to be reduced, the dose of amlodipine may be reduced (See Table * Note: The mean of the blood pressure levels measured for the last 5 days during the 2-week period throughout the study period.Three years after the start of study.The home blood pressure levels after getting up are < 125 mm Hg systolic and < 80 mm Hg diastolic.Note: The mean of the levels measured for the last 5 days during the 2-week period (during the 14-day period between 14 days before the day of ambulatory examination and the previous day of the ambulatory examination day) before the ambulatory examination day (the reference day of the months without ambulatory examination).* (1) The following drugs may be concomitantly used with AII antagonist under individual conditions1) Antihypertensive drugs used concomitantly with AII antagonist before the start of the observation period 2) Antihypertensive drugs other than the study drug from 8 weeks onward after the start of the study.3) Drugs used for the treatment of complications(2) The drugs prohibited to be concomitantly usedAntihypertensive drugs other than the study drug for 8 weeks after the start of the study.(3) Combined therapyCombined therapy including standard diet therapy, therapeutic exercise, prohibition of smoking, etc. is not restricted.A chart of steps to increase doses of the study drug and antihypertensive drugs other than the study drug and to use concomitantly an antihypertensive drug other than the study drug is shown below  period of the increase in dose or the concomitant use .• Changes in the home blood pressures after getting up (home blood pressure levels)• The rate of home blood pressure levels accomplishing the target levels (< 125 mm Hg systolic and < 80 mm Hg diastolic)• Changes in the blood pressure levels measured on an outpatient basis (ambulatory blood pressure level)• The rate of the ambulatory blood pressure levels accomplishing the reference levels (< 130 mm Hg systolic and < 80 mm Hg diastolic)• Changes in the home blood pressures before going to bed• Changes in IMT of the cervical artery• Changes in PWV• Changes in echocardiographic findings• Changes in urinary albumin level• Changes in BNP• Changes in hs-CRP• Medical cost-effectiveness• Adverse events, adverse drug reactions• Clinical laboratory dataThe Clinical Protocols Committee and members of the Clinical Protocols Preparation Subcommittee decide the transaction of the cases and to fix the data collected for 12 months and 36 months after the start of the study.1) Population to be analyzed for efficacy• The major population to be analyzed for efficacy includes those defined according to the principle of intention-to-treat principle.2) Population to be analyzed for safety• The population to be analyzed for safety include the population in which the dose of the AII antagonist is increased or the additional concomitant use of amlodipine is conducted after the start of the study.Main outcome measures and analytical methods:1) Main outcome measures(a) Changes in the home blood pressures after getting up (home blood pressure level)(b) The rate of home blood pressure levels accomplishing the target levels2) Analytical methods2 test.With regard to (a), the subjects include "the population to be analyzed for efficacy", and summarized statistics about difference in blood pressure (the extent of antihypertensive effect) at each instant of survey are calculated from blood pressure at each instant of survey and from blood pressure levels during the observation period. Analysis of variance is applied for the inter-group comparison. In each group the blood pressure levels during the observation period are compared with the blood pressure levels at the instant of survey for reference. The extent of antihypertensive effect is also compared between the groups at each instant of survey. With regard to (b), the subjects include "the population to be analyzed for efficacy", and the rates of the blood pressure levels measured 8 and 12 months after the start of the study, which accomplish the target blood pressure levels, are calculated and the frequencies with which the rates are obtained are compared by χSecondary outcome measures and analytical methods:1) Secondary outcome measures(a) Changes in ambulatory blood pressure levels(b) The rate of ambulatory blood pressure levels accomplishing the reference levels(c) Changes in home blood pressure levels measured before going to bed(d) Changes in carotid IMT(e) Changes in PWV(f) Changes in echocardiographic findings(g) Changes in urinary albumin level(h) Changes in BNP(i) Changes in hs-CRP(j) Medical cost-effectiveness2) Analytical methodsWith regard to items (a) and (c), the analysis includes "the population to be analyzedfor efficacy", and conforms to " (3) 1) (a) Changes in blood pressure levels measuredat home after getting up". With regard to item (b), the analysis includes "thepopulation to be analyzed for efficacy", and conforms to "(3) 1) (b) The rate of homeblood pressure levels accomplishing the target levels". With regard to items (d)through (i), the analysis includes "the population to be analyzed for efficacy", and theblood pressure levels during the observation period are compared with those at eachtime point of survey in each group. The difference between the blood pressure levelduring the observation period and that at each instant of survey is comparedbetween the groups. With regard to item (j), the analysis includes "the population tobe analyzed for efficacy", and the drugs used, the contents of events, and medicalfees required are compiled according to groups for comparison.The statistical analysis follows the fixation of the data collected for 12 months after the start of the study and of the data collected (for 36 months after the start of the study) during the follow-up period.The target number of the patients is 300 patients consisting of 150 in the increased AII antagonist dose group and 150 in the combined amlodipine group.Selection of methods for antihypertensive therapy has been a matter of controversy, but the results of meta-analysis of the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC), in which the results of large-scale clinical studies in recent years were comprehensively interpreted, have suggested that the way to decrease the blood pressure, rather than the types of antihypertensive drugs, is important for prevention not only of stroke but of coronary arterial diseases such as myocardial infarction. When the efficacy of the initiated antihypertensive drug is inadequate, physicians adopt either the increase in dose of the antihypertensive drug or the combined use of another antihypertensive drug with the initiated drug as alternative choices. However, there are hardly any studies on comparison of these alternatives in terms of the antihypertensive effect or the influence on cardiovascular events.Some reports have shown that the combined use of antihypertensive drugs is needed to particularly HT patients with DM or nephropathy. Of these drugs, A II antagonists have been reported to have favorable influence on the renal function. In recent years the use of A II antagonists is increasingly used as the first-line medicine for HT patients with DM or nephropathy. On the other hand, it is also true that there are many patients who receive treatment by the combined use of a Ca blocker with the antagonist in many studies of evaluation of the efficacy of these drugs. The results of the meta-analysis in recent years have suggested that adequate control of blood pressure levels is also necessary for adequate exertion of the usefulness of RA system depressants in hypertensive patients.While it has been reported that there is correlation between the antihypertensive action and the dose of A II antagonists, some reports have shown that the increase in the antihypertensive effect is limited even by the increase in dose to more than the usual dose. Since an adverse effect of ACE inhibitors, a dry cough, is frequently observed in Japanese people, the shift to A.R.B. rapidly proceeded. However, NHI drug price of A.R.B. is high. With regard to the use at dose more than the usual dose, its efficacy needs to be reviewed from a viewpoint of medical cost-effectiveness. Based on the background, the ADVANCED-J study was designed to compare the increase in dose of A II antagonists and the combined use of amlodipine with an antagonist in terms of the antihypertensive effect in hypertensive patients whose blood pressure levels were inadequately controlled by single therapy with an A II antagonist.The primary outcome measure of the ADVANCED-J study included the home blood pressure measured in the early morning. The prevalence of home blood pressure monitor in recent years has allowed comprehension of details of the blood pressure condition. As a result, the presence of so-called masked hypertension, which shows the inadequately controlled home blood pressure in spite of the controlled ambulatory blood pressure, has increasingly been revealed.It has been reported that the risk of cardiovascular events in masked hypertension patients is as high as that in persistent hypertension patients. The importance of 24-hour blood pressure control involving home blood pressure is increasingly recognized. In fact, it is not realistic on a point of principle or from the aspect of medical cost-effectiveness to conduct the ambulatory blood pressure monitoring (ABPM) in all hypertensive patients. On the other hand, at least 30,000,000 home blood pressure monitors have been put on the market up to date in Japan, and it can be said from the global aspect that they have become more widespread in Japan. The blood pressure levels measured with home blood pressure monitors, particularly those measured at the time of rising in the morning, have been reported to reflect changes in blood pressure during the course from the night to the early morning. The correlation between blood pressure levels at home in the morning and the onset of cardiovascular events has also been reported. It is considered important for suppression of cardiovascular events in HT patients with DM to control the home blood pressures measured in the morning.There are many DM patients who show the non-dipper type of changes in blood pressure, i.e., the type which shows an only slight spontaneous decrease in blood pressure during the night , and the home blood pressures measured in the morning are predicted to be high in them. It is therefore considered important for prevention of the onset of cardiovascular events to control the home blood pressure measured in the morning even in HT patients with DM.However, there have been only few or no comparative studies on drugs, which have focused on home blood pressures measured in the morning in HT patients with DM. There have been no studies on the point of which is more efficient for controlling of home blood pressures measured in the early morning, the increase in dose of A II antagonists or the additional combined use of a Ca blocker. Based on these circumstances, the home blood pressures in the morning were adopted to evaluation of blood pressure control in this study.The compliance of recording by patients and bias due to selection of levels at the time of data recording have influence on reliability of the measurement of blood pressure levels at home. For this reason, the i-monitoring system was adopted to the ADVANCED-J study, and all the blood pressure levels measured were semiautomatically accumulated in the Data Center. All the data from the measurements and the summary data were supplied to physicians via web when necessary.It has been believed that arteriosclerosis is more likely to progress in DM patients. According to Kawamori et al., it is clear that intimal-medial thickening (IMT), i.e., an indicator of systemic arteriosclerosis, has been increased even in the pre-stage of DM . As methods of assessing arteriosclerosis in the coronary artery, various techniques, such as quantitative coronary arteriography, intravascular ultrasonography, multi-slice CT, MRI, etc., have been developed. It is impossible to widely use these techniques because of some problems with invasion to patients, exposure to radiation and magnetism, etc. and of procedural complexity of measurement. The assessment of IMT by cervical arterial echography or the evaluation of baPWV by measurements of pulse waves at the wrist and ankle yields no invasion to patients. These techniques are methods of assessing arteriosclerosis, which rarely allow physical load to patients. Even for general clinics, these techniques are the less invasive methods for assessment, which are simple to maneuver. IMT and baPWV were applied as indicators in this study, and the influence of antihypertensive therapy on progression of arteriosclerosis was also evaluated.The ADVANCED-J study is a prospective clinical study that is designed to compare the increase in dose of A II antagonist and the combined use of a Ca blocker, amlodipine, in terms of the efficacy for blood pressure control in DM+HT patients whose blood pressure levels are inadequately controlled by the single treatment with an A II antagonist. This study is different from the usual previous studies in that home blood pressures are assessed as indicators of evaluation of blood pressure.The ADVANCED-J study may have much influence on selection of antihypertensive drugs for treatment in HT patients with DM. It is expected to give an important hint for considering the validity of selection of antihypertensive drugs from the aspects not only of the antihypertensive effect but medical cost-effectiveness.The author(s) declare that they have no competing interests.RK and HD functioned as the general control physicians. JK drafted the statistical analysis plan. YI contributed to set out standard blood pressure levels. TY took the initiative in designing study protocol. YT, KM, AK, DH and SI also participated cooperatively to design study protocol. All authors read and approved the final manuscript.Ryuzo Kawamori; Hiroyuki Daida; Yasushi Tanaka; Katsumi Miyauchi; Akira Kitagawa; Dobun Hayashi; Junji Kishimoto; Shunya Ikeda; Yutaka Imai; Tsutomu Yamazaki for ADVANCED-J Study GroupControl physician: Ryuzo Kawamori; Hiroyuki Daida(Department of Cardiovascular Medicine); Responsible physician: Hirotaka Watada; Katsumi Miyauchi(Department of Cardiovascular Medicine); Participating physician: Takahisa Hirose; Hiromasa Suzuki(Department of Cardiovascular Medicine); Takeshi Kurata(Department of Cardiovascular Medicine); Tetsuro Miyazaki(Department of Cardiovascular Medicine); IMT in charge: Emi Miyazawa; Noriko Iijima; CRC: Atsuko Shiratori; Takagi Hospital: Responsible physician: Yasukazu Sato; Participating physician: Chiyoko Endo; Kaoru Tanaka; Keiki Yoshida; Kimihiro Nakahara; Kyosuke Yamamoto; Masahito Sakai; Masao Ohashi; Noriaki Matsumoto; Noriko Fukushima; Rieko Sakamoto; Satomi Fujimatsu; Yasuhiro Ono; CRC: Junko Matsuda; Kumiko Sasaoka; Noriko Takemata; Clerical work: Eisuke Mizokami; Hidenori Seki; International Hospital of Health and Welfare: Responsible physician: Fumio Murayama; Participating physician: Kenichi Oya ; Masao Hiwatari; CRC: Yasuko Otsuki; Clerical work: Kazuya Murakami; Kanazawa Medical Clinic: Participating physician: Shunichi Tanaka; CRC: Keiko Kikuchi; IUHW Atami Hospital: Responsible physician: Motoo Tsushima; Participating physician: Eiko Ikoma; Hisaichiro Tsukiyama; Izumi Kobayashi; Jin Oshikawa; Keiichi Shimoda; Kozo Okada; Ryu Sasaki; Takashi Orii; Tetsuya Fujikawa; Tomohiko Shigemasa; Yoshihiko Yamada; CRC: Asei Kaji; Junko Yamanaka; Takahiro Suzuki; Yoshiko Harakawa; Clerical work: Yoshiyuki Sato; Juntendo University Shizuoka Hospital: Responsible physician: Masahiko Kawasumi; Satoshi Kojima; Participating physician: Akihisa Nishino; Fuki Ikeda; Hidenori Yoshii; Masataka Niwa; Satoru Suwa; CRC: Atsushi Kobayashi; Takuya Uematsu; Yoshiaki Matsui; Juntendo University Urayasu Hospital: Responsible physician: Tatsuji Kanoh; Participating physician: Jong Bock Choi; Kenji Watanabe; Shigeru Matsuda; Takayuki Yokoyama; CRC: Miki Kubota; Shigeko Oyanagi; Sanno Hospital: Responsible physician: Kazuhide Yamaoki; Ikuo Yokoyama; Noriko Tajima; Wataru Hayashida; CRC: Chiyako Minamikawa; Sanno Medical Plaza: Participating physician: Atsurou Kishimoto; Tetsu Matsubara; Tomoko Yamazaki; Clerical work: Koichi Maeda; Kurata Clinic: Responsible physician: Takeshi Kurata; Nakakinen Clinic: Responsible physician: Takeshi Osonoi; Participating physician: Miyoko Saitou; Naoki Owada; Naoko Takayanagi; Shimada General Hospital: Responsible physician: Issei Shimada; Clerical work: Mika Wakaumi; Chiba Tokusyukai Hospital: Responsible physician: Michiko Abe; Participating physician: Miki Takagi; Takahisa Hirose; Koto Hospital: Responsible physician: Eiji Tamiya; IUHW Mita Hospital: Responsible physician: Kunio Ohyama; Participating physician: Atsuhisa Sato; Hideki Koh; Katsumasa Yui; Kunio Nakano; Yoshitaka Akiyama; CRC: Tomoko Shigeoka; National Hospital Organization Ureshino Medical Center: Responsible physician: Shiro Hata; Fukuoka Chuo Hospital: Responsible physician: Masao Ohashi; International Goodwill Hospital: Responsible physician : Akio Kanazawa; Participating physician: Yasuhiro Amagasaki; Ochanomizuhijiribashi Clinic: Responsible physician: Koshiro Monzen; The University of Tokyo Hospital: Responsible physician: Tsutomu Yamazaki; Participating physician: Dobun Hayashi; Koshiro Monzen; Ryozo Nagai; Takahide Kohro; Yasushi Imai; Arisaka Clinic: Responsible physician: Tomoyuki Arisaka; Hatori Medical Clinic: Responsible physician: Hiroshi Hatori; Hattori Clinic: Responsible physician: Akira Hattori; Hayashi Medical Clinic: Responsible physician: Yoshitaka Hayashi; Iwase Clinic of Cardiology and internal medicine:Responsible physician: Takashi Iwase; Junseikai Hospital: Participating physician: Kohji Komiya; Tomoaki Yoshihara; Yoshifumi Tamura; Kitanarashino Hanawa Hospital: Responsible physician: Mikio Tanaka; Matsumoto Clinic: Responsible physician: Yoshihisa Matsumoto; Mizuma Kouhoukai Hospital: Responsible physician: Masayasu Higashijima; CRC: Noriko Takemata; Clerical work: Hideki Nogami; Masayuki Matsufuji; Clinical Trial Management, Graduate School, International University of Health and Welfare: CRC: Ayako Nakahara; Kaoru Hatanaka; Mika Nozawa; Taka Ikarashi; Clerical work: Hideka Ishii; Kazuo Takeshita; Mari Kanno; Masami YoshidaJuntendo University School of Medicine: Metabolism and Endocrinology, Department of Medicine, Juntendo University School of Medicine; Department of Cardiovascular Medicine Juntendo University School of Medicine; Juntendo University Urayasu Hospital; Juntendo University Shizuoka Hospital; Chiba Tokusyukai Hospital; Junseikai Hospital; Sanno Hospital; Sanno Medical Plaza; Takagi Hospital; Mizuma Kouhoukai Hospital; IUHW Atami Hospital; International Hospital of Health and Welfare; Iwase Clinic of Cardiology and Internal Medicine; Ochanomizu Hijiribashi Clinic; The University of Tokyo Hospital; Nakakinen Clinic; Shimada General Hospital; Koto Hospital; Hatori Medical Clinic; Kurata Clinic; Matsumoto Clinic; Kitanarashino Hanawa Hospital; Hayashi Medical Clinic; Arisaka Clinic; International Goodwill Hospital; IUHW Mita Hospital; Kanazawa Medical Clinic; Hattori Clinic; Fukuoka Chuo Hospital; National Hospital Organization Ureshino Medical CenterThe pre-publication history for this paper can be accessed here:


In the present study, we seek to determine whether Ado can increase circulating levels of VEGF protein in the intact human.Many -1 min-1) in conjunction with sestamibi myocardial perfusion scans. Mean blood pressure  and heart rate (HR) were determined before Ado infusion and every 2 min for the next 10 min. Plasma VEGF concentrations (ELISA) were determined immediately before Ado infusion and 1 h, 2 h, and 8 h after the infusion.Five outpatients 49.3 ± 6.7 years of age and weighing 88.2 ± 8.5 kg were selected. They were given a 6 min intravenous infusion of Ado . VEGF plasma concentration returned to basal levels 2 h after infusion (23.3 ± 3.4 pg ml-1). MBP averaged 116 ± 7 mmHg and heart rate averaged 70 ± 7 prior to Ado infusion. MBP decreased by a maximum of ~22% and HR increased by a maximum of ~17% during the infusion.Plasma VEGF concentration averaged 20.3 ± 2.0 pg mlWe conclude from these preliminary findings that intravenous infusion of adenosine can increase plasma levels of VEGF in humans. The adenosine released under these conditions is thought to play an important role in reestablishing a balance between oxygen supply and demand  by virtue of its potent vasodilatory  and anti-adrenergic effects .It is well-established that adenosine is an important physiological regulator for maintaining oxygen homeostasis in the heart . Adenosine formation increases when the oxygen requirements of the myocardium exceed the oxygen supply, which leads to an increase in adenosine levels in the tissues . Adenosine can stimulate endothelial proliferation in vitro  as well as angioge nesis in a variety of in vivo models . Although the angiogenic effects of adenosine are poorly understood, it is known that adenosine, mediated by way of adenosine A2 receptors can upregulate VEGF mRNA and protein expression in many different cell types . Numerous investigators have postulated that this adenosine-mediated expression of VEGF might have a role in mediating adenosine-induced angiogenesis ; however, it is still not clear whether adenosine can induce VEGF expression in the intact organism.Mounting evidence suggests that adenosine may also have a long-term role to increase tissue oxygenation by stimulating angiogenesis  caused the plasma levels of VEGF protein to increase (P1–P5) one hour after the infusion  to a 329% increase , as shown in Figure -1 before the infusion, and increased to an average of 62.7 ± 18.1 pg ml-1 (p < 0.05) one hour after the infusion. VEGF protein levels returned to control values by 2 h after the Ado infusion (23.3 ± 3.4 pg ml-1) and remained at control levels at 8 h post- infusion (24.3 ± 7.0 pg ml-1), as shown in Figure The intravenous infusion of Ado  to a 59 mmHg decrease in P5 . This maximum decrease in MBP occurred after 2 minutes of Ado infusion in two subjects  and after 6 min of infusion in three subjects . Note on Figure The infusion of Ado caused MBP to decrease in most of the subjects Figure , rangingThe decrease in MBP was associated with decreases in both systolic (SBP) and diastolic (DBP) pressures Table . Note alet al. 1994; Fischer et al. 1995; Takagi et al. 1996; Pueyo et al. 1998; Grant et al. 1999; Gu et al. 1999; Grant et al. 2001; Leibovich et al. 2002; Gardener & Olah, 2003; Feoktistov et al. 2003) or upregulation of endogenous adenosine  can enhance VEGF protein and/or mRNA expression in a variety of cultured cells . However, the present study is the first, to our knowledge, that demonstrates that the infusion of adenosine can increase circulating levels of VEGF in vivo.The results have shown that adenosine can increase plasma levels of VEGF protein in humans. The intravenous infusion of adenosine caused a three-fold increase in plasma VEGF protein levels one hour after the infusion Figure . Previou1 and A2 (subtypes A2A and A2B) receptors . Responses to activation of the A1 receptor include slowing of the heart and slowing of impulse conduction through the atrioventricular node, reduction of atrial contractility, inhibition of beta-adrenergic effects, and vasodilatation . Activation of A2 receptors causes (a) vascular smooth muscle relaxation , which can lead to decreases in blood pressure, and (b) induction of VEGF expression from a variety of cell types . Recent development of selective agonists and antagonists for A2 receptor subtypes suggests that vasodilatation is mediated by A2A  and perhaps A2B receptors . The A2B receptor subtype appears to mediate the induction of VEGF protein and mRNA in various human cell types. Grant et al. (1999) have shown that activation of the adenosine A2B receptor (but not the A2A receptor) can increase VEGF mRNA and protein expression in cultured human retinal endothelial cells. Feoktistov et al. (2003) established that adenosine acting by way of the A2B receptor can stimulate VEGF expression in human mast cells. These latter investigators  also showed that adenosine can induce VEGF expression in human microvascular endothelial cells, where A2B receptors are abundant, but not in human umbilical vein endothelial cells, which preferentially express A2A receptors. Therefore, the available data suggest that adenosine induced vasodilatation and VEGF expression could be mediated to some extent by similar receptors.The known cardiovascular effects of adenosine are mediated by the Aet al. (1996) found a fourfold increase in VEGF mRNA at the termination of a one hour bout of treadmill exercise in rats. Gu and Adair (1997) showed that exposing dog myocardial vascular smooth muscle cells to a hypoxic environment caused a twofold increase in VEGF protein concentration in the media after only one hour of exposure to the hypoxic environment. Therefore, it is conceivable that adenosine could induce VEGF transcription and translation resulting in elevated plasma levels of VEGF at one hour post infusion. However, additional studies will be required to determine whether the increase in circulating VEGF caused by adenosine did in fact result from adenosine-induced production of VEGF.It is not clear from the present study whether the infusion of adenosine actually induced the transcription and translation of VEGF ; however, it is known that both VEGF mRNA and protein can be induced within a one hour period of time. Breen in vitro and in vivo . However, it seems unlikely that this indirect induction of VEGF by adenosine could explain entirely the results of the present study for the following reasons: (a) adenosine can induce VEGF mRNA and protein expression in vitro where blood pressure is not an issue, as discussed previously; (b) adenosine increased the plasma levels of VEGF in two patients in whom the blood pressure had decreased by less than 15 mmHg, a decrease that should not cause significant perfusion problems or hypoxia in the tissues; (c) mean blood pressure did not fall below 69 mmHg in any of the subjects; and (d) none of the subjects experienced symptoms suggestive of cerebral hypoxia during the infusion of adenosine. All subjects were supine during the infusion of adenosine to minimize potential perfusion problems. Furthermore, adenosine induced vasodilatation would be expected to improve the distribution of oxygen within a tissue, also arguing against tissue hypoxia. Therefore, it is unlikely that the adenosine induced decrease in blood pressure contributed significantly to the rise in VEGF.A possibility that must be considered is that the transient decrease in blood pressure caused by adenosine leads to transient hypoxia in the tissues, and that the hypoxia, in turn, leads to the induction of VEGF expression. Hypoxia is a well-known stimulus for the induction of VEGF expression both In conclusion, this study provides preliminary data showing that an intravenous infusion of adenosine can increase plasma levels of VEGF in humans. Additional studies will be required to determine whether the increase in plasma VEGF caused by adenosine results from the transcription and translation of VEGF.4) was paced at 66 beats per minute. Also, one individual (P3) had a history of multiple myeloma and was being evaluated for kidney transplantation.The study protocol was approved by the University of Mississippi Medical Center Internal Review Board. The subjects underwent routine sestamibi myocardial perfusion scans because of suspected coronary artery disease. They consisted of one man and four women; mean age was 49.3 ± 6.7 years and mean weight was 88.2 ± 8.5 kg. None of the subjects had taken caffeine prior to the test, had a history of asthma or myocardial infarction, or were being treated with blood pressure medications. Their mean blood pressure  prior to testing was 116 ± 7 mmHg . MBP was calculated as the diastolic pressure plus one third of the pulse pressure. Mean heart rate was 70 ± 3 beats per minute; one patient  was infused intravenously at 0.14 mg kg-1 min-1 for six minutes . MBP was measured before the adenosine infusion and then every two minutes for the next ten minutes. Technetium-99 (sestamibi) was administered three minutes into the adenosine infusion and a nuclear scan was performed. The infusion of Ado was well tolerated by all subjects. There were no significant ECG abnormalities during the test and no myocardial perfusion abnormalities were found. None of the subjects were diagnosed with cardiovascular disease. Three mL of blood were collected in EDTA coated tubes before the adenosine infusion and at 1, 2, and 8 h after the adenosine infusion. The blood samples were centrifuged at 700 g for 5 minutes at 4°C, and plasma was stored at -80°C.Adenosine (Adenoscan-1) were calculated using an equation generated from the regression analysis of standard VEGF concentrations.Plasma levels of VEGF were measured in duplicate by sandwich ELISA . In these assays, the test sample is sandwiched between a monoclonal antibody against human recombinant VEGF. A second polyclonal antibody against VEGF is conjugated to horseradish peroxidase and then added to the mixture. Color develops by addition of hydrogen peroxide and chromagen tetramethylbenzidine, and the intensity is measured at 450 nm. VEGF plasma protein levels (pg mlThe results are expressed as means ± standard errors of the mean (S.E.M.). Differences between the groups  were compared using analysis of variance for repeated measurements and Dunnett's multiple comparison test .Ado, adenosineVEGF, vascular endothelial growth factorHR, heart rateMBP, mean blood pressureSBP, systolic blood pressureDBP, diastolic blood pressureThomas H. Adair, Jean-Pierre Montani, and Reid Cotten designed the study. Reid Cotten, Kenneth R. Bennett, and Michael R. McMullan performed the myocardial perfusion scans and collected the blood samples. Thomas H. Adair, Jian-Wei Gu, Janelle S. Pryor, and Preston B. McDonnell performed the various analyses. All authors contributed to writing the manuscript.


Possible mechanisms behind psychophysiological hyperreactivity may be located at a cognitive-emotional level. Several personality traits have been associated with increased cardiovascular reactivity. Subjects with white coat hypertension, which may constitute a kind of hyperreactivity, are found to suppress their emotions and adapt to the surroundings to a larger extent than controls.We hypothesized in this study that a) stress reactivity is related to personality, and that b) responses to cold pressor test (CPT) and mental stress test (MST) are associated with different personality traits.st, 50th and 99th percentile of a blood pressure screening. Cardiovascular and catecholamine responses to MST and CPT were recorded. Fifteen personality traits were assessed using the Karolinska Scale of Personality. Possible independent explanatory predictors for cardiovascular and catecholamine variables at baseline and during stress were analyzed in multiple linear regression analyses using a stepwise forward procedure.87 men were selected from the 1Multiple regression analyses showed that muscular tension , irritability , detachment , psychasthenia  and somatic anxiety  were significant explanatory variables of reactivity to CPT. During MST, verbal aggression  and detachment  were significant predictors of norepinephrine and diastolic blood pressure response, respectively.th quartile, while Δ norepinephrine was significantly related to muscular tension (p = 0.033). Δ systolic and Δ diastolic blood pressure responses to CPT were dependent on detachment  and psychasthenia (p = 0.020 and p = 0.015), while high verbal aggression was associated with lower reactivity measured by Δ norepinephrine (p = 0.037).Based on KSP-trait quartiles, delta (Δ) systolic (p = 0.025) and Δ diastolic blood pressure (p = 0.003) during MST were related to detachment score, with the highest reactivity in the 4The present study indicates that stress reactivity is clearly related to different personality traits, without any single trait being dominant over others. Furthermore, personality seems to have as much, or even more, importance of predicting responses to CPT than responses to MST. We have previously demonstrated that blood pressure level at a military draft screening in healthy, young men reflects blood pressure, heart rate and arterial catecholamine reactivity to a mental arithmetic stress test (MST) . This diThe first is the cognitive-emotional level. The cortex and the limbic system  are responsible for temperament and personality, and several personality traits have been associated with increased cardiovascular reactivity ,4. WhiteA second possibility is at the subcortical level. The translation of emotional reactions into autonomic or endocrine outputs in the hypothalamus and brain stem is complex, and has received much attention. One of the areas of interest is the dorsomedial hypothalamus, which plays a key role in integrating acute psychological stress into cardiovascular responses. Stimulation of this center elicits cardiovascular responses similar to the fight-or-flight reactions . Even moIncreased cardiovascular reactivity could also be an indicator of alterations in the peripheral tissue, like vascular wall thickening or altered receptor sensitivity. An otherwise normal central activation would lead to abnormal cardiovascular responses.In our previous study , we founAll 19-year-old men in Norway have to attend a medical examination for the military draft procedure. The draft procedure usually takes a whole day and includes a psychological test, a test of physical strength and endurance, and a medical examination. Blood pressure measurements after 5 minutes sitting by means of an automatic auscultatory device were collected from all 19-year-old men attending in Oslo (N = 4137) during one year. Mean blood pressure was calculated as diastolic blood pressure + pulse pressure/3. The physicians were carefully instructed not to inform the subjects of the blood pressure reading. Therefore, they all got their final military physical fitness score and medical evaluation independent of the blood pressure recording. Rostrup et al have previously showed that awareness of hypertension induce higher detachment and lower impulsiveness, monotony avoidance, verbal aggression and irritability compared to unaware [We selected a total of 87 subjects from the screening, based on their mean blood pressure. 30 subjects belonged to the 1st percentile (70 ± 1 mmHg (mean ± SEM), Gr. 1), 30 to the 50th percentile  and 27 to the 99th percentile of mean blood pressure . There was an overrepresentation of hypo- and hypertensives, as regression to the mean may lead to insufficient dispersion in the laboratory. All were previously healthy without any history of diabetes, renal disease, elevated blood pressure or other cardiovascular disease. They had a normal physical examination and normal electrocardiogram, routine blood tests and urinalysis. None was on medical treatment or abused drugs or alcohol.The study was approved by the local Ethics Committee, and informed consent was obtained from each subject selected from the screening. All subjects were examined by the same physician and only one subject each day. The physician was unaware to which group the subjects belonged. The examination started 08:00 a.m. following an 8-hour fast and at least 8-hour abstaining from nicotine and caffeine, and 24 hours abstaining from alcohol. Heart rate andblood pressure were recorded after 15 minutes at rest insitting position, by the same automatic auscultatory device as used atscreening.®, 19G, Viggo AB, Hälsingborg, Sweden) was introduced under local anaesthesia without epinephrine  into the left brachial artery for blood sampling and intraarterial pressure monitoring as previously described [A short teflon catheter  for one minute. Thereafter, the subjects rested for 30 minutes before MST was announced. The subjects were asked to mentally subtract the number "13" repetitively for 5 minutes starting with "1079". A metronome making noise at a frequency of 2 Hz was used to distract the subjects. They were informed about any miscalculation. The other half did the tests in the opposite sequence.Arterial blood for catecholamine assay was collected into polypropylene syringes after 30 minutes of supine rest, after 1/2 and 1 minutes of CPT, after 1, 3 and 5 minutes of MST, and after 5, 15 and 30 minutes of each recovery period.Blood samples were immediately mixed with glutathione and EGTA, placed on ice, centrifuged at 4°C and the plasma frozen at -70°C until measurements of the catecholamines within a few weeks. A technician helped with blood sampling during the MST, and left the room thereafter. In all other parts of the study the subject and the physician were left alone.Blood was drawn in 10 mL glass tubes containing glutathione and EGTA, and plasma catecholamines were measured by a radioenzymatic technique according to Peuler and Johnsen  as previTo assess the different personality traits, we used the Karolinska Scale of Personality (KSP). KSP is a questionnaire comprising 135 questions, where each question is presented as a statement with a four-point response format ranging from 'does not apply at all' (= 1) to 'applies completely' (= 4). The items are grouped into 15 scales, and the values are summarized for each personality trait: Somatic anxiety (bodily signs of heightened anxiety such as restlessness and tachycardia), muscular tension , psychic anxiety (worrying and low self-confidence), psychasthenia , inhibition of aggression (low assertiveness), impulsivity (tendency to act on impulse), monotony avoidance (experience-seeking behavior), detachment (no need for close relationships), socialization (relation with the respondent and his/her parents and other significant others during childhood), social desirability , indirect aggression (e.g. slamming doors), irritability , verbal aggression , suspicion , and guilt (feeling of remorse and shame) . A longiThe data were analyzed using the statistical package SPSS version 12.0 for Windows . Parametric tests were used for normally distributed data and non-parametric when normality was not achieved by natural log transformation.We analyzed possible independent explanatory predictors for cardiovascular and catecholamine variables at baseline and during stress in multiple linear regression analyses using a stepwise forward procedure. The independent variables were included in the model if p ≤ 0.2 in univariate analysis, and the dependent variables were not allowed to have inter-correlations with an r > 0.7. To create more separation between groups with different KSP scores, the subjects were divided into quartiles based on the score of the 15 KSP traits, with subsequent Chi-Square testing using linear-by-linear association to detect any relations with cardiovascular or catecholamine variables during rest and stress.As a measurement of cardiovascular and catecholamine responses during stress, we used percentage change from baseline to mean stress. Data are presented as mean ± standard error of mean unless indicated otherwise, and null hypotheses were rejected if two-tailed p < 0.05.Baseline characteristics are given in Table When we divided the subjects into quartiles based on the KSP score, suspicion was the only personality trait that showed a significant association with systolic (p = 0.036) and diastolic blood pressure (p = 0.026) figure  and noreMean cardiovascular and catecholamine responses during stress tests are shown in table th quartile  systolic (p = 0.025) and Δ diastolic blood pressure (p = 0.003) during MST were related to detachment score, with the highest reactivity in the 4e Figure , while Δe Figure , while sThe purpose of the present study was to examine whether responses to MST and CPT are influenced by personality, and identify possible personality traits related to increased reactivity. Our findings indicate that personality is related to cardiovascular and catecholamine levels both at rest and during stress. When the subjects were divided into quartiles based on the various personality scores, only suspicion was associated with resting values. There was no single personality trait that explained most of the stress response. However, detachment was related to both MST and CPT responses. Reactivity during MST was related to the level of detachment and muscular tension, while responses to CPT were influenced by detachment, psychasthenia and verbal aggression.Blood pressure and catecholamine levels at rest and during stress tests represent two different kinds of physiological states. One may consider blood pressure as having two components – a basal or tonic level, and phasic fluctuations around this . ReactivCardiovascular reactivity has been associated with a new personality construct, the type D or distressed personality . Type D Detachment was the only trait that was related to both MST and CPT reactivity. This trait is characterized by a need to remain distant, and a fear of closeness, and it is regarded as the opposite of attachment in the closeness-separateness dimension . Social Inhibition of emotions has been associated with higher cardiovascular reactivity , lower cWe had prior to the study expected that the psychological test MST would be more influenced by personality than the physical test CPT. However, CPT is not a pure physical test, and may involve other psychological elements like pain, expectations, fear, motivation and irritability. These factors may explain why many personality traits turned out to be important predictors of CPT reactivity.The fact that we found increasing resting blood pressure with increasing suspicion score makes sense. The subjects did not know what to expect from the coming examination, and a high level of suspicion may have influenced the blood pressure due to a lack of control in the laboratory setting. Borderline hypertensives have been described as being more hostile and suspicious . Others In the current study, suspicion did not turn out to be an explanatory variable for stress reactivity, unlike in the resting condition, indicating that different personality traits may have different impact of cardiovascular regulation at rest and during stress. This is further supported by the fact that irritability was negatively related to resting heart rate and positively related to heart rate during stress.The multiple regression analyses demonstrated that the various reactivity variables (BP and catecholamines) were negatively predicted by their baseline variables. This finding may seem unlikely, but is believed to be a statistical phenomenon, where a higher baseline value involves a lower potential to increase during stress.Our results should be interpreted cautiously. In a cross sectional study it is impossible to state whether personality influences stress reactivity or the opposite. A statistical relation does not mean that there is a causal relationship. Although the KSP covers a wide range of personalities, one may question whether the questionnaire comprises the traits that are important in a fight-or-flight situation. As the KSP constitutes 15 variables, and we take several blood pressure and catecholamine measurements during the session, multiple correlation analyzes may give us some false positive results. The statistical power to detect differences was limited because of the relatively small number of subjects. Despite these limitations, the findings were consistent. Confounding factors were eliminated to a minimum in our study, as all subjects were Caucasian men at the same age with no medication and similar body mass index. The population in Oslo, as in Norway in general, is stable, thus is genetically homogenous. Arterial catecholamines assessed in the study is a better estimate of overall sympathetic activation compared to venous . All theThe present study demonstrates how certain personalities may be a threat against health and well-being, as exaggerated cardiovascular responses to stressful situations are well known predictors of future morbidity and mortality . Our finThe author(s) declare that they have no competing interests.AF carried out the statistical analyses and drafted the manuscript. ØE participated in the design of the study, helped with statistical analyses. SEK helped to draft the manuscript. MR conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.


In an elderly, community based population we aimed at investigating antihypertensive and lipid lowering medication use in relation to own and familiar cardiovascular morbidity and diabetes mellitus, as well as to lifestyle factors and general health. We also examined levels of blood pressure in untreated and treated residents, to investigate factors correlating with blood pressure control.A health survey carried out in 1997-9 in the county of Hordaland, Norway included a self-administered questionnaire mailed to 4 338 persons born in 1925-7. Drug use the day prior to filling in the questionnaire was reported. A health check-up was carried out, where their systolic and diastolic blood pressure (SBP and DBP), body mass index (BMI), and serum-cholesterol level were recorded.One third of respondents used one or more antihypertensive drugs, while 13% of men and women were treated with a statin. Diabetes mellitus, own or relatives'cardiovascular disease, having quit smoking, physical inactivity, and overweight correlated with antihypertensive treatment. Mean blood pressure was lower in respondents not on treatment. Among those on treatment, 38% of men and 29% of women had reached a target BP-level of lower than 140/90 mm Hg. Own cardiovascular disease and a low BMI correlated with good BP-control.One third of 70–74 year old individuals living in the community used one or more antihypertensive drugs. Only around one third of those treated had reached a target BP-level of less than 140/90 mm Hg. Own cardiovascular disease and a low BMI correlated with good BP-control. During the past decades, an increasing body of evidence has emerged on the importance of blood pressure as a risk factor for cardiovascular disease also in elderly people. Current European and US guidelines reinforce that doctors should not focus solely on hypertension, but include blood lipids and lifestyle factors in a multi-factorial risk assessment ,2. SinceMost pharmacological interventions for modifying cardiovascular risk factors take place in general practice. However, two conflicting concerns have emerged. The first, often expressed by general practitioners (GPs), is that the cut-off points are now so low that only a minority of elderly persons will be regarded as "normal" or "healthy" without a need for drug treatment . The secThe aim of this study was first, to analyze the level of elderly peoples' use of antihypertensive and lipid lowering drugs in relation to own and relatives' cardiovascular disease and diabetes mellitus, own lifestyle factors, BMI and general health status. The second aim was to investigate present BP in elderly people with or without treatment, and factors correlating with good BP-control.In 1997-9 a population based health survey was carried out in Hordaland County in western Norway : The Hordaland Health Survey (HUSK) . In totaA questionnaire was mailed to the invited persons, along with an invitation to a health check-up. The questionnaire included the following questions regarding drug consumption: Did you take any drugs yesterday? (yes/no). If yes: report the name of the drug, the reason for taking it, and whether you usually take this drug every day (yes/no). The questionnaire provided space for reporting up to nine different drugs, and participants were asked to continue on a separate sheet if needed. The questionnaire also addressed physical exercise, smoking, alcohol use, general health, and depressive symptoms, duration of formal education, previous or present diabetes mellitus and cardio- and cerebrovascular disease (including family history). Some variables were dichotomized during data analysis  and diastolic blood pressure (DBP), (average of the last two out of three recordings), as well as height and weight for calculating body mass index (BMI) were recorded. Blood samples were drawn for analyzing (among others) serum cholesterol.The drugs reported to be used were subsequently coded according to the 1996- version of the Anatomical Therapeutic Chemical (ATC) classification system [Reported reasons for drug use were coded based on a modified list of diagnoses according to the International Classification for Primary Care (ICPC) .The study was approved by the Regional Committee for Medical Research Ethics and the Norwegian Data Inspectorate.Statistical analyses were performed using SPSS version 11. Bivariate comparisons were performed using chi-square test or independent samples t-test. Level of statistical significance was set at 5% (p < 0.05).Out of the 4 438 elderly persons invited, 3 341 (77%) responded by filling in the questionnaire and attending the health check-up. They comprise the material for this study. 1 301 persons  reported daily use of antihypertensives or statins. Mean number of these drugs per user was 1.62. Among the 445 statin users, 286 (64%) were also on antihypertensive treatment. Out of the 518 men (35%) and 626 women (33%) using antihypertensives, 51% reported "elevated blood pressure" as indication for use, 20% reported "cardiac problems," and 29% reported some other indications or gave no explicit reason for use.The distribution of the antihypertensives according to ATC-groups was: anti-adrenergic agents: 95, diuretics: 233, beta blocking agents: 515, calcium channel blockers: 390, and agents affecting the renin-angiotensin system: 439.Among persons who had suffered myocardial infarction, 70% of men and 82% of women were on antihypertensive drug treatment. For cerebral stroke, corresponding figures were 63% (men) and 47% (women), and for angina pectoris 67% (men) and 74% (women). Among men with diabetes mellitus, 58% were on antihypertensive treatment while this applied to 57% in women.2. Formal education < 12 years, feeling depressed (women), and a less than good self-reported health all correlated positively to treatment.Cardiovascular morbidity in close relatives  was strongly correlated with antihypertensive drug use Table . Among pIn the population on antihypertensive treatment, 23% reported angina pectoris, 21% myocardial infarction, 11% diabetes mellitus, and 7% apoplexia.Statins were used by 195 men 13%) and 244 women (13%) (Table % and 244SBP was significantly higher in persons on antihypertensive treatment compared to persons not on BP-lowering medications Table . DBP wasThe high response rate (77%) contributes to strengthen the external validity of the findings. Furthermore, we consider data quality to be good, as drug names generally were correctly written and only few questionnaires had to be rejected because of inconsistencies.the previous day  probably minimized recall bias [However, some limitations have to be considered. First, people with a poor health, low socioeconomic status and an unhealthy lifestyle are generally known to be over-represented among non-respondents in health surveys , and unpall bias . Asking all bias ,14. Thisall bias , which sWe chose to include all use of drugs with ATC-codes C02, C03, C07, C08, or C09 in the analyses and to label them as "antihypertensive drugs", although some patients obviously used e.g. diuretics or beta-blockers for other cardiovascular reasons. Out of all users of the listed ATC-drugs, as many as 29% reported no explicit diagnostic reason for taking them, and some gave very unspecific or obviously wrong indications. In addition, as many as 63 persons reported "elevated BP" for use of drugs not relevant for antihypertensive treatment. Our figures here correspond well with results in a comprehensive British interview study among people aged 65 +, where 24% did not know the reason for taking their medications . We therIn Western countries, elderly people are the major drug consumers and the average number of daily drugs used per person is increasing ,16-19. IThere were no significant differences between the two genders' total use of BP- and cholesterol lowering drugs, whereas a low formal education correlated with more use. This is also reported by others ,22 and pNot surprisingly, performing no regular exercise or reporting a less than good general health were also associated with more use of BP- and cholesterol lowering drugs, corresponding to the results of others . It may Use of alcohol every second day or more often did not correlate with antihypertensive treatment. Underreporting of actual drinking may have occurred, but contrary to smoking, regular, moderate alcohol consumption seems to be associated with less cardiovascular morbidity and mortality . In an AIn the medical community, a tension exists between avoiding excessive use of medications for the elderly and to provide access to therapies that have beneficial effects on mortality, morbidity, functioning and quality of life ,29. ThisOn the other hand: Our finding that less than 40% of those already on BP-lowering drugs had actually reached the recommended BP levels, indicates substantial potentials for improving their treatment. This finding, which is in line with others, indicate that a large proportion of treated patients still have inadequate control of their BP. In particular, being overweight correlated with a poor BP-control ,31. CorrAround one third of 70–74 year old men and women living in the community used one or more antihypertensive drugs, and 13% of men and women used a statin. Diabetes mellitus, own or relatives' cardiovascular disease, being physically inactive, overweight, and being an ex-smoker correlated with antihypertensive treatment.Among those on drug treatment, less than 40% of men and 30% of women had reached the recommended target values for blood pressure (below 140/90 mmHg), and being overweight correlated with poor BP control.The author(s) declare that they have no competing interests.JS and SH planned the study and carried out the data collection. MB carried out the analyses and drafted the paper. JS and SH participated in the discussion and in the writing of the article.All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Autonomic disturbances in tetanus are traditionally associated with adrenergic variations and/or cardiac dysfunction, based on case report data. The objective of this study was to measure catecholamines, (TNF)-α and troponin T relative to and left ventricular ejection fraction (LVEF) in patients with severe tetanus.This prospective study was carried out at two general Intensive Care Units and included 21 patients consecutively admitted with severe tetanus. Catecholamines , tumor necrosis factor (TNF)-α and LVEF were assessed during the first week of autonomic instability and following tetanus recovery. Troponin T was measured during autonomic instability only.Mean age of patients was 46 ± 17 years, median Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 8 (range 1–23). All patients had both blood pressure and heart rate instability. Two patients were recuperated from cardiac arrest. Intensive Care Unit mortality was 14% (3 cases). No increase in total catecholamines or in TNF-α levels was observed during autonomic instability or in the recovery period. Six patients had troponin T >0.01 ng/ml and six had >0.1 ng/ml. Mean LVEF was similar during autonomic instability and after tetanus recovery, 67 ± 7% and 65 ± 7%, respectively. Troponin T levels correlated with pressoric instability during autonomic instability.Our study demonstrated that in patients with severe tetanus no significant increased levels of catecholamines or TNF-α or evidence of cardiac systolic dysfunction was observed either during autonomic instability or in the recovery period. Elevated values of troponin T detected during autonomic instability were not associated with left ventricular dysfunction. Our data do not support the hypothesis that autonomic disturbances in tetanus are associated with adrenergic variations or cardiac dysfunction. Autonomic dysfunction, sudden death and complications of prolonged critical disease, such as nosocomial infections, thromboembolism and gastrointestinal bleeding are main causes of death in tetanus . In a prAutonomic instability as defined by Kerr et al., is a characteristic syndrome whose features include sustained but labile hypertension and tachycardia, irregularities of cardiac rhythm, peripheral vascular constriction, profuse sweating, pyrexia, increased carbon dioxide output, increased urinary catecholamine excretion, and, in some cases, the development of hypotension . Severe Prolonged stimulation of the sympathetic nervous system or the continuous release of catecholamines may cause vascular and myocardial damage ,10. HoweThe objective of the present study was to evaluate the temporal behavior of catecholamines and of TNF-α relative to left ventricular ejection fraction obtained by two-dimensional transthoracic echocardiography at two time points: during autonomic instability and after recovery from tetanus. Levels of the troponin T were used to identify potential myocardial damage in the period of autonomic instability. In this report our data failed to indicate associations between adrenergic and cytokine activation with changes in cardiac performance in patients with tetanus.This cohort study included all patients with a diagnosis of severe tetanus characterized by marked rigidity, frequent generalized spasms, dysphagia, respiratory compromise or apnea according to the modified Abblett's scale, ,18 conseThe main variables of the study were: plasma catecholamines, TNF-α, troponin T levels and transthoracic echocardiographic-based LVEF. These variables were assessed both during the autonomic instability and after recovery from tetanus, with the exception of troponin T, only measured during autonomic instability. The following variables were also recorded: age, sex, APACHE II score in the first 24 hrs of ICU admission, temporal development of symptoms, periods of the disease , clinical characteristics, clinical and infectious complications and electrocardiogram (EKG).Autonomic instability was characterized by the presence of blood pressure and heart rate lability, arrhythmias and/or cardio respiratory arrest recorded by continuous noninvasive monitoring , as reported previously . VariatiAt the end of the first week of autonomic instability and after recovery from tetanus, 10 ml blood sample was collected into an EDTA-containing tube and kept under refrigeration. Samples were immediately centrifuged at 5°C, plasma was placed in 1.5 ml Eppendorf tubes and stored at -80°C for later measurement of plasma catecholamines and TNF-α levels. Catecholamine levels  were measured at CRIESP laboratory  using high performance liquid chromatography (HPLC). Commercially available Elisa assays were used to measure TNF-α plasma levels using duplicate samples to minimize inter-assay variability. Lower detection limits of the assay were typically less than 4.4 pg/ml .During autonomic instability, blood samples collected were also used for measurement of plasma troponin T levels using a sandwich electrochemiluminescence immunoassay (ECLIA), Elecsys Troponin T STAT . Detection band ranges from 0.01 ng/ml to 25 ng/ml in this assay. In 99% of healthy volunteers, the cutoff point was lower than 0.01 ng/ml, and the cutoff point for myocardial infarction was 0.1 ng/ml -21.Two-dimensional color Doppler transthoracic echocardiography was performed at the two collection time points (autonomic instability and after recovery period) to measure LVEF by the M-mode (Teicholtz method), in accordance to the recommendations of the American Society of Echocardiography. Whenever possible, hemodynamic status of patients were kept at the best possible care according to the ICU protocols in order to avoid confounding load variables interfering with ejection fraction measurements. Simultaneously to echocardiogram, blood pressure and heart rate were recorded as well as blood sampling to measure biological variables. Additional echocardiography-based cardiac findings were also recorded. Data were recorded and later re-evaluated by another blinded echocardiographist.t test was used to compare continuous and normally distributed variables; Mann Whitney test was used for asymmetric continuous variables, and the chi-square test for categorical variables. Paired samples t tests and Wilcoxon test were used to compare continuous variables during and after autonomic instability. Pearson and Spearman tests were used to evaluate correlation between variables. Significance level was established at p < 0.05 for all comparisons.Continuous variables are described as means and standard deviation or medians and range; categorical variables are described by frequency tables and proportions. Magnitude of variation from minimum to maximum values of variables (heart rate and blood pressure) were calculated and expressed as delta values. Discrimination between parametric and non-parametric variables was performed using histograms and the Kolmogorov-Smirnov test. Student We evaluated 21 patients with severe tetanus, 18 (84%) males, mean age 46 ± 17 years, with median APACHE II score of 8 (range – 1–23). Incubation period was 7.0 ± 4 days, onset period was 3 ± 3 days and symptomatic period was 40 ± 10 days. All patients were mechanically ventilated (mean 41 ± 12 days) and the length of stay in the ICU was 45 ± 13 days. ICU mortality rate was 14% (three patients), thus 18 patients underwent after recovery assessments. Seven patients had chronic obstructive pulmonary disease, six had history of alcohol abuse, three had hypertension, and three had history of coronary artery disease. Patients received diazepam (mean dose = 33.9 ± 8.0 mg/h), pancuronium (mean dose = 0.8 ± 0.08 mg/kg/h) and morphine  intravenously, continuously. In addition to drugs used for sedation, seven patients also received clonidine 0.150 mg/day. All patients received antibiotics – nine for tetanus only, and 12 for other infections also. The most frequent clinical and infectious complications were: pulmonary atelectasis (57%), renal failure (24%), respiratory infection (90%), urinary infection (81%), and central line infection (38%). Individual clinical characteristics are shown in Table All patients had autonomic instability characterized by blood pressure or heart rate variation, other arrhythmias or cardiac arrest. During autonomic dysfunction, mean maximum heart rate was 143 ± 17 bpm and mean minimum heart rate was 59 ± 18 bpm. Ten patients had marked bradycardia (two had third degree AV block requiring pacemaker implants), two had recuperated cardiac arrest and one had atrial fibrillation. Mean blood pressure during hypertension periods ranged from 109 to 199 mmHg and from 15 to 73 mmHg during hypotension periods.versus 239 ± 105 pg/ml), norepinephrine (218 ± 88 versus 261 ± 96 pg/ml), dopamine (198 ± 109 versus 204 ± 111 pg/ml) and total catecholamines (414 ± 138 versus 500 ± 174 pg/ml) tended to be higher after recovery from tetanus, although within normal limits  pg/ml and 4.1 (range -1.2–6.8) pg/ml in autonomic instability and after tetanus recovery, respectively p > 0.05 , greater delta mean blood pressure values  and were older  than patients with troponin T levels < 0.01 pg/ml. Troponin T was inversely associated with systolic pressure  during autonomic instability period.Analysis of plasma troponin T concentrations during autonomic instability revealed that nine patients had values lower than 0.01 ng/ml, and that 12 had values greater than 0.01 ng/ml. Of these, six patients had troponin T concentrations greater than 0.1 ng/ml. Patients with plasma troponin T concentrations greater than 0.01 ng/ml (n = 12) had greater delta systolic pressure values (142 ± 50 mmHg EKG findings performed at different time points were similar to baseline EKG (including the fact that no new Q waves were identified), except for arrhythmias.Transthoracic two-dimensional echocardiography with Doppler was performed at the bedside during autonomic instability. In some patients, important variations of blood pressure occurred during the echocardiograms, but LVEF values remained within normal limits. The exam was repeated in the echocardiography laboratory under optimal conditions, after recovery from tetanus. Mean ejection fraction measured during autonomic instability and in the recovery period was 67 ± 7% and 65 ± 7%, respectively (p = 0.41).In this study in severe tetanus, all patients had autonomic instability characterized by cardiac arrhythmias, blood pressure instability, and/or cardiac arrest. However, these findings were not associated with increase in plasma catecholamine levels or in biological markers of inflammatory response. In spite of an increase in levels of the myocardial damage marker troponin T in 12 patients, this was not associated with cardiac dysfunction, as assessed by LVEF.In our study, plasma catecholamine levels were within normal ranges during autonomic instability; in fact, mean levels tended to be higher after recovery from tetanus. Autonomic instability in tetanus suggests intense sympathetic activity ; this haNormal catecholamine concentrations observed during autonomic instability may also be explained by the pharmacological treatment and resources available nowadays in ICUs, which allow the patient to be kept under deep sedation to control spasms and under adequate mechanical ventilation. Thus, our findings cannot be truly compared to previous reports mentioned above regarding catecholamine levels ,22,23, mIn this study, levels of TNF-α were not above expected normal limits. To our knowledge, no previous studies attempted to characterize cytokine profile in patients with tetanus, which limits our ability to compare ours to findings from others. Our group, as well as others, has shown that TNF-α levels are increased in the context of sepsis . In thisin vitro models of tetanus have demonstrated increased traditional cardiac enzymes [In our series, most patients had elevated levels of this marker but no new Q waves were observed in the EKGs performed afterwards. Few reports in experimental  enzymes . This is enzymes , probabl enzymes . TherefoIn our study, echocardiography evaluation during autonomic instability failed to identify systolic ventricular dysfunction or regional contractility abnormalities. In spite of the occurrence of variable values of blood pressure during echocardiography, practically all patients maintained normal ejection fraction, indicating a well preserved cardiac reserve in this setting. These findings were confirmed by transthoracic echocardiography performed under ideal conditions after recovery from tetanus. These observations were compatible with the absence of ischemic or necrosis areas by EKG, in spite of elevated troponin T levels.Previous studies of severe tetanus with autonomic instability suggested the occurrence of myocardial dysfunction secondary to myocardial necrosis caused by tetanic toxin and to elevated catecholamine concentrations ,11,31-33Only one measurement of catecholamine and TNF-α concentrations was performed during the autonomic instability period, which may not have coincided with the peak of release of these substances. However, according to previous reports available ,5,22,23 In patients with severe tetanus, during the period of autonomic instability, our data failed to demonstrate the presence of increased levels of catecholamines or the presence of cardiac dysfunction. Thus, our data do not support the hypothesis that autonomic disturbances in tetanus are secondary to adrenergic variations or cardiac dysfunction. Additionally, it may be suggested that within-normal limits levels of catecholamines in the autonomic instability period may be explained by overblurred of the autonomic system in tetanus.We speculate that additional mechanisms, perhaps of central origin, may play more important roles in the pathogenesis of autonomic dysfunction in tetanus, and that levels of catecholamines and cardiac dysfunction contribute less importantly. Experimental studies are required to further elucidate cause-effect relationship between these events in tetanus.APACHE II = Acute Physiology and Chronic Health Evaluation IIECLIA = electrochemiluminescence immunoassayEKG = electrocardiogramHPLC = high performance liquid chromatographyICU = intensive care unitsLVEF = left ventricular ejection fractionTNF = tumor necrosis factorJSB participated in study conception, data collection, data analysis and drafting.NC participated in study conception, study design and coordination, and drafting.Both authors have read and approved the final version of the manuscript.