I. Alonso

RELATIONSHIP BETWEEN METABOLIC SYNDROME, TIME OF TREATMENT AND BLOOD PRESSURE NON-DIPPING PROFILE IN ESSENTIAL HYPERTENSION: PP.3.112

Objectives: There is a strong association between metabolic syndrome (MS) and increased cardiovascular risk. Moreover, non-dipping (<10% sleep-time relative blood pressure (BP) decline) has also been linked to increased cardiovascular morbidity and mortality. Several studies have documented that non-dipping is partly related to the absence of 24 h therapeutic coverage in hypertensive subjects treated with single morning doses. Accordingly, we investigated the association between MS, time of treatment and the circadian BP pattern in essential hypertension. Methods: We studied 3352 non-diabetic treated hypertensive patients (1576 men), 53.7 ± 13.1 years of age. Among them, 2056 were ingesting all their antihypertensive medication upon awakening and 1296 were taken medication at bedtime. BP was measured every 20-min from 07:00 to 23:00 h and every 30-min at night for 48 h. Blood and urine tests were performed within the same week before starting BP monitoring. Results: MS was present in 52.6% of the subjects. The prevalence of a non-dipper BP profile was significantly higher in subjects with MS (52.0 vs. 39.5% in subjects without MS, P < 0.001). Non-dipping was significantly more prevalent among subjects receiving all medication on awakening (56.8%) than among those receiving medication at bedtime (29.1%; P < 0.001 between groups). Subjects with MS had significantly higher uric acid (6.0 vs. 5.3 mg/dl, P < 0.001), fibrinogen (331 vs. 315 mg/dl, P < 0.001), and erythrocyte sedimentation rate (14.8 vs. 12.4 mm, P < 0.001). Non-dipping was significantly associated to the presence of MS and treatment on awakening in a multiple logistic regression model adjusted by other significant confounding factors, including age, serum creatinine, erythrocyte sedimentation rate, and cigarette smoking. The single most relevant factor in the definition of MS associated to non-dipping was diminished HDL-cholesterol. Conclusions: This study documents a significant increase of a blunted nocturnal BP decline in treated hypertensive subjects with MS. Bedtime treatment significantly reduces the prevalence of an altered non-dipper BP profile, associated with an increased cardiovascular risk, while providing higher BP control and improved metabolic profile in essential hypertension.

PROGNOSTIC VALUE OF AWAKE AND ASLEEP AMBULATORY BLOOD PRESSURE FOR PREDICTION OF CARDIOVASCULAR MORBIDITY: RESULTS OF THE MAPEC STUDY: PP.3.90

Objectives: Target organ damage and cardiovascular risk are more closely associated with ambulatory (ABPM) than with clinic blood pressure (BP). Moreover, it has been suggested that nighttime BP is a better predictor of risk than daytime or 24 h BP. All previous trials on the prognostic value of ABPM have relied only on a single baseline profile from each participant, without accounting for changes in BP during follow-up. We have compared to prognostic value of ABPM and clinic BP in the MAPEC study, where participants were systematically evaluated by repeated ABPM. Methods: This prospective study investigated 3344 subjects (1718 men), 52.6 ± 14.5 years of age. At baseline, BP was measured every 20-min from 07:00 to 23:00 h and every 30-min at night for 48 h. Just before starting ABPM, six clinic BP measurements were obtained with a validated oscillometric device. ABPM was scheduled yearly or more frequently (quarterly) if treatment adjustment was required. The Cox proportional-hazard model was used to estimate relative risks of cardiovascular events associated to clinic and ambulatory BP. Results: After a median follow-up time of 5.6 years, ambulatory BP predicted outcome better than clinic BP. Moreover, the asleep BP mean was consistently a stronger predictor than the awake or 24 h BP mean. Based on the baseline ABPM, with adjustment for gender, age, diabetes, antihypertensive treatment, and clinic BP, the relative hazard ratio (HR) for each 10-mmHg increase in systolic BP was 1.18 (1.09–1.28; P < 0.001) for awake mean and 1.29 (1.21–1.37; P < 0.001) for asleep mean. Cardiovascular morbidity was even more strongly associated with systolic asleep BP when data were analyzed on the basis of the ABPM profile closer to the event (1.30, 1.23–1.38, P < 0.001). Conclusions: ABPM is superior to clinic BP in predicting cardiovascular morbidity and mortality. After adjustment for relevant confounding risk factors, the asleep BP mean provides higher prognostic value than awake BP mean. Results further indicate that decreasing asleep BP reduces cardiovascular risk beyond 24h-mean BP lowering.

INFLUENCE OF TIME OF DAY OF ANTIHYPERTENSIVE TREATMENT ON PLASMA FIBRINOGEN IN SUBJECTS WITH ESSENTIAL HYPERTENSION: PP.15.47

Objectives: Several studies have consistently documented differences in blood pressure (BP)-lowering efficacy, duration of action, safety profile and/or effects on the circadian BP pattern depending on the administration-time of antihypertensive medication. Clinical trials and epidemiological observations have also indicated that elevated fibrinogen is strongly correlated with an increased frequency of vascular events. Accordingly, we investigated the potential influence of time of day of antihypertensive treatment on the relationship between fibrinogen and ambulatory BP (ABPM) in subjects with essential hypertension. Methods: We studied 5000 hypertensive subjects (2392 men), 53.2 ± 13.6 years of age. Among them, 1672 patients were untreated at the time of the study, 1963 were treated with all drugs on awakening, and 1365 were receiving treatment at bedtime. BP was measured every 20-min from 07:00 to 23:00 h and every 30-min at night for 48 h. Blood samples were obtained in the early morning after nocturnal fasting, within the same week before starting ABPM. Results: For all three groups of subjects, independently of treatment scheme, plasma fibrinogen was comparable between extreme-dippers and dippers, but significantly elevated in non-dippers and, to a larger extent, in risers (P < 0.001 compared to all other groups). Compared with untreated subjects (315 mg/dl), fibrinogen was much higher among those treated with all drugs on awakening (330 mg/dl) than among those receiving treatment at bedtime (323 mg/dl). On the contrary, the sleep-time relative BP decline was significantly lower in subjects treated with all drugs on awakening (8.4%) compared to untreated subjects (10.9%, P < 0.001), and was highest among subjects treated with all drugs at bedtime (11.1%). Conclusions: Plasma fibrinogen is significantly correlated with the progressive loss in asleep BP regulation towards a more non-dipper or even riser profile. Compared with subjects receiving all their prescribed antihypertensive medication on awakening, treatment at bedtime was associated with higher sleep-time relative BP decline, significantly lower prevalence of non-dipping, and, simultaneously, lower plasma fibrinogen levels, what could all provide a diminished cardiovascular risk.

INCREASING THE SLEEP-TIME RELATIVE BLOOD PRESSURE DECLINE TOWARDS A MORE DIPPING PATTERN REDUCES CARDIOVASCULAR RISK: RESULTS OF THE MAPEC STUDY: PP.16.83

Objectives: Independent studies have concluded that non-dipping and an elevated asleep blood pressure (BP) are relevant predictors of cardiovascular risk. The potential reduction in cardiovascular risk associated with increasing the dipping of the BP pattern has never been evaluated and is still a matter of debate. The MAPEC study was designed to investigate whether normalization of the circadian BP profile towards a more dipper pattern by increasing the sleep-time relative BP decline results in reduced cardiovascular risk. Methods: This prospective study investigated 3344 subjects (1718 men), 52.6 ± 14.5 years of age. At inclusion, 649 subjects were normotensive and 2695 were hypertensive. At baseline, BP was measured by ambulatory monitoring (ABPM) every 20-min from 07:00 to 23:00 h and every 30-min at night for 48 h. ABPM was scheduled yearly or more frequently (quarterly) if treatment adjustment was required to improve BP control. The Cox proportional-hazard model was used to estimate relative risks of cardiovascular events associated to changes in sleep-time relative BP decline and other ABPM parameters. Results: The median time of follow-up was 5.6 years. Based on either the single first or the last available ABPM profile from each subject, the sleep-time relative BP decline and the asleep BP mean were the best joint predictors of cardiovascular risk in a Cox proportional-hazard model adjusted for sex, age, diabetes, antihypertensive treatment, and clinic BP. When data were analyzed on the basis of changes in BP during follow-up, decreased cardiovascular risk was significantly associated with progressive increase in sleep-time relative systolic BP decline (P < 0.001). The increased event-free survival associated with normalizing the BP pattern was significant whether ambulatory BP level was at the normotensive or at the hypertensive range. Conclusions: The sleep-time relative BP decline is a prognostic marker of cardiovascular morbidity and mortality, independent from 24 h BP mean. Most important, increasing this relative decline towards a more dipping pattern decreases cardiovascular risk at all BP levels, even within the normotensive range.

RELATIONSHIP BETWEEN PLASMA FIBRINOGEN AND SLEEP-TIME RELATIVE BLOOD PRESSURE DECLINE IN ESSENTIAL HYPERTENSION: PP.3.91

Objectives: Elevated fibrinogen is strongly correlated with increased cardiovascular morbidity and mortality. Several features of the circadian blood pressure (BP) pattern, including an elevated morning BP rise, a blunted nocturnal BP decline, or a high BP variability, have also been related to increased cardiovascular risk. Accordingly, we investigated the relationship between plasma fibrinogen and parameters derived from clinic as well as ambulatory BP (ABPM). Methods: We studied 3328 treated hypertensive subjects (1616 men), 55.4 ± 13.2 years of age. BP was measured every 20-min from 07:00 to 23:00 h and every 30-min at night for 48 h. Blood samples were obtained in the early morning after nocturnal fasting, within the same week before starting ABPM. Results: The correlation between fibrinogen and BP was larger for ambulatory than clinic BP. Correlations were systematically larger with parameters derived from ambulatory pulse pressure (PP) and mostly non-significant with those of diastolic BP. The largest correlations with fibrinogen were found for the asleep PP mean, AASI, asleep systolic BP mean and sleep-time relative systolic BP decline. Apart from BP, fibrinogen also showed significant correlations with higher age, female gender, larger waist perimeter, smoking and presence of diabetes. There was no significant relationship between fibrinogen and morning BP rise. According to the ambulatory BP pattern, mean fibrinogen values were comparable between subjects with extreme-dipper and dipper profile, but significantly elevated in non-dippers and, to a much larger extent, in risers (P < 0.001). Conclusions: Plasma fibrinogen is significantly correlated with the progressive loss in asleep BP regulation towards a more non-dipper profile, independently of age, gender, and presence of diabetes. Other parameters derived from ABPM, including AASI, morning BP rise and variability, were not significantly related to fibrinogen in a multiple regression model corrected by these influential factors. Results indicate that the sleep-time relative BP decline and the asleep mean values of systolic BP and PP may jointly be the most relevant ABPM characteristics for cardiovascular risk assessment in subjects under antihypertensive treatment.

INFLUENCE OF CIRCADIAN TIME OF ANTIHYPERTENSIVE TREATMENT ON CARDIOVASCULAR RISK: RESULTS OF THE MAPEC STUDY: PP.16.102

Objectives: Clinical studies have documented morning-evening, administration-time differences in antihypertensive efficacy, duration of action, safety profile and/or effects on the circadian blood pressure (BP) pattern of several different classes of BP-lowering medications. Despite these findings, most hypertensive subjects ingest all their BP-lowering agents in a single morning dose. The MAPEC study investigated if chronotherapy of hypertension has any influence in cardiovascular morbidity and mortality. Methods: This prospective study investigated 3344 subjects (1718 men), 52.6 ± 14.5 years of age. At baseline, BP was measured every 20-min intervals 07:00 to 23:00 h and every 30-min at night for 48 h. Physical activity was simultaneously monitored every minute by wrist actigraphy. The same evaluation procedure was scheduled yearly or more frequently (quarterly) if treatment adjustment was required to improve BP control. The Cox proportional-hazard model was used to estimate relative risks of cardiovascular events associated with use of antihypertensive treatment and circadian time of treatment. Results: At the last evaluation, 625 subjects were normotensive and 606 untreated hypertensives according to ambulatory BP criteria. Among the remaining subjects, 1068 were receiving all antihypertensive medication on awakening, and 1045 were ingesting some antihypertensive agent at bedtime. Compared with normotensive subjects, the relative risk of cardiovascular events was highest for patients ingesting all drugs on awakening (3.84 [2.48–5.95]) and lowest for those receiving all medication at bedtime (0.95 [0.44–2.07]; P = 0.907 compared to normotensive subjects; P < 0.001 compared to all other groups). Compared with untreated subjects, cardiovascular risk was significantly higher with increasing number of drugs on awakening, but consistently lower, independently of the number of drugs, when medication was ingested at bedtime. Non-dipping was significantly lower (28 vs. 61%) among subjects treated at bedtime. Conclusions: In subjects with essential hypertension, pharmacologic therapy should take into account when to treat with respect to the rest-activity pattern of each patient. Treatment at bedtime not only improves BP control and decreases the prevalence of non-dipping, but also significantly reduces cardiovascular risk to the level of normotension.

FACTORS INFLUENCING THE AMBULATORY BLOOD PRESSURE RESPONSE TO LOW-DOSE ASPIRIN IN SUBJECTS WITH UNTREATED MILD HYPERTENSION: PP.16.103

Objectives: Aspirin (ASA) is a potent antioxidative agent that reduces vascular production of superoxide, prevents angiotensin II-induced hypertension and cardiovascular hypertrophy, and induces nitric oxide release from vascular endothelium. Low-dose ASA has also been shown to reduce ambulatory blood pressure (BP) when administered at bedtime, as opposed to upon awakening, in pre-hypertensive as well as in untreated hypertensive subjects. We investigated clinical factors that, apart from time of treatment, could influence the response of ambulatory BP to low-dose ASA. Methods: We studied 316 untreated hypertensive subjects (130 men), 44.1 ± 13.2 years of age, assigned to receive aspirin (100 mg/day), in a prospective, open-label study, either on awakening or at bedtime. BP was measured every 20-min from 07:00 to 23:00 h and every 30-min at night for 48 h before after 3 months of treatment. Blood samples were obtained between 08:00 and 09:00 h after nocturnal fast. Results: Ambulatory BP was unchanged in subjects ingesting ASA on awakening. A significant ambulatory BP reduction was, however, observed in the subjects who received 100 mg/day ASA at bedtime (decrease of 7.0/4.7 mmHg in the 24 h systolic/diastolic BP mean; P < 0.001). The BP reduction after bedtime dosing was significantly larger for women (8.0/5.5 mmHg in systolic/diastolic BP) as compared to men (5.5/3.4 mmHg, respectively; P < 0.009 for gender differences). Multiple regression analysis indicated the BP-lowering after low-dose ASA was simultaneously and significantly related to bedtime treatment, female gender, higher baseline 24 h systolic BP mean, higher glomerular filtration rate, and the interaction between gender and treatment-time. For subjects ingesting ASA at bedtime, the significant factors influencing a higher BP reduction were female gender, higher baseline 24 h systolic BP mean, higher fasting glucose, and higher glomerular filtration rate. Conclusions: This prospective study corroborates the highly significant administration-time-dependent effect of low-dose ASA on ambulatory BP. The BP response to ASA ingested at bedtime is significantly larger in women as compared to men, as well as in subjects with impaired fasting glucose and preserved renal function.

RELATIVE INFLUENCE OF NIGHTTIME BLOOD PRESSURE DECLINE AND AMBULATORY BLOOD PRESSURE LEVEL AS PREDICTORS FOR CARDIOVASCULAR RISK: RESULTS OF THE MAPEC STUDY: PP.16.84

Objectives: A population Japanese study suggested that a diminished nighttime decline in blood pressure (BP) (non-dipper pattern) is a risk factor for cardiovascular mortality independent of the 24 h mean BP level [J Hypertens. 2002;20:2183–9]. We compared the relative influence of the BP level and the sleep-time relative BP decline as contributing factors for cardiovascular morbidity and mortality in the MAPEC study, designed to investigate whether increasing the sleep-time relative BP decline results in reduced cardiovascular risk. Methods: This prospective study investigated 3344 subjects (1718 men), 52.6 ± 14.5 years of age. At baseline, BP was measured every 20-min from 07:00 to 23:00 h and every 30-min at night for 48 h. Subjects were classified as having elevated BP if the awake mean was >135/85 mmHg for systolic/diastolic BP or the asleep mean >120/70 mmHg, and of normal BP otherwise. The Cox proportional-hazard model was used to estimate relative risks of cardiovascular events associated to elevated BP and/or diminished sleep-time relative BP decline. Results: After a median time of follow-up of 5.6 years and with adjustment for significant confounding factors including gender, age, antihypertensive treatment and diabetes, the relative hazard ratio of cardiovascular events for dipper subjects with elevated BP as compared to dipper subjects with normal BP was 1.57 (95% confidence interval [1.03–2.39]; P = 0.036). Subjects with a non-dipper BP pattern had higher cardiovascular risk, whether BP was within the normotensive range (1.95 [1.33–2.87]; P < 0.001; P = 0.218 compared to dipper subjects with elevated BP) or above it (4.01 [2.89–5.56]; P < 0.001). Conclusions: Cardiovascular risk is more closely related to a diminished sleep-time relative BP decline than to an elevated BP. Among subjects with BP in the normotensive range, non-dippers have twofold cardiovascular risk than dippers. Moreover, cardiovascular risk was 40% higher for non-dippers with normal BP (who would not be treated according to current guidelines) than for dippers with elevated BP. ABPM is a diagnostic technique that should be extended and recommended for proper cardiovascular risk assessment.

BLOOD PRESSURE PATTERNS IN NORMAL PREGNANCY, GESTATIONAL HYPERTENSION, AND PREECLAMPSIA: P1.150

With the aim to describe the daily pattern of blood pressure during the trimesters of pregnancy in clinically healthy women as well as in pregnant women who developed gestational hypertension or preeclampsia, we analyzed 1494 blood pressure series systematically sampled by ambulatory monitoring for 48 hours every 4 weeks after the first obstetric visit in 124 women with uncomplicated pregnancies, 55 with gestational hypertension, and 23 with a final diagnosis of preeclampsia. The circadian pattern of blood pressure variation for each group and trimester of gestation was established by population multiple-component analysis. A highly statistically significant circadian pattern represented by a linear model that includes components with periods of 24 and 12 hours is demonstrated for systolic and diastolic blood pressure for all groups of pregnant women in all trimesters (P:<0.001 in all cases). The differences in circadian rhythm-adjusted mean between complicated and uncomplicated pregnancies are highly statistically significant in all trimesters (always P:<0.001). There is also a statistically significant difference in circadian amplitude (extent of daily change) of blood pressure between healthy and complicated pregnancies in all trimesters (always P:<0.004). Results further indicate similar circadian characteristics between women who later developed gestational hypertension or preeclampsia in the first trimester of pregnancy. The difference between these 2 groups in circadian mean is statistically significant in the second trimester for systolic (P:=0.022) but not for diastolic blood pressure (P:=0.986). In the third trimester, the difference in circadian mean is highly statistically significant for both variables (P:<0.001). The differences in blood pressure between healthy and complicated pregnancies can be observed as early as in the first trimester of pregnancy. Those highly significant differences are found when both systolic and diastolic blood pressure for women with a later diagnosis of gestational hypertension or preeclampsia are well within the accepted normal physiological range of blood pressure variability. These differing changes in the circadian pattern of blood pressure with advancing gestational age between healthy and complicated pregnancies offer new end points that may lead to an early identification of hypertensive complications in pregnancy as well as to the establishment of prophylactic intervention.