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Brief Report: Clinical Science

Negative Influence of HIV Infection on Day-Night Blood Pressure Variability

De Socio, Giuseppe Vittorio L MD*; Bonfanti, Paolo MD; Martinelli, Canio MD§; Ricci, Elena PhD; Pucci, Giacomo MD; Marinoni, Marinella MD; Vitiello, Paola MD; Menzaghi, Barbara MD; Rizzardini, Giuliano MD; Schillaci, Giuseppe MD

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes: November 1, 2010 - Volume 55 - Issue 3 - p 356-360
doi: 10.1097/QAI.0b013e3181e46456

Abstract

INTRODUCTION

HIV-infected subjects are considered to be at increased risk of cardiovascular (CV) diseases. Hypertension is a major established risk factor for CV diseases and a common condition in HIV-infected people, with prevalences ranging from 13% to 34%.1-3 Most studies investigating the relation between HIV infection and blood pressure (BP) have been based on the traditional sphygmomanometric technique, which is prone to inaccuracy and human error. Twenty four-hour noninvasive ambulatory BP monitoring is more representative of an individual's true BP load, has superior reproducibility, and provides a better prediction of clinical outcome than conventional office-based BP measurements.4 More importantly, ambulatory BP monitoring provides unique information on circadian BP patterns. In normal subjects, BP decreases during sleep by 10%-20% and increases on waking.5 Subjects with a reduced nocturnal BP fall, referred to as nondippers, exhibit more extensive subclinical target organ damage,6 and are at increased risk of CV complications.7,8 Thus, assessment of day-night BP changes by noninvasive ambulatory BP monitoring improves global CV risk evaluation compared with office BP and other traditional risk markers. The relation between HIV infection and the circadian rhythm of BP is largely unknown. Some data report a reduced day-night BP fall in HIV subjects mostly receiving antiretroviral treatment,9 but to the best of our knowledge, no data are currently available on treatment-naive subjects. The aim of this study was to compare circadian BP profile in treatment-naive HIV-infected patients and in healthy control subjects without HIV infection.

METHODS

The HIV Exposure and Risk of Metabolic Syndrome (HERMES) study was conducted from January through December 2007 by the Coordinamento Italiano per lo Studio Allergia e Infezione da HIV (Italian coordination group for the study of allergies and HIV infection). Over this period, all antiretroviral therapy-naive patients attending scheduled or unscheduled visits at hospitals involved in the Coordinamento Italiano per lo Studio Allergia e Infezione da HIV group were eligible. After providing written informed consent, sex, age, body weight, height, targeted anthropometric measures, smoking habits, BP, waist circumference, and presence of diabetes were recorded using a standard data collection form. Laboratory tests included absolute CD4+ T-lymphocyte counts, fasting total and high-density lipoprotein cholesterol, triglycerides, and blood glucose. Four centers (Milan, Florence, Busto Arsizio, and Perugia) asked all consecutive patients enrolled in the HERMES Study, not matching exclusion criteria, to undergo a noninvasive ambulatory BP monitoring, to evaluate an abnormal circadian BP profile. Except for information on HIV characteristics, the same procedures (ie, fasting condition at the time of blood tests, same BP, and waist circumference measurement methods) were followed in the control population. One-hundred fifty-six HIV-negative individuals were selected as control subjects. All were recruited among the hospital staff and individuals examined for clinical checkups and found healthy. HIV-negative subjects were individually matched with patients with HIV by age (±10 years), sex (same sex), and office systolic BP (±10 mm Hg). A matching ratio of 1:3 was chosen because it has been shown to provide better information than a 1:1 ratio for small studies.10 Both patients with HIV and controls meeting the following criteria were excluded from the study: subjects with arterial hypertension, known diabetes, renal diseases (serum creatinine concentration < 132 micromol/L), clinical or laboratory evidence of coronary heart disease, previous stroke, treatment with any CV drug including nitrates, any clinical or laboratory evidence of inflammation over a period of at least 1 month before the study began, and night or shift work. Office BP was measured by a physician in the hospital outpatient clinic with a mercury sphygmomanometer, after the subject was seated for ≥10 minutes. The average of 2 consecutive measurements was considered for the analysis. Noninvasive ambulatory BP monitoring was performed on a weekday with an automatic device (SpaceLabs 90207), which recorded BP (by the oscillometric method) and heart rate at 20-minute intervals during the day (07:00-22:00) and at 30-minute intervals during the night (22:00-07:00). For both systolic and diastolic BP, the nocturnal BP fall (%) was calculated as 100 × [1 − (sleep BP/awake BP ratio)]. To abide by the actual wakefulness-sleep rhythm reported on patients' diaries, daytime was defined as the interval between 10.00 and 22.00 and night was the interval between 01:00 and 06:00. We excluded the morning and evening transition hours, during which a varying number of patients were awake and active, from the analysis; in fact, longer fixed nocturnal intervals, including transition hours, may lead to an overestimation of the true sleeping BP.11 Subjects with a nocturnal reduction of systolic BP ≥10% were defined dippers, the others nondippers.12

Statistical Analysis

Between-group differences were assessed by the use of Student t and Mann-Whitney-Wilcoxon tests for continuous normally and non-normally distributed variables, respectively. The χ2 test was used for comparing categorical variables. Pearson or Spearman correlation coefficients, as appropriate, examined the degree of association between examined variables. Linear regression analysis was used to estimate association to nocturnal systolic BP reduction, by including the following variables simultaneously in the model: sex, office systolic BP, age, smoking habits, and HIV infection status. Composite measures to assess global CV risk and AIDS prognostic scores were used in univariate and multivariate analyses. The global CV risk score was assessed by a recently developed algorithm derived from the Framingham Heart Study.13 The AIDS risk score is a validated composite index that utilizes CD4+ cell count, viral load, and age to stratify the probability of progressing to AIDS or death at 6 months from the time of analysis.14

RESULTS

As expected, age and sex distribution were identical in individuals with HIV and in HIV-negative subjects due to selection criteria (Table 1). HIV-infected subjects had a lower body mass index and total and high-density lipoprotein cholesterol concentrations and a nonsignificantly higher proportion of smoking subjects. Estimated 10-year global CV risk using Framingham risk score in patients with HIV and controls was 7.4% ± 10.1% vs 6.1% ± 4.8% (P = 0.23). Most of the subjects were asymptomatic (stage A according to the CDC classification). Office and ambulatory BP and heart rate data in patients with HIV and controls are shown in Table 2. Office systolic and diastolic BP values were identical in the 2 groups. Average daytime BP did not differ between HIV and control subjects either. Nighttime BP values were significantly higher in HIV-infected subjects. Nocturnal systolic BP reduction was 8.8% in HIV-positive subjects and 11.7% in controls (P = 0.002); a similar difference was found for nocturnal diastolic BP fall (13.2% vs 17.2%, P = 0.001). Twenty four-hour ambulatory BP profile in treatment-naive patients with HIV and in healthy control subjects is displayed online (see Figure, Supplemental Digital Content 1,http://links.lww.com/QAI/A66). The proportion of “nondippers” (see Figure, Supplemental Digital Content 2,http://links.lww.com/QAI/A67) was higher in HIV-infected subjects than in controls (35% vs 15%, P = 0.003). The independent contribution of HIV infection and other variables (sex, office systolic BP, age, smoking status) to nocturnal BP reduction was tested in a stepwise multiple linear regression analysis. HIV infection was the only independent determinant of nocturnal systolic BP fall. The resulting equation was percent nocturnal systolic BP reduction = 18.906 − (3.701 × HIV infection), in which HIV was coded as 1 if negative and 2 if positive (P = 0.001). Determinants of nondipping status were tested in a multiple logistic regression analysis. Again, after adjusting for the effect of sex, office BP, and smoking status, HIV infection was associated with an almost 4-fold likelihood of being nondipper (odds ratio 3.93, 95% confidence interval 1.9 to 8.2). The relationship between infection-related variables and day-night BP changes was assessed in subjects with HIV. Nocturnal systolic BP fall was inversely correlated with the HIV viral load (Figure 1, upper panel; r = −0.39, P = 0.004), and directly with current CD4+ cell count (Figure 1, lower panel; r = 0.48, P < 0.001) and nadir CD4+ count (r = 0.45, P = 0.001). Accordingly, the global AIDS risk score had an inverse relationship with systolic BP fall (r = −0.53, P < 0.001). The time of HIV infection was unrelated with nocturnal systolic BP reduction. Infection-related variables showed no significant relation with office BP values.

TABLE 1
TABLE 1:
Demographic, Clinical, and Laboratory Variables in 52 Patients With HIV and in 156 Control Subjects
TABLE 2
TABLE 2:
Office and Ambulatory BP and Heart Rate in 52 Patients With HIV and in 156 Control Subjects
FIGURE 1
FIGURE 1:
Bivariate relation of nocturnal systolic BP fall with HIV viral load (upper panel) and with current CD4 cell count (lower panel) in 52 treatment-naive patients with HIV.

DISCUSSION

In our study, HIV-infected patients who had never undergone antiretroviral treatment had a higher prevalence of abnormal diurnal BP rhythm and a reduced nocturnal BP fall compared with age-, sex- and BP-matched HIV-negative subjects. Target organ damage6,15 is more advanced, and CV morbidity and mortality is higher7,8 when the BP load is persistent throughout the 24 hours than when it is limited to daytime hours. Notably, a reduced nocturnal BP fall predicts CV and all-cause mortality in the (mostly normotensive) general population, even after adjusting for the effect of average 24-hour BP.8 Thus, a “nondipping” profile is an established predictor of CV disease and death in different clinical settings. To our knowledge, the present study was the first to evaluate diurnal BP changes in untreated patients with HIV. Because the relative potential contribution of HIV to arteriosclerotic disease is difficult to distinguish from that of classic CV risk factors and antiretroviral drugs, we chose to examine only HIV treatment-naive subjects who were free from overt CV disease, hypertension, diabetes, and renal disease and were not being treated with CV or hypolipidemic drugs. Moreover, patients and controls were accurately matched by age, sex, and BP, to minimize the confounding effect of these important conditions on the study findings; in fact, Framingham risk score was equivalent in the 2 groups. A further result of the present study is the significant and robust relation between attenuated nocturnal systolic BP fall and a number of infection-related variables, including HIV viral load, CD4+ cell count, and AIDS risk progression. These data suggest that viral burden and/or immunodeficiency might play a role in blunting day-night BP changes and are in line with prior data showing that a low CD4+ cell count16 and a high viral load17 are both related to subclinical atherosclerotic damage. The duration of HIV infection was unrelated with the degree of nocturnal systolic BP fall. This result, apparently in contrast to the above reported, may be explained considering that it was measured from the time of first HIV-positive serology, so this time could be inaccurate and underestimated mainly in patients with advanced disease (late HIV diagnosis). Several mechanisms may explain the association between HIV infection and nocturnal BP fall, which is a complex physiologic trait determined by a number of factors.18 Autonomic dysfunction is often associated with an abnormal circadian BP pattern19 and has been reported in HIV infection, particularly in patients with advanced disease.20 HIV-associated endocrine abnormalities, such as hypercortisolism and aldosteronism,21 might also play a role. Impaired sleep quality and quantity is an obvious determinant of attenuated sleep BP reduction, and sleep disturbances are common in patients with HIV.22 Patients with chronic medical disorders such as HIV infection often have a shorter and less restorative sleep than healthy individuals.23 The effects of a lesser daytime physical activity on the flattened day-night BP profile cannot be excluded, although none of the examined HIV subjects had disabling disease at the time of the study. It has been recently reported that HIV infection and/or antiretroviral treatment could induce both endothelial dysfunction24 and arterial stiffness,25,26 both of which have been related to an impairment of nocturnal BP fall.27,28

This study has several limitations besides the limited sample size. Ambulatory BP monitoring was performed in a nonrandomized subset of patients enrolled in the HERMES study, and this may have introduced bias. HIV-infected subjects had a lower body mass index and a nonsignificantly higher prevalence of smokers; however, these differences further strengthen our results because they both tend to increase the day-night BP change. The present findings have a number of clinical implications. First, an attenuated nocturnal BP fall may represent an additional possible mechanism of vascular damage in HIV-infected subjects. Second, BP measurement in the clinical setting may underestimate the true BP burden in HIV subjects, thus we suggest that noninvasive ambulatory BP monitoring should be considered to make better informed treatment decisions in HIV-infected individuals with borderline or mildly elevated BP levels. Third, the potentially harmful reduction in day-night BP change is linked to viral burden and immunodeficiency. These findings add to the current body of evidence,16,17,29 which links HIV infection per se to increased CV risk. Maintaining virological suppression and improving immunological status remains the main concern in HIV-infected patients, possibly with the aim of reducing long-term CV damage as well.

ACKNOWLEDGEMENTS

We thank all the patients, physicians, and nurses who were involved in this study. The HERMES study was approved by the local ethics committees. Data were partially presented at the Conference of Retrovirus and Opportunistic Infections (CROI), February 16-19, 2010, San Francisco, CA. The HERMES Study Group-Coordination: Paolo Bonfanti, Tiziana Quirino, Elena Ricci. Recruitment sites and investigators: Giuseppe V. De Socio, Franco Baldelli (Perugia); Carlo Magni, Gloria Giani, Daria Pocaterra, Laura Carenzi, Giuliano Rizzardini (Milano, I Divisione Malattie Infettive, Ospedale Sacco); Martinelli Canio, Francesco Leoncini (Firenze, Ospedale Careggi); Laura Cordier, Laura Valsecchi (Milano, II Divisione di Malattie Infettive, Ospedale Sacco); Paola Vitiello, Erika Gianelli, Stefano Rusconi (Milano, Clinica Malattie Infettive, Ospedale Luigi Sacco); Clara Abeli, Barbara Menzaghi (Busto Arsizio).

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Keywords:

ambulatory blood pressure; nocturnal blood pressure; dipping; HIV; cardiovascular

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