Abstract
Background. Non-dipper pattern, characterized by diminished nocturnal decline in blood pressure (BP), is associated with an increase in cardiovascular events. Carotid–femoral pulse wave velocity (CF-PWV) has been accepted as the gold standard measurement of arterial stiffness. CF-PWV is a well-recognized predictor of an adverse cardiovascular outcome with higher predictive value than classical cardiovascular risk factors. In this study, we investigated the association between PWV as the surrogate of arterial stiffness and non-dipper pattern in untreated hypertensive patients. Methods. The present study was cross-sectional and observational. Hypertensive patients were diagnosed according to ambulatory BP measurements (mean BP $ 130/80 mmHg). Eighty-four hypertensive patients, consulted for initial evaluation of hypertension, were enrolled. CF-PWV as the indicator of arterial stiffness was measured by a validated tonometry system (SphygmoCor). Patients with the history of any cardiovascular disease were excluded from the study. Results. Fifty-six patients had non-dipper pattern and 28 patients had dipper pattern in the study. Baseline characteristics were not significantly different between the two groups, except the CF-PWV (non-dipper vs dipper; 8.91 ± 2.53 vs 7.66 ± 1.08 m/s, p = 0.002), female gender (55% vs 32%, p = 0.045) and nocturnal BP measurements (for mean BP; 106 ± 11 vs 92 ± 8 mmHg, p < 0.001). Multiple logistic regression analysis including age, gender, BP and PWV measurements, revealed female gender (odds ratio, OR = 5.112, 95% confidence interval, CI 1.282–20.4, p = 0.021), nocturnal mean BP (OR = 1.243, 95% CI 1.107–1.396, p < 0.001) and CF-PWV (OR = 1.992, 95% CI 1.240–3.198, p = 0.004) as the independent predictors of non-dipper hypertensive pattern. Conclusion. Our results suggest that diminished nocturnal decline in BP is independently associated with PWV and nocturnal BP rather than daytime BP. Non-dipper pattern, mainly related to increased PWV and impaired modulation of vascular smooth muscle tone during the night, may justify an increased cardiovascular risk in these patients.
Introduction
Hypertension (HT) is a multifactorial and heterogeneous disease, presenting with high blood pressure (BP). HT is one of the leading causes of cardiovascular morbidity and mortality. Despite the advances in diagnosis, pathophysiological mechanisms and treatment of HT, cardiovascular mortality due to HT is still high and frequently presents as sudden cardiac death (Citation1).
Pathological increases in BP may begin throughout life with varying clinical entities and possible different dominant mechanisms. BP is a continuous variable and cut-off values, defined for treatment, are somewhat arbitrary. Therefore, HT may not be recognized in the normotensive stage because we do not have any differential diagnostic criteria to establish the diagnosis. Some patients with end organ damage without an evident causative factor in the normotensive stage may represent the early stage in the hypertensive process. The concept of prehypertension was proposed in order to implement therapeutic lifestyle changes and prevent progressive rise in BP (Citation2).
BP drops 10–20% during the night in most people; those with blunted nocturnal decline in BP appear to have increased cardiovascular complications. Circadian BP pattern assessed by ambulatory BP monitoring (ABPM) improve risk stratification above office BP values and traditional cardiovascular risk factors (Citation3,Citation4). The most recent NICE guidelines recommend ABPM readings as the primary diagnostic tool for HT (Citation5).
Arterial stiffness (AS) due to decreased arterial compliance is one of the major signs of vascular aging (Citation6). Several studies have documented the prognostic importance of arterial stiffness as an independent predictor of all-cause mortality and cardiovascular mortality (Citation7,Citation8). Carotid–femoral pulse wave velocity (CF-PWV) has been accepted as the gold standard measurement of arterial stiffness. CF-PWV is a well-recognized predictor of an adverse cardiovascular outcome with higher predictive value than classical cardiovascular risk factors and requires little technical expertise (Citation9).
Non-dipper pattern, characterized by diminished nocturnal decline in BP, may also be related to premature vascular aging, which could increase cardiovascular complications. In this study, we investigated the association between non-dipper pattern and PWV as the surrogate of arterial stiffness, in untreated hypertensive patients.
Methods
This study was carried out with a cross-sectional design. All patients underwent 24-h ABPM. Eighty-four hypertensive patients referred for initial evaluation of HT were enrolled according to ambulatory BP measurements (mean BP $130/80 mmHg). The study population was divided into two subgroups as dipper vs non-dipper with regard to nocturnal decline in mean BP ($10% vs < 10%).
CF-PWV was measured as an index of arterial stiffness. A single experienced cardiologist blind to patient data performed vascular assessments in patients, in the morning after an overnight fast with refraining from cigarette smoking for the last 8 h. PWV was calculated from measurements of pulse transmit time and the distance between two recording sites by a validated non-invasive device (SphygmoCor, AtCor Medical, Sydney, Australia). Measured distance travelled by the pulse wave over the surface of the body with a tape measure (from sternal notch to right carotid artery and from sternal notch to right femoral artery) was divided by the transit time and the result was expressed as meters/second (m/s). Since recent consensus suggests 80% of the direct carotid–femoral distance as the most accurate estimate (Citation10), we converted our subtracted measurements using [estimated direct distance = 0.45 × subtracted distance + 0.21 × height + 0.08] formula and multiplied the result with 0.8 (Citation11). We expressed both the original PWV and values after conversion. Resting BP was detected by traditional auscultatory method using a sphygmomanometer.
Ambulatory BP measurements (PhysioQuant Ambulatory Blood Pressure Monitor system, EnviteC-Wismar, Germany) were recorded in all patients and the following formula was used to calculate percentage of nocturnal decline: [1 − (mean night systolic BP (SBP)/mean day SBP)] × 100.
Patients with the history of any cardiovascular disease were excluded from the study. The study was approved by the local ethics committee of Rize University Faculty of Medicine and was in accordance with the principles stated in the Declaration of Helsinki.
Blood samples were drawn by venipuncture to evaluate routine blood parameters after fasting for at least 8 h. Fasting blood glucose, total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol and triglyceride levels were recorded. Glucose and lipid profile were determined by standard methods.
Statistical analysis
Continuous variables were summarized as mean ± standard deviation (SD), and categorical variables were summarized as counts and percentages. Data were tested for normal distribution using the Kolmogorov–Smirnov test. The Student's t-test was used for the univariate analysis of the continuous variables and the χ2 test for the categorical variables. Logistic regression was used for multivariate analysis of independent variable. All tests of significance were two-tailed. Statistical significance was defined as p < 0.05. The SPSS statistical software (SPSS 15.0 for windows, Inc., Chicago, IL, USA) was used for all statistical calculations.
Results
Demographic characteristics and laboratory measurements of patients are detailed in . BP measurements are given in .
Table I. Clinical characteristics of untreated dipper and non-dipper hypertensive patients.
Table II. Blood pressure measurements in untreated dipper and non-dipper hypertensive patients.
Fifty-six patients (66.7%) had non-dipper pattern and 28 patients (33.3%) had dipper pattern in the study. Baseline characteristics were not significantly different between the two groups, except the CF-PWV (non-dipper vs dipper; 8.91 ± 2.53 vs 7.66 ± 1.08 m/s, p = 0.002), female gender (55% vs 32%, p = 0.045) and nocturnal BP measurements (for mean BP; 106 ± 11 vs 92 ± 8 mmHg, p < 0.001).
Multiple logistic regression analysis including age, gender, BP and PWV measurements revealed female gender (OR = 5.112, 95% CI 1.282–20.4, p = 0.021), night mean BP (OR = 1.243, 95% CI 1.107–1.396, p < 0.001) and CF-PWV (OR = 1.992, 95% CI 1.240–3.198, p = 0.004) as the independent predictors of non-dipper hypertensive pattern ().
Table III. Multivariate logistic regression analysis: Predictors for non-dipping blood pressure pattern among individuals with essential hypertension.
Discussion
The present study revealed an increased CF-PWV in non-dipper hypertensive patients. We also documented that blunted nocturnal decline in BP is mainly associated with PWV and nocturnal BP rather than daytime BP in a group of middle-aged patients with low cardiovascular risk profile.
Arterial stiffness, one of the earliest manifestations of adverse structural and functional changes within the arterial wall, is mainly associated with aging and HT (Citation12). PWV, the gold-standard measure of arterial stiffness, has been shown to be an independent predictor of mortality and stroke in the general population (Citation7), end-stage renal disease (Citation13), patients with HT (Citation14) and diabetes (Citation15). PWV was significantly associated with the markers of subclinical target organ damage in the coronary, peripheral arterial and cerebral vascular beds (Citation16). Therefore, PWV may be considered a test of target organ damage in hypertensive patients according to European guidelines on cardiovascular disease prevention (Citation17).
Recently, frequent use of ABPM in clinical practice has developed interest for new diagnostic and prognostic concepts in HT, the most popular of which is the non-dipper status. BP drops 10–20% during the night in most people; hypertensive patients with blunted nocturnal decline in BP suffer increased cardiovascular complications (Citation18). Accordingly, each 5% attenuation in nocturnal SBP/diastolic BP (DBP) represented an approximately 20% higher risk of cardiovascular mortality in the Ohasama study (Citation19). Data suggest that, in addition to an increased cardiovascular mortality, left ventricular hypertrophy (Citation20), microalbuminuria (Citation21) and progression of renal damage (Citation22) (e.g. proteinuria and decline in creatinine clearance) are also significantly higher in non-dipper than dipper hypertensive patients.
There has been considerable debate regarding the prognostic utility of nocturnal BP over daytime BP and reproducibility of non-dipper status (Citation23,Citation24). A recent meta-analysis demonstrated nocturnal BP to be a superior predictor of cardiovascular risk than daytime BP (Citation25). In contrast, Boggia et al. evaluated cardiovascular risk associated with diurnal and nocturnal BP in 7458 patients. According to their results, predictive accuracies of diurnal and nocturnal HT varied for fatal, non-fatal and composite outcomes (Citation26).
Underlying causative mechanisms of non-dipper pattern and nocturnal HT have not been revealed until now. Proposed pathophysiological mechanisms include decreased sympathetic modulation during night-time (Citation27), sleep apnoea (Citation28) and increased salt sensitivity (Citation29). Although nocturnal HT is often associated with non-dipper status, both are not always present together. In addition, the clinical significance of these conditions is not the same. BP measurements during the day show considerable variation possibly due to physical and mental activity. Conversely, the distribution of nocturnal BT is narrower and more stable than daytime leading to consistent results. Consistently high BP throughout the night exerts a negative effect on the cardiovascular system, possibly causing an increased cardiovascular risk. Non-dipper pattern, on the other hand, is more likely to be associated with advanced stage of HT. A recent study, including almost 43,000 patients, demonstrated that blunted nocturnal BP decline was associated with increased age, obesity, diabetes mellitus, number of antihypertensive medication, and overt cardiovascular or renal disease (Citation30).
Arterial stiffness is closely related to HT. Maintaining high nocturnal BP and non-dipper pattern, both possibly related to impaired modulation of vascular smooth muscle tone during the night, may increase vascular remodelling in the arterial wall and consequently arterial stiffness. Therefore, increased PWV in patients with non-dipper HT may justify an increased cardiovascular risk.
Study limitations
The main limitation of our study is small sample size. In addition, we specifically included untreated hypertensive patients in the early stage of HT rather than patients with long-standing HT. This and low sample size of current study might have resulted in low correlations among study parameters. Nevertheless, significant differences were determined between two groups.
Conclusion
Our results suggest that diminished nocturnal decline in BP is independently associated with PWV and nocturnal BP rather than daytime BP. Although our study population consisted of individuals with relatively low risk, low BP values and no significant end-organ damage, we were able to determine these significant relationships. Non-dipper pattern, mainly related to increased PWV and impaired modulation of vascular smooth muscle tone during the night, may justify an increased cardiovascular risk in these patients. Further clinical studies targeting PWV and impaired modulation of vascular smooth muscle tone are needed to clarify our study findings in HT.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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