Impact of Blunted Nocturnal Blood Pressure Dipping on Cardiac Systolic Function in Community Participants Not Receiving Antihypertensive Therapy

Impact of Blunted Nocturnal Blood Pressure Dipping on Cardiac Systolic Function in Community... Abstract BACKGROUND Blunted nocturnal blood pressure (BP) dipping (nondipping) predicts cardiovascular morbidity and mortality, and is associated with heart failure (HF) independent of office BP. Whether nondipping is independently associated with cardiac systolic function prior to the development of HF is uncertain. METHODS We assessed whether nocturnal BP dipping pattern and nocturnal BP were associated with indexes of cardiac systolic function [endocardial fractional shortening (endFS), midwall FS (mFS), ejection fraction (EF)] independent of left ventricular mass index (LVMI) and relative wall thickness (RWT) in 491 randomly selected community participants not receiving antihypertensive therapy. Nocturnal BP and dipping pattern were determined from 24-hour BP monitoring where nighttime was defined from fixed-clock time intervals. BP dipping was defined as night-to-day BP ratio. Pulse wave velocity (PWV) was determined using SphygmoCor, and total peripheral resistance (TPR) was calculated from echocardiographic data. RESULTS On bivariate analyses, nocturnal BP and BP dipping but not day BP were correlated with indexes of cardiac systolic function (P < 0.005). After adjustments for potential confounders including age, LVMI (or RWT) and 24 hour (or day) BP, endFS (P < 0.01), mFS (P < 0.05), and EF (P < 0.01) were associated with nocturnal BP and BP dipping. These relationships survived further adjustments for PWV, and the homeostasis model of insulin resistance. The decreased mFS in reverse dippers was in-part explained by an increased TPR. CONCLUSIONS In an untreated community sample, blunted nocturnal BP dipping is independently and inversely associated with cardiac systolic function. Hence, nondipping is related to a reduced cardiac systolic function prior to the development of HF. ambulatory blood pressure, blood pressure, blood pressure dipping, cardiac systolic function, hypertension, nocturnal blood pressure Nocturnal blood pressure (BP) and blunted nocturnal BP dipping (nondipping) are associated with increased cardiovascular mortality and morbidity, independent of office BP and cardiovascular risk factors.1,2 Moreover, in a longitudinal study (~9 years follow-up), nocturnal BP and nondipping conveyed risk for the development of congestive heart failure (HF), excluding myocardial infarction, beyond office BP, and cardiovascular risk factors.3 In addition, in patients with HF, nondipping has been independently associated with both HF with reduced ejection fraction (EF) as well as HF with preserved EF.4 However, patients in HF have increased activation of the sympathetic nervous system as well as the renin–angiotensin–aldosterone system,5 both of which have been implicated in the blunting of nocturnal BP dipping.6,7 Hence, whether nondipping is causally related to reductions in cardiac systolic function prior to the development of HF is unclear. Although a number of previous studies have explored the relationship between BP dipping and cardiac diastolic function, there is limited data on cardiac systolic function. Indeed, a recent systematic review and meta-analysis in untreated hypertensives reported increases in left ventricular mass index (LVMI), relative wall thickness (RWT), and left atrial diameter and reductions in the ratio of early (E) to late (A) mitral inflow velocity (E/A ratio) (not significant after correction for publication bias) in nondippers compared to dippers.8 However, no studies assessing cardiac systolic function were included in this systematic review and meta-analysis. To our knowledge, only 2 previous small (n = 56–133) studies9,10 and 1 large study (n = 1,702)11 have assessed the impact of BP dipping on cardiac systolic function in participants not receiving antihypertensive therapy. As antihypertensive therapy has an impact on both BP dipping12–14 and cardiac function, it is important that only untreated participants are assessed in order to avoid the potential confounding effects of treatment. Although in both of the previous small studies,9,10 EF was decreased in nondippers compared to dippers, in comparing these 2 groups of participants no adjustments were made for potential confounding variables. In this regard, several factors are associated with blunted nocturnal BP dipping include age,15,16 sex,15,16 obesity,15,16 insulin resistance,17 BP level,16 pulse wave velocity (PWV),18,19 total peripheral resistance (TPR),20 LVMI,21 and RWT.21 Moreover, although relations between cardiac systolic function and day–night BP changes were noted in the large study,11 patients with a depressed systolic function also had a higher LVMI and a more concentric geometry. In addition, in this large study, adjustments were made for only age and sex.11 Hence, in the present study, we assessed whether the nocturnal BP dipping pattern and nocturnal BP were associated with indexes of cardiac systolic function [endocardial fractional shortening (endFS), midwall FS (mFS), EF] independent of LVMI and RWT in randomly selected participants not receiving antihypertensive therapy from an urban, developing community. In addition, we assessed whether relationships between nocturnal BP dipping and indexes of cardiac systolic function were explained by variations in PWV, TPR, or insulin resistance. METHODS Study group The present study was approved by the Committee for Research on Human Subjects of the University of the Witwatersrand (approval number: M02-04-72, renewed as M07-04-69, M12-04-108, and M17-04-01). Participants gave informed written consent. The study design and the population sampled has previously been described.22–25 Briefly, 1,445 participants older than 16 years of age from nuclear families of Black African ancestry (Nguni and Sotho chiefdoms) were randomly recruited from the South West Township (SOWETO) of Johannesburg, South Africa from 2002 to 2017 using the population census figures of 2001. Of these participants, 1,082 were not receiving antihypertensive therapy, and in a substudy, 491 had both 24-hour ambulatory BP monitoring that met with the European Society of Hypertension (ESH) guidelines (longer than 14 and 7 readings for the computation of day and night means, respectively),26 and echocardiographic assessments. Clinical, demographic, and anthropometric measurements A standardized questionnaire was administered to obtain demographic and clinical data as previously described.22–25 As this was a community-based study, nontreatment of hypertension was by self-report on the questionnaire. In addition, however, the participants brought all prescribed medications with them so that the medications could be confirmed as antihypertensive agents or not. Conventional BP was determined from the mean of 5 nurse-derived BP measurements obtained with a mercury sphygmomanometer as previously described.24 From height and weight measurements, body mass index (BMI) was calculated and participants were identified as being overweight if their BMI was ≥25 kg/m2 and obese if their BMI was ≥30 kg/m2. Waist circumference was assessed using a standard approach. Blood lipid profiles and percentage glycated hemoglobin (HbA1c) were determined. Diabetes mellitus or abnormal blood glucose control was defined as the use of insulin or oral hypoglycemic agents or an HbA1c value greater than 6.1%.27 Participants were classified as hypertensive if conventional BP values were ≥140/90 mm Hg. Fasting plasma insulin concentrations were determined from an insulin Immulite, solid phase, 2-site chemiluminescent immunometric assay (Diagnostic Products Corporation, Los Angeles, CA). Insulin resistance was estimated by the homeostasis model assessment of insulin resistance (HOMA-IR) using the formula (insulin [μU/ml] × glucose [mmol/l])/22.5. Ambulatory BP Twenty four-hour ambulatory BP monitoring was performed using oscillometric monitors (SpaceLabs, model 90207) as previously described (see online Supplemental Methods).24,25 The average (±SD) number of BP readings obtained was 59.8 ± 12.2 (range = 24–81) for the 24-hour period, 29.5 ± 6.6 (range = 14–41) for the day and 9.6 ± 0.8 (range = 7–11) for the night periods. Systolic and diastolic BP dipping were calculated for each participant as night-to-day BP ratio expressed as a percentage. Four BP dipping patterns (extreme dipper, dipper, nondipper, reverse dipper) were defined as extreme dipper if night-to-day BP ratio was ≤0.8; dipper if night-to-day BP ratio >0.8 and ≤0.9; nondipper if night-to-day BP ratio >0.9 and ≤1.0; and reverse dipper if night-to-day BP ratio >1.0.2,28 Pulse wave analysis On the same day as ambulatory BP monitoring was performed, aortic (carotid-femoral) PWV was estimated using carotid and femoral applanation tonomtery (high-fidelity SPC-301 micromanometer, Millar Instrument, Inc., Houston, TX) interfaced with a computer employing SphygmoCor, version 9.0 software (AtCor Medical Pty. Ltd., West Ryde, New South Wales, Australia) as described previously (see online Supplementary Data).22,24 Echocardiography Echocardiographic measurements were recorded and analyzed offline by experienced investigators who were unaware of the clinical data of the participants and whom had a low degree of interobserver and intraobserver variability.29 The LV dimensions were measured only when appropriate visualization of both the right and the left septal surfaces occurred and where the endocardial surfaces of both the septal and posterior wall were clearly visible. Left ventricular EF was calculated using the biplane Simpson method. In addition, left ventricular function was assessed at both the chamber (endFS) and the mFS level. Midwall FS was calculated using a modified ellipsoidal model as previously described30 which accounts for epicardial migration of the midwall during systole. Total peripheral resistance was calculated as mean arterial pressure/cardiac output. Left ventricular mass index was determined from transthoracic 2-dimensional targeted M-mode echocardiography with the participants in the partial left decubitus position, as previously described.24,29 Echocardiography recordings were analyzed according to the American Society of Echocardiography convention.30 Left ventricular mass was determined using a standard formula31 and indexed (LVMI) to height1.7. Left ventricular hypertrophy was identified as LVMI >80 g/m1.7 for men and >60 g/m1.7 for women.32 Left ventricular diastolic function was assessed from a pulsed wave Doppler examination of the mitral inflow at rest and using TDI (see online Supplementary Data).33 Data analysis For database management and statistical analysis, SAS software, version 9.4 (SAS Institute Inc., Cary, NC) was employed. Data are shown as mean ± SD. Multivariate-adjusted linear (continuous data) or logistic (discrete data) regression analysis was performed to determine independent relations. Potential confounders were identified on bivariate relationships with indexes of cardiac function or BP dipping. In multivariate analyses adjustments were made for age, sex, BMI, regular smoking, regular alcohol consumption, diabetes mellitus, and/or HbA1c >6.1%, 24 hour (or day) heart rate, and 24 hour (or day) BP. To determine whether BP dipping vs. cardiac function relations were independent of LVMI or RWT, further adjustments were made for LVMI and RWT, respectively. Similarly, to determine whether relationships between nocturnal BP dipping and indexes of cardiac systolic function were explained by variations in PWV, TPR, or insulin resistance, in separate models further adjustments were made for PWV, TPR, or log HOMA-IR (transformed to improve distribution). RESULTS Characteristics of the participants Comparisons between the characteristics of those included and those not included in the study are shown in the online supplement (Supplementary Table S1). Participants with 24-hour ambulatory BP monitoring and high-quality echocardiographic data had similar characteristics to participants without either high-quality 24-hour ambulatory BP monitoring or echocardiographic data. Table 1 compares the characteristics of the participants in the 4 SBP dipping patterns. The reverse dippers were older and had a higher BMI than the dippers. Moreover, the reverse dippers had higher 24-hour BP, night BP, and TPR but not day BP and day HR than the other 3 groups. The nondippers also had a higher night BP than the dippers and extreme dippers; but day BP was lower than the extreme dippers. The reverse dippers had an increased night HR than the dippers, but neither 24 hour nor day HR differed from that of the other 3 groups. Neither LVMI, nor the proportion of participants with LV hypertrophy differed across the 4 groups (extreme dippers = 39.5%, dippers = 35.7%, nondippers = 40.6%; reverse dippers = 48.0%). Supplementary Table S2 compares the characteristics of the participants who were dippers compared to those who were nondippers according to SBP. The nondippers were older and had a higher BMI, PWV, 24 hour BP, night BP, and night HR; but not day BP. Table 1. Demographic, clinical, and hemodynamic characteristics of the 491 study participants according to SBP dipping pattern   Extreme dippers  Dippers  Nondippers  Reverse dippers  Number (%)  38 (7.7)  216 (44.0)  187 (38.1)  50 (10.2)  % Women  55.3  56.0  65.8  64.0  Age (years)  40.8 ± 16.2  36.8 ± 16.2  42.0 ± 16.4‡  48.0 ± 17.0‡‡  Body mass index (kg/m2)  26.9 ± 6.6  26.9 ± 7.2  28.7 ± 7.4  30.4 ± 8.6‡  Regular tobacco intake (% subjects)  18.4  18.5  15.0  20.0  Regular alcohol intake (% subjects)  21.1  24.1  21.4  20.0  % With diabetes mellitus or HbA1c > 6.1%  15.8  13.0  13.4  18.0  % With hypertension  31.6  19.9  29.4  42.0‡$  Conventional BP (mm Hg)  125 ± 18/82 ± 12  121 ± 16/80 ± 10  127 ± 20‡/83 ± 12‡  134 ± 24*/87 ± 14*  24-Hour BP (mm Hg)  116 ± 15/73 ± 11  114 ± 11/70 ± 9  118 ± 15‡/73 ± 10‡  126 ± 19**/78 ± 13*  Day BP (mm Hg)  128 ± 15/83 ± 11  121 ± 12#/77 ± 9#  121 ± 15#/77 ± 11#  124 ± 18/79 ± 13  Night BP (mm Hg)  98 ± 12/57 ± 10  103 ± 10/60 ± 9  113 ± 15††/67 ± 11††  129 ± 20***/76 ± 13***  Night-to-day SBP ratio  0.76 ± 0.03  0.86 ± 0.03###  0.94 ± 0.03†††  1.04 ± 0.04***  Night-to-day DBP ratio  0.68 ± 0.06  0.78 ± 0.07###  0.88 ± 0.07†††  0.97 ± 0.08***  24-Hour HR (beats/min)  76.4 ± 10.3  76.0 ± 8.9  77.9 ± 10.0  76.5 ± 7.7  Day HR (beats/min)  83.3 ± 12.5  82.5 ± 10.2  83.1 ± 10.8  80.2 ± 10.3  Night HR (beats/min)  65.9 ± 9.8  66.3 ± 9.4  70.0 ± 10.8†  70.3 ± 8.5‡  LVEDD (cm)  4.71 ± 0.57  4.72 ± 0.52  4.72 ± 0.63  4.69 ± 0.61  E/A  1.32 ± 0.35  1.47 ± 0.49  1.32 ± 0.47‡  1.25 ± 0.54‡  E/e’ (n=)  6.64 ± 2.83 (22)  6.25 ± 3.06 (125)  7.61 ± 5.52 (120)  7.50 ± 3.50 (35)  LV mass index (g/m1.7)  64.74 ± 22.84  61.83 ± 17.53  63.72 ± 24.16  69.39 ± 22.37  RWT  0.37 ± 0.06  0.37 ± 0.07  0.37 ± 0.08  0.40 ± 0.09‡  Aortic pulse wave velocity (m/sec)  5.64 ± 2.46  5.40 ± 2.13  5.85 ± 2.16  6.86 ± 3.11‡$  TPR (mm Hg. min/ml)  22.12 ± 5.43  22.57 ± 7.07  22.98 ± 7.56  26.14 ± 8.04*  Log HOMA-IR  0.66 ± 1.14  0.48 ± 1.04  0.44 ± 0.93  0.59 ± 1.16    Extreme dippers  Dippers  Nondippers  Reverse dippers  Number (%)  38 (7.7)  216 (44.0)  187 (38.1)  50 (10.2)  % Women  55.3  56.0  65.8  64.0  Age (years)  40.8 ± 16.2  36.8 ± 16.2  42.0 ± 16.4‡  48.0 ± 17.0‡‡  Body mass index (kg/m2)  26.9 ± 6.6  26.9 ± 7.2  28.7 ± 7.4  30.4 ± 8.6‡  Regular tobacco intake (% subjects)  18.4  18.5  15.0  20.0  Regular alcohol intake (% subjects)  21.1  24.1  21.4  20.0  % With diabetes mellitus or HbA1c > 6.1%  15.8  13.0  13.4  18.0  % With hypertension  31.6  19.9  29.4  42.0‡$  Conventional BP (mm Hg)  125 ± 18/82 ± 12  121 ± 16/80 ± 10  127 ± 20‡/83 ± 12‡  134 ± 24*/87 ± 14*  24-Hour BP (mm Hg)  116 ± 15/73 ± 11  114 ± 11/70 ± 9  118 ± 15‡/73 ± 10‡  126 ± 19**/78 ± 13*  Day BP (mm Hg)  128 ± 15/83 ± 11  121 ± 12#/77 ± 9#  121 ± 15#/77 ± 11#  124 ± 18/79 ± 13  Night BP (mm Hg)  98 ± 12/57 ± 10  103 ± 10/60 ± 9  113 ± 15††/67 ± 11††  129 ± 20***/76 ± 13***  Night-to-day SBP ratio  0.76 ± 0.03  0.86 ± 0.03###  0.94 ± 0.03†††  1.04 ± 0.04***  Night-to-day DBP ratio  0.68 ± 0.06  0.78 ± 0.07###  0.88 ± 0.07†††  0.97 ± 0.08***  24-Hour HR (beats/min)  76.4 ± 10.3  76.0 ± 8.9  77.9 ± 10.0  76.5 ± 7.7  Day HR (beats/min)  83.3 ± 12.5  82.5 ± 10.2  83.1 ± 10.8  80.2 ± 10.3  Night HR (beats/min)  65.9 ± 9.8  66.3 ± 9.4  70.0 ± 10.8†  70.3 ± 8.5‡  LVEDD (cm)  4.71 ± 0.57  4.72 ± 0.52  4.72 ± 0.63  4.69 ± 0.61  E/A  1.32 ± 0.35  1.47 ± 0.49  1.32 ± 0.47‡  1.25 ± 0.54‡  E/e’ (n=)  6.64 ± 2.83 (22)  6.25 ± 3.06 (125)  7.61 ± 5.52 (120)  7.50 ± 3.50 (35)  LV mass index (g/m1.7)  64.74 ± 22.84  61.83 ± 17.53  63.72 ± 24.16  69.39 ± 22.37  RWT  0.37 ± 0.06  0.37 ± 0.07  0.37 ± 0.08  0.40 ± 0.09‡  Aortic pulse wave velocity (m/sec)  5.64 ± 2.46  5.40 ± 2.13  5.85 ± 2.16  6.86 ± 3.11‡$  TPR (mm Hg. min/ml)  22.12 ± 5.43  22.57 ± 7.07  22.98 ± 7.56  26.14 ± 8.04*  Log HOMA-IR  0.66 ± 1.14  0.48 ± 1.04  0.44 ± 0.93  0.59 ± 1.16  Values are mean ± SD or proportions. SBP dipping patterns: extreme dipper = SBPn/SBPd ≤0.8; dipper = SBPn/SBPd >0.8 and ≤0.9; nondipper = SBPn/SBPd >0.9 and ≤1.0; reverse dipper = SBPn/SBPd ≥1.0. *P < 0.05, **P < 0.001, ***P < 0.0001 vs. other 3 groups; †P < 0.05, ††P < 0.001, †††P < 0.0001 vs. dippers and extreme dippers; ‡P < 0.05, ‡‡P < 0.001 vs. dippers; #P < 0.05, ##P < 0.001, ###P < 0.0001 vs. extreme dippers; $P < 0.05 vs. nondippers. Abbreviations: BP, blood pressure; DBP, diastolic BP; E/A, early-to-late transmitral velocity; E/e’, early transmitral blood flow velocity/mean of lateral and septal wall myocardial tissue lengthening at the mitral annulus; HbA1c, glycosylated hemoglobin; HR, heart rate; Log HOMA-IR, Logarithm of homeostasis model of insulin resistance; LV, left ventricle; LVEDD, left ventricular end diastolic diameter; RWT, relative wall thickness; SBP, systolic BP; SBPd, day SBP; SBPn, night SBP; TPR, total peripheral resistance. View Large Table 1. Demographic, clinical, and hemodynamic characteristics of the 491 study participants according to SBP dipping pattern   Extreme dippers  Dippers  Nondippers  Reverse dippers  Number (%)  38 (7.7)  216 (44.0)  187 (38.1)  50 (10.2)  % Women  55.3  56.0  65.8  64.0  Age (years)  40.8 ± 16.2  36.8 ± 16.2  42.0 ± 16.4‡  48.0 ± 17.0‡‡  Body mass index (kg/m2)  26.9 ± 6.6  26.9 ± 7.2  28.7 ± 7.4  30.4 ± 8.6‡  Regular tobacco intake (% subjects)  18.4  18.5  15.0  20.0  Regular alcohol intake (% subjects)  21.1  24.1  21.4  20.0  % With diabetes mellitus or HbA1c > 6.1%  15.8  13.0  13.4  18.0  % With hypertension  31.6  19.9  29.4  42.0‡$  Conventional BP (mm Hg)  125 ± 18/82 ± 12  121 ± 16/80 ± 10  127 ± 20‡/83 ± 12‡  134 ± 24*/87 ± 14*  24-Hour BP (mm Hg)  116 ± 15/73 ± 11  114 ± 11/70 ± 9  118 ± 15‡/73 ± 10‡  126 ± 19**/78 ± 13*  Day BP (mm Hg)  128 ± 15/83 ± 11  121 ± 12#/77 ± 9#  121 ± 15#/77 ± 11#  124 ± 18/79 ± 13  Night BP (mm Hg)  98 ± 12/57 ± 10  103 ± 10/60 ± 9  113 ± 15††/67 ± 11††  129 ± 20***/76 ± 13***  Night-to-day SBP ratio  0.76 ± 0.03  0.86 ± 0.03###  0.94 ± 0.03†††  1.04 ± 0.04***  Night-to-day DBP ratio  0.68 ± 0.06  0.78 ± 0.07###  0.88 ± 0.07†††  0.97 ± 0.08***  24-Hour HR (beats/min)  76.4 ± 10.3  76.0 ± 8.9  77.9 ± 10.0  76.5 ± 7.7  Day HR (beats/min)  83.3 ± 12.5  82.5 ± 10.2  83.1 ± 10.8  80.2 ± 10.3  Night HR (beats/min)  65.9 ± 9.8  66.3 ± 9.4  70.0 ± 10.8†  70.3 ± 8.5‡  LVEDD (cm)  4.71 ± 0.57  4.72 ± 0.52  4.72 ± 0.63  4.69 ± 0.61  E/A  1.32 ± 0.35  1.47 ± 0.49  1.32 ± 0.47‡  1.25 ± 0.54‡  E/e’ (n=)  6.64 ± 2.83 (22)  6.25 ± 3.06 (125)  7.61 ± 5.52 (120)  7.50 ± 3.50 (35)  LV mass index (g/m1.7)  64.74 ± 22.84  61.83 ± 17.53  63.72 ± 24.16  69.39 ± 22.37  RWT  0.37 ± 0.06  0.37 ± 0.07  0.37 ± 0.08  0.40 ± 0.09‡  Aortic pulse wave velocity (m/sec)  5.64 ± 2.46  5.40 ± 2.13  5.85 ± 2.16  6.86 ± 3.11‡$  TPR (mm Hg. min/ml)  22.12 ± 5.43  22.57 ± 7.07  22.98 ± 7.56  26.14 ± 8.04*  Log HOMA-IR  0.66 ± 1.14  0.48 ± 1.04  0.44 ± 0.93  0.59 ± 1.16    Extreme dippers  Dippers  Nondippers  Reverse dippers  Number (%)  38 (7.7)  216 (44.0)  187 (38.1)  50 (10.2)  % Women  55.3  56.0  65.8  64.0  Age (years)  40.8 ± 16.2  36.8 ± 16.2  42.0 ± 16.4‡  48.0 ± 17.0‡‡  Body mass index (kg/m2)  26.9 ± 6.6  26.9 ± 7.2  28.7 ± 7.4  30.4 ± 8.6‡  Regular tobacco intake (% subjects)  18.4  18.5  15.0  20.0  Regular alcohol intake (% subjects)  21.1  24.1  21.4  20.0  % With diabetes mellitus or HbA1c > 6.1%  15.8  13.0  13.4  18.0  % With hypertension  31.6  19.9  29.4  42.0‡$  Conventional BP (mm Hg)  125 ± 18/82 ± 12  121 ± 16/80 ± 10  127 ± 20‡/83 ± 12‡  134 ± 24*/87 ± 14*  24-Hour BP (mm Hg)  116 ± 15/73 ± 11  114 ± 11/70 ± 9  118 ± 15‡/73 ± 10‡  126 ± 19**/78 ± 13*  Day BP (mm Hg)  128 ± 15/83 ± 11  121 ± 12#/77 ± 9#  121 ± 15#/77 ± 11#  124 ± 18/79 ± 13  Night BP (mm Hg)  98 ± 12/57 ± 10  103 ± 10/60 ± 9  113 ± 15††/67 ± 11††  129 ± 20***/76 ± 13***  Night-to-day SBP ratio  0.76 ± 0.03  0.86 ± 0.03###  0.94 ± 0.03†††  1.04 ± 0.04***  Night-to-day DBP ratio  0.68 ± 0.06  0.78 ± 0.07###  0.88 ± 0.07†††  0.97 ± 0.08***  24-Hour HR (beats/min)  76.4 ± 10.3  76.0 ± 8.9  77.9 ± 10.0  76.5 ± 7.7  Day HR (beats/min)  83.3 ± 12.5  82.5 ± 10.2  83.1 ± 10.8  80.2 ± 10.3  Night HR (beats/min)  65.9 ± 9.8  66.3 ± 9.4  70.0 ± 10.8†  70.3 ± 8.5‡  LVEDD (cm)  4.71 ± 0.57  4.72 ± 0.52  4.72 ± 0.63  4.69 ± 0.61  E/A  1.32 ± 0.35  1.47 ± 0.49  1.32 ± 0.47‡  1.25 ± 0.54‡  E/e’ (n=)  6.64 ± 2.83 (22)  6.25 ± 3.06 (125)  7.61 ± 5.52 (120)  7.50 ± 3.50 (35)  LV mass index (g/m1.7)  64.74 ± 22.84  61.83 ± 17.53  63.72 ± 24.16  69.39 ± 22.37  RWT  0.37 ± 0.06  0.37 ± 0.07  0.37 ± 0.08  0.40 ± 0.09‡  Aortic pulse wave velocity (m/sec)  5.64 ± 2.46  5.40 ± 2.13  5.85 ± 2.16  6.86 ± 3.11‡$  TPR (mm Hg. min/ml)  22.12 ± 5.43  22.57 ± 7.07  22.98 ± 7.56  26.14 ± 8.04*  Log HOMA-IR  0.66 ± 1.14  0.48 ± 1.04  0.44 ± 0.93  0.59 ± 1.16  Values are mean ± SD or proportions. SBP dipping patterns: extreme dipper = SBPn/SBPd ≤0.8; dipper = SBPn/SBPd >0.8 and ≤0.9; nondipper = SBPn/SBPd >0.9 and ≤1.0; reverse dipper = SBPn/SBPd ≥1.0. *P < 0.05, **P < 0.001, ***P < 0.0001 vs. other 3 groups; †P < 0.05, ††P < 0.001, †††P < 0.0001 vs. dippers and extreme dippers; ‡P < 0.05, ‡‡P < 0.001 vs. dippers; #P < 0.05, ##P < 0.001, ###P < 0.0001 vs. extreme dippers; $P < 0.05 vs. nondippers. Abbreviations: BP, blood pressure; DBP, diastolic BP; E/A, early-to-late transmitral velocity; E/e’, early transmitral blood flow velocity/mean of lateral and septal wall myocardial tissue lengthening at the mitral annulus; HbA1c, glycosylated hemoglobin; HR, heart rate; Log HOMA-IR, Logarithm of homeostasis model of insulin resistance; LV, left ventricle; LVEDD, left ventricular end diastolic diameter; RWT, relative wall thickness; SBP, systolic BP; SBPd, day SBP; SBPn, night SBP; TPR, total peripheral resistance. View Large Factors associated with BP dipping The factors associated with indexes of BP dipping on bivariate analyses are shown in Supplementary Table S3. Night-to-day BP ratios were associated with night but not day BP. Night-to-day BP ratios were also associated with age, BMI, and hypertension. Although sex, diabetes mellitus, or an HbA1c >6.1%, regular smoking and drinking were associated with night and/or day BP values, these factors were not associated with night-to-day BP ratios. Relationships between BP dipping, day and night BP and indexes of cardiac systolic and diastolic function On bivariate analysis, EF, endFS, and mFS were correlated with BP dipping (night-to-day BP ratios) and night BP; but not day BP (Table 2). In comparison, E/A and E/e’ were associated with BP dipping and both night and day BP (Table 2). After adjusting for confounding variables in multivariate analyses including 24-hour BP (Table 3) or day BP (Supplementary Table S4), the associations of EF, endFS, and mFS with BP dipping and night BP remained (Table 3 and Supplementary Table S4). With regards to indexes of cardiac diastolic function, on multivariate analyses no relationships with indexes of BP dipping were noted (Table 3 and Supplementary Table S4). The multivariate-adjusted relationships between BP dipping or night BP and EF, endFS, and mFS survived further adjustments for either LVMI or RWT (Table 4 and Supplementary Table S5) and were not explained by variations in PWV or log HOMA-IR (Table 4 and Supplementary Table S5). Further adjustments for TPR had no impact on the relationships between EF or endFS and BP dipping. However, the multivariate relationships between SBP dipping or night SBP (but not DBP) and mFS were abolished by further adjustments for TPR (Table 4 and Supplementary Table S5). Table 2. Bivariate relationships between indexes of BP dipping and cardiac function in 491 study participants   SBPn/SBPd ratio  DBPn/DBPd ratio  SBPn  DBPn  SBPd  DBPd    r  P value  r  P value  r  P value  r  P value  r  P value  r  P value  EF  −0.12  0.006  −0.14  0.002  −0.10  0.02  −0.12  0.006  −0.04  0.42  −0.04  0.40  endFS  −0.12  0.006  −0.14  0.001  −0.10  0.03  −0.12  0.006  −0.03  0.56  −0.03  0.44  mFS  −0.12  0.008  −0.15  0.001  −0.13  0.003  −0.15  0.0006  −0.08  0.09  −0.07  0.10  E/A  −0.13  0.003  −0.16  0.0003  −0.31  <0.0001  −0.34  <0.0001  −0.28  <0.0001  −0.29  <0.0001  E/e’ (n = 302)  0.13  0.02  0.15  0.01  0.25  <0.0001  0.19  0.0007  0.19  0.0007  0.11  0.06  LVMI  0.07  0.10  0.12  0.009  0.32  <0.0001  0.25  <0.0001  0.33  <0.0001  0.20  <0.0001  RWT  0.09  0.04  0.09  0.04  0.21  <0.0001  0.21  <0.0001  0.18  <0.0001  0.18  <0.0001    SBPn/SBPd ratio  DBPn/DBPd ratio  SBPn  DBPn  SBPd  DBPd    r  P value  r  P value  r  P value  r  P value  r  P value  r  P value  EF  −0.12  0.006  −0.14  0.002  −0.10  0.02  −0.12  0.006  −0.04  0.42  −0.04  0.40  endFS  −0.12  0.006  −0.14  0.001  −0.10  0.03  −0.12  0.006  −0.03  0.56  −0.03  0.44  mFS  −0.12  0.008  −0.15  0.001  −0.13  0.003  −0.15  0.0006  −0.08  0.09  −0.07  0.10  E/A  −0.13  0.003  −0.16  0.0003  −0.31  <0.0001  −0.34  <0.0001  −0.28  <0.0001  −0.29  <0.0001  E/e’ (n = 302)  0.13  0.02  0.15  0.01  0.25  <0.0001  0.19  0.0007  0.19  0.0007  0.11  0.06  LVMI  0.07  0.10  0.12  0.009  0.32  <0.0001  0.25  <0.0001  0.33  <0.0001  0.20  <0.0001  RWT  0.09  0.04  0.09  0.04  0.21  <0.0001  0.21  <0.0001  0.18  <0.0001  0.18  <0.0001  r, correlation coefficient; SBPn/SBPd ratio, ratio of night SBP to day SBP; DBPn/DBPd ratio, ratio of night DBP to day DBP; SBPn, night SBP; DBPn, night DBP; SBPd, day SBP; DBPd, day DBP; EF, ejection fraction; endFS, endocardial fractional shortening; mFS, midwall fractional shortening; E/A, left ventricular early-to-late transmitral flow velocity; E/e’, early transmitral blood flow velocity/mean of lateral and septal wall myocardial tissue lengthening at the mitral annulus; LVMI, left ventricular mass indexed to height1.7; RWT, relative wall thickness. View Large Table 2. Bivariate relationships between indexes of BP dipping and cardiac function in 491 study participants   SBPn/SBPd ratio  DBPn/DBPd ratio  SBPn  DBPn  SBPd  DBPd    r  P value  r  P value  r  P value  r  P value  r  P value  r  P value  EF  −0.12  0.006  −0.14  0.002  −0.10  0.02  −0.12  0.006  −0.04  0.42  −0.04  0.40  endFS  −0.12  0.006  −0.14  0.001  −0.10  0.03  −0.12  0.006  −0.03  0.56  −0.03  0.44  mFS  −0.12  0.008  −0.15  0.001  −0.13  0.003  −0.15  0.0006  −0.08  0.09  −0.07  0.10  E/A  −0.13  0.003  −0.16  0.0003  −0.31  <0.0001  −0.34  <0.0001  −0.28  <0.0001  −0.29  <0.0001  E/e’ (n = 302)  0.13  0.02  0.15  0.01  0.25  <0.0001  0.19  0.0007  0.19  0.0007  0.11  0.06  LVMI  0.07  0.10  0.12  0.009  0.32  <0.0001  0.25  <0.0001  0.33  <0.0001  0.20  <0.0001  RWT  0.09  0.04  0.09  0.04  0.21  <0.0001  0.21  <0.0001  0.18  <0.0001  0.18  <0.0001    SBPn/SBPd ratio  DBPn/DBPd ratio  SBPn  DBPn  SBPd  DBPd    r  P value  r  P value  r  P value  r  P value  r  P value  r  P value  EF  −0.12  0.006  −0.14  0.002  −0.10  0.02  −0.12  0.006  −0.04  0.42  −0.04  0.40  endFS  −0.12  0.006  −0.14  0.001  −0.10  0.03  −0.12  0.006  −0.03  0.56  −0.03  0.44  mFS  −0.12  0.008  −0.15  0.001  −0.13  0.003  −0.15  0.0006  −0.08  0.09  −0.07  0.10  E/A  −0.13  0.003  −0.16  0.0003  −0.31  <0.0001  −0.34  <0.0001  −0.28  <0.0001  −0.29  <0.0001  E/e’ (n = 302)  0.13  0.02  0.15  0.01  0.25  <0.0001  0.19  0.0007  0.19  0.0007  0.11  0.06  LVMI  0.07  0.10  0.12  0.009  0.32  <0.0001  0.25  <0.0001  0.33  <0.0001  0.20  <0.0001  RWT  0.09  0.04  0.09  0.04  0.21  <0.0001  0.21  <0.0001  0.18  <0.0001  0.18  <0.0001  r, correlation coefficient; SBPn/SBPd ratio, ratio of night SBP to day SBP; DBPn/DBPd ratio, ratio of night DBP to day DBP; SBPn, night SBP; DBPn, night DBP; SBPd, day SBP; DBPd, day DBP; EF, ejection fraction; endFS, endocardial fractional shortening; mFS, midwall fractional shortening; E/A, left ventricular early-to-late transmitral flow velocity; E/e’, early transmitral blood flow velocity/mean of lateral and septal wall myocardial tissue lengthening at the mitral annulus; LVMI, left ventricular mass indexed to height1.7; RWT, relative wall thickness. View Large Table 3. Multivariate-adjusted relationships between indexes of BP dipping and cardiac function in 491 study participants.   SBPn/SBPd ratio  DBPn/DBPd ratio  SBPn  DBPn  SBPd  DBPd  βa  P value  βa  P value  βa  P value  βa  P value  βa  P value  βa  P value  (95% CI)a  (95% CI)a  (95% CI)a  (95% CI)a  (95% CI)a  (95% CI)a  EF  −15.2  0.01  −13.1  0.004  −0.19  0.008  −0.22  0.008  0.19  0.07  0.28  0.02    (−27.0 to −3.4)  (−21.9 to −4.3)  (−0.33 to −0.05)  (−0.38 to −0.06)  (−0.02 to 0.40)  (0.05 to 0.52)  endFS  −12.3  0.01  −10.9  0.003  −0.15  0.009  −0.18  0.008  0.16  0.07  0.25  0.01    (−21.9 to −2.7)  (−18.1 to −3.7)  (−0.27 to −0.04)  (−0.31 to −0.05)  (−0.01 to 0.33)  (0.06 to 0.44)  mFS  −9.5  0.04  −8.5  0.01  −0.11  0.04  −0.14  0.03  0.13  0.13  0.24  0.01    (−18.7 to −0.4)  (−15.3 to −1.7)  (−0.22 to −0.004)  (−0.26 to −0.01)  (−0.04 to 0.29)  (0.06 to 0.42)  E/A  0.12  0.60  0.14  0.42  0.002  0.48  0.003  0.30  −0.002  0.55  −0.003  0.51    (−0.34 to 0.58)  (−0.20 to 0.48)  (−0.004 to 0.008)  (−0.003 to 0.009)  (−0.011 to 0.006)  (−0.012 to 0.006)  E/e’ (n = 302)  4.4  0.17  3.4  0.16  0.045  0.24  0.05  0.26  −0.11  0.07  −0.13  0.03    (−1.9 to 10.7)  (−1.3 to 8.0)  (−0.03 to 0.12)  (−0.04 to 0.14)  (−0.22 to 0.01)  (−0.26 to −0.01)  LVMI  −2.9  0.82  6.4  0.48  0.12  0.40  0.25  0.13  0.33  0.12  −0.02  0.92    (−25.9 to 20.5)  (−11.2 to 24.0)  (−0.15 to 0.40)  (−0.08 to 0.57)  (−0.08 to 0.73)  (−0.50 to 0.45)  RWT  0.02  0.71  0.004  0.91  0.001  0.11  0.001  0.36  0.001  0.33  0.001  0.39    (−0.07 to 0.11)  (−0.064 to 0.072)  (−0.0002 to 0.002)  (−0.001 to 0.002)  (−0.001 to 0.002)  (−0.001 to 0.003)    SBPn/SBPd ratio  DBPn/DBPd ratio  SBPn  DBPn  SBPd  DBPd  βa  P value  βa  P value  βa  P value  βa  P value  βa  P value  βa  P value  (95% CI)a  (95% CI)a  (95% CI)a  (95% CI)a  (95% CI)a  (95% CI)a  EF  −15.2  0.01  −13.1  0.004  −0.19  0.008  −0.22  0.008  0.19  0.07  0.28  0.02    (−27.0 to −3.4)  (−21.9 to −4.3)  (−0.33 to −0.05)  (−0.38 to −0.06)  (−0.02 to 0.40)  (0.05 to 0.52)  endFS  −12.3  0.01  −10.9  0.003  −0.15  0.009  −0.18  0.008  0.16  0.07  0.25  0.01    (−21.9 to −2.7)  (−18.1 to −3.7)  (−0.27 to −0.04)  (−0.31 to −0.05)  (−0.01 to 0.33)  (0.06 to 0.44)  mFS  −9.5  0.04  −8.5  0.01  −0.11  0.04  −0.14  0.03  0.13  0.13  0.24  0.01    (−18.7 to −0.4)  (−15.3 to −1.7)  (−0.22 to −0.004)  (−0.26 to −0.01)  (−0.04 to 0.29)  (0.06 to 0.42)  E/A  0.12  0.60  0.14  0.42  0.002  0.48  0.003  0.30  −0.002  0.55  −0.003  0.51    (−0.34 to 0.58)  (−0.20 to 0.48)  (−0.004 to 0.008)  (−0.003 to 0.009)  (−0.011 to 0.006)  (−0.012 to 0.006)  E/e’ (n = 302)  4.4  0.17  3.4  0.16  0.045  0.24  0.05  0.26  −0.11  0.07  −0.13  0.03    (−1.9 to 10.7)  (−1.3 to 8.0)  (−0.03 to 0.12)  (−0.04 to 0.14)  (−0.22 to 0.01)  (−0.26 to −0.01)  LVMI  −2.9  0.82  6.4  0.48  0.12  0.40  0.25  0.13  0.33  0.12  −0.02  0.92    (−25.9 to 20.5)  (−11.2 to 24.0)  (−0.15 to 0.40)  (−0.08 to 0.57)  (−0.08 to 0.73)  (−0.50 to 0.45)  RWT  0.02  0.71  0.004  0.91  0.001  0.11  0.001  0.36  0.001  0.33  0.001  0.39    (−0.07 to 0.11)  (−0.064 to 0.072)  (−0.0002 to 0.002)  (−0.001 to 0.002)  (−0.001 to 0.002)  (−0.001 to 0.003)  β, beta coefficient; BMI, body mass index; BP, blood pressure; CI, confidence interval; DBPd, day DBP; DBPn, night DBP; DBPn/DBPd ratio, ratio of night DBP to day DBP; E/A, left ventricular early-to-late transmitral flow velocity; E/e’, early transmitral blood flow velocity/mean of lateral and septal wall myocardial tissue lengthening at the mitral annulus; EF, ejection fraction; endFS, endocardial fractional shortening; HbA1c, glycosylated hemoglobin; LVMI, left ventricular mass indexed to height1.7; RWT, relative wall thickness; SBPd, day SBP; SBPn, night SBP; SBPn/SBPd ratio, ratio of night SBP to day SBP; mFS, midwall fractional shortening. aAdjusted for age, sex, BMI, regular smoking, regular alcohol consumption, diabetes or HbA1c > 6.1%, 24-hour pulse rate, 24-hour BP. View Large Table 3. Multivariate-adjusted relationships between indexes of BP dipping and cardiac function in 491 study participants.   SBPn/SBPd ratio  DBPn/DBPd ratio  SBPn  DBPn  SBPd  DBPd  βa  P value  βa  P value  βa  P value  βa  P value  βa  P value  βa  P value  (95% CI)a  (95% CI)a  (95% CI)a  (95% CI)a  (95% CI)a  (95% CI)a  EF  −15.2  0.01  −13.1  0.004  −0.19  0.008  −0.22  0.008  0.19  0.07  0.28  0.02    (−27.0 to −3.4)  (−21.9 to −4.3)  (−0.33 to −0.05)  (−0.38 to −0.06)  (−0.02 to 0.40)  (0.05 to 0.52)  endFS  −12.3  0.01  −10.9  0.003  −0.15  0.009  −0.18  0.008  0.16  0.07  0.25  0.01    (−21.9 to −2.7)  (−18.1 to −3.7)  (−0.27 to −0.04)  (−0.31 to −0.05)  (−0.01 to 0.33)  (0.06 to 0.44)  mFS  −9.5  0.04  −8.5  0.01  −0.11  0.04  −0.14  0.03  0.13  0.13  0.24  0.01    (−18.7 to −0.4)  (−15.3 to −1.7)  (−0.22 to −0.004)  (−0.26 to −0.01)  (−0.04 to 0.29)  (0.06 to 0.42)  E/A  0.12  0.60  0.14  0.42  0.002  0.48  0.003  0.30  −0.002  0.55  −0.003  0.51    (−0.34 to 0.58)  (−0.20 to 0.48)  (−0.004 to 0.008)  (−0.003 to 0.009)  (−0.011 to 0.006)  (−0.012 to 0.006)  E/e’ (n = 302)  4.4  0.17  3.4  0.16  0.045  0.24  0.05  0.26  −0.11  0.07  −0.13  0.03    (−1.9 to 10.7)  (−1.3 to 8.0)  (−0.03 to 0.12)  (−0.04 to 0.14)  (−0.22 to 0.01)  (−0.26 to −0.01)  LVMI  −2.9  0.82  6.4  0.48  0.12  0.40  0.25  0.13  0.33  0.12  −0.02  0.92    (−25.9 to 20.5)  (−11.2 to 24.0)  (−0.15 to 0.40)  (−0.08 to 0.57)  (−0.08 to 0.73)  (−0.50 to 0.45)  RWT  0.02  0.71  0.004  0.91  0.001  0.11  0.001  0.36  0.001  0.33  0.001  0.39    (−0.07 to 0.11)  (−0.064 to 0.072)  (−0.0002 to 0.002)  (−0.001 to 0.002)  (−0.001 to 0.002)  (−0.001 to 0.003)    SBPn/SBPd ratio  DBPn/DBPd ratio  SBPn  DBPn  SBPd  DBPd  βa  P value  βa  P value  βa  P value  βa  P value  βa  P value  βa  P value  (95% CI)a  (95% CI)a  (95% CI)a  (95% CI)a  (95% CI)a  (95% CI)a  EF  −15.2  0.01  −13.1  0.004  −0.19  0.008  −0.22  0.008  0.19  0.07  0.28  0.02    (−27.0 to −3.4)  (−21.9 to −4.3)  (−0.33 to −0.05)  (−0.38 to −0.06)  (−0.02 to 0.40)  (0.05 to 0.52)  endFS  −12.3  0.01  −10.9  0.003  −0.15  0.009  −0.18  0.008  0.16  0.07  0.25  0.01    (−21.9 to −2.7)  (−18.1 to −3.7)  (−0.27 to −0.04)  (−0.31 to −0.05)  (−0.01 to 0.33)  (0.06 to 0.44)  mFS  −9.5  0.04  −8.5  0.01  −0.11  0.04  −0.14  0.03  0.13  0.13  0.24  0.01    (−18.7 to −0.4)  (−15.3 to −1.7)  (−0.22 to −0.004)  (−0.26 to −0.01)  (−0.04 to 0.29)  (0.06 to 0.42)  E/A  0.12  0.60  0.14  0.42  0.002  0.48  0.003  0.30  −0.002  0.55  −0.003  0.51    (−0.34 to 0.58)  (−0.20 to 0.48)  (−0.004 to 0.008)  (−0.003 to 0.009)  (−0.011 to 0.006)  (−0.012 to 0.006)  E/e’ (n = 302)  4.4  0.17  3.4  0.16  0.045  0.24  0.05  0.26  −0.11  0.07  −0.13  0.03    (−1.9 to 10.7)  (−1.3 to 8.0)  (−0.03 to 0.12)  (−0.04 to 0.14)  (−0.22 to 0.01)  (−0.26 to −0.01)  LVMI  −2.9  0.82  6.4  0.48  0.12  0.40  0.25  0.13  0.33  0.12  −0.02  0.92    (−25.9 to 20.5)  (−11.2 to 24.0)  (−0.15 to 0.40)  (−0.08 to 0.57)  (−0.08 to 0.73)  (−0.50 to 0.45)  RWT  0.02  0.71  0.004  0.91  0.001  0.11  0.001  0.36  0.001  0.33  0.001  0.39    (−0.07 to 0.11)  (−0.064 to 0.072)  (−0.0002 to 0.002)  (−0.001 to 0.002)  (−0.001 to 0.002)  (−0.001 to 0.003)  β, beta coefficient; BMI, body mass index; BP, blood pressure; CI, confidence interval; DBPd, day DBP; DBPn, night DBP; DBPn/DBPd ratio, ratio of night DBP to day DBP; E/A, left ventricular early-to-late transmitral flow velocity; E/e’, early transmitral blood flow velocity/mean of lateral and septal wall myocardial tissue lengthening at the mitral annulus; EF, ejection fraction; endFS, endocardial fractional shortening; HbA1c, glycosylated hemoglobin; LVMI, left ventricular mass indexed to height1.7; RWT, relative wall thickness; SBPd, day SBP; SBPn, night SBP; SBPn/SBPd ratio, ratio of night SBP to day SBP; mFS, midwall fractional shortening. aAdjusted for age, sex, BMI, regular smoking, regular alcohol consumption, diabetes or HbA1c > 6.1%, 24-hour pulse rate, 24-hour BP. View Large Table 4. Multivariate-adjusted relationships between indexes of BP dipping and cardiac systolic function after further adjustments for LVMI, RWT, PWV, or TPR in 491 study participants   SBPn/SBPd ratio  DBPn/DBPd ratio  SBPn  DBPn  βa  P value  βa  P value  βa  P value  βa  P value  (95% CI)a    (95% CI)a    (95% CI)a    (95% CI)a    adj + LVMI   EF  −15.1  0.01  −12.9  0.004  −0.18  0.01  −0.21  0.01    (−26.9 to −3.4)  (−21.6 to −4.1)  (−0.32 to −0.04)  (−0.37 to −0.05)   endFS  −12.3  0.01  −10.8  0.003  −0.15  0.01  −0.17  0.01    (−21.8 to −2.7)  (−18.0 to −3.7)  (−0.26 to −0.03)  (−0.30 to −0.04)   mFS  −9.5  0.04  −9.0  0.009  −0.12  0.03  −0.13  0.04    (−18.6 to −0.4)  (−15.8 to −2.3)  (−0.23 to −0.01)  (−0.26 to −0.007)  adj + RWT   EF  −15.2  0.01  −13.1  0.004  −0.19  0.009  −0.22  0.008    (−27.0 to −3.3)  (−21.9 to −4.3)  (−0.33 to −0.05)  (−0.38 to −0.06)   endFS  −12.2  0.01  −10.9  0.003  −0.15  0.01  −0.18  0.009    (−21.8 to −2.6)  (−18.1 to −3.7)  (−0.26 to −0.03)  (−0.31 to −0.04)   mFS  −9.1  0.04  −9.1  0.008  −0.11  0.05  −0.13  0.04    (−18.0 to −0.2)  (−15.7 to −2.4)  (−0.22 to 0.00)  (−0.25 to −0.004)  adj + TPR   EF  −12.5  0.03  −12.8  0.002  −0.16  0.02  −0.21  0.006    (−23.6 to −1.5)  (−21.1 to −4.6)  (−0.29 to −0.02)  (−0.37 to −0.06)   endFS  −9.9  0.03  −10.7  0.002  −0.12  0.03  −0.17  0.005    (−18.8 to −1.0)  (−17.3 to −4.1)  (−0.23 to −0.01)  (−0.30 to −0.05)   mFS  −6.2  0.14  −8.3  0.008  −0.08  0.13  −0.13  0.03    (−14.3 to 2.0)  (−14.4 to −2.2)  (−0.17 to 0.02)  (−0.24 to −0.02)  adj + PWV (n = 442)   EF  −16.9  0.008  −16.3  0.0007  −0.21  0.006  −0.28  0.001    (−29.4 to −4.3)  (−25.6 to −7.0)  (−0.36 to −0.06)  (−0.45 to −0.11)   endFS  −13.5  0.009  −13.5  0.0005  −0.17  0.007  −0.23  0.001    (−23.7 to −3.3)  (−21.1 to −6.0)  (−0.29 to −0.05)  (−0.37 to −0.09)   mFS  −9.7  0.045  −10.7  0.003  −0.12  0.046  −0.16  0.02    (−19.2 to −0.22)  (−17.7 to −3.7)  (−0.23 to −0.002)  (−0.29 to −0.03)  Adj + Log HOMA-IR (n = 451)   EF  −18.8  0.002  −16.1  0.0005  −0.23  0.002  −0.28  0.0009    (−30.8 to −6.7)  (−25.1 to −7.1)  (−0.38 to −0.09)  (−0.45 to −0.12)   endFS  −15.4  0.002  −13.2  0.0005  −0.19  0.002  −0.23  0.001    (−25.4 to −5.5)  (−20.6 to −5.8)  (−0.31 to −0.07)  (−0.36 to −0.09)   mFS  −12.0  0.01  −10.2  0.005  −0.14  0.01  −0.18  0.01    (−21.6 to −2.4)  (−17.4 to −3.0)  (−0.26 to −0.03)  (−0.31 to −0.04)    SBPn/SBPd ratio  DBPn/DBPd ratio  SBPn  DBPn  βa  P value  βa  P value  βa  P value  βa  P value  (95% CI)a    (95% CI)a    (95% CI)a    (95% CI)a    adj + LVMI   EF  −15.1  0.01  −12.9  0.004  −0.18  0.01  −0.21  0.01    (−26.9 to −3.4)  (−21.6 to −4.1)  (−0.32 to −0.04)  (−0.37 to −0.05)   endFS  −12.3  0.01  −10.8  0.003  −0.15  0.01  −0.17  0.01    (−21.8 to −2.7)  (−18.0 to −3.7)  (−0.26 to −0.03)  (−0.30 to −0.04)   mFS  −9.5  0.04  −9.0  0.009  −0.12  0.03  −0.13  0.04    (−18.6 to −0.4)  (−15.8 to −2.3)  (−0.23 to −0.01)  (−0.26 to −0.007)  adj + RWT   EF  −15.2  0.01  −13.1  0.004  −0.19  0.009  −0.22  0.008    (−27.0 to −3.3)  (−21.9 to −4.3)  (−0.33 to −0.05)  (−0.38 to −0.06)   endFS  −12.2  0.01  −10.9  0.003  −0.15  0.01  −0.18  0.009    (−21.8 to −2.6)  (−18.1 to −3.7)  (−0.26 to −0.03)  (−0.31 to −0.04)   mFS  −9.1  0.04  −9.1  0.008  −0.11  0.05  −0.13  0.04    (−18.0 to −0.2)  (−15.7 to −2.4)  (−0.22 to 0.00)  (−0.25 to −0.004)  adj + TPR   EF  −12.5  0.03  −12.8  0.002  −0.16  0.02  −0.21  0.006    (−23.6 to −1.5)  (−21.1 to −4.6)  (−0.29 to −0.02)  (−0.37 to −0.06)   endFS  −9.9  0.03  −10.7  0.002  −0.12  0.03  −0.17  0.005    (−18.8 to −1.0)  (−17.3 to −4.1)  (−0.23 to −0.01)  (−0.30 to −0.05)   mFS  −6.2  0.14  −8.3  0.008  −0.08  0.13  −0.13  0.03    (−14.3 to 2.0)  (−14.4 to −2.2)  (−0.17 to 0.02)  (−0.24 to −0.02)  adj + PWV (n = 442)   EF  −16.9  0.008  −16.3  0.0007  −0.21  0.006  −0.28  0.001    (−29.4 to −4.3)  (−25.6 to −7.0)  (−0.36 to −0.06)  (−0.45 to −0.11)   endFS  −13.5  0.009  −13.5  0.0005  −0.17  0.007  −0.23  0.001    (−23.7 to −3.3)  (−21.1 to −6.0)  (−0.29 to −0.05)  (−0.37 to −0.09)   mFS  −9.7  0.045  −10.7  0.003  −0.12  0.046  −0.16  0.02    (−19.2 to −0.22)  (−17.7 to −3.7)  (−0.23 to −0.002)  (−0.29 to −0.03)  Adj + Log HOMA-IR (n = 451)   EF  −18.8  0.002  −16.1  0.0005  −0.23  0.002  −0.28  0.0009    (−30.8 to −6.7)  (−25.1 to −7.1)  (−0.38 to −0.09)  (−0.45 to −0.12)   endFS  −15.4  0.002  −13.2  0.0005  −0.19  0.002  −0.23  0.001    (−25.4 to −5.5)  (−20.6 to −5.8)  (−0.31 to −0.07)  (−0.36 to −0.09)   mFS  −12.0  0.01  −10.2  0.005  −0.14  0.01  −0.18  0.01    (−21.6 to −2.4)  (−17.4 to −3.0)  (−0.26 to −0.03)  (−0.31 to −0.04)  β, beta coefficient; BMI, body mass index; BP, blood pressure; CI, confidence interval; DBPd, day DBP; DBPn, night DBP; DBPn/DBPd ratio, ratio of night DBP to day DBP; EF, ejection fraction; endFS, endocardial fractional shortening; HbA1c, glycosylated hemoglobin; Log HOMA-IR, logarithm homeostasis model of insulin resistance; LVMI, left ventricular mass indexed to height1.7; mFS, midwall fractional shortening; PWV, pulse wave velocity RWT, relative wall thickness; SBPd, day SBP; SBPn, night SBP; SBPn/SBPd ratio, ratio of night SBP to day SBP; TPR, total peripheral resistance. aAdjusted for age, sex, BMI (only body weight for LVMI), regular smoking, regular alcohol consumption, diabetes or HbA1c > 6.1%, 24-hour pulse rate, 24-hour BP. View Large Table 4. Multivariate-adjusted relationships between indexes of BP dipping and cardiac systolic function after further adjustments for LVMI, RWT, PWV, or TPR in 491 study participants   SBPn/SBPd ratio  DBPn/DBPd ratio  SBPn  DBPn  βa  P value  βa  P value  βa  P value  βa  P value  (95% CI)a    (95% CI)a    (95% CI)a    (95% CI)a    adj + LVMI   EF  −15.1  0.01  −12.9  0.004  −0.18  0.01  −0.21  0.01    (−26.9 to −3.4)  (−21.6 to −4.1)  (−0.32 to −0.04)  (−0.37 to −0.05)   endFS  −12.3  0.01  −10.8  0.003  −0.15  0.01  −0.17  0.01    (−21.8 to −2.7)  (−18.0 to −3.7)  (−0.26 to −0.03)  (−0.30 to −0.04)   mFS  −9.5  0.04  −9.0  0.009  −0.12  0.03  −0.13  0.04    (−18.6 to −0.4)  (−15.8 to −2.3)  (−0.23 to −0.01)  (−0.26 to −0.007)  adj + RWT   EF  −15.2  0.01  −13.1  0.004  −0.19  0.009  −0.22  0.008    (−27.0 to −3.3)  (−21.9 to −4.3)  (−0.33 to −0.05)  (−0.38 to −0.06)   endFS  −12.2  0.01  −10.9  0.003  −0.15  0.01  −0.18  0.009    (−21.8 to −2.6)  (−18.1 to −3.7)  (−0.26 to −0.03)  (−0.31 to −0.04)   mFS  −9.1  0.04  −9.1  0.008  −0.11  0.05  −0.13  0.04    (−18.0 to −0.2)  (−15.7 to −2.4)  (−0.22 to 0.00)  (−0.25 to −0.004)  adj + TPR   EF  −12.5  0.03  −12.8  0.002  −0.16  0.02  −0.21  0.006    (−23.6 to −1.5)  (−21.1 to −4.6)  (−0.29 to −0.02)  (−0.37 to −0.06)   endFS  −9.9  0.03  −10.7  0.002  −0.12  0.03  −0.17  0.005    (−18.8 to −1.0)  (−17.3 to −4.1)  (−0.23 to −0.01)  (−0.30 to −0.05)   mFS  −6.2  0.14  −8.3  0.008  −0.08  0.13  −0.13  0.03    (−14.3 to 2.0)  (−14.4 to −2.2)  (−0.17 to 0.02)  (−0.24 to −0.02)  adj + PWV (n = 442)   EF  −16.9  0.008  −16.3  0.0007  −0.21  0.006  −0.28  0.001    (−29.4 to −4.3)  (−25.6 to −7.0)  (−0.36 to −0.06)  (−0.45 to −0.11)   endFS  −13.5  0.009  −13.5  0.0005  −0.17  0.007  −0.23  0.001    (−23.7 to −3.3)  (−21.1 to −6.0)  (−0.29 to −0.05)  (−0.37 to −0.09)   mFS  −9.7  0.045  −10.7  0.003  −0.12  0.046  −0.16  0.02    (−19.2 to −0.22)  (−17.7 to −3.7)  (−0.23 to −0.002)  (−0.29 to −0.03)  Adj + Log HOMA-IR (n = 451)   EF  −18.8  0.002  −16.1  0.0005  −0.23  0.002  −0.28  0.0009    (−30.8 to −6.7)  (−25.1 to −7.1)  (−0.38 to −0.09)  (−0.45 to −0.12)   endFS  −15.4  0.002  −13.2  0.0005  −0.19  0.002  −0.23  0.001    (−25.4 to −5.5)  (−20.6 to −5.8)  (−0.31 to −0.07)  (−0.36 to −0.09)   mFS  −12.0  0.01  −10.2  0.005  −0.14  0.01  −0.18  0.01    (−21.6 to −2.4)  (−17.4 to −3.0)  (−0.26 to −0.03)  (−0.31 to −0.04)    SBPn/SBPd ratio  DBPn/DBPd ratio  SBPn  DBPn  βa  P value  βa  P value  βa  P value  βa  P value  (95% CI)a    (95% CI)a    (95% CI)a    (95% CI)a    adj + LVMI   EF  −15.1  0.01  −12.9  0.004  −0.18  0.01  −0.21  0.01    (−26.9 to −3.4)  (−21.6 to −4.1)  (−0.32 to −0.04)  (−0.37 to −0.05)   endFS  −12.3  0.01  −10.8  0.003  −0.15  0.01  −0.17  0.01    (−21.8 to −2.7)  (−18.0 to −3.7)  (−0.26 to −0.03)  (−0.30 to −0.04)   mFS  −9.5  0.04  −9.0  0.009  −0.12  0.03  −0.13  0.04    (−18.6 to −0.4)  (−15.8 to −2.3)  (−0.23 to −0.01)  (−0.26 to −0.007)  adj + RWT   EF  −15.2  0.01  −13.1  0.004  −0.19  0.009  −0.22  0.008    (−27.0 to −3.3)  (−21.9 to −4.3)  (−0.33 to −0.05)  (−0.38 to −0.06)   endFS  −12.2  0.01  −10.9  0.003  −0.15  0.01  −0.18  0.009    (−21.8 to −2.6)  (−18.1 to −3.7)  (−0.26 to −0.03)  (−0.31 to −0.04)   mFS  −9.1  0.04  −9.1  0.008  −0.11  0.05  −0.13  0.04    (−18.0 to −0.2)  (−15.7 to −2.4)  (−0.22 to 0.00)  (−0.25 to −0.004)  adj + TPR   EF  −12.5  0.03  −12.8  0.002  −0.16  0.02  −0.21  0.006    (−23.6 to −1.5)  (−21.1 to −4.6)  (−0.29 to −0.02)  (−0.37 to −0.06)   endFS  −9.9  0.03  −10.7  0.002  −0.12  0.03  −0.17  0.005    (−18.8 to −1.0)  (−17.3 to −4.1)  (−0.23 to −0.01)  (−0.30 to −0.05)   mFS  −6.2  0.14  −8.3  0.008  −0.08  0.13  −0.13  0.03    (−14.3 to 2.0)  (−14.4 to −2.2)  (−0.17 to 0.02)  (−0.24 to −0.02)  adj + PWV (n = 442)   EF  −16.9  0.008  −16.3  0.0007  −0.21  0.006  −0.28  0.001    (−29.4 to −4.3)  (−25.6 to −7.0)  (−0.36 to −0.06)  (−0.45 to −0.11)   endFS  −13.5  0.009  −13.5  0.0005  −0.17  0.007  −0.23  0.001    (−23.7 to −3.3)  (−21.1 to −6.0)  (−0.29 to −0.05)  (−0.37 to −0.09)   mFS  −9.7  0.045  −10.7  0.003  −0.12  0.046  −0.16  0.02    (−19.2 to −0.22)  (−17.7 to −3.7)  (−0.23 to −0.002)  (−0.29 to −0.03)  Adj + Log HOMA-IR (n = 451)   EF  −18.8  0.002  −16.1  0.0005  −0.23  0.002  −0.28  0.0009    (−30.8 to −6.7)  (−25.1 to −7.1)  (−0.38 to −0.09)  (−0.45 to −0.12)   endFS  −15.4  0.002  −13.2  0.0005  −0.19  0.002  −0.23  0.001    (−25.4 to −5.5)  (−20.6 to −5.8)  (−0.31 to −0.07)  (−0.36 to −0.09)   mFS  −12.0  0.01  −10.2  0.005  −0.14  0.01  −0.18  0.01    (−21.6 to −2.4)  (−17.4 to −3.0)  (−0.26 to −0.03)  (−0.31 to −0.04)  β, beta coefficient; BMI, body mass index; BP, blood pressure; CI, confidence interval; DBPd, day DBP; DBPn, night DBP; DBPn/DBPd ratio, ratio of night DBP to day DBP; EF, ejection fraction; endFS, endocardial fractional shortening; HbA1c, glycosylated hemoglobin; Log HOMA-IR, logarithm homeostasis model of insulin resistance; LVMI, left ventricular mass indexed to height1.7; mFS, midwall fractional shortening; PWV, pulse wave velocity RWT, relative wall thickness; SBPd, day SBP; SBPn, night SBP; SBPn/SBPd ratio, ratio of night SBP to day SBP; TPR, total peripheral resistance. aAdjusted for age, sex, BMI (only body weight for LVMI), regular smoking, regular alcohol consumption, diabetes or HbA1c > 6.1%, 24-hour pulse rate, 24-hour BP. View Large Relationships between BP dipping pattern and indexes of cardiac systolic function Figure 1 shows the multivariate-adjusted mean values of indexes of cardiac systolic function in the 4 BP dipping patterns. When dipping pattern was defined according to systolic BP, extreme dippers had significantly increased EF, endFS, and mFS compared to the other 3 groups (Figure 1, upper panels). However, when dipping pattern was defined according to diastolic BP, reverse dippers had significantly decreased EF, endFS, and mFS compared to the other 3 groups (Figure 1, lower panels). When nondippers were compared to dippers defined according to systolic BP, adjusted EF (69.5 ± 0.6% vs. 67.7 ± 0.5%, P = 0.04) and endFS (39.7 ± 0.5% vs. 38.3 ± 0.5%, P = 0.05) but not mFS (26.2 ± 0.5% vs. 25.4 ± 0.5%, P = 0.25) were decreased. When nondippers were compared to dippers defined according to diastolic BP, adjusted EF (69.1 ± 0.5% vs. 66.3 ± 1.0%, P = 0.01), endFS (39.4 ± 0.4% vs. 37.3 ± 0.8%, P = 0.02), and mFS (26.1 ± 0.4% vs. 24.3 ± 0.7%, P = 0.03) were decreased. Figure 1. View largeDownload slide Multivariate-adjusted mean values of indexes of cardiac systolic function in the 4 BP dipping patterns defined according to SBP dipping (upper panels) or DBP dipping (lower panels). Adjustments are for age, sex, body mass index, regular smoking, regular alcohol consumption, diabetes mellitus and/or HbA1c > 6.1%, 24-hour heart rate, and 24 hour SBP or DBP. *P < 0.05, **P < 0.005, ***P < 0.0005 vs. extreme dippers; †P < 0.0005 vs. dippers; #P < 0.005 vs. nondippers. Abbreviations: BP, blood pressure; DBP, diastolic BP; EF, ejection fraction; endFS, endocardial fractional shortening; HbA1c, glycosylated hemoglobin; mFS, midwall fractional shortening; SBP, systolic BP. Figure 1. View largeDownload slide Multivariate-adjusted mean values of indexes of cardiac systolic function in the 4 BP dipping patterns defined according to SBP dipping (upper panels) or DBP dipping (lower panels). Adjustments are for age, sex, body mass index, regular smoking, regular alcohol consumption, diabetes mellitus and/or HbA1c > 6.1%, 24-hour heart rate, and 24 hour SBP or DBP. *P < 0.05, **P < 0.005, ***P < 0.0005 vs. extreme dippers; †P < 0.0005 vs. dippers; #P < 0.005 vs. nondippers. Abbreviations: BP, blood pressure; DBP, diastolic BP; EF, ejection fraction; endFS, endocardial fractional shortening; HbA1c, glycosylated hemoglobin; mFS, midwall fractional shortening; SBP, systolic BP. Impact of TPR on relationships between BP dipping pattern and indexes of cardiac systolic function Figure 2 shows the impact of further adjustments for TPR on the multivariate-adjusted mean values of indexes of cardiac systolic function in the 4 BP dipping patterns. After further adjustments for TPR, EF, endFS, and mFS remained increased in the extreme dippers compared to the other 3 groups, when dipping pattern was defined according to systolic BP (Figure 2, upper panels). When dipping pattern was defined according to diastolic BP, further adjustments for TPR also had no impact on the decreased EF, endFS, and mFS in the reverse dippers compared to the other 3 groups (Figure 2, lower panels). Figure 2. View largeDownload slide Impact of further adjustment for TPR on multivariate-adjusted mean values of indexes of cardiac systolic function in the 4 BP dipping patterns defined according to SBP dipping (upper panels) or DBP dipping (lower panels). Adjustments are for age, sex, body mass index, regular smoking, regular alcohol consumption, diabetes mellitus and/or HbA1c > 6.1%, 24-hour heart rate, 24-hour SBP or DBP and TPR. *P < 0.05, **P < 0.005, ***P < 0.0005 vs. extreme dippers; †P < 0.005 vs. dippers; #P < 0.01 vs. nondippers. Abbreviations: BP, blood pressure; DBP, diastolic BP; EF, ejection fraction; endFS, endocardial fractional shortening; HbA1c, glycosylated hemoglobin; mFS, midwall fractional shortening; SBP, systolic BP; TPR, total peripheral resistance. Figure 2. View largeDownload slide Impact of further adjustment for TPR on multivariate-adjusted mean values of indexes of cardiac systolic function in the 4 BP dipping patterns defined according to SBP dipping (upper panels) or DBP dipping (lower panels). Adjustments are for age, sex, body mass index, regular smoking, regular alcohol consumption, diabetes mellitus and/or HbA1c > 6.1%, 24-hour heart rate, 24-hour SBP or DBP and TPR. *P < 0.05, **P < 0.005, ***P < 0.0005 vs. extreme dippers; †P < 0.005 vs. dippers; #P < 0.01 vs. nondippers. Abbreviations: BP, blood pressure; DBP, diastolic BP; EF, ejection fraction; endFS, endocardial fractional shortening; HbA1c, glycosylated hemoglobin; mFS, midwall fractional shortening; SBP, systolic BP; TPR, total peripheral resistance. DISCUSSION The main findings of the present study are as follows: In participants from a community sample who were not receiving antihypertensive therapy, BP dipping and hence nocturnal but not day BP was associated with indexes of cardiac systolic function independent of confounders including 24 hour (or day) BP, LVMI, and RWT. Hence, it is possible that blunted nocturnal BP dipping contributes to a reduced cardiac systolic function prior to the development of HF with a reduced systolic function. The negative impact of BP dipping on cardiac systolic function was not explained by variations in PWV or HOMA-IR, but was in-part explained by variations in TPR. To our knowledge, only 3 previous studies have assessed the impact of BP dipping on cardiac systolic function in untreated participants.9–11 In a small study sample (n = 56) of untreated hypertensive participants,9 EF was reduced in nondippers (defined as absence of nocturnal BP fall [day MAP minus night MAP/day MAP × 100%] ≥10%) compared to dippers. However, in comparing these 2 groups, no adjustments were made for potential confounding variables. Similarly, in a study including hypertensives with LV hypertrophy (n = 75), hypertensives without LV hypertrophy (n = 35), and normotensives (n = 23), none of whom were receiving antihypertensive therapy, decreases in EF and increases in BNP and ANP were reported in nondippers (defined as night/day MAP >0.9) compared to dippers, without adjustments for confounding variables.10 In this regard, the nondippers were older than the dippers; but no data on BMI were given. In a large cohort (n = 1702), of never-treated essential hypertensives, those with depressed endFS or mFS in the absence of HF, had reduced day–night BP changes compared to patients with normal endFS or mFS.11 Moreover, after adjustments for age and gender, the night-to-day systolic BP ratio was associated with both endocardial and midwall FS in these patients.11 However, in that study11 despite higher LVMI values and a more concentric geometry in patients with a depressed endFS and mFS, associations between night-to-day BP ratios and FS were only adjusted for age and gender. Hence, in that study,11 LV concentric hypertrophy may have explained the relationship between night-to-day BP ratio and FS. Indeed, FS showed stronger relationships with LVM than with night-to-day BP ratio.11 Our data strengthen these previous reports,9–11 by indicating in a relatively large study sample of untreated participants that indexes of cardiac systolic function are associated with nocturnal BP dipping and nocturnal but not day BP independent of several possible confounding variables. Importantly, we report that these associations are independent of LVMI and RWT, which are associated with both BP dipping21 and cardiac dysfunction. Although the multivariate-adjusted associations reported in the current study are fairly weak (correlation coefficients ranging from −0.10 to −0.15), they translated into differences of 6.6% in EF, 5.5% in endFS, and 4.3% in mFS between extreme dippers and reverse dippers. In addition, the associations reported in the current study are similar to the correlation coefficients of −0.07 between night-to-day SBP ratio and endFS, and −0.09 between night-to-day SBP ratio and mFS, previously reported.11 In the current study, nondipping was due to a higher night but not day BP. Neurohormonal factors implicated in blunted nocturnal dipping include increased activation of the sympathetic nervous system6 and the renin–angiotensin–aldosterone system.7 In addition, nondippers have increased plasma catecholamine concentrations34 and a decrease in the activity of the parasympathetic nervous system35 compared to dippers. With respect to the increased sympathetic nervous system activation, blunted nocturnal dipping is mediated by elevated nocturnal norepinephrine levels (reduced nocturnal fall in excretion of norepinephrine) which are not related to physical or mental activity.6 In addition, increased alpha-1 adrenergic receptor responsiveness in the absence of changes in beta adrenergic receptor responsiveness occurs in nondippers compared to dippers.6 The heightened sympathetic nervous system activity during sleep would translate into increases in nocturnal BP secondary to increases in TPR. Indeed, in the present study increases in TPR were noted in the reverse dippers compared to the other 3 groups. The increased TPR in the reverse dippers is likely to reflect an enhanced vasoconstriction mediated by augmented sympathetic nervous system activity in this group. Indeed, the reverse dippers had an increased night HR compared to the dippers which could be attributed to increased sympathetic nervous system activity and/or decreased parasympathetic nervous system activity at night. Possible explanations for the association of BP dipping with cardiac systolic function warrant discussion. In this regard, although BP dipping has been associated with aging,15,16 male gender,15,16 obesity,15,16 and BP level,16 only age is associated with BP dipping independent of daytime BP.15 Other factors reported to be associated with BP dipping include insulin resistance17 and PWV.18,19 In this regard, hypertensives who were reverse dippers are reported to have higher multivariate-adjusted PWV compared to dippers or nondippers.18 Indeed, PWV is reported to be an independent predictor of diminished nocturnal BP dipping.19 In addition, in patients with essential hypertension, increases in LVMI and RWT have been reported in nondippers compared to dippers.21 Hence, in order to determine the independent effect of reduced BP dipping on cardiac systolic function, adjustments for these confounding factors are paramount, an approach not conducted in previous studies.9–11 In the present study, the negative impact of blunted BP dipping on cardiac systolic function was independent of the potential confounding effects of age, gender, obesity, LVMI, RWT, and BP level. However, TPR which was increased in the reverse dippers compared to the other 3 groups in-part explained the inverse relationship between SBP dipping and mFS. Conversely, the negative relationship between dipping and systolic function may reflect reverse causality. Indeed, reductions in systolic function would reduce BP, hence resulting in compensatory vasoconstriction and an increase in TPR. Nevertheless, the lack of impact of adjustments for TPR on the relationship between nondipping and endFS in the present study may be a consequence of TPR being calculated during the day rather than at night. Hence, further studies are required to determine whether increases in nocturnal TPR account for the negative relationship between dipping and systolic function. Although, the relationships between BP dipping and cardiac function in patients who are in HF are difficult to interpret, it is worth noting that previous studies have reported an association between nondipping and HF with reduced EF.4,36 In addition, in a longitudinal follow-up study (~9 years), night DBP and nondipping were predictors of the development of congestive HF independent of antihypertensive medication, myocardial infarction, diabetes, smoking, BMI, serum cholesterol, and 24-hour ambulatory BP.36 In contrast, a high morning surge of BP (>23 mm Hg) in dippers was independently associated with risk of development of HF with reduced EF, whereas nondipping was independently associated with risk of development of HF with preserved EF over ~9 years in elderly hypertensive patients.36 The present data are of clinical importance as they indicate that blunted nocturnal BP dipping is associated with reduced cardiac systolic function prior to the development of HF with a reduced EF. The implications are that the reversal of BP dipping could be beneficial in the prevention and/or slowing of the progression from cardiac systolic dysfunction to HF with reduced EF. In this regard, a number of studies have reported the restoration of BP dipping after the administration of various antihypertensive agents.12–14 However, longitudinal studies are required to determine whether changes in BP dipping translate into changes in cardiac systolic function. The limitations of the present study are the cross-sectional, rather than prospective nature of the study design and the lack of outcomes data. Although cause and effect cannot be concluded from a cross-sectional study, it is important to note that in a small study (n = 42), the restoration of BP dipping, with calcium channel blocker therapy in 8 patients with hypertension and diabetes mellitus, was associated with increases in EF.37 No changes in EF were noted in the patients in whom BP dipping patterns remained unaltered after calcium channel blocker therapy.37 Secondly, as the data were collected in a population consisting predominantly of women, it is possible that the results of the present study pertain primarily to women. As the current data were collected in a cross-sectional population (27% hypertensive) of participants of Black African ancestry, and previous data were collected in hypertensive and normotensive Caucasian patients,10,11 or in hypertensive and normotensive patients from Japan,9 it is unlikely that these data pertain only to hypertensives or to participants of Black African ancestry. In conclusion, the results of the present study suggest that blunted nocturnal BP dipping is implicated in reductions in cardiac systolic function. Moreover, the data suggest that the relationships between BP dipping and indexes of cardiac systolic function are not explained by variations in insulin resistance, arterial stiffness, LVMI, or concentric LV remodeling but are associated with an increased nocturnal BP which may in-part be determined by variations in vascular resistance. Further longitudinal studies are, however, required to assess whether changes in BP dipping status translate into changes in cardiac systolic function in the absence of HF. SUPPLEMENTARY DATA Supplementary data are available at American Journal of Hypertension online. DISCLOSURE The authors declared no conflict of interest. ACKNOWLEDGMENTS The present study was supported by the Medical Research Council of South Africa, the South African National Research Foundation, the Circulatory Disorders Research Trust, and the University Research Council of the University of the Witwatersrand,. This study would not have been possible without the voluntary collaboration of the participants. We are very grateful for the excellent technical assistance of Mthuthuzeli Kiviet, Nkele Maseko, Nomonde Molebatsi, and Delene Nciweni. REFERENCES 1. Sega R, Facchetti R, Bombelli M, Cesana G, Corrao G, Grassi G, Mancia G. Prognostic value of ambulatory and home blood pressures compared with office blood pressure in the general population: follow-up results from the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study. Circulation   2005; 111: 1777– 1783. Google Scholar CrossRef Search ADS PubMed  2. 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Afsar B, Elsurer R, Kirkpantur A, Kanbay M. Urinary sodium excretion and ambulatory blood pressure findings in patients with hypertension. J Clin Hypertens (Greenwich)   2015; 17: 200– 206. Google Scholar CrossRef Search ADS PubMed  21. Verdecchia P, Schillaci G, Guerrieri M, Gatteschi C, Benemio G, Boldrini F, Porcellati C. Circadian blood pressure changes and left ventricular hypertrophy in essential hypertension. Circulation   1990; 81: 528– 536. Google Scholar CrossRef Search ADS PubMed  22. Norton GR, Maseko M, Libhaber E, Libhaber CD, Majane OH, Dessein P, Sareli P, Woodiwiss AJ. Is prehypertension an independent predictor of target organ changes in young-to-middle-aged persons of African descent? J Hypertens   2008; 26: 2279– 2287. Google Scholar CrossRef Search ADS PubMed  23. Woodiwiss AJ, Libhaber CD, Majane OH, Libhaber E, Maseko M, Norton GR. Obesity promotes left ventricular concentric rather than eccentric geometric remodeling and hypertrophy independent of blood pressure. Am J Hypertens   2008; 21: 1144– 1151. Google Scholar CrossRef Search ADS PubMed  24. Woodiwiss AJ, Molebatsi N, Maseko MJ, Libhaber E, Libhaber C, Majane OH, Paiker J, Dessein P, Brooksbank R, Sareli P, Norton GR. Nurse-recorded auscultatory blood pressure at a single visit predicts target organ changes as well as ambulatory blood pressure. J Hypertens   2009; 27: 287– 297. Google Scholar CrossRef Search ADS PubMed  25. Majane OH, Norton GR, Maseko MJ, Makaula S, Crowther N, Paiker J, Thijs L, Brooksbank R, Sareli P, Staessen JA, Woodiwiss AJ. The association of waist circumference with ambulatory blood pressure is independent of alternative adiposity indices. J Hypertens   2007; 25: 1798– 1806. Google Scholar CrossRef Search ADS PubMed  26. 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Autonomic nervous system activity in dipper and non-dipper essential hypertensive patients. What about sex differences? J Hypertens   1999; 17: 1805– 1811. Google Scholar CrossRef Search ADS PubMed  36. Pierdomenico SD, Pierdomenico AM, Coccina F, Lapenna D, Porreca E. Ambulatory blood pressure parameters and heart failure with reduced or preserved ejection fraction in elderly treated hypertensive patients. Am J Hypertens   2016; 29: 1001– 1007. Google Scholar CrossRef Search ADS PubMed  37. Ko GT, Chan HC. Restoration of nocturnal dip in blood pressure is associated with improvement in left ventricular ejection fraction. A 1-year clinical study comparing the effects of amlodipine and nifedipine retard on ambulatory blood pressure and left ventricular systolic function in Chinese hypertensive type 2 diabetic patients. Int J Cardiol   2003; 89: 159– 166. Google Scholar CrossRef Search ADS PubMed  © American Journal of Hypertension, Ltd 2018. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png American Journal of Hypertension Oxford University Press

Impact of Blunted Nocturnal Blood Pressure Dipping on Cardiac Systolic Function in Community Participants Not Receiving Antihypertensive Therapy

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Oxford University Press
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© American Journal of Hypertension, Ltd 2018. All rights reserved. For Permissions, please email: journals.permissions@oup.com
ISSN
0895-7061
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1941-7225
D.O.I.
10.1093/ajh/hpy075
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Abstract

Abstract BACKGROUND Blunted nocturnal blood pressure (BP) dipping (nondipping) predicts cardiovascular morbidity and mortality, and is associated with heart failure (HF) independent of office BP. Whether nondipping is independently associated with cardiac systolic function prior to the development of HF is uncertain. METHODS We assessed whether nocturnal BP dipping pattern and nocturnal BP were associated with indexes of cardiac systolic function [endocardial fractional shortening (endFS), midwall FS (mFS), ejection fraction (EF)] independent of left ventricular mass index (LVMI) and relative wall thickness (RWT) in 491 randomly selected community participants not receiving antihypertensive therapy. Nocturnal BP and dipping pattern were determined from 24-hour BP monitoring where nighttime was defined from fixed-clock time intervals. BP dipping was defined as night-to-day BP ratio. Pulse wave velocity (PWV) was determined using SphygmoCor, and total peripheral resistance (TPR) was calculated from echocardiographic data. RESULTS On bivariate analyses, nocturnal BP and BP dipping but not day BP were correlated with indexes of cardiac systolic function (P < 0.005). After adjustments for potential confounders including age, LVMI (or RWT) and 24 hour (or day) BP, endFS (P < 0.01), mFS (P < 0.05), and EF (P < 0.01) were associated with nocturnal BP and BP dipping. These relationships survived further adjustments for PWV, and the homeostasis model of insulin resistance. The decreased mFS in reverse dippers was in-part explained by an increased TPR. CONCLUSIONS In an untreated community sample, blunted nocturnal BP dipping is independently and inversely associated with cardiac systolic function. Hence, nondipping is related to a reduced cardiac systolic function prior to the development of HF. ambulatory blood pressure, blood pressure, blood pressure dipping, cardiac systolic function, hypertension, nocturnal blood pressure Nocturnal blood pressure (BP) and blunted nocturnal BP dipping (nondipping) are associated with increased cardiovascular mortality and morbidity, independent of office BP and cardiovascular risk factors.1,2 Moreover, in a longitudinal study (~9 years follow-up), nocturnal BP and nondipping conveyed risk for the development of congestive heart failure (HF), excluding myocardial infarction, beyond office BP, and cardiovascular risk factors.3 In addition, in patients with HF, nondipping has been independently associated with both HF with reduced ejection fraction (EF) as well as HF with preserved EF.4 However, patients in HF have increased activation of the sympathetic nervous system as well as the renin–angiotensin–aldosterone system,5 both of which have been implicated in the blunting of nocturnal BP dipping.6,7 Hence, whether nondipping is causally related to reductions in cardiac systolic function prior to the development of HF is unclear. Although a number of previous studies have explored the relationship between BP dipping and cardiac diastolic function, there is limited data on cardiac systolic function. Indeed, a recent systematic review and meta-analysis in untreated hypertensives reported increases in left ventricular mass index (LVMI), relative wall thickness (RWT), and left atrial diameter and reductions in the ratio of early (E) to late (A) mitral inflow velocity (E/A ratio) (not significant after correction for publication bias) in nondippers compared to dippers.8 However, no studies assessing cardiac systolic function were included in this systematic review and meta-analysis. To our knowledge, only 2 previous small (n = 56–133) studies9,10 and 1 large study (n = 1,702)11 have assessed the impact of BP dipping on cardiac systolic function in participants not receiving antihypertensive therapy. As antihypertensive therapy has an impact on both BP dipping12–14 and cardiac function, it is important that only untreated participants are assessed in order to avoid the potential confounding effects of treatment. Although in both of the previous small studies,9,10 EF was decreased in nondippers compared to dippers, in comparing these 2 groups of participants no adjustments were made for potential confounding variables. In this regard, several factors are associated with blunted nocturnal BP dipping include age,15,16 sex,15,16 obesity,15,16 insulin resistance,17 BP level,16 pulse wave velocity (PWV),18,19 total peripheral resistance (TPR),20 LVMI,21 and RWT.21 Moreover, although relations between cardiac systolic function and day–night BP changes were noted in the large study,11 patients with a depressed systolic function also had a higher LVMI and a more concentric geometry. In addition, in this large study, adjustments were made for only age and sex.11 Hence, in the present study, we assessed whether the nocturnal BP dipping pattern and nocturnal BP were associated with indexes of cardiac systolic function [endocardial fractional shortening (endFS), midwall FS (mFS), EF] independent of LVMI and RWT in randomly selected participants not receiving antihypertensive therapy from an urban, developing community. In addition, we assessed whether relationships between nocturnal BP dipping and indexes of cardiac systolic function were explained by variations in PWV, TPR, or insulin resistance. METHODS Study group The present study was approved by the Committee for Research on Human Subjects of the University of the Witwatersrand (approval number: M02-04-72, renewed as M07-04-69, M12-04-108, and M17-04-01). Participants gave informed written consent. The study design and the population sampled has previously been described.22–25 Briefly, 1,445 participants older than 16 years of age from nuclear families of Black African ancestry (Nguni and Sotho chiefdoms) were randomly recruited from the South West Township (SOWETO) of Johannesburg, South Africa from 2002 to 2017 using the population census figures of 2001. Of these participants, 1,082 were not receiving antihypertensive therapy, and in a substudy, 491 had both 24-hour ambulatory BP monitoring that met with the European Society of Hypertension (ESH) guidelines (longer than 14 and 7 readings for the computation of day and night means, respectively),26 and echocardiographic assessments. Clinical, demographic, and anthropometric measurements A standardized questionnaire was administered to obtain demographic and clinical data as previously described.22–25 As this was a community-based study, nontreatment of hypertension was by self-report on the questionnaire. In addition, however, the participants brought all prescribed medications with them so that the medications could be confirmed as antihypertensive agents or not. Conventional BP was determined from the mean of 5 nurse-derived BP measurements obtained with a mercury sphygmomanometer as previously described.24 From height and weight measurements, body mass index (BMI) was calculated and participants were identified as being overweight if their BMI was ≥25 kg/m2 and obese if their BMI was ≥30 kg/m2. Waist circumference was assessed using a standard approach. Blood lipid profiles and percentage glycated hemoglobin (HbA1c) were determined. Diabetes mellitus or abnormal blood glucose control was defined as the use of insulin or oral hypoglycemic agents or an HbA1c value greater than 6.1%.27 Participants were classified as hypertensive if conventional BP values were ≥140/90 mm Hg. Fasting plasma insulin concentrations were determined from an insulin Immulite, solid phase, 2-site chemiluminescent immunometric assay (Diagnostic Products Corporation, Los Angeles, CA). Insulin resistance was estimated by the homeostasis model assessment of insulin resistance (HOMA-IR) using the formula (insulin [μU/ml] × glucose [mmol/l])/22.5. Ambulatory BP Twenty four-hour ambulatory BP monitoring was performed using oscillometric monitors (SpaceLabs, model 90207) as previously described (see online Supplemental Methods).24,25 The average (±SD) number of BP readings obtained was 59.8 ± 12.2 (range = 24–81) for the 24-hour period, 29.5 ± 6.6 (range = 14–41) for the day and 9.6 ± 0.8 (range = 7–11) for the night periods. Systolic and diastolic BP dipping were calculated for each participant as night-to-day BP ratio expressed as a percentage. Four BP dipping patterns (extreme dipper, dipper, nondipper, reverse dipper) were defined as extreme dipper if night-to-day BP ratio was ≤0.8; dipper if night-to-day BP ratio >0.8 and ≤0.9; nondipper if night-to-day BP ratio >0.9 and ≤1.0; and reverse dipper if night-to-day BP ratio >1.0.2,28 Pulse wave analysis On the same day as ambulatory BP monitoring was performed, aortic (carotid-femoral) PWV was estimated using carotid and femoral applanation tonomtery (high-fidelity SPC-301 micromanometer, Millar Instrument, Inc., Houston, TX) interfaced with a computer employing SphygmoCor, version 9.0 software (AtCor Medical Pty. Ltd., West Ryde, New South Wales, Australia) as described previously (see online Supplementary Data).22,24 Echocardiography Echocardiographic measurements were recorded and analyzed offline by experienced investigators who were unaware of the clinical data of the participants and whom had a low degree of interobserver and intraobserver variability.29 The LV dimensions were measured only when appropriate visualization of both the right and the left septal surfaces occurred and where the endocardial surfaces of both the septal and posterior wall were clearly visible. Left ventricular EF was calculated using the biplane Simpson method. In addition, left ventricular function was assessed at both the chamber (endFS) and the mFS level. Midwall FS was calculated using a modified ellipsoidal model as previously described30 which accounts for epicardial migration of the midwall during systole. Total peripheral resistance was calculated as mean arterial pressure/cardiac output. Left ventricular mass index was determined from transthoracic 2-dimensional targeted M-mode echocardiography with the participants in the partial left decubitus position, as previously described.24,29 Echocardiography recordings were analyzed according to the American Society of Echocardiography convention.30 Left ventricular mass was determined using a standard formula31 and indexed (LVMI) to height1.7. Left ventricular hypertrophy was identified as LVMI >80 g/m1.7 for men and >60 g/m1.7 for women.32 Left ventricular diastolic function was assessed from a pulsed wave Doppler examination of the mitral inflow at rest and using TDI (see online Supplementary Data).33 Data analysis For database management and statistical analysis, SAS software, version 9.4 (SAS Institute Inc., Cary, NC) was employed. Data are shown as mean ± SD. Multivariate-adjusted linear (continuous data) or logistic (discrete data) regression analysis was performed to determine independent relations. Potential confounders were identified on bivariate relationships with indexes of cardiac function or BP dipping. In multivariate analyses adjustments were made for age, sex, BMI, regular smoking, regular alcohol consumption, diabetes mellitus, and/or HbA1c >6.1%, 24 hour (or day) heart rate, and 24 hour (or day) BP. To determine whether BP dipping vs. cardiac function relations were independent of LVMI or RWT, further adjustments were made for LVMI and RWT, respectively. Similarly, to determine whether relationships between nocturnal BP dipping and indexes of cardiac systolic function were explained by variations in PWV, TPR, or insulin resistance, in separate models further adjustments were made for PWV, TPR, or log HOMA-IR (transformed to improve distribution). RESULTS Characteristics of the participants Comparisons between the characteristics of those included and those not included in the study are shown in the online supplement (Supplementary Table S1). Participants with 24-hour ambulatory BP monitoring and high-quality echocardiographic data had similar characteristics to participants without either high-quality 24-hour ambulatory BP monitoring or echocardiographic data. Table 1 compares the characteristics of the participants in the 4 SBP dipping patterns. The reverse dippers were older and had a higher BMI than the dippers. Moreover, the reverse dippers had higher 24-hour BP, night BP, and TPR but not day BP and day HR than the other 3 groups. The nondippers also had a higher night BP than the dippers and extreme dippers; but day BP was lower than the extreme dippers. The reverse dippers had an increased night HR than the dippers, but neither 24 hour nor day HR differed from that of the other 3 groups. Neither LVMI, nor the proportion of participants with LV hypertrophy differed across the 4 groups (extreme dippers = 39.5%, dippers = 35.7%, nondippers = 40.6%; reverse dippers = 48.0%). Supplementary Table S2 compares the characteristics of the participants who were dippers compared to those who were nondippers according to SBP. The nondippers were older and had a higher BMI, PWV, 24 hour BP, night BP, and night HR; but not day BP. Table 1. Demographic, clinical, and hemodynamic characteristics of the 491 study participants according to SBP dipping pattern   Extreme dippers  Dippers  Nondippers  Reverse dippers  Number (%)  38 (7.7)  216 (44.0)  187 (38.1)  50 (10.2)  % Women  55.3  56.0  65.8  64.0  Age (years)  40.8 ± 16.2  36.8 ± 16.2  42.0 ± 16.4‡  48.0 ± 17.0‡‡  Body mass index (kg/m2)  26.9 ± 6.6  26.9 ± 7.2  28.7 ± 7.4  30.4 ± 8.6‡  Regular tobacco intake (% subjects)  18.4  18.5  15.0  20.0  Regular alcohol intake (% subjects)  21.1  24.1  21.4  20.0  % With diabetes mellitus or HbA1c > 6.1%  15.8  13.0  13.4  18.0  % With hypertension  31.6  19.9  29.4  42.0‡$  Conventional BP (mm Hg)  125 ± 18/82 ± 12  121 ± 16/80 ± 10  127 ± 20‡/83 ± 12‡  134 ± 24*/87 ± 14*  24-Hour BP (mm Hg)  116 ± 15/73 ± 11  114 ± 11/70 ± 9  118 ± 15‡/73 ± 10‡  126 ± 19**/78 ± 13*  Day BP (mm Hg)  128 ± 15/83 ± 11  121 ± 12#/77 ± 9#  121 ± 15#/77 ± 11#  124 ± 18/79 ± 13  Night BP (mm Hg)  98 ± 12/57 ± 10  103 ± 10/60 ± 9  113 ± 15††/67 ± 11††  129 ± 20***/76 ± 13***  Night-to-day SBP ratio  0.76 ± 0.03  0.86 ± 0.03###  0.94 ± 0.03†††  1.04 ± 0.04***  Night-to-day DBP ratio  0.68 ± 0.06  0.78 ± 0.07###  0.88 ± 0.07†††  0.97 ± 0.08***  24-Hour HR (beats/min)  76.4 ± 10.3  76.0 ± 8.9  77.9 ± 10.0  76.5 ± 7.7  Day HR (beats/min)  83.3 ± 12.5  82.5 ± 10.2  83.1 ± 10.8  80.2 ± 10.3  Night HR (beats/min)  65.9 ± 9.8  66.3 ± 9.4  70.0 ± 10.8†  70.3 ± 8.5‡  LVEDD (cm)  4.71 ± 0.57  4.72 ± 0.52  4.72 ± 0.63  4.69 ± 0.61  E/A  1.32 ± 0.35  1.47 ± 0.49  1.32 ± 0.47‡  1.25 ± 0.54‡  E/e’ (n=)  6.64 ± 2.83 (22)  6.25 ± 3.06 (125)  7.61 ± 5.52 (120)  7.50 ± 3.50 (35)  LV mass index (g/m1.7)  64.74 ± 22.84  61.83 ± 17.53  63.72 ± 24.16  69.39 ± 22.37  RWT  0.37 ± 0.06  0.37 ± 0.07  0.37 ± 0.08  0.40 ± 0.09‡  Aortic pulse wave velocity (m/sec)  5.64 ± 2.46  5.40 ± 2.13  5.85 ± 2.16  6.86 ± 3.11‡$  TPR (mm Hg. min/ml)  22.12 ± 5.43  22.57 ± 7.07  22.98 ± 7.56  26.14 ± 8.04*  Log HOMA-IR  0.66 ± 1.14  0.48 ± 1.04  0.44 ± 0.93  0.59 ± 1.16    Extreme dippers  Dippers  Nondippers  Reverse dippers  Number (%)  38 (7.7)  216 (44.0)  187 (38.1)  50 (10.2)  % Women  55.3  56.0  65.8  64.0  Age (years)  40.8 ± 16.2  36.8 ± 16.2  42.0 ± 16.4‡  48.0 ± 17.0‡‡  Body mass index (kg/m2)  26.9 ± 6.6  26.9 ± 7.2  28.7 ± 7.4  30.4 ± 8.6‡  Regular tobacco intake (% subjects)  18.4  18.5  15.0  20.0  Regular alcohol intake (% subjects)  21.1  24.1  21.4  20.0  % With diabetes mellitus or HbA1c > 6.1%  15.8  13.0  13.4  18.0  % With hypertension  31.6  19.9  29.4  42.0‡$  Conventional BP (mm Hg)  125 ± 18/82 ± 12  121 ± 16/80 ± 10  127 ± 20‡/83 ± 12‡  134 ± 24*/87 ± 14*  24-Hour BP (mm Hg)  116 ± 15/73 ± 11  114 ± 11/70 ± 9  118 ± 15‡/73 ± 10‡  126 ± 19**/78 ± 13*  Day BP (mm Hg)  128 ± 15/83 ± 11  121 ± 12#/77 ± 9#  121 ± 15#/77 ± 11#  124 ± 18/79 ± 13  Night BP (mm Hg)  98 ± 12/57 ± 10  103 ± 10/60 ± 9  113 ± 15††/67 ± 11††  129 ± 20***/76 ± 13***  Night-to-day SBP ratio  0.76 ± 0.03  0.86 ± 0.03###  0.94 ± 0.03†††  1.04 ± 0.04***  Night-to-day DBP ratio  0.68 ± 0.06  0.78 ± 0.07###  0.88 ± 0.07†††  0.97 ± 0.08***  24-Hour HR (beats/min)  76.4 ± 10.3  76.0 ± 8.9  77.9 ± 10.0  76.5 ± 7.7  Day HR (beats/min)  83.3 ± 12.5  82.5 ± 10.2  83.1 ± 10.8  80.2 ± 10.3  Night HR (beats/min)  65.9 ± 9.8  66.3 ± 9.4  70.0 ± 10.8†  70.3 ± 8.5‡  LVEDD (cm)  4.71 ± 0.57  4.72 ± 0.52  4.72 ± 0.63  4.69 ± 0.61  E/A  1.32 ± 0.35  1.47 ± 0.49  1.32 ± 0.47‡  1.25 ± 0.54‡  E/e’ (n=)  6.64 ± 2.83 (22)  6.25 ± 3.06 (125)  7.61 ± 5.52 (120)  7.50 ± 3.50 (35)  LV mass index (g/m1.7)  64.74 ± 22.84  61.83 ± 17.53  63.72 ± 24.16  69.39 ± 22.37  RWT  0.37 ± 0.06  0.37 ± 0.07  0.37 ± 0.08  0.40 ± 0.09‡  Aortic pulse wave velocity (m/sec)  5.64 ± 2.46  5.40 ± 2.13  5.85 ± 2.16  6.86 ± 3.11‡$  TPR (mm Hg. min/ml)  22.12 ± 5.43  22.57 ± 7.07  22.98 ± 7.56  26.14 ± 8.04*  Log HOMA-IR  0.66 ± 1.14  0.48 ± 1.04  0.44 ± 0.93  0.59 ± 1.16  Values are mean ± SD or proportions. SBP dipping patterns: extreme dipper = SBPn/SBPd ≤0.8; dipper = SBPn/SBPd >0.8 and ≤0.9; nondipper = SBPn/SBPd >0.9 and ≤1.0; reverse dipper = SBPn/SBPd ≥1.0. *P < 0.05, **P < 0.001, ***P < 0.0001 vs. other 3 groups; †P < 0.05, ††P < 0.001, †††P < 0.0001 vs. dippers and extreme dippers; ‡P < 0.05, ‡‡P < 0.001 vs. dippers; #P < 0.05, ##P < 0.001, ###P < 0.0001 vs. extreme dippers; $P < 0.05 vs. nondippers. Abbreviations: BP, blood pressure; DBP, diastolic BP; E/A, early-to-late transmitral velocity; E/e’, early transmitral blood flow velocity/mean of lateral and septal wall myocardial tissue lengthening at the mitral annulus; HbA1c, glycosylated hemoglobin; HR, heart rate; Log HOMA-IR, Logarithm of homeostasis model of insulin resistance; LV, left ventricle; LVEDD, left ventricular end diastolic diameter; RWT, relative wall thickness; SBP, systolic BP; SBPd, day SBP; SBPn, night SBP; TPR, total peripheral resistance. View Large Table 1. Demographic, clinical, and hemodynamic characteristics of the 491 study participants according to SBP dipping pattern   Extreme dippers  Dippers  Nondippers  Reverse dippers  Number (%)  38 (7.7)  216 (44.0)  187 (38.1)  50 (10.2)  % Women  55.3  56.0  65.8  64.0  Age (years)  40.8 ± 16.2  36.8 ± 16.2  42.0 ± 16.4‡  48.0 ± 17.0‡‡  Body mass index (kg/m2)  26.9 ± 6.6  26.9 ± 7.2  28.7 ± 7.4  30.4 ± 8.6‡  Regular tobacco intake (% subjects)  18.4  18.5  15.0  20.0  Regular alcohol intake (% subjects)  21.1  24.1  21.4  20.0  % With diabetes mellitus or HbA1c > 6.1%  15.8  13.0  13.4  18.0  % With hypertension  31.6  19.9  29.4  42.0‡$  Conventional BP (mm Hg)  125 ± 18/82 ± 12  121 ± 16/80 ± 10  127 ± 20‡/83 ± 12‡  134 ± 24*/87 ± 14*  24-Hour BP (mm Hg)  116 ± 15/73 ± 11  114 ± 11/70 ± 9  118 ± 15‡/73 ± 10‡  126 ± 19**/78 ± 13*  Day BP (mm Hg)  128 ± 15/83 ± 11  121 ± 12#/77 ± 9#  121 ± 15#/77 ± 11#  124 ± 18/79 ± 13  Night BP (mm Hg)  98 ± 12/57 ± 10  103 ± 10/60 ± 9  113 ± 15††/67 ± 11††  129 ± 20***/76 ± 13***  Night-to-day SBP ratio  0.76 ± 0.03  0.86 ± 0.03###  0.94 ± 0.03†††  1.04 ± 0.04***  Night-to-day DBP ratio  0.68 ± 0.06  0.78 ± 0.07###  0.88 ± 0.07†††  0.97 ± 0.08***  24-Hour HR (beats/min)  76.4 ± 10.3  76.0 ± 8.9  77.9 ± 10.0  76.5 ± 7.7  Day HR (beats/min)  83.3 ± 12.5  82.5 ± 10.2  83.1 ± 10.8  80.2 ± 10.3  Night HR (beats/min)  65.9 ± 9.8  66.3 ± 9.4  70.0 ± 10.8†  70.3 ± 8.5‡  LVEDD (cm)  4.71 ± 0.57  4.72 ± 0.52  4.72 ± 0.63  4.69 ± 0.61  E/A  1.32 ± 0.35  1.47 ± 0.49  1.32 ± 0.47‡  1.25 ± 0.54‡  E/e’ (n=)  6.64 ± 2.83 (22)  6.25 ± 3.06 (125)  7.61 ± 5.52 (120)  7.50 ± 3.50 (35)  LV mass index (g/m1.7)  64.74 ± 22.84  61.83 ± 17.53  63.72 ± 24.16  69.39 ± 22.37  RWT  0.37 ± 0.06  0.37 ± 0.07  0.37 ± 0.08  0.40 ± 0.09‡  Aortic pulse wave velocity (m/sec)  5.64 ± 2.46  5.40 ± 2.13  5.85 ± 2.16  6.86 ± 3.11‡$  TPR (mm Hg. min/ml)  22.12 ± 5.43  22.57 ± 7.07  22.98 ± 7.56  26.14 ± 8.04*  Log HOMA-IR  0.66 ± 1.14  0.48 ± 1.04  0.44 ± 0.93  0.59 ± 1.16    Extreme dippers  Dippers  Nondippers  Reverse dippers  Number (%)  38 (7.7)  216 (44.0)  187 (38.1)  50 (10.2)  % Women  55.3  56.0  65.8  64.0  Age (years)  40.8 ± 16.2  36.8 ± 16.2  42.0 ± 16.4‡  48.0 ± 17.0‡‡  Body mass index (kg/m2)  26.9 ± 6.6  26.9 ± 7.2  28.7 ± 7.4  30.4 ± 8.6‡  Regular tobacco intake (% subjects)  18.4  18.5  15.0  20.0  Regular alcohol intake (% subjects)  21.1  24.1  21.4  20.0  % With diabetes mellitus or HbA1c > 6.1%  15.8  13.0  13.4  18.0  % With hypertension  31.6  19.9  29.4  42.0‡$  Conventional BP (mm Hg)  125 ± 18/82 ± 12  121 ± 16/80 ± 10  127 ± 20‡/83 ± 12‡  134 ± 24*/87 ± 14*  24-Hour BP (mm Hg)  116 ± 15/73 ± 11  114 ± 11/70 ± 9  118 ± 15‡/73 ± 10‡  126 ± 19**/78 ± 13*  Day BP (mm Hg)  128 ± 15/83 ± 11  121 ± 12#/77 ± 9#  121 ± 15#/77 ± 11#  124 ± 18/79 ± 13  Night BP (mm Hg)  98 ± 12/57 ± 10  103 ± 10/60 ± 9  113 ± 15††/67 ± 11††  129 ± 20***/76 ± 13***  Night-to-day SBP ratio  0.76 ± 0.03  0.86 ± 0.03###  0.94 ± 0.03†††  1.04 ± 0.04***  Night-to-day DBP ratio  0.68 ± 0.06  0.78 ± 0.07###  0.88 ± 0.07†††  0.97 ± 0.08***  24-Hour HR (beats/min)  76.4 ± 10.3  76.0 ± 8.9  77.9 ± 10.0  76.5 ± 7.7  Day HR (beats/min)  83.3 ± 12.5  82.5 ± 10.2  83.1 ± 10.8  80.2 ± 10.3  Night HR (beats/min)  65.9 ± 9.8  66.3 ± 9.4  70.0 ± 10.8†  70.3 ± 8.5‡  LVEDD (cm)  4.71 ± 0.57  4.72 ± 0.52  4.72 ± 0.63  4.69 ± 0.61  E/A  1.32 ± 0.35  1.47 ± 0.49  1.32 ± 0.47‡  1.25 ± 0.54‡  E/e’ (n=)  6.64 ± 2.83 (22)  6.25 ± 3.06 (125)  7.61 ± 5.52 (120)  7.50 ± 3.50 (35)  LV mass index (g/m1.7)  64.74 ± 22.84  61.83 ± 17.53  63.72 ± 24.16  69.39 ± 22.37  RWT  0.37 ± 0.06  0.37 ± 0.07  0.37 ± 0.08  0.40 ± 0.09‡  Aortic pulse wave velocity (m/sec)  5.64 ± 2.46  5.40 ± 2.13  5.85 ± 2.16  6.86 ± 3.11‡$  TPR (mm Hg. min/ml)  22.12 ± 5.43  22.57 ± 7.07  22.98 ± 7.56  26.14 ± 8.04*  Log HOMA-IR  0.66 ± 1.14  0.48 ± 1.04  0.44 ± 0.93  0.59 ± 1.16  Values are mean ± SD or proportions. SBP dipping patterns: extreme dipper = SBPn/SBPd ≤0.8; dipper = SBPn/SBPd >0.8 and ≤0.9; nondipper = SBPn/SBPd >0.9 and ≤1.0; reverse dipper = SBPn/SBPd ≥1.0. *P < 0.05, **P < 0.001, ***P < 0.0001 vs. other 3 groups; †P < 0.05, ††P < 0.001, †††P < 0.0001 vs. dippers and extreme dippers; ‡P < 0.05, ‡‡P < 0.001 vs. dippers; #P < 0.05, ##P < 0.001, ###P < 0.0001 vs. extreme dippers; $P < 0.05 vs. nondippers. Abbreviations: BP, blood pressure; DBP, diastolic BP; E/A, early-to-late transmitral velocity; E/e’, early transmitral blood flow velocity/mean of lateral and septal wall myocardial tissue lengthening at the mitral annulus; HbA1c, glycosylated hemoglobin; HR, heart rate; Log HOMA-IR, Logarithm of homeostasis model of insulin resistance; LV, left ventricle; LVEDD, left ventricular end diastolic diameter; RWT, relative wall thickness; SBP, systolic BP; SBPd, day SBP; SBPn, night SBP; TPR, total peripheral resistance. View Large Factors associated with BP dipping The factors associated with indexes of BP dipping on bivariate analyses are shown in Supplementary Table S3. Night-to-day BP ratios were associated with night but not day BP. Night-to-day BP ratios were also associated with age, BMI, and hypertension. Although sex, diabetes mellitus, or an HbA1c >6.1%, regular smoking and drinking were associated with night and/or day BP values, these factors were not associated with night-to-day BP ratios. Relationships between BP dipping, day and night BP and indexes of cardiac systolic and diastolic function On bivariate analysis, EF, endFS, and mFS were correlated with BP dipping (night-to-day BP ratios) and night BP; but not day BP (Table 2). In comparison, E/A and E/e’ were associated with BP dipping and both night and day BP (Table 2). After adjusting for confounding variables in multivariate analyses including 24-hour BP (Table 3) or day BP (Supplementary Table S4), the associations of EF, endFS, and mFS with BP dipping and night BP remained (Table 3 and Supplementary Table S4). With regards to indexes of cardiac diastolic function, on multivariate analyses no relationships with indexes of BP dipping were noted (Table 3 and Supplementary Table S4). The multivariate-adjusted relationships between BP dipping or night BP and EF, endFS, and mFS survived further adjustments for either LVMI or RWT (Table 4 and Supplementary Table S5) and were not explained by variations in PWV or log HOMA-IR (Table 4 and Supplementary Table S5). Further adjustments for TPR had no impact on the relationships between EF or endFS and BP dipping. However, the multivariate relationships between SBP dipping or night SBP (but not DBP) and mFS were abolished by further adjustments for TPR (Table 4 and Supplementary Table S5). Table 2. Bivariate relationships between indexes of BP dipping and cardiac function in 491 study participants   SBPn/SBPd ratio  DBPn/DBPd ratio  SBPn  DBPn  SBPd  DBPd    r  P value  r  P value  r  P value  r  P value  r  P value  r  P value  EF  −0.12  0.006  −0.14  0.002  −0.10  0.02  −0.12  0.006  −0.04  0.42  −0.04  0.40  endFS  −0.12  0.006  −0.14  0.001  −0.10  0.03  −0.12  0.006  −0.03  0.56  −0.03  0.44  mFS  −0.12  0.008  −0.15  0.001  −0.13  0.003  −0.15  0.0006  −0.08  0.09  −0.07  0.10  E/A  −0.13  0.003  −0.16  0.0003  −0.31  <0.0001  −0.34  <0.0001  −0.28  <0.0001  −0.29  <0.0001  E/e’ (n = 302)  0.13  0.02  0.15  0.01  0.25  <0.0001  0.19  0.0007  0.19  0.0007  0.11  0.06  LVMI  0.07  0.10  0.12  0.009  0.32  <0.0001  0.25  <0.0001  0.33  <0.0001  0.20  <0.0001  RWT  0.09  0.04  0.09  0.04  0.21  <0.0001  0.21  <0.0001  0.18  <0.0001  0.18  <0.0001    SBPn/SBPd ratio  DBPn/DBPd ratio  SBPn  DBPn  SBPd  DBPd    r  P value  r  P value  r  P value  r  P value  r  P value  r  P value  EF  −0.12  0.006  −0.14  0.002  −0.10  0.02  −0.12  0.006  −0.04  0.42  −0.04  0.40  endFS  −0.12  0.006  −0.14  0.001  −0.10  0.03  −0.12  0.006  −0.03  0.56  −0.03  0.44  mFS  −0.12  0.008  −0.15  0.001  −0.13  0.003  −0.15  0.0006  −0.08  0.09  −0.07  0.10  E/A  −0.13  0.003  −0.16  0.0003  −0.31  <0.0001  −0.34  <0.0001  −0.28  <0.0001  −0.29  <0.0001  E/e’ (n = 302)  0.13  0.02  0.15  0.01  0.25  <0.0001  0.19  0.0007  0.19  0.0007  0.11  0.06  LVMI  0.07  0.10  0.12  0.009  0.32  <0.0001  0.25  <0.0001  0.33  <0.0001  0.20  <0.0001  RWT  0.09  0.04  0.09  0.04  0.21  <0.0001  0.21  <0.0001  0.18  <0.0001  0.18  <0.0001  r, correlation coefficient; SBPn/SBPd ratio, ratio of night SBP to day SBP; DBPn/DBPd ratio, ratio of night DBP to day DBP; SBPn, night SBP; DBPn, night DBP; SBPd, day SBP; DBPd, day DBP; EF, ejection fraction; endFS, endocardial fractional shortening; mFS, midwall fractional shortening; E/A, left ventricular early-to-late transmitral flow velocity; E/e’, early transmitral blood flow velocity/mean of lateral and septal wall myocardial tissue lengthening at the mitral annulus; LVMI, left ventricular mass indexed to height1.7; RWT, relative wall thickness. View Large Table 2. Bivariate relationships between indexes of BP dipping and cardiac function in 491 study participants   SBPn/SBPd ratio  DBPn/DBPd ratio  SBPn  DBPn  SBPd  DBPd    r  P value  r  P value  r  P value  r  P value  r  P value  r  P value  EF  −0.12  0.006  −0.14  0.002  −0.10  0.02  −0.12  0.006  −0.04  0.42  −0.04  0.40  endFS  −0.12  0.006  −0.14  0.001  −0.10  0.03  −0.12  0.006  −0.03  0.56  −0.03  0.44  mFS  −0.12  0.008  −0.15  0.001  −0.13  0.003  −0.15  0.0006  −0.08  0.09  −0.07  0.10  E/A  −0.13  0.003  −0.16  0.0003  −0.31  <0.0001  −0.34  <0.0001  −0.28  <0.0001  −0.29  <0.0001  E/e’ (n = 302)  0.13  0.02  0.15  0.01  0.25  <0.0001  0.19  0.0007  0.19  0.0007  0.11  0.06  LVMI  0.07  0.10  0.12  0.009  0.32  <0.0001  0.25  <0.0001  0.33  <0.0001  0.20  <0.0001  RWT  0.09  0.04  0.09  0.04  0.21  <0.0001  0.21  <0.0001  0.18  <0.0001  0.18  <0.0001    SBPn/SBPd ratio  DBPn/DBPd ratio  SBPn  DBPn  SBPd  DBPd    r  P value  r  P value  r  P value  r  P value  r  P value  r  P value  EF  −0.12  0.006  −0.14  0.002  −0.10  0.02  −0.12  0.006  −0.04  0.42  −0.04  0.40  endFS  −0.12  0.006  −0.14  0.001  −0.10  0.03  −0.12  0.006  −0.03  0.56  −0.03  0.44  mFS  −0.12  0.008  −0.15  0.001  −0.13  0.003  −0.15  0.0006  −0.08  0.09  −0.07  0.10  E/A  −0.13  0.003  −0.16  0.0003  −0.31  <0.0001  −0.34  <0.0001  −0.28  <0.0001  −0.29  <0.0001  E/e’ (n = 302)  0.13  0.02  0.15  0.01  0.25  <0.0001  0.19  0.0007  0.19  0.0007  0.11  0.06  LVMI  0.07  0.10  0.12  0.009  0.32  <0.0001  0.25  <0.0001  0.33  <0.0001  0.20  <0.0001  RWT  0.09  0.04  0.09  0.04  0.21  <0.0001  0.21  <0.0001  0.18  <0.0001  0.18  <0.0001  r, correlation coefficient; SBPn/SBPd ratio, ratio of night SBP to day SBP; DBPn/DBPd ratio, ratio of night DBP to day DBP; SBPn, night SBP; DBPn, night DBP; SBPd, day SBP; DBPd, day DBP; EF, ejection fraction; endFS, endocardial fractional shortening; mFS, midwall fractional shortening; E/A, left ventricular early-to-late transmitral flow velocity; E/e’, early transmitral blood flow velocity/mean of lateral and septal wall myocardial tissue lengthening at the mitral annulus; LVMI, left ventricular mass indexed to height1.7; RWT, relative wall thickness. View Large Table 3. Multivariate-adjusted relationships between indexes of BP dipping and cardiac function in 491 study participants.   SBPn/SBPd ratio  DBPn/DBPd ratio  SBPn  DBPn  SBPd  DBPd  βa  P value  βa  P value  βa  P value  βa  P value  βa  P value  βa  P value  (95% CI)a  (95% CI)a  (95% CI)a  (95% CI)a  (95% CI)a  (95% CI)a  EF  −15.2  0.01  −13.1  0.004  −0.19  0.008  −0.22  0.008  0.19  0.07  0.28  0.02    (−27.0 to −3.4)  (−21.9 to −4.3)  (−0.33 to −0.05)  (−0.38 to −0.06)  (−0.02 to 0.40)  (0.05 to 0.52)  endFS  −12.3  0.01  −10.9  0.003  −0.15  0.009  −0.18  0.008  0.16  0.07  0.25  0.01    (−21.9 to −2.7)  (−18.1 to −3.7)  (−0.27 to −0.04)  (−0.31 to −0.05)  (−0.01 to 0.33)  (0.06 to 0.44)  mFS  −9.5  0.04  −8.5  0.01  −0.11  0.04  −0.14  0.03  0.13  0.13  0.24  0.01    (−18.7 to −0.4)  (−15.3 to −1.7)  (−0.22 to −0.004)  (−0.26 to −0.01)  (−0.04 to 0.29)  (0.06 to 0.42)  E/A  0.12  0.60  0.14  0.42  0.002  0.48  0.003  0.30  −0.002  0.55  −0.003  0.51    (−0.34 to 0.58)  (−0.20 to 0.48)  (−0.004 to 0.008)  (−0.003 to 0.009)  (−0.011 to 0.006)  (−0.012 to 0.006)  E/e’ (n = 302)  4.4  0.17  3.4  0.16  0.045  0.24  0.05  0.26  −0.11  0.07  −0.13  0.03    (−1.9 to 10.7)  (−1.3 to 8.0)  (−0.03 to 0.12)  (−0.04 to 0.14)  (−0.22 to 0.01)  (−0.26 to −0.01)  LVMI  −2.9  0.82  6.4  0.48  0.12  0.40  0.25  0.13  0.33  0.12  −0.02  0.92    (−25.9 to 20.5)  (−11.2 to 24.0)  (−0.15 to 0.40)  (−0.08 to 0.57)  (−0.08 to 0.73)  (−0.50 to 0.45)  RWT  0.02  0.71  0.004  0.91  0.001  0.11  0.001  0.36  0.001  0.33  0.001  0.39    (−0.07 to 0.11)  (−0.064 to 0.072)  (−0.0002 to 0.002)  (−0.001 to 0.002)  (−0.001 to 0.002)  (−0.001 to 0.003)    SBPn/SBPd ratio  DBPn/DBPd ratio  SBPn  DBPn  SBPd  DBPd  βa  P value  βa  P value  βa  P value  βa  P value  βa  P value  βa  P value  (95% CI)a  (95% CI)a  (95% CI)a  (95% CI)a  (95% CI)a  (95% CI)a  EF  −15.2  0.01  −13.1  0.004  −0.19  0.008  −0.22  0.008  0.19  0.07  0.28  0.02    (−27.0 to −3.4)  (−21.9 to −4.3)  (−0.33 to −0.05)  (−0.38 to −0.06)  (−0.02 to 0.40)  (0.05 to 0.52)  endFS  −12.3  0.01  −10.9  0.003  −0.15  0.009  −0.18  0.008  0.16  0.07  0.25  0.01    (−21.9 to −2.7)  (−18.1 to −3.7)  (−0.27 to −0.04)  (−0.31 to −0.05)  (−0.01 to 0.33)  (0.06 to 0.44)  mFS  −9.5  0.04  −8.5  0.01  −0.11  0.04  −0.14  0.03  0.13  0.13  0.24  0.01    (−18.7 to −0.4)  (−15.3 to −1.7)  (−0.22 to −0.004)  (−0.26 to −0.01)  (−0.04 to 0.29)  (0.06 to 0.42)  E/A  0.12  0.60  0.14  0.42  0.002  0.48  0.003  0.30  −0.002  0.55  −0.003  0.51    (−0.34 to 0.58)  (−0.20 to 0.48)  (−0.004 to 0.008)  (−0.003 to 0.009)  (−0.011 to 0.006)  (−0.012 to 0.006)  E/e’ (n = 302)  4.4  0.17  3.4  0.16  0.045  0.24  0.05  0.26  −0.11  0.07  −0.13  0.03    (−1.9 to 10.7)  (−1.3 to 8.0)  (−0.03 to 0.12)  (−0.04 to 0.14)  (−0.22 to 0.01)  (−0.26 to −0.01)  LVMI  −2.9  0.82  6.4  0.48  0.12  0.40  0.25  0.13  0.33  0.12  −0.02  0.92    (−25.9 to 20.5)  (−11.2 to 24.0)  (−0.15 to 0.40)  (−0.08 to 0.57)  (−0.08 to 0.73)  (−0.50 to 0.45)  RWT  0.02  0.71  0.004  0.91  0.001  0.11  0.001  0.36  0.001  0.33  0.001  0.39    (−0.07 to 0.11)  (−0.064 to 0.072)  (−0.0002 to 0.002)  (−0.001 to 0.002)  (−0.001 to 0.002)  (−0.001 to 0.003)  β, beta coefficient; BMI, body mass index; BP, blood pressure; CI, confidence interval; DBPd, day DBP; DBPn, night DBP; DBPn/DBPd ratio, ratio of night DBP to day DBP; E/A, left ventricular early-to-late transmitral flow velocity; E/e’, early transmitral blood flow velocity/mean of lateral and septal wall myocardial tissue lengthening at the mitral annulus; EF, ejection fraction; endFS, endocardial fractional shortening; HbA1c, glycosylated hemoglobin; LVMI, left ventricular mass indexed to height1.7; RWT, relative wall thickness; SBPd, day SBP; SBPn, night SBP; SBPn/SBPd ratio, ratio of night SBP to day SBP; mFS, midwall fractional shortening. aAdjusted for age, sex, BMI, regular smoking, regular alcohol consumption, diabetes or HbA1c > 6.1%, 24-hour pulse rate, 24-hour BP. View Large Table 3. Multivariate-adjusted relationships between indexes of BP dipping and cardiac function in 491 study participants.   SBPn/SBPd ratio  DBPn/DBPd ratio  SBPn  DBPn  SBPd  DBPd  βa  P value  βa  P value  βa  P value  βa  P value  βa  P value  βa  P value  (95% CI)a  (95% CI)a  (95% CI)a  (95% CI)a  (95% CI)a  (95% CI)a  EF  −15.2  0.01  −13.1  0.004  −0.19  0.008  −0.22  0.008  0.19  0.07  0.28  0.02    (−27.0 to −3.4)  (−21.9 to −4.3)  (−0.33 to −0.05)  (−0.38 to −0.06)  (−0.02 to 0.40)  (0.05 to 0.52)  endFS  −12.3  0.01  −10.9  0.003  −0.15  0.009  −0.18  0.008  0.16  0.07  0.25  0.01    (−21.9 to −2.7)  (−18.1 to −3.7)  (−0.27 to −0.04)  (−0.31 to −0.05)  (−0.01 to 0.33)  (0.06 to 0.44)  mFS  −9.5  0.04  −8.5  0.01  −0.11  0.04  −0.14  0.03  0.13  0.13  0.24  0.01    (−18.7 to −0.4)  (−15.3 to −1.7)  (−0.22 to −0.004)  (−0.26 to −0.01)  (−0.04 to 0.29)  (0.06 to 0.42)  E/A  0.12  0.60  0.14  0.42  0.002  0.48  0.003  0.30  −0.002  0.55  −0.003  0.51    (−0.34 to 0.58)  (−0.20 to 0.48)  (−0.004 to 0.008)  (−0.003 to 0.009)  (−0.011 to 0.006)  (−0.012 to 0.006)  E/e’ (n = 302)  4.4  0.17  3.4  0.16  0.045  0.24  0.05  0.26  −0.11  0.07  −0.13  0.03    (−1.9 to 10.7)  (−1.3 to 8.0)  (−0.03 to 0.12)  (−0.04 to 0.14)  (−0.22 to 0.01)  (−0.26 to −0.01)  LVMI  −2.9  0.82  6.4  0.48  0.12  0.40  0.25  0.13  0.33  0.12  −0.02  0.92    (−25.9 to 20.5)  (−11.2 to 24.0)  (−0.15 to 0.40)  (−0.08 to 0.57)  (−0.08 to 0.73)  (−0.50 to 0.45)  RWT  0.02  0.71  0.004  0.91  0.001  0.11  0.001  0.36  0.001  0.33  0.001  0.39    (−0.07 to 0.11)  (−0.064 to 0.072)  (−0.0002 to 0.002)  (−0.001 to 0.002)  (−0.001 to 0.002)  (−0.001 to 0.003)    SBPn/SBPd ratio  DBPn/DBPd ratio  SBPn  DBPn  SBPd  DBPd  βa  P value  βa  P value  βa  P value  βa  P value  βa  P value  βa  P value  (95% CI)a  (95% CI)a  (95% CI)a  (95% CI)a  (95% CI)a  (95% CI)a  EF  −15.2  0.01  −13.1  0.004  −0.19  0.008  −0.22  0.008  0.19  0.07  0.28  0.02    (−27.0 to −3.4)  (−21.9 to −4.3)  (−0.33 to −0.05)  (−0.38 to −0.06)  (−0.02 to 0.40)  (0.05 to 0.52)  endFS  −12.3  0.01  −10.9  0.003  −0.15  0.009  −0.18  0.008  0.16  0.07  0.25  0.01    (−21.9 to −2.7)  (−18.1 to −3.7)  (−0.27 to −0.04)  (−0.31 to −0.05)  (−0.01 to 0.33)  (0.06 to 0.44)  mFS  −9.5  0.04  −8.5  0.01  −0.11  0.04  −0.14  0.03  0.13  0.13  0.24  0.01    (−18.7 to −0.4)  (−15.3 to −1.7)  (−0.22 to −0.004)  (−0.26 to −0.01)  (−0.04 to 0.29)  (0.06 to 0.42)  E/A  0.12  0.60  0.14  0.42  0.002  0.48  0.003  0.30  −0.002  0.55  −0.003  0.51    (−0.34 to 0.58)  (−0.20 to 0.48)  (−0.004 to 0.008)  (−0.003 to 0.009)  (−0.011 to 0.006)  (−0.012 to 0.006)  E/e’ (n = 302)  4.4  0.17  3.4  0.16  0.045  0.24  0.05  0.26  −0.11  0.07  −0.13  0.03    (−1.9 to 10.7)  (−1.3 to 8.0)  (−0.03 to 0.12)  (−0.04 to 0.14)  (−0.22 to 0.01)  (−0.26 to −0.01)  LVMI  −2.9  0.82  6.4  0.48  0.12  0.40  0.25  0.13  0.33  0.12  −0.02  0.92    (−25.9 to 20.5)  (−11.2 to 24.0)  (−0.15 to 0.40)  (−0.08 to 0.57)  (−0.08 to 0.73)  (−0.50 to 0.45)  RWT  0.02  0.71  0.004  0.91  0.001  0.11  0.001  0.36  0.001  0.33  0.001  0.39    (−0.07 to 0.11)  (−0.064 to 0.072)  (−0.0002 to 0.002)  (−0.001 to 0.002)  (−0.001 to 0.002)  (−0.001 to 0.003)  β, beta coefficient; BMI, body mass index; BP, blood pressure; CI, confidence interval; DBPd, day DBP; DBPn, night DBP; DBPn/DBPd ratio, ratio of night DBP to day DBP; E/A, left ventricular early-to-late transmitral flow velocity; E/e’, early transmitral blood flow velocity/mean of lateral and septal wall myocardial tissue lengthening at the mitral annulus; EF, ejection fraction; endFS, endocardial fractional shortening; HbA1c, glycosylated hemoglobin; LVMI, left ventricular mass indexed to height1.7; RWT, relative wall thickness; SBPd, day SBP; SBPn, night SBP; SBPn/SBPd ratio, ratio of night SBP to day SBP; mFS, midwall fractional shortening. aAdjusted for age, sex, BMI, regular smoking, regular alcohol consumption, diabetes or HbA1c > 6.1%, 24-hour pulse rate, 24-hour BP. View Large Table 4. Multivariate-adjusted relationships between indexes of BP dipping and cardiac systolic function after further adjustments for LVMI, RWT, PWV, or TPR in 491 study participants   SBPn/SBPd ratio  DBPn/DBPd ratio  SBPn  DBPn  βa  P value  βa  P value  βa  P value  βa  P value  (95% CI)a    (95% CI)a    (95% CI)a    (95% CI)a    adj + LVMI   EF  −15.1  0.01  −12.9  0.004  −0.18  0.01  −0.21  0.01    (−26.9 to −3.4)  (−21.6 to −4.1)  (−0.32 to −0.04)  (−0.37 to −0.05)   endFS  −12.3  0.01  −10.8  0.003  −0.15  0.01  −0.17  0.01    (−21.8 to −2.7)  (−18.0 to −3.7)  (−0.26 to −0.03)  (−0.30 to −0.04)   mFS  −9.5  0.04  −9.0  0.009  −0.12  0.03  −0.13  0.04    (−18.6 to −0.4)  (−15.8 to −2.3)  (−0.23 to −0.01)  (−0.26 to −0.007)  adj + RWT   EF  −15.2  0.01  −13.1  0.004  −0.19  0.009  −0.22  0.008    (−27.0 to −3.3)  (−21.9 to −4.3)  (−0.33 to −0.05)  (−0.38 to −0.06)   endFS  −12.2  0.01  −10.9  0.003  −0.15  0.01  −0.18  0.009    (−21.8 to −2.6)  (−18.1 to −3.7)  (−0.26 to −0.03)  (−0.31 to −0.04)   mFS  −9.1  0.04  −9.1  0.008  −0.11  0.05  −0.13  0.04    (−18.0 to −0.2)  (−15.7 to −2.4)  (−0.22 to 0.00)  (−0.25 to −0.004)  adj + TPR   EF  −12.5  0.03  −12.8  0.002  −0.16  0.02  −0.21  0.006    (−23.6 to −1.5)  (−21.1 to −4.6)  (−0.29 to −0.02)  (−0.37 to −0.06)   endFS  −9.9  0.03  −10.7  0.002  −0.12  0.03  −0.17  0.005    (−18.8 to −1.0)  (−17.3 to −4.1)  (−0.23 to −0.01)  (−0.30 to −0.05)   mFS  −6.2  0.14  −8.3  0.008  −0.08  0.13  −0.13  0.03    (−14.3 to 2.0)  (−14.4 to −2.2)  (−0.17 to 0.02)  (−0.24 to −0.02)  adj + PWV (n = 442)   EF  −16.9  0.008  −16.3  0.0007  −0.21  0.006  −0.28  0.001    (−29.4 to −4.3)  (−25.6 to −7.0)  (−0.36 to −0.06)  (−0.45 to −0.11)   endFS  −13.5  0.009  −13.5  0.0005  −0.17  0.007  −0.23  0.001    (−23.7 to −3.3)  (−21.1 to −6.0)  (−0.29 to −0.05)  (−0.37 to −0.09)   mFS  −9.7  0.045  −10.7  0.003  −0.12  0.046  −0.16  0.02    (−19.2 to −0.22)  (−17.7 to −3.7)  (−0.23 to −0.002)  (−0.29 to −0.03)  Adj + Log HOMA-IR (n = 451)   EF  −18.8  0.002  −16.1  0.0005  −0.23  0.002  −0.28  0.0009    (−30.8 to −6.7)  (−25.1 to −7.1)  (−0.38 to −0.09)  (−0.45 to −0.12)   endFS  −15.4  0.002  −13.2  0.0005  −0.19  0.002  −0.23  0.001    (−25.4 to −5.5)  (−20.6 to −5.8)  (−0.31 to −0.07)  (−0.36 to −0.09)   mFS  −12.0  0.01  −10.2  0.005  −0.14  0.01  −0.18  0.01    (−21.6 to −2.4)  (−17.4 to −3.0)  (−0.26 to −0.03)  (−0.31 to −0.04)    SBPn/SBPd ratio  DBPn/DBPd ratio  SBPn  DBPn  βa  P value  βa  P value  βa  P value  βa  P value  (95% CI)a    (95% CI)a    (95% CI)a    (95% CI)a    adj + LVMI   EF  −15.1  0.01  −12.9  0.004  −0.18  0.01  −0.21  0.01    (−26.9 to −3.4)  (−21.6 to −4.1)  (−0.32 to −0.04)  (−0.37 to −0.05)   endFS  −12.3  0.01  −10.8  0.003  −0.15  0.01  −0.17  0.01    (−21.8 to −2.7)  (−18.0 to −3.7)  (−0.26 to −0.03)  (−0.30 to −0.04)   mFS  −9.5  0.04  −9.0  0.009  −0.12  0.03  −0.13  0.04    (−18.6 to −0.4)  (−15.8 to −2.3)  (−0.23 to −0.01)  (−0.26 to −0.007)  adj + RWT   EF  −15.2  0.01  −13.1  0.004  −0.19  0.009  −0.22  0.008    (−27.0 to −3.3)  (−21.9 to −4.3)  (−0.33 to −0.05)  (−0.38 to −0.06)   endFS  −12.2  0.01  −10.9  0.003  −0.15  0.01  −0.18  0.009    (−21.8 to −2.6)  (−18.1 to −3.7)  (−0.26 to −0.03)  (−0.31 to −0.04)   mFS  −9.1  0.04  −9.1  0.008  −0.11  0.05  −0.13  0.04    (−18.0 to −0.2)  (−15.7 to −2.4)  (−0.22 to 0.00)  (−0.25 to −0.004)  adj + TPR   EF  −12.5  0.03  −12.8  0.002  −0.16  0.02  −0.21  0.006    (−23.6 to −1.5)  (−21.1 to −4.6)  (−0.29 to −0.02)  (−0.37 to −0.06)   endFS  −9.9  0.03  −10.7  0.002  −0.12  0.03  −0.17  0.005    (−18.8 to −1.0)  (−17.3 to −4.1)  (−0.23 to −0.01)  (−0.30 to −0.05)   mFS  −6.2  0.14  −8.3  0.008  −0.08  0.13  −0.13  0.03    (−14.3 to 2.0)  (−14.4 to −2.2)  (−0.17 to 0.02)  (−0.24 to −0.02)  adj + PWV (n = 442)   EF  −16.9  0.008  −16.3  0.0007  −0.21  0.006  −0.28  0.001    (−29.4 to −4.3)  (−25.6 to −7.0)  (−0.36 to −0.06)  (−0.45 to −0.11)   endFS  −13.5  0.009  −13.5  0.0005  −0.17  0.007  −0.23  0.001    (−23.7 to −3.3)  (−21.1 to −6.0)  (−0.29 to −0.05)  (−0.37 to −0.09)   mFS  −9.7  0.045  −10.7  0.003  −0.12  0.046  −0.16  0.02    (−19.2 to −0.22)  (−17.7 to −3.7)  (−0.23 to −0.002)  (−0.29 to −0.03)  Adj + Log HOMA-IR (n = 451)   EF  −18.8  0.002  −16.1  0.0005  −0.23  0.002  −0.28  0.0009    (−30.8 to −6.7)  (−25.1 to −7.1)  (−0.38 to −0.09)  (−0.45 to −0.12)   endFS  −15.4  0.002  −13.2  0.0005  −0.19  0.002  −0.23  0.001    (−25.4 to −5.5)  (−20.6 to −5.8)  (−0.31 to −0.07)  (−0.36 to −0.09)   mFS  −12.0  0.01  −10.2  0.005  −0.14  0.01  −0.18  0.01    (−21.6 to −2.4)  (−17.4 to −3.0)  (−0.26 to −0.03)  (−0.31 to −0.04)  β, beta coefficient; BMI, body mass index; BP, blood pressure; CI, confidence interval; DBPd, day DBP; DBPn, night DBP; DBPn/DBPd ratio, ratio of night DBP to day DBP; EF, ejection fraction; endFS, endocardial fractional shortening; HbA1c, glycosylated hemoglobin; Log HOMA-IR, logarithm homeostasis model of insulin resistance; LVMI, left ventricular mass indexed to height1.7; mFS, midwall fractional shortening; PWV, pulse wave velocity RWT, relative wall thickness; SBPd, day SBP; SBPn, night SBP; SBPn/SBPd ratio, ratio of night SBP to day SBP; TPR, total peripheral resistance. aAdjusted for age, sex, BMI (only body weight for LVMI), regular smoking, regular alcohol consumption, diabetes or HbA1c > 6.1%, 24-hour pulse rate, 24-hour BP. View Large Table 4. Multivariate-adjusted relationships between indexes of BP dipping and cardiac systolic function after further adjustments for LVMI, RWT, PWV, or TPR in 491 study participants   SBPn/SBPd ratio  DBPn/DBPd ratio  SBPn  DBPn  βa  P value  βa  P value  βa  P value  βa  P value  (95% CI)a    (95% CI)a    (95% CI)a    (95% CI)a    adj + LVMI   EF  −15.1  0.01  −12.9  0.004  −0.18  0.01  −0.21  0.01    (−26.9 to −3.4)  (−21.6 to −4.1)  (−0.32 to −0.04)  (−0.37 to −0.05)   endFS  −12.3  0.01  −10.8  0.003  −0.15  0.01  −0.17  0.01    (−21.8 to −2.7)  (−18.0 to −3.7)  (−0.26 to −0.03)  (−0.30 to −0.04)   mFS  −9.5  0.04  −9.0  0.009  −0.12  0.03  −0.13  0.04    (−18.6 to −0.4)  (−15.8 to −2.3)  (−0.23 to −0.01)  (−0.26 to −0.007)  adj + RWT   EF  −15.2  0.01  −13.1  0.004  −0.19  0.009  −0.22  0.008    (−27.0 to −3.3)  (−21.9 to −4.3)  (−0.33 to −0.05)  (−0.38 to −0.06)   endFS  −12.2  0.01  −10.9  0.003  −0.15  0.01  −0.18  0.009    (−21.8 to −2.6)  (−18.1 to −3.7)  (−0.26 to −0.03)  (−0.31 to −0.04)   mFS  −9.1  0.04  −9.1  0.008  −0.11  0.05  −0.13  0.04    (−18.0 to −0.2)  (−15.7 to −2.4)  (−0.22 to 0.00)  (−0.25 to −0.004)  adj + TPR   EF  −12.5  0.03  −12.8  0.002  −0.16  0.02  −0.21  0.006    (−23.6 to −1.5)  (−21.1 to −4.6)  (−0.29 to −0.02)  (−0.37 to −0.06)   endFS  −9.9  0.03  −10.7  0.002  −0.12  0.03  −0.17  0.005    (−18.8 to −1.0)  (−17.3 to −4.1)  (−0.23 to −0.01)  (−0.30 to −0.05)   mFS  −6.2  0.14  −8.3  0.008  −0.08  0.13  −0.13  0.03    (−14.3 to 2.0)  (−14.4 to −2.2)  (−0.17 to 0.02)  (−0.24 to −0.02)  adj + PWV (n = 442)   EF  −16.9  0.008  −16.3  0.0007  −0.21  0.006  −0.28  0.001    (−29.4 to −4.3)  (−25.6 to −7.0)  (−0.36 to −0.06)  (−0.45 to −0.11)   endFS  −13.5  0.009  −13.5  0.0005  −0.17  0.007  −0.23  0.001    (−23.7 to −3.3)  (−21.1 to −6.0)  (−0.29 to −0.05)  (−0.37 to −0.09)   mFS  −9.7  0.045  −10.7  0.003  −0.12  0.046  −0.16  0.02    (−19.2 to −0.22)  (−17.7 to −3.7)  (−0.23 to −0.002)  (−0.29 to −0.03)  Adj + Log HOMA-IR (n = 451)   EF  −18.8  0.002  −16.1  0.0005  −0.23  0.002  −0.28  0.0009    (−30.8 to −6.7)  (−25.1 to −7.1)  (−0.38 to −0.09)  (−0.45 to −0.12)   endFS  −15.4  0.002  −13.2  0.0005  −0.19  0.002  −0.23  0.001    (−25.4 to −5.5)  (−20.6 to −5.8)  (−0.31 to −0.07)  (−0.36 to −0.09)   mFS  −12.0  0.01  −10.2  0.005  −0.14  0.01  −0.18  0.01    (−21.6 to −2.4)  (−17.4 to −3.0)  (−0.26 to −0.03)  (−0.31 to −0.04)    SBPn/SBPd ratio  DBPn/DBPd ratio  SBPn  DBPn  βa  P value  βa  P value  βa  P value  βa  P value  (95% CI)a    (95% CI)a    (95% CI)a    (95% CI)a    adj + LVMI   EF  −15.1  0.01  −12.9  0.004  −0.18  0.01  −0.21  0.01    (−26.9 to −3.4)  (−21.6 to −4.1)  (−0.32 to −0.04)  (−0.37 to −0.05)   endFS  −12.3  0.01  −10.8  0.003  −0.15  0.01  −0.17  0.01    (−21.8 to −2.7)  (−18.0 to −3.7)  (−0.26 to −0.03)  (−0.30 to −0.04)   mFS  −9.5  0.04  −9.0  0.009  −0.12  0.03  −0.13  0.04    (−18.6 to −0.4)  (−15.8 to −2.3)  (−0.23 to −0.01)  (−0.26 to −0.007)  adj + RWT   EF  −15.2  0.01  −13.1  0.004  −0.19  0.009  −0.22  0.008    (−27.0 to −3.3)  (−21.9 to −4.3)  (−0.33 to −0.05)  (−0.38 to −0.06)   endFS  −12.2  0.01  −10.9  0.003  −0.15  0.01  −0.18  0.009    (−21.8 to −2.6)  (−18.1 to −3.7)  (−0.26 to −0.03)  (−0.31 to −0.04)   mFS  −9.1  0.04  −9.1  0.008  −0.11  0.05  −0.13  0.04    (−18.0 to −0.2)  (−15.7 to −2.4)  (−0.22 to 0.00)  (−0.25 to −0.004)  adj + TPR   EF  −12.5  0.03  −12.8  0.002  −0.16  0.02  −0.21  0.006    (−23.6 to −1.5)  (−21.1 to −4.6)  (−0.29 to −0.02)  (−0.37 to −0.06)   endFS  −9.9  0.03  −10.7  0.002  −0.12  0.03  −0.17  0.005    (−18.8 to −1.0)  (−17.3 to −4.1)  (−0.23 to −0.01)  (−0.30 to −0.05)   mFS  −6.2  0.14  −8.3  0.008  −0.08  0.13  −0.13  0.03    (−14.3 to 2.0)  (−14.4 to −2.2)  (−0.17 to 0.02)  (−0.24 to −0.02)  adj + PWV (n = 442)   EF  −16.9  0.008  −16.3  0.0007  −0.21  0.006  −0.28  0.001    (−29.4 to −4.3)  (−25.6 to −7.0)  (−0.36 to −0.06)  (−0.45 to −0.11)   endFS  −13.5  0.009  −13.5  0.0005  −0.17  0.007  −0.23  0.001    (−23.7 to −3.3)  (−21.1 to −6.0)  (−0.29 to −0.05)  (−0.37 to −0.09)   mFS  −9.7  0.045  −10.7  0.003  −0.12  0.046  −0.16  0.02    (−19.2 to −0.22)  (−17.7 to −3.7)  (−0.23 to −0.002)  (−0.29 to −0.03)  Adj + Log HOMA-IR (n = 451)   EF  −18.8  0.002  −16.1  0.0005  −0.23  0.002  −0.28  0.0009    (−30.8 to −6.7)  (−25.1 to −7.1)  (−0.38 to −0.09)  (−0.45 to −0.12)   endFS  −15.4  0.002  −13.2  0.0005  −0.19  0.002  −0.23  0.001    (−25.4 to −5.5)  (−20.6 to −5.8)  (−0.31 to −0.07)  (−0.36 to −0.09)   mFS  −12.0  0.01  −10.2  0.005  −0.14  0.01  −0.18  0.01    (−21.6 to −2.4)  (−17.4 to −3.0)  (−0.26 to −0.03)  (−0.31 to −0.04)  β, beta coefficient; BMI, body mass index; BP, blood pressure; CI, confidence interval; DBPd, day DBP; DBPn, night DBP; DBPn/DBPd ratio, ratio of night DBP to day DBP; EF, ejection fraction; endFS, endocardial fractional shortening; HbA1c, glycosylated hemoglobin; Log HOMA-IR, logarithm homeostasis model of insulin resistance; LVMI, left ventricular mass indexed to height1.7; mFS, midwall fractional shortening; PWV, pulse wave velocity RWT, relative wall thickness; SBPd, day SBP; SBPn, night SBP; SBPn/SBPd ratio, ratio of night SBP to day SBP; TPR, total peripheral resistance. aAdjusted for age, sex, BMI (only body weight for LVMI), regular smoking, regular alcohol consumption, diabetes or HbA1c > 6.1%, 24-hour pulse rate, 24-hour BP. View Large Relationships between BP dipping pattern and indexes of cardiac systolic function Figure 1 shows the multivariate-adjusted mean values of indexes of cardiac systolic function in the 4 BP dipping patterns. When dipping pattern was defined according to systolic BP, extreme dippers had significantly increased EF, endFS, and mFS compared to the other 3 groups (Figure 1, upper panels). However, when dipping pattern was defined according to diastolic BP, reverse dippers had significantly decreased EF, endFS, and mFS compared to the other 3 groups (Figure 1, lower panels). When nondippers were compared to dippers defined according to systolic BP, adjusted EF (69.5 ± 0.6% vs. 67.7 ± 0.5%, P = 0.04) and endFS (39.7 ± 0.5% vs. 38.3 ± 0.5%, P = 0.05) but not mFS (26.2 ± 0.5% vs. 25.4 ± 0.5%, P = 0.25) were decreased. When nondippers were compared to dippers defined according to diastolic BP, adjusted EF (69.1 ± 0.5% vs. 66.3 ± 1.0%, P = 0.01), endFS (39.4 ± 0.4% vs. 37.3 ± 0.8%, P = 0.02), and mFS (26.1 ± 0.4% vs. 24.3 ± 0.7%, P = 0.03) were decreased. Figure 1. View largeDownload slide Multivariate-adjusted mean values of indexes of cardiac systolic function in the 4 BP dipping patterns defined according to SBP dipping (upper panels) or DBP dipping (lower panels). Adjustments are for age, sex, body mass index, regular smoking, regular alcohol consumption, diabetes mellitus and/or HbA1c > 6.1%, 24-hour heart rate, and 24 hour SBP or DBP. *P < 0.05, **P < 0.005, ***P < 0.0005 vs. extreme dippers; †P < 0.0005 vs. dippers; #P < 0.005 vs. nondippers. Abbreviations: BP, blood pressure; DBP, diastolic BP; EF, ejection fraction; endFS, endocardial fractional shortening; HbA1c, glycosylated hemoglobin; mFS, midwall fractional shortening; SBP, systolic BP. Figure 1. View largeDownload slide Multivariate-adjusted mean values of indexes of cardiac systolic function in the 4 BP dipping patterns defined according to SBP dipping (upper panels) or DBP dipping (lower panels). Adjustments are for age, sex, body mass index, regular smoking, regular alcohol consumption, diabetes mellitus and/or HbA1c > 6.1%, 24-hour heart rate, and 24 hour SBP or DBP. *P < 0.05, **P < 0.005, ***P < 0.0005 vs. extreme dippers; †P < 0.0005 vs. dippers; #P < 0.005 vs. nondippers. Abbreviations: BP, blood pressure; DBP, diastolic BP; EF, ejection fraction; endFS, endocardial fractional shortening; HbA1c, glycosylated hemoglobin; mFS, midwall fractional shortening; SBP, systolic BP. Impact of TPR on relationships between BP dipping pattern and indexes of cardiac systolic function Figure 2 shows the impact of further adjustments for TPR on the multivariate-adjusted mean values of indexes of cardiac systolic function in the 4 BP dipping patterns. After further adjustments for TPR, EF, endFS, and mFS remained increased in the extreme dippers compared to the other 3 groups, when dipping pattern was defined according to systolic BP (Figure 2, upper panels). When dipping pattern was defined according to diastolic BP, further adjustments for TPR also had no impact on the decreased EF, endFS, and mFS in the reverse dippers compared to the other 3 groups (Figure 2, lower panels). Figure 2. View largeDownload slide Impact of further adjustment for TPR on multivariate-adjusted mean values of indexes of cardiac systolic function in the 4 BP dipping patterns defined according to SBP dipping (upper panels) or DBP dipping (lower panels). Adjustments are for age, sex, body mass index, regular smoking, regular alcohol consumption, diabetes mellitus and/or HbA1c > 6.1%, 24-hour heart rate, 24-hour SBP or DBP and TPR. *P < 0.05, **P < 0.005, ***P < 0.0005 vs. extreme dippers; †P < 0.005 vs. dippers; #P < 0.01 vs. nondippers. Abbreviations: BP, blood pressure; DBP, diastolic BP; EF, ejection fraction; endFS, endocardial fractional shortening; HbA1c, glycosylated hemoglobin; mFS, midwall fractional shortening; SBP, systolic BP; TPR, total peripheral resistance. Figure 2. View largeDownload slide Impact of further adjustment for TPR on multivariate-adjusted mean values of indexes of cardiac systolic function in the 4 BP dipping patterns defined according to SBP dipping (upper panels) or DBP dipping (lower panels). Adjustments are for age, sex, body mass index, regular smoking, regular alcohol consumption, diabetes mellitus and/or HbA1c > 6.1%, 24-hour heart rate, 24-hour SBP or DBP and TPR. *P < 0.05, **P < 0.005, ***P < 0.0005 vs. extreme dippers; †P < 0.005 vs. dippers; #P < 0.01 vs. nondippers. Abbreviations: BP, blood pressure; DBP, diastolic BP; EF, ejection fraction; endFS, endocardial fractional shortening; HbA1c, glycosylated hemoglobin; mFS, midwall fractional shortening; SBP, systolic BP; TPR, total peripheral resistance. DISCUSSION The main findings of the present study are as follows: In participants from a community sample who were not receiving antihypertensive therapy, BP dipping and hence nocturnal but not day BP was associated with indexes of cardiac systolic function independent of confounders including 24 hour (or day) BP, LVMI, and RWT. Hence, it is possible that blunted nocturnal BP dipping contributes to a reduced cardiac systolic function prior to the development of HF with a reduced systolic function. The negative impact of BP dipping on cardiac systolic function was not explained by variations in PWV or HOMA-IR, but was in-part explained by variations in TPR. To our knowledge, only 3 previous studies have assessed the impact of BP dipping on cardiac systolic function in untreated participants.9–11 In a small study sample (n = 56) of untreated hypertensive participants,9 EF was reduced in nondippers (defined as absence of nocturnal BP fall [day MAP minus night MAP/day MAP × 100%] ≥10%) compared to dippers. However, in comparing these 2 groups, no adjustments were made for potential confounding variables. Similarly, in a study including hypertensives with LV hypertrophy (n = 75), hypertensives without LV hypertrophy (n = 35), and normotensives (n = 23), none of whom were receiving antihypertensive therapy, decreases in EF and increases in BNP and ANP were reported in nondippers (defined as night/day MAP >0.9) compared to dippers, without adjustments for confounding variables.10 In this regard, the nondippers were older than the dippers; but no data on BMI were given. In a large cohort (n = 1702), of never-treated essential hypertensives, those with depressed endFS or mFS in the absence of HF, had reduced day–night BP changes compared to patients with normal endFS or mFS.11 Moreover, after adjustments for age and gender, the night-to-day systolic BP ratio was associated with both endocardial and midwall FS in these patients.11 However, in that study11 despite higher LVMI values and a more concentric geometry in patients with a depressed endFS and mFS, associations between night-to-day BP ratios and FS were only adjusted for age and gender. Hence, in that study,11 LV concentric hypertrophy may have explained the relationship between night-to-day BP ratio and FS. Indeed, FS showed stronger relationships with LVM than with night-to-day BP ratio.11 Our data strengthen these previous reports,9–11 by indicating in a relatively large study sample of untreated participants that indexes of cardiac systolic function are associated with nocturnal BP dipping and nocturnal but not day BP independent of several possible confounding variables. Importantly, we report that these associations are independent of LVMI and RWT, which are associated with both BP dipping21 and cardiac dysfunction. Although the multivariate-adjusted associations reported in the current study are fairly weak (correlation coefficients ranging from −0.10 to −0.15), they translated into differences of 6.6% in EF, 5.5% in endFS, and 4.3% in mFS between extreme dippers and reverse dippers. In addition, the associations reported in the current study are similar to the correlation coefficients of −0.07 between night-to-day SBP ratio and endFS, and −0.09 between night-to-day SBP ratio and mFS, previously reported.11 In the current study, nondipping was due to a higher night but not day BP. Neurohormonal factors implicated in blunted nocturnal dipping include increased activation of the sympathetic nervous system6 and the renin–angiotensin–aldosterone system.7 In addition, nondippers have increased plasma catecholamine concentrations34 and a decrease in the activity of the parasympathetic nervous system35 compared to dippers. With respect to the increased sympathetic nervous system activation, blunted nocturnal dipping is mediated by elevated nocturnal norepinephrine levels (reduced nocturnal fall in excretion of norepinephrine) which are not related to physical or mental activity.6 In addition, increased alpha-1 adrenergic receptor responsiveness in the absence of changes in beta adrenergic receptor responsiveness occurs in nondippers compared to dippers.6 The heightened sympathetic nervous system activity during sleep would translate into increases in nocturnal BP secondary to increases in TPR. Indeed, in the present study increases in TPR were noted in the reverse dippers compared to the other 3 groups. The increased TPR in the reverse dippers is likely to reflect an enhanced vasoconstriction mediated by augmented sympathetic nervous system activity in this group. Indeed, the reverse dippers had an increased night HR compared to the dippers which could be attributed to increased sympathetic nervous system activity and/or decreased parasympathetic nervous system activity at night. Possible explanations for the association of BP dipping with cardiac systolic function warrant discussion. In this regard, although BP dipping has been associated with aging,15,16 male gender,15,16 obesity,15,16 and BP level,16 only age is associated with BP dipping independent of daytime BP.15 Other factors reported to be associated with BP dipping include insulin resistance17 and PWV.18,19 In this regard, hypertensives who were reverse dippers are reported to have higher multivariate-adjusted PWV compared to dippers or nondippers.18 Indeed, PWV is reported to be an independent predictor of diminished nocturnal BP dipping.19 In addition, in patients with essential hypertension, increases in LVMI and RWT have been reported in nondippers compared to dippers.21 Hence, in order to determine the independent effect of reduced BP dipping on cardiac systolic function, adjustments for these confounding factors are paramount, an approach not conducted in previous studies.9–11 In the present study, the negative impact of blunted BP dipping on cardiac systolic function was independent of the potential confounding effects of age, gender, obesity, LVMI, RWT, and BP level. However, TPR which was increased in the reverse dippers compared to the other 3 groups in-part explained the inverse relationship between SBP dipping and mFS. Conversely, the negative relationship between dipping and systolic function may reflect reverse causality. Indeed, reductions in systolic function would reduce BP, hence resulting in compensatory vasoconstriction and an increase in TPR. Nevertheless, the lack of impact of adjustments for TPR on the relationship between nondipping and endFS in the present study may be a consequence of TPR being calculated during the day rather than at night. Hence, further studies are required to determine whether increases in nocturnal TPR account for the negative relationship between dipping and systolic function. Although, the relationships between BP dipping and cardiac function in patients who are in HF are difficult to interpret, it is worth noting that previous studies have reported an association between nondipping and HF with reduced EF.4,36 In addition, in a longitudinal follow-up study (~9 years), night DBP and nondipping were predictors of the development of congestive HF independent of antihypertensive medication, myocardial infarction, diabetes, smoking, BMI, serum cholesterol, and 24-hour ambulatory BP.36 In contrast, a high morning surge of BP (>23 mm Hg) in dippers was independently associated with risk of development of HF with reduced EF, whereas nondipping was independently associated with risk of development of HF with preserved EF over ~9 years in elderly hypertensive patients.36 The present data are of clinical importance as they indicate that blunted nocturnal BP dipping is associated with reduced cardiac systolic function prior to the development of HF with a reduced EF. The implications are that the reversal of BP dipping could be beneficial in the prevention and/or slowing of the progression from cardiac systolic dysfunction to HF with reduced EF. In this regard, a number of studies have reported the restoration of BP dipping after the administration of various antihypertensive agents.12–14 However, longitudinal studies are required to determine whether changes in BP dipping translate into changes in cardiac systolic function. The limitations of the present study are the cross-sectional, rather than prospective nature of the study design and the lack of outcomes data. Although cause and effect cannot be concluded from a cross-sectional study, it is important to note that in a small study (n = 42), the restoration of BP dipping, with calcium channel blocker therapy in 8 patients with hypertension and diabetes mellitus, was associated with increases in EF.37 No changes in EF were noted in the patients in whom BP dipping patterns remained unaltered after calcium channel blocker therapy.37 Secondly, as the data were collected in a population consisting predominantly of women, it is possible that the results of the present study pertain primarily to women. As the current data were collected in a cross-sectional population (27% hypertensive) of participants of Black African ancestry, and previous data were collected in hypertensive and normotensive Caucasian patients,10,11 or in hypertensive and normotensive patients from Japan,9 it is unlikely that these data pertain only to hypertensives or to participants of Black African ancestry. In conclusion, the results of the present study suggest that blunted nocturnal BP dipping is implicated in reductions in cardiac systolic function. Moreover, the data suggest that the relationships between BP dipping and indexes of cardiac systolic function are not explained by variations in insulin resistance, arterial stiffness, LVMI, or concentric LV remodeling but are associated with an increased nocturnal BP which may in-part be determined by variations in vascular resistance. Further longitudinal studies are, however, required to assess whether changes in BP dipping status translate into changes in cardiac systolic function in the absence of HF. SUPPLEMENTARY DATA Supplementary data are available at American Journal of Hypertension online. DISCLOSURE The authors declared no conflict of interest. ACKNOWLEDGMENTS The present study was supported by the Medical Research Council of South Africa, the South African National Research Foundation, the Circulatory Disorders Research Trust, and the University Research Council of the University of the Witwatersrand,. This study would not have been possible without the voluntary collaboration of the participants. We are very grateful for the excellent technical assistance of Mthuthuzeli Kiviet, Nkele Maseko, Nomonde Molebatsi, and Delene Nciweni. REFERENCES 1. Sega R, Facchetti R, Bombelli M, Cesana G, Corrao G, Grassi G, Mancia G. Prognostic value of ambulatory and home blood pressures compared with office blood pressure in the general population: follow-up results from the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study. Circulation   2005; 111: 1777– 1783. Google Scholar CrossRef Search ADS PubMed  2. 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American Journal of HypertensionOxford University Press

Published: May 4, 2018

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