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1.  Sympathovagal Imbalance Contributes to Prehypertension Status and Cardiovascular Risks Attributed by Insulin Resistance, Inflammation, Dyslipidemia and Oxidative Stress in First Degree Relatives of Type 2 Diabetics 
PLoS ONE  2013;8(11):e78072.
Though cardiovascular (CV) risks are reported in first-degree relatives (FDR) of type 2 diabetics, the pathophysiological mechanisms contributing to these risks are not known. We investigated the association of sympathovagal imbalance (SVI) with CV risks in these subjects.
Subjects and Methods
Body mass index (BMI), basal heart rate (BHR), blood pressure (BP), rate-pressure product (RPP), spectral indices of heart rate variability (HRV), autonomic function tests, insulin resistance (HOMA-IR), lipid profile, inflammatory markers, oxidative stress (OS) marker, rennin, thyroid profile and serum electrolytes were measured and analyzed in subjects of study group (FDR of type 2 diabetics, n = 72) and control group (subjects with no family history of diabetes, n = 104).
BMI, BP, BHR, HOMA-IR, lipid profile, inflammatory and OS markers, renin, LF-HF (ratio of low-frequency to high-frequency power of HRV, a sensitive marker of SVI) were significantly increased (p<0.0001) in study group compared to the control group. SVI in study group was due to concomitant sympathetic activation and vagal inhibition. There was significant correlation and independent contribution of markers of insulin resistance, dyslipidemia, inflammation and OS to LF-HF ratio. Multiple-regression analysis demonstrated an independent contribution of LF-HF ratio to prehypertension status (standardized beta 0.415, p<0.001) and bivariate logistic-regression showed significant prediction (OR 2.40, CI 1.128–5.326, p = 0.002) of LF-HF ratio of HRV to increased RPP, the marker of CV risk, in study group.
SVI in FDR of type 2 diabetics occurs due to sympathetic activation and vagal withdrawal. The SVI contributes to prehypertension status and CV risks caused by insulin resistance, dyslipidemia, inflammation and oxidative stress in FDR of type 2 diabetics.
PMCID: PMC3827034  PMID: 24265679
2.  Sympathovagal Imbalance in Prehypertensive Offspring of Two Parents versus One Parent Hypertensive 
Objective. Though prehypertension has strong familial predisposition, difference in pathophysiological mechanisms in its genesis in offspring of both parents and single parent hypertensive have not been elucidated. Methods. Body mass index (BMI), waist-hip ratio (WHR), basal heart rate (BHR), blood pressure (BP), HR and BP response to standing, deep breathing difference, BP response to handgrip and spectral indices of heart rate variability (HRV) were analyzed in normotensive offspring of two parents hypertensive (Group I), normotensive offspring of one parent hypertensive (Group II), prehypertensive offspring of two parents hypertensive (Group III) and prehypertensive offspring of one parent hypertensive (Group IV). Results. Sympathovagal imbalance (SVI) in prehypertensive offspring was observed due to increased sympathetic and decreased vagal activity. In group III, SVI was more prominent with greater contribution by vagal withdrawal. LF-HF ratio, the marker of SVI was correlated more with diastolic pressure, 30 : 15 ratio and E : I ratio in prehypertensives and the degree of correlation was more in group III prehypertensives. Conclusion. Vagal withdrawal plays a critical role in development of SVI in prehypertensive offspring of hypertensive parents. The intensity of SVI was more in offspring of two parents hypertensive compared to single parent hypertensive.
PMCID: PMC3202093  PMID: 22121472
3.  Association of hypertension status and cardiovascular risks with sympathovagal imbalance in first degree relatives of type 2 diabetics 
As reports show cardiovascular (CV) risks in first‐degree relatives (FDR) of type 2 diabetics, and autonomic imbalance predisposing to CV risks, in the present study we have assessed the contribution of sympathovagal imbalance (SVI) to CV risks in these subjects.
Materials and Methods
Body mass index (BMI), waist‐to‐hip ratio (WHR), basal heart rate (BHR), blood pressure (BP), rate pressure product (RPP), and spectral indices of heart rate variability (HRV) were reordered and analyzed in FDR of type 2 diabetics (study group, n = 293) and in subjects with no family history of diabetes (control group, n = 405).
The ratio of low‐frequency (LF) to high‐frequency (HF) power of HRV (LF–HF), a sensitive marker of SVI, was significantly increased (P < 0.001) in the study group compared with the control group. The SVI in the study group was due to concomitant sympathetic activation (increased LF) and vagal inhibition (decreased HF). In the study group, the LF–HF ratio was significantly correlated with BMI, WHR, BHR, BP and RPP. Multiple regression analysis showed an independent contribution of LF–HF to hypertension status (P = 0.000), and bivariate logistic regression showed significant prediction (odds ratio 2.16, confidence interval 1.130–5.115) of LF–HF to increased RPP, the marker of CV risk, in the study group.
Sympathovagal imbalance in the form of increased sympathetic and decreased parasympathetic activity is present in FDR of type 2 diabetics. Increased resting heart rate, elevated hypertension status, decreased HRV and increased RPP in these subjects make them vulnerable to CV risks. SVI in these subjects contributes to CV risks independent of the degree of adiposity.
PMCID: PMC4210069  PMID: 25411606
Autonomic imbalance; Cardiovascular risk; First‐degree relatives of type 2 diabetics
4.  Vagal Withdrawal and Sympathetic Overactivity Contribute to the Genesis of Early-Onset Pregnancy-Induced Hypertension 
Objective. In this study, we have assessed sympathovagal imbalance (SVI) by spectral analysis of heart rate variability (HRV) that contributes to the genesis of early-onset PIH. Methods. Body mass index (BMI), basal heart rate (BHR), blood pressure (BP) and HRV indices such as LFnu, HFnu, LF-HF ratio, mean RR, SDNN and RMSSD were assessed in normal pregnant women (Control group) and pregnant women having risk factors for PIH (Study group) at all the trimesters pregnancy. Retrospectively, those who did not develop PIH (Study group I) were separated from those who developed PIH (Study group II). Study group II was subdivided into early-onset and late-onset PIH. Sympathovagal balance (LF-HF ratio) was correlated with BMI, BHR and BP. Results. LF-HF ratio was significantly high in study group II compared to study group I and control group, and in early-onset PIH group compared to the late-onset category at all the trimesters of pregnancy, which was significantly correlated with BHR and BP. Alteration in HFnu in early-onset category was more prominent than the alteration in LFnu. Conclusion. Though the SVI in PIH is contributed by both sympathetic overactivity and vagal withdrawal, especially in early-onset type, SVI is mainly due to vagal inhibition.
PMCID: PMC3095942  PMID: 21629868
5.  Association of Sympathovagal Imbalance with Cardiovascular Risks in Overt Hypothyroidism 
Cardiovascular morbidities have been reported in hypothyroidism.
The objective of this study is to investigate the link of sympathovagal imbalance (SVI) to cardiovascular risks (CVRs) and the plausible mechanisms of CVR in hypothyroidism.
Materials and Methods:
Age-matched 104 females (50 controls, 54 hypothyroids) were recruited and their body mass index (BMI), cardiovascular parameters, autonomic function tests by spectral analysis of heart rate variability (HRV), heart rate response to standing, deep breathing and blood pressure response to isometric handgrip were studied. Thyroid profile, lipid profile, immunological and inflammatory markers were estimated and their association with low-frequency to the high-frequency ratio (LF-HF) of HRV, the marker of SVI was assessed by multivariate regression.
Increased diastolic pressure, decreased HRV, increased LF-HF, dyslipidemia and increased high-sensitive C-reactive protein (hsCRP) were observed in hypothyroid patients and all these parameters had significant correlation with LF-HF. BMI had no significant association with LF-HF. Atherogenic index (β 1.144, P = 0.001) and hsCRP (b 0.578, P = 0.009) had independent contribution to LF-HF. LF-HF could significantly predict hypertension status (odds ratio 2.05, confidence interval 1.110-5.352, P = 0.008) in hypothyroid subjects.
SVI due to sympathetic activation and vagal withdrawal occurs in hypothyroidism. Dyslipidemia and low-grade inflammation, but not obesity contribute to SVI and SVI contributes to cardiovascular risks.
PMCID: PMC3818829  PMID: 24251274
Autonomic imbalance; Body mass index; Cardiovascular risks; Dyslipidemia; High-sensitive C-reactive protein; Hypothyroidism; Sympathovagal imbalance
6.  Impact of Prehypertension on Left Ventricular Structure, Function and Geometry 
Background: Awareness of prevalence, determinants, and prognosis of asymptomatic untreated prehypertension is still lacking especially in India and subcontinent. The present study was to assess the effects of prehypertension on structure, function and geometrical pattern of left ventricle on the basis of left ventricular mass (LVM), left ventricular mass indexed to height (LVMI/Ht), and relative wall thickness (RWT) recorded by echocardiography based on the American society of echocardiography (ASE) convention.
Methods: The study population included prehypertensives (n 61; 31 M, 30 F) and normotensives (n 38; 19 M, 19 F) between age 25 and 65 years, and were assessed by echocardiography.
Results: It was observed that the stroke volume (SV), cardiac output (CO), cardiac index (CI), body mass index (BMI), body surface area (BSA), were found to be little elevated but was not significant in hypertensive females compared to normotensives. Systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), pulse pressure (PP), mean arterial pressure (MAP), end systolic stress (ESS), and end isovolumetric systolic stress (EISS) were significantly elevated (p<0.001) in female prehypertensives compared to normotensives. Left ventricular mass (LVM) was significantly (p< 0.05) elevated, indicating alterations in cardiac morphology and functions even during prehypertensive stage. However, in prehypertensive males, SBP, DBP, HR, PP, MAP, ESS, and EISS were significantly (<0.001) raised; ejection fraction (EF%) and fractional fibre shortening (FS%) were noted to be within normal range in both sexes. Prehypertensive males showed changes in left ventricular geometry in the form of concentric remodeling (CR-3.44%), eccentric hypertrophy (EH-3.44%) and concentric hypertrophy (CH-13.79%). Prehypertensive females showed (CR-6.45%), (EH-3.22%) and (CH-6.4%).
Conclusion: Such findings carry prognostic implication and require further population survey involving a larger group. Early diagnosis of prehypertension will help to take necessary preventive measures to reduce mainly the future cardiovascular complications. The care of prehypertensive subjects should include, to reduce the afterload in order to improve the left ventricular contractile state as early as possible. So it is advisable to do routine echocardiography after the age of 40 years.
PMCID: PMC4064896  PMID: 24959434
Prehypertension; Left ventricular mass; Relative wall thickness
7.  Heart Rate Variability in Overweight Health Care Students: Correlation with Visceral Fat 
Background and Objectives: Increased sympathetic activity, decreased parasympathetic activity and sympathovagal imbalance (SVI) has been reported in obese individuals. However, the SVI and its association with visceral fat in overweight health care students have not been explored. Therefore, in the present study, we have assessed heart rate variability (HRV) and its association with visceral fat in overweight health care students.
Materials and Methods: Frequency domain parameters of HRV, body fat distribution and baseline anthropometric parameters were recorded in the control (n=40) and overweight (n=40) individuals. Further, the association of visceral fat with HRV was analysed.
Results: There was no significant difference in age and height of overweight group and control group (p = 0.732). The baseline heart rate and blood pressure (p<0.001) were higher in the overweight group. Total body fat, subcutaneous fat and visceral fat were higher in the overweight group (p<0.001). Among frequency domain parameter of HRV, LFnu and LF: HF were more in the overweight group (p<0.001). Further, HFnu was less in the overweight group (p<0.001).
Conclusion: Sympathovagal imbalance due to increased sympathetic activity and its association with visceral fat was observed in overweight individuals.
PMCID: PMC4347071  PMID: 25737980
Obesity; Sympathovagal imbalance; Vagal tone
8.  Prevalence of prehypertension and associated risk factors among Chinese adults from a large-scale multi-ethnic population survey 
BMC Public Health  2016;16:775.
Up to date, most of previous studies about Chinese prehypertension were conducted based on a small sample or in only one province, which could not represent the general population in China. Furthermore, no information on the ethnic difference in prevalence of prehypertension has been reported in China. The aim of this study is to examine the sex-specific, age-specific and ethnic-specific prevalence of prehypertension and associated risk factors in a large-scale multi-ethnic Chinese adult population.
The subjects came from a large-scale population survey about Chinese physiological constants and health conditions conducted in six provinces. 47, 495 adults completed blood pressure measurement. Prehypertension was defined as not being on antihypertensive medications and having SBP of 120–139 mmHg and/or DBP of 80–89 mmHg. Odds ratio (OR) and its 95 % confidence interval (CI) from logistic models were used to reflect the prevalence of prehypertension.
The mean age of all subjects was 43.9 ± 16.8 years. The prevalence of hypertension and prehypertension for all them was 29.5 and 36.4 %, respectively. The prevalence of hypertension and prehypertension for males (33.2 and 41.1 %, respectively) was higher than that for females (27.0 and 33.2 %, respectively), and P < 0.001. The mean age of the subjects was 54.8 ± 14.0 years for hypertensive, 44.0 ± 16.0 years for prehypertensive and 35.3 ± 14.5 years for normotensive. With aging, subjects had more odds of getting prehypertension. Multivariate logistic model indicated that males (OR = 2.076, 95 % CI: 1.952–2.208), laborers with mental work (OR = 1.084, 95 % CI: 1.020–1.152), Yi (OR = 1.347, 95 %CI: 1.210–1.500) and Hui subjects (OR = 1.133, 95 % CI: 1.024–1.253), alcohol drinkers (OR = 1.147, 95 % CI: 1.072–1.228), the generally obese (OR = 2.460, 95 % CI: 2.190–2.763), the overweight (OR = 1.667, 95 % CI: 1.563–1.788), the abdominally obese (OR = 1.371, 95 % CI: 1.280–1.467) and subjects with family history of cardiovascular diseases (OR = 1.132, 95 % CI: 1.045–1.226) had higher prevalence of prehypertension. Subjects with higher educational level (OR = 0.687, 95 % CI: 0.627–0.752 for university) and Miao (OR = 0.753, 95 % CI: 0.623–0.910), Tibetan (OR = 0.521, 95 % CI: 0.442–0.613), Tujia (OR = 0.779, 95 % CI: 0.677–0.898) subjects had lower prevalence.
High prevalence rate of prehypertension was general in Chinese adults. Many sociodemographic characteristics were significantly associated with prehypertension. There were important clinical significance and public health significance about age-specific, gender-specific and ethnic-specific Chinese prehypertension conditions studies.
PMCID: PMC4982422  PMID: 27515034
Prehypertension; China; Adult; Risk factor; Ethnicity
9.  Prehypertension Tsunami: A Decade Follow-Up of an Iranian Adult Population 
PLoS ONE  2015;10(10):e0139412.
Prehypertension is associated with cardiovascular disease (CVD). There is no study to examine the incidence and risk factors of prehypertension in a sex stratified setting. The aim of this study was to examine the effect modification of sex for different risk factors which predicts the progression from normotension to prehypertension in a Middle East population-based cohort, during a median follow-up of 9.2 years.
A multivariate Cox analysis was performed among 1466 and 2131 Iranian men and women, respectively, who were free of prehypertension, hypertension, CVD and diabetes at baseline and free of incident hypertension without preceding prehypertension at follow-up. Incident prehypertension at follow-up was defined as systolic blood pressure (SBP) of 120–139 mmHg and/or diastolic blood pressure (DBP) of 80–89 mmHg.
Overall, 1440 new cases of prehypertension were identified resulting in an incidence rate of 593/10000 person-years; the corresponding values for women and men were 489/10000 and 764/10000person-years, respectively. There were significant interactions between gender with age, DBP, waist-to-hip-ratio (WHpR) and estimated glomerular filtration rate (eGFR) (all P-values <0.05) in multivariate analysis. Strong associations were found between age, body mass index (BMI) and SBP with incident prehypertension in both genders. However, the effect of DBP and WHpR was significant among women and 2-hour post challenge plasma glucose (2h-PCPG)was an independent risk factor for men. In the sex-adjusted analysis, glomerular hyperfiltration [Hazard ratio (HR) and 95%CI: 1.01 (1.00–1.01), P-value = 0.02], age, BMI, WHpR, SBP and DBP had higher risks while being female [HR (95%CI): 0.81(0.69–0.94), P-value = 0.01] had a lower risk for incident prehypertension.
According to this study results, among Iranian population with high incidence of prehypertension, general adiposity and glomerular hyperfiltration in total, 2h-PCPG in men and central adiposity in women should be emphasized as risk factors for prehypertension.
PMCID: PMC4595371  PMID: 26439847
10.  Linear and nonlinear analysis of heart rate variability in healthy subjects and after acute myocardial infarction in patients 
The objectives of this study were to evaluate and compare the use of linear and nonlinear methods for analysis of heart rate variability (HRV) in healthy subjects and in patients after acute myocardial infarction (AMI). Heart rate (HR) was recorded for 15 min in the supine position in 10 patients with AMI taking β-blockers (aged 57 ± 9 years) and in 11 healthy subjects (aged 53 ± 4 years). HRV was analyzed in the time domain (RMSSD and RMSM), the frequency domain using low- and high-frequency bands in normalized units (nu; LFnu and HFnu) and the LF/HF ratio and approximate entropy (ApEn) were determined. There was a correlation (P < 0.05) of RMSSD, RMSM, LFnu, HFnu, and the LF/HF ratio index with the ApEn of the AMI group on the 2nd (r = 0.87, 0.65, 0.72, 0.72, and 0.64) and 7th day (r = 0.88, 0.70, 0.69, 0.69, and 0.87) and of the healthy group (r = 0.63, 0.71, 0.63, 0.63, and 0.74), respectively. The median HRV indexes of the AMI group on the 2nd and 7th day differed from the healthy group (P < 0.05): RMSSD = 10.37, 19.95, 24.81; RMSM = 23.47, 31.96, 43.79; LFnu = 0.79, 0.79, 0.62; HFnu = 0.20, 0.20, 0.37; LF/HF ratio = 3.87, 3.94, 1.65; ApEn = 1.01, 1.24, 1.31, respectively. There was agreement between the methods, suggesting that these have the same power to evaluate autonomic modulation of HR in both AMI patients and healthy subjects. AMI contributed to a reduction in cardiac signal irregularity, higher sympathetic modulation and lower vagal modulation.
PMCID: PMC3854283  PMID: 22370707
Myocardial infarction; Heart rate variability; Autonomic nervous system; Spectral analysis; Nonlinear dynamics
11.  The effects of a glucose load and sympathetic challenge on autonomic function in obese women with and without type 2 diabetes 
This study examined the effect of glucose ingestion on cardiac autonomic function in non-obese women and obese women with and without type 2 diabetes. Heart rate variability (HRV) was measured via continuous ECG and beat-by-beat blood pressure was recorded with finger photoplethysmography (Portapress) in a fasted state and in response to a 75 g glucose load in 42 middle-aged women (40–60 yr). Upright tilt was also utilized as an orthostatic stress to provide a clinically relevant challenge to the cardiovascular system. Significant main effects for log transformed (Ln) total power (TP, msec2) were observed with upright tilt (P<0.01) and glucose challenge (P<0.05). LnTP decreased in all groups in both the fasted and fed state with upright tilt (P<0.01), but glucose ingestion resulted in higher LnTP in the supine position only (P=0.008). Tilt resulted in a significant main effect for low frequency (LFnu, normalized units) and high frequency (Hfnu) power (P<0.000), while the glucose challenge had no effect on LFnu or HFnu power. LFnu approached significance for group differences (P=0.07), such that the non-obese had lower LF power than either of the obese groups. Sympathovagal balance (LnLF/HF ratio) was affected by position (P<0.000) and group (P<0.05), with a lower LnLF/HF in the non-obese than in the obese women. Baroreceptor sensitivity decreased (P<0.01) during upright tilt but was not changed by the glucose challenge. In conclusion, basal sympathovagal balance is higher in obese individuals with and without type 2 diabetes. Women with type 2 diabetes showed no differences in autonomic function with an orthostatic challenge or glucose load than non-diabetic, obese women. The glucose load did alter total spectral power in all of these middle-aged women, but had no impact on baroreceptor sensitivity.
PMCID: PMC1978097  PMID: 17512310
12.  Hypertension is an independent risk factor for type 2 diabetes: the Korean genome and epidemiology study 
Hypertension Research  2015;38(11):783-789.
Hypertension and diabetes share common risk factors and frequently co-occur. Although high blood pressure (BP) was reported as a significant predictor of type 2 diabetes, little is known about this association in Korea. This study investigated the relationship of prehypertension and hypertension with type 2 diabetes in 7150 middle-aged Koreans, as well as the effect of BP control on diabetes development over 8 years. At 8 years, 1049 (14.7%) of the 7150 participants had newly developed diabetes, including 11.2, 16.7 and 21.5% of baseline normotensive, prehypertensive and hypertensive subjects, respectively. The overall incidence rate of diabetes was 22.3 events per 1000 person-years. Subjects with baseline prehypertension (hazard ratio (HR), 1.27; 95% confidence interval (CI), 1.09–1.48) and hypertension (HR 1.51; 95% CI, 1.29–1.76) were at higher risk of diabetes than normotensive subjects after controlling for potential confounders (P-value for trend <0.001). These associations persisted even when subjects were stratified by baseline glucose status, sex and body mass index (BMI). The risk of diabetes was significantly higher in subjects who had normal BP at baseline and progressed to prehypertention or hypertension at 8 years (HR, 1.48; 95% CI, 1.20–1.83) than those with controlled BP, but these associations were not observed in subjects with baseline prehypertension and hypertension. These findings showed that prehypertension and hypertension are significantly associated with the development of diabetes, independent of baseline glucose status, sex and BMI. Active BP control reduced incident diabetes only in normotensive individuals, suggesting the need for early BP management.
PMCID: PMC4644940  PMID: 26178151
blood pressure; diabetes; incidence
13.  Is Prehypertension a Risk Factor for the Development of Type 2 Diabetes? 
Diabetes Care  2009;32(10):1870-1872.
Prehypertension is associated with cardiovascular disease and insulin resistance. However, whether subjects with prehypertension have more diabetes risk is not known. We examine whether prehypertension is a risk factor for developing type 2 diabetes.
Incident diabetes was examined in nondiabetic normotensive participants in the San Antonio Heart Study (n = 2,767; aged 25–65 years; median follow-up 7.8 years).
Incident diabetes was 12.4% in subjects with prehypertension and 5.6% in subjects with normal blood pressure. The odds of incident diabetes were 2.21 greater for individuals with prehypertension than for those with normal blood pressure (95% CI 1.63–2.98) after adjusting for age, sex, and ethnicity. Prehypertension was not associated with incident diabetes after additional adjustment for BMI, impaired glucose tolerance, insulin resistance and secretion, and family history of diabetes (odds ratio 1.42 [95% CI 0.99–2.02]).
Subjects with prehypertension are at increased risk of diabetes. Much of this risk is explained by disorders related to the insulin resistance syndrome.
PMCID: PMC2752916  PMID: 19628813
14.  Blood Pressure and the Risk of Developing Diabetes in African Americans and Whites 
Diabetes Care  2011;34(4):873-879.
We examined the association between high blood pressure and incident type 2 diabetes in African Americans and whites aged 35–54 years at baseline.
We combined data from the Atherosclerosis Risk in Communities (ARIC) study, the Coronary Artery Risk Development in Young Adults (CARDIA) study, and the Framingham Heart Study offspring cohort. Overall, 10,893 participants (57% women; 23% African American) were categorized by baseline blood pressure (normal, prehypertension, hypertension) and examined for incident diabetes (median follow-up 8.9 years).
Overall, 14.6% of African Americans and 7.9% of whites developed diabetes. Age-adjusted incidence was increasingly higher across increasing blood pressure groups (P values for trend: <0.05 for African American men; <0.001 for other race-sex groups). After adjustment for age, sex, BMI, fasting glucose, HDL cholesterol, and triglycerides, prehypertension or hypertension (compared with normal blood pressure) was associated with greater risks of diabetes in whites (hazard ratio [HR] for prehypertension: 1.32 [95% CI 1.09–1.61]; for hypertension: 1.25 [1.03–1.53]), but not African Americans (HR for prehypertension: 0.86 [0.63–1.17]; for hypertension: 0.92 [0.70–1.21]). HRs for developing diabetes among normotensive, prehypertensive, and hypertensive African Americans versus normotensive whites were: 2.75, 2.28, and 2.36, respectively (P values <0.001).
In African Americans, higher diabetes incidence among hypertensive individuals may be explained by BMI, fasting glucose, triglyceride, and HDL cholesterol. In whites, prehypertension and hypertension are associated with greater risk of diabetes, beyond that explained by other risk factors. African Americans, regardless of blood pressure, have greater risks of developing diabetes than whites.
PMCID: PMC3064044  PMID: 21346180
15.  Early Inflammatory and Metabolic Changes in Association With AGTR1 Polymorphisms in Prehypertensive Subjects 
American journal of hypertension  2010;24(2):225-233.
The Seventh Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure in 2003 created a prehypertension category for persons with blood pressures ranging from systolic blood pressure (SBP) of 120–139 mm Hg or diastolic blood pressure (DBP) from 80 to 89 mm Hg, due to increased risk of cardiovascular disease.
Our study utilized the University of California-San Diego (UCSD) Twin Hypertension Cohort. We measured comprehensive plasma cholesterol levels and metabolic (glucose, insulin, leptin) and inflammatory markers (interleukin-6 (IL-6), C-reactive protein (CRP), free fatty acids) to determine the differences between normotensive and prehypertensive subjects. Additionally, we determined whether angiotensin II receptor type-1 (AGTR1) polymorphisms, previously associated with hypertension, could predict prehypertension.
A total of 455 white subjects were included in the study (mean age 37.1 years). Prehypertensive subjects were older with greater body mass index (BMI) than the normotensives, and after adjusting for sex and age, had greater plasma glucose, insulin, and IL-6. The common AGTR1 A1166C (rs5186) polymorphism in the 3′-UTR region, particularly the presence of the 1166C allele, which fails to downregulate gene expression, predicted greater likelihood of being in the prehypertension group and higher SBP. A lesser-studied polymorphism in intron-2 of AGTR1 (A/G; rs2276736) was associated with plasma high-density lipoprotein (HDL) and apolipoprotein A-1. In a subgroup analysis of nonobese subjects (N = 405), similar associations were noted.
Prehypertensive subjects already exhibit early pathophysiologic changes putting them at risk of future cardiovascular disease, and AGTR1 may also contribute to this increased risk. Further investigation is needed to confirm these findings and the precise molecular mechanisms of action.
PMCID: PMC3101264  PMID: 20864943
AGTR1; angiotensin II receptor; blood pressure; hypertension; inflammation; prehypertension
16.  Differentiation of Overweight from Normal Weight Young Adults by Postprandial Heart Rate Variability and Systolic Blood Pressure 
Obesity and cardiovascular disease are inextricably linked and the health community’s response to the current epidemic of adolescent obesity may be improved by the ability to target adolescents at highest risk for developing cardiovascular disease in the future. Overweight manifests early as autonomic dysregulation and current methods do not permit differentiation of overweight adolescents or young adults at highest risk for developing cardiovascular disease.
This study was designed to test the hypothesis that scaling exponents motivated by nonlinear fractal analyses of Heart Rate Variability (HRV) differentiate overweight, otherwise healthy adolescent/young adult subjects at risk for developing prehypertension, the primary forerunner of cardiovascular disease.
Materials and Methods
The subjects were 18-20year old males with Body Mass Index (BMI) 20.1-42.5kg/m2. Electrocardiographic inter-beat (RR) intervals were measured during 3h periods of bed rest after overnight fasting and ingestion of 900Cal high-carbohydrate and high-fat test beverages on separate days. Detrended Fluctuation Analysis (DFA), k-means cluster and ANOVA analyses of scaling coefficients α, α1, and α2, showed dependencies on hourly measurements of systolic blood pressure and on premeasured BMI.
It was observed that α value increased during the caloric challenge, appears to represent metabolically-induced changes in HRV across the participants. An ancillary analysis was performed to determine the dependency on BMI without BMI as a parameter. Cluster analysis of the high-carbohydrate test beverage treatment and the high-fat treatment produced grouping with very little overlap. ANOVA on both clusters demonstrated significance at p<0.001. We were able to demonstrate increased sympathetic modulation of our study group during ingestion and metabolism of isocaloric high-carbohydrate and high-fat test beverages.
These findings demonstrate significantly different clustering of α, α1, and α2 and Systolic Blood Pressure (SBP) with respect to normal, overweight and obese BMI.
PMCID: PMC5028518  PMID: 27656434
Body mass index; Detrended fluctuation analysis; Energy substrate metabolism; K-means cluster analysis; Obesity
17.  Prehypertension in young females, where do they stand? 
Indian Heart Journal  2012;64(3):280-283.
To determine the prevalence of prehypertension in young females and its correlation to various parameters like body mass index (BMI), waist hip ratio (WHR), waist circumference (WC) and family history, and blood pressure (BP) response to exercise stress testing.
One hundred and fifty apparently healthy females of age group 18–25-years were randomly selected from the student population of Jawaharlal Nehru Medical College, Sawangi (Meghe), Wardha, after satisfying all the inclusion criteria and written informed consent. Along with all the anthropometric parameters BMI, WHR, WC and family history of hypertension (HTN) and/or diabetes, resting BP, and BP response to exercise stress testing were measured in the study.
Amongst 150 subjects, 63 (42%) subjects were normotensive and 87 (58%) were prehypertensive. Body mass index, WHR, WC and family history of HTN were significantly higher in prehypertensive group. Prehypertensive group also had an exaggerated BP response to exercise stress testing and higher BP during recovery.
Prevalence of prehypertension was found to be high in females, also there was a strong correlation between prehypertension and BMI, WHR and WC suggesting a positive correlation between obesity and prehypertension. Prehypertensive group also showed an exaggerated BP response to exercise stress testing.
PMCID: PMC3860851  PMID: 22664811
Exercise stress testing; Prehypertension; Young females
18.  Elevated serum neutrophil elastase is related to prehypertension and airflow limitation in obese women 
BMC Women's Health  2011;11:1.
Neutrophil elastase level/activity is elevated in a variety of diseases such as atherosclerosis, systolic hypertension and obstructive pulmonary disease. It is unknown whether obese individuals with prehypertension also have elevated neutrophil elastase, and if so, whether it has a deleterious effect on pulmonary function. Objectives: To determine neutrophil elastase levels in obese prehypertensive women and investigate correlations with pulmonary function tests.
Thirty obese prehypertensive women were compared with 30 obese normotensive subjects and 30 healthy controls. The study groups were matched for age. Measurements: The following were determined: body mass index, waist circumference, blood pressure, lipid profile, high sensitivity C-reactive protein, serum neutrophil elastase, and pulmonary function tests including forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio.
Serum neutrophil elastase concentration was significantly higher in both prehypertensive (405.8 ± 111.6 ng/ml) and normotensive (336.5 ± 81.5 ng/ml) obese women than in control non-obese women (243.9 ± 23.9 ng/ml); the level was significantly higher in the prehypertensive than the normotensive obese women. FEV1, FVC and FEV1/FVC ratio in both prehypertensive and normotensive obese women were significantly lower than in normal controls, but there was no statistically significant difference between the prehypertensive and normotensive obese women. In prehypertensive obese women, there were significant positive correlations between neutrophil elastase and body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, total cholesterol, triglyceride, low density lipoprotein cholesterol, high sensitivity C-reactive protein and negative correlations with high density lipoprotein cholesterol, FEV1, FVC and FEV1/FVC.
Neutrophil elastase concentration is elevated in obese prehypertensive women along with an increase in high sensitivity C-reactive protein which may account for dyslipidemia and airflow dysfunction in the present study population.
PMCID: PMC3031240  PMID: 21247478
19.  Cardio-metabolic risk factors and prehypertension in persons without diabetes, hypertension, and cardiovascular disease 
BMC Public Health  2013;13:730.
Prehypertension has been shown to be an early risk factor of cardiovascular disease (CVD). We investigated the prevalence and pattern of cardiometabolic risk factors in prehypertension in three ethnic Asian populations in Singapore.
We examined data from Chinese (n = 1177), Malay (n = 774), and Indian (n = 985) adults aged 40–80 years who participated in three independent population based studies conducted from 2004–2011 in Singapore who were free of diabetes, hypertension and previous CVD. Prehypertension was defined as systolic blood pressure (BP) 120–139 mm Hg or diastolic BP 80–89 mm Hg. Random blood glucose, glycated haemoglobin (HbA1c), body mass index (BMI), triglycerides, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol were examined as indicators of adverse cardiometabolic profile. The association between metabolic variables and prehypertension was examined using logistic regression models adjusting for potential confounders.
The prevalence of prehypertension was 59.8% (Chinese), 68.9% (Malays) and 57.7% Indians. Higher levels of blood glucose, HbA1c and BMI were significantly associated with prehypertension in all three ethnic groups, odds ratio (95% confidence interval) of prehypertension in Chinese, Malays and Indians were: 1.42 (1.10, 1.83), 1.53 (1.05, 2.24), 1.49 (1.13, 1.98) for high-glucose; 3.50 (1.01, 12.18), 3.72 (1.29, 10.75), 2.79 (1.31, 5.94) for high-HbA1c; 1.86 (1.34, 2.56), 2.96 (2.10, 4.18), 1.68 (1.28, 2.20) for high-BMI. In addition, higher levels of LDL cholesterol in Chinese and higher levels of triglycerides were significantly associated with prehypertension. These associations persisted when metabolic variables were analysed as continuous variables.
Higher levels of blood glucose, HbA1c and BMI were associated with prehypertension in all three ethnic groups in Singapore. Screening for prehypertension and lifestyle modifications could potentially reduce the burden of CVD in otherwise healthy Asian adults living in Singapore.
PMCID: PMC3751051  PMID: 23919264
Prehypertension; Metabolic syndrome; Indian; Cardiometabolic
20.  Prevalence of prehypertension and its relationship to risk factors for cardiovascular disease in Jamaica: Analysis from a cross-sectional survey 
Recent studies have documented an increased risk of cardiovascular disease (CVD) in persons with systolic blood pressures of 120–139 mmHg and/or diastolic blood pressures of 80–89 mmHg, classified as prehypertension in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. In this paper we estimate the prevalence of prehypertension in Jamaica and evaluate the relationship between prehypertension and other risk factors for CVD.
The study used data from participants in the Jamaica Lifestyle Survey conducted from 2000–2001. A sample of 2012 persons, 15–74 years old, completed an interviewer administered questionnaire and had anthropometric and blood pressure measurements performed by trained observers using standardized procedures. Fasting glucose and total cholesterol were measured using a capillary blood sample. Analysis yielded crude, and sex-specific prevalence estimates for prehypertension and other CVD risk factors. Odds ratios for associations of prehypertension with CVD risk factors were obtained using logistic regression.
The prevalence of prehypertension among Jamaicans was 30% (95% confidence interval [CI] 27%–33%). Prehypertension was more common in males, 35% (CI 31%–39%), than females, 25% (CI 22%–28%). Almost 46% of participants were overweight; 19.7% were obese; 14.6% had hypercholesterolemia; 7.2% had diabetes mellitus and 17.8% smoked cigarettes. With the exception of cigarette smoking and low physical activity, all the CVD risk factors had significantly higher prevalence in the prehypertensive and hypertensive groups (p for trend < 0.001) compared to the normotensive group. Odds of obesity, overweight, high cholesterol and increased waist circumference were significantly higher among younger prehypertensive participants (15–44 years-old) when compared to normotensive young participants, but not among those 45–74 years-old. Among men, being prehypertensive increased the odds of having >/=3 CVD risk factors versus no risk factors almost three-fold (odds ratio [OR] 2.8 [CI 1.1–7.2]) while among women the odds of >/=3 CVD risk factors was increased two-fold (OR 2.0 [CI 1.3–3.8])
Prehypertension occurs in 30% of Jamaicans and is associated with increased prevalence of other CVD risk factors. Health-care providers should recognize the increased CVD risk of prehypertension and should seek to identify and treat modifiable risk factors in these persons.
PMCID: PMC2551581  PMID: 18752689
21.  Autonomic and hemodynamic origins of prehypertension: Central role of heredity 
To better understand the origins and progression of prehypertension.
Prehypertension is a risk factor for progression to hypertension, cardiovascular disease and increased mortality. We used a cross-sectional twin study design to probe the role of heredity in likely pathophysiological events (autonomic or hemodynamic) in prehypertension.
812 individuals (337 normotensive, 340 prehypertensive, 135 hypertensive) were evaluated in a sample of twin pairs, their siblings and other family members. They underwent non-invasive hemodynamic, autonomic and biochemical testing, as well as estimates of trait heritability (h2: % of trait variance accounted for by heredity) and pleiotropy (rG: genetic covariance or shared genetic determination of traits) by variance components.
In the hemodynamic realm, an elevation of cardiac contractility (LV dP/dT max) prompted increased stroke volume, in turn increasing CO, which elevated blood pressure into the prehypertension range. Autonomic monitoring detected an elevation of norepinephrine secretion plus a decline in cardiac parasympathetic tone. Twin pair variance components documented substantial heritability as well as joint genetic determination for blood pressure and the contributory autonomic and hemodynamic traits. Genetic variation at a pathway locus also indicated pleiotropic effects on contractility and blood pressure.
Elevated blood pressure in prehypertension results from increased CO, driven by contractility as well as heart rate, which may reflect both diminished parasympathetic and increased sympathetic tone. In the face of increased CO, SVR fails to decline homeostatically. Such traits display substantial heritability and shared genetic determination, though by loci not yet elucidated. These findings clarify the role of heredity in the origin of prehypertension and its autonomic and hemodynamic pathogenesis. The results also establish pathways that suggest new therapeutic targets for prehypertension, or approaches to its prevention.
PMCID: PMC3374873  PMID: 22676942
Hypertension; genetics; nervous system; autonomic
22.  Geometrical and functional changes of left heart in adults with prehypertension and hypertension: a cross-sectional study from China 
Studies regarding the association between prehypertension and the structual changes of left heart are scanty. However, which type of the geometrical change of left heart is predominated one in prehypertension and hypertension is controversial. It is therefore important to investigate geometrical and functional changes of left heart in adults with prehypertension and hypertension because of their prognostic significance.
The study was based on a cross-sectional design, a total of 10547 participants were classified into normotension group, prehypertension group and hypertension group. We analyzed clinical characteristics, echocardiographic parameters and distribution of left ventricular (LV) geometrical patterns in different groups.
Participants with prehypertension had higher values of most of echocardiographic parameters than those with normotension. The prevalence of left ventricular hypertrophy(LVH) was statistically different among three groups (P <0.001), and the rates of LVH in the three groups were 5.9, 8.6, 28.4 % by indexation to height2.7 and 4.9, 5.3, 19.3 % by indexation to BSA, respectively. The prevalence rates of eccentric hypertrophy, concentric remodeling and concentric hypertrophy were 7.3 %, 5.3 % and 1.4 % in prehypertension group, and 17.8 %, 8.8 % and 10.6 % in hypertension group. Logistic regression analysis showed that systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean artery pressure (MAP) were all independent risk factors for left cardiac structural changes, and pulse pressure (PP) was independent risk factor for concentric and eccentric hypertrophy. Among four indices, DBP levels with OR values of 1.192, 1.759 and 1.278 were the strongest indicator for concentric remodeling, concentric hypertrophy and eccentric hypertrophy, respectively (P <0.001).
There exists LV geometrical change in adults with prehypertension and hypertension in rural Chinese population, and the eccentric hypertrophy was the highest proportion of geometric alterations. SBP, DBP, MAP and PP were all positively associated with left cardiac structural changes, and the association of DBP was the strongest.
PMCID: PMC4884422  PMID: 27234840
Echocardiography; Hypertension; Prehypertension; Left ventricular geometry
23.  Cold Exposure Can Induce an Exaggerated Early-Morning Blood Pressure Surge in Young Prehypertensives 
PLoS ONE  2016;11(2):e0150136.
Prehypertension is related to a higher risk of cardiovascular events than normotension. Our previous study reported that cold exposure elevates the amplitude of the morning blood pressure surge (MBPS) and is associated with a sympathetic increase during the final sleep transition, which might be critical for sleep-related cardiovascular events in normotensives. However, few studies have explored the effects of cold exposure on autonomic function during sleep transitions and changes of autonomic function among prehypertensives. Therefore, we conducted an experiment for testing the effects of cold exposure on changes of autonomic function during sleep and the MBPS among young prehypertensives are more exaggerate than among young normotensives. The study groups consisted of 12 normotensive and 12 prehypertensive male adults with mean ages of 23.67 ± 0.70 and 25.25 ± 0.76 years, respectively. The subjects underwent cold (16°C) and warm (23°C) conditions randomly. The room temperature was maintained at either 23°C or 16°C by central air conditioning and recorded by a heat-sensitive sensor placed on the forehead and extended into the air. BP was measured every 30 minutes by using an autonomic BP monitor. Electroencephalograms, electrooculograms, electromyograms, electrocardiograms, and near body temperature were recorded by miniature polysomnography. Under cold exposure, a significantly higher amplitude of MBPS than under the warm condition among normotensives; however, this change was more exaggerated in prehypertensives. Furthermore, there was a significant decrease in parasympathetic-related RR and HF during the final sleep transition and a higher early-morning surge in BP and in LF% among prehypertensives, but no such change was found in normotensives. Our study supports that cold exposure might increase the risk of sleep-related cardiovascular events in prehypertensives.
PMCID: PMC4769082  PMID: 26919177
24.  Exercise Training Improves Heart Rate Variability after Methamphetamine Dependency 
Heart rate variability (HRV) reflects a healthy autonomic nervous system and is increased with physical training. Methamphetamine dependence (MD) causes autonomic dysfunction and diminished HRV. We compared recently abstinent MD participants with age-matched, drug free controls (DF) and also investigated whether HRV can be improved with exercise training in the MD participants.
In 50 participants (MD=28; DF=22) resting heart rate (R-R intervals) was recorded over 5 min while seated using a monitor affixed to a chest strap. Previously reported time-domain (SDNN, RMSSD, pNN50) and frequency-domain (LFnu, HFnu, LF/HF) parameters of HRV were calculated with customized software. MD were randomized to thrice weekly exercise training (ME=14) or equal attention without training (MC=14) over 8 weeks. Groups were compared using paired and unpaired t-tests. Statistical significance was set at P≤0.05.
Participant characteristics were matched between groups: age 33±6 years; body mass 82.7±12 kg, BMI 26.8±4.1 kg•min−2, mean±SD. Compared with DF, the MD group had significantly higher resting heart rate (P<0.05), LFnu, and LF/HF (P<0.001) as well as lower SDNN, RMSSD, pNN50 and HFnu (all P<0.001). At randomization, HRV indices were similar between ME and MC groups. However, after training, the ME group significantly (all P<0.001) increased SDNN (+14.7±2.0 ms, +34%), RMSSD (+19.6±4.2 ms, +63%), pNN50 (+22.6±2.7%, +173%), HFnu (+14.2±1.9, +60%) and decreased HR (−5.2±1.1 beats·min−1, −7%), LFnu (−9.6±1.5, −16%) and LF/HF (−0.7±0.3, −19%). These measures did not change from baseline in the MC group.
HRV, based on several conventional indices, was diminished in recently abstinent, methamphetamine dependent individuals. Moreover, physical training yielded a marked increase of HRV representing increased vagal modulation or improved autonomic balance.
PMCID: PMC3999306  PMID: 24162556
HRV; substance use; autonomic nervous system; vagal modulation
25.  Exercise training improves endothelial function in young prehypertensives 
Prehypertensives exhibit marked endothelial dysfunction, a risk factor for future cardiovascular morbidity and mortality. However, the ability of exercise to ameliorate endothelial dysfunction in prehypertensives is grossly underinvestigated. This prospective randomized and controlled study examined the separate effects of resistance and endurance training on conduit artery endothelial function in young prehypertensives. Forty-three unmedicated prehypertensive (systolic blood pressure [SBP]=120–139 mmHg; diastolic blood pressure [DBP]=80–89 mmHg) but otherwise healthy men and women and 15 normotensive matched time-controls (NMTC); n = 15) between 18 and 35 y of age met screening requirements and participated in the study. Prehypertensive subjects were randomly assigned to either a resistance exercise training (PHRT; n = 15), endurance exercise training (PHET; n = 13) or time-control group (PHTC; n = 15). The treatment groups performed exercise training three days per week for eight weeks. The control groups did not initiate exercise programs throughout the study. Flow mediated dilation (FMD) of the brachial artery, biomarkers of enodothelial function and peripheral blood pressure were evaluated before and after exercise intervention or time-matched control. PHRT and PHET reduced resting SBP (9.6 ± 3.6 and 11.9 ± 3.4 mmHg, respectively; P < 0.05) and DBP (8.0 ± 5.1 and 7.2 ± 3.4 mmHg, respectively; P < 0.05). Exercise training improved brachial artery FMD absolute diameter, percent dilation and normalized percent dilation by 30%, 34% and 19% for PHRT, P < 0.05; and by 54%, 63% and 75% for PHET, P < 0.05; respectively. PHRT and PHET increased plasma concentrations of 6-keto prostaglandin F1α (19% and 22%, respectively; P < 0.05), NOx (19% and 23%, respectively; P < 0.05), and reduced endothelin-1 by (16% and 24%, respectively; P < 0.01). This study provides novel evidence that resistance and endurance exercise separately have beneficial effects on resting peripheral blood pressure, brachial artery FMD and endothelial-derived vasoactive agents in young prehypertensives.
PMCID: PMC4457439  PMID: 23760009
endothelial function; endothelin; exercise; nitric-oxide; prehypertension

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