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1.  Dissecting the genetic components of a quantitative trait locus for blood pressure and renal pathology on rat chromosome 3 
Journal of Hypertension  2017;35(2):319-329.
Background:
We have previously confirmed the importance of rat chromosome 3 (RNO3) genetic loci on blood pressure elevation, pulse pressure (PP) variability and renal pathology during salt challenge in the stroke-prone spontaneously hypertensive (SHRSP) rat. The aims of this study were to generate a panel of RNO3 congenic sub-strains to genetically dissect the implicated loci and identify positional candidate genes by microarray expression profiling and analysis of next-generation sequencing data.
Method and results:
A panel of congenic sub-strains were generated containing Wistar–Kyoto (WKY)-introgressed segments of varying size on the SHRSP genetic background, focused within the first 50 Mbp of RNO3. Haemodynamic profiling during salt challenge demonstrated significantly reduced systolic blood pressure, diastolic blood pressure and PP variability in SP.WKYGla3a, SP.WKYGla3c, SP.WKYGla3d and SP.WKYGla3e sub-strains. Only SBP and DBP were significantly reduced during salt challenge in SP.WKYGla3b and SP.WKYGla3f sub-strains, whereas SP.WKYGla3g rats did not differ in haemodynamic response to SHRSP. Those sub-strains demonstrating significantly reduced PP variability during salt challenge also demonstrated significantly reduced renal pathology and proteinuria. Microarray expression profiling prioritized two candidate genes for blood pressure regulation (Dnm1, Tor1b), localized within the common congenic interval shared by SP.WKYGla3d and SP.WKYGla3f strains, and one candidate gene for salt-induced PP variability and renal pathology (Rabgap1), located within the region unique to the SP.WKYGla3d strain. Comparison of next-generation sequencing data identified variants within additional positional genes that are likely to affect protein function.
Conclusion:
This study has identified distinct intervals on RNO3-containing genes that may be important for blood pressure regulation and renal pathology during salt challenge.
doi:10.1097/HJH.0000000000001155
PMCID: PMC5214373  PMID: 27755386
blood pressure; congenic; gene expression; next-generation sequencing; profiling; pulse pressure; radiotelemetry; salt-sensitivity; stroke-prone spontaneously hypertensive rat; Wistar–Kyoto rat
2.  The antihypertensive MTHFR gene polymorphism rs17367504-G is a possible novel protective locus for preeclampsia 
Journal of Hypertension  2016;35(1):132-139.
Objective:
Preeclampsia is a complex heterogeneous disease commonly defined by new-onset hypertension and proteinuria in pregnancy. Women experiencing preeclampsia have increased risk for cardiovascular diseases (CVD) later in life. Preeclampsia and CVD share risk factors and pathophysiologic mechanisms, including dysregulated inflammation and raised blood pressure. Despite commonalities, little is known about the contribution of shared genes (pleiotropy) to these diseases. This study aimed to investigate whether genetic risk factors for hypertension or inflammation are pleiotropic by also being associated with preeclampsia.
Methods:
We genotyped 122 single nucleotide polymorphisms (SNPs) in women with preeclampsia (n = 1006) and nonpreeclamptic controls (n = 816) from the Norwegian HUNT Study. SNPs were chosen on the basis of previously reported associations with either nongestational hypertension or inflammation in genome-wide association studies. The SNPs were tested for association with preeclampsia in a multiple logistic regression model.
Results:
The minor (G) allele of the intronic SNP rs17367504 in the gene methylenetetrahydrofolate reductase (MTHFR) was associated with a protective effect on preeclampsia (odds ratio 0.65, 95% confidence interval 0.53–0.80) in the Norwegian cohort. This association did not replicate in an Australian preeclampsia case–control cohort (P = 0.68, odds ratio 1.05, 95% confidence interval 0.83–1.32, minor allele frequency = 0.15).
Conclusion:
MTHFR is important for regulating transmethylation processes and is involved in regulation of folate metabolism. The G allele of rs17367504 has previously been shown to protect against nongestational hypertension. Our study suggests a novel association between this allele and reduced risk for preeclampsia. This is the first study associating the minor (G) allele of a SNP within the MTHFR gene with a protective effect on preeclampsia, and in doing so identifying a possible pleiotropic protective effect on preeclampsia and hypertension.
doi:10.1097/HJH.0000000000001131
PMCID: PMC5131692  PMID: 27755385
blood pressure regulation; hypertension; methylenetetrahydrofolate reductase; pleiotropy; preeclampsia; single nucleotide polymorphism
3.  Target Organ Complications and Prognostic Significance of Alerting Reaction: Analysis from the Dallas Heart Study 
Journal of hypertension  2016;34(2):226-234.
Objective
Noninvasive BP measurement often triggers a transient rise in BP, known as an alerting reaction. However, the prevalence and prognostic significance of the alerting reaction has never been assessed in the general population.
Methods
We evaluated the association between the alerting reaction and left ventricular mass (LVM) by magnetic resonance imaging and urinary-albumin-to-creatinine ratio (UACR) in the Dallas Heart Study, a large population sample of 3,069 subjects. Participants were categorized into 4 groups based on levels of consecutive BP: 1.normal 1st BP and average 3rd to 5th (avg3-5) BP of <140/90 mmHg (control group), 2.high 1st BP of ≥140/90 mmHg and normal (avg3-5) BP (HN), 3.normal 1st BP and high (avg3-5) BP, and 4.high 1st to 5th BP. Then, associations between BP categories with incident cardiovascular outcomes (coronary heart disease, stroke, atrial fibrillation, heart failure, and cardiovascular death) over a median follow-up period of 9.4 years were assessed.
Results
The sample-weighted prevalence of isolated hypertension during the first BP measurement was 9.6%. Presence of an alerting reaction was independently associated with increased LVM, UACR, cardiovascular events after adjustment for traditional cardiovascular risk factors and baseline BP (adjusted HR 1.24, 95%CI 1.07-1.43).
Conclusions
Our study indicated that the alerting reaction is independently associated with increased cardiovascular and renal complications.
doi:10.1097/HJH.0000000000000774
PMCID: PMC5127693  PMID: 26485459
Blood pressure measurement; systemic hypertension; prognosis; cardiovascular events; target organ damage
4.  Lifetime risk of stroke in young-aged and middle-aged Chinese population: the Chinese Multi-Provincial Cohort Study 
Journal of Hypertension  2016;34(12):2434-2440.
Supplemental Digital Content is available in the text
Objective:
Stroke is a major cause of premature death in China. Early prevention of stroke requires a more effective method to differentiate the stroke risk among young-aged and middle-aged individuals than the 10-year risk of cardiovascular disease. This study aimed to establish a lifetime stroke risk model and risk charts for the young-aged and middle-aged population in China.
Methods:
The Chinese Multi-Provincial Cohort Study participants (n = 21 953) aged 35–84 years without cardiovascular disease at baseline were followed for 18 years (263 016 person-years). Modified Kaplan–Meier method was used to estimate the mean lifetime stroke risk up to age of 80 years and the lifetime stroke risk according to major stroke risk factors for the population aged 35–60 years.
Results:
A total of 917 participants developed first-ever strokes. For the participants aged 35–40 years (98 stroke cases), the lifetime stroke risk was 18.0 and 14.7% in men and women, respectively. Blood pressure most effectively discriminated the lifetime stroke risk. The lifetime risk of stroke for the individuals with all risk factors optimal was 8–10 times lower compared with those with two or more high risk factors at age 35–60 years at baseline.
Conclusion:
In young-aged and middle-aged population, the lifetime stroke risk will keep very low if major risk factors especially blood pressure level is at optimal levels, but the risk substantially increases even with a slight elevation of major risk factors, which could not be identified using 10-year risk estimation.
doi:10.1097/HJH.0000000000001084
PMCID: PMC5106079  PMID: 27512963
blood pressure; lifetime risk; risk assessment; stroke
5.  PTPRD gene associated with blood pressure response to atenolol and resistant hypertension 
Journal of hypertension  2015;33(11):2278-2285.
Objective
The aim of this study is to identify single-nucleotide polymorphisms (SNPs) influencing blood pressure (BP) response to the β-blocker atenolol.
Methods
Genome-wide association analysis of BP response to atenolol monotherapy was performed in 233 white participants with uncomplicated hypertension in the pharmacogenomic evaluation of antihypertensive responses study. Forty-two polymorphisms with P less than 10−5 for association with either diastolic or systolic response to atenolol monotherapy were validated in four independent groups of hypertensive individuals (total n = 2114).
Results
In whites, two polymorphisms near the gene PTPRD (rs12346562 and rs1104514) were associated with DBP response to atenolol (P = 3.2 × 10−6 and P = 5.9 × 10−6, respectively) with directionally opposite association for response to hydrochlorothiazide in another group of 228 whites (P = 0.0018 and P = 0.00012). A different polymorphism (rs10739150) near PTPRD was associated with response to atenolol in 150 black hypertensive individuals (P = 8.25 ×10−6). rs12346562 had a similar trend in association with response to bisoprolol (a different β-blocker) in 207 Finnish men in the genetics of drug responsiveness in essential hypertension study. In addition, an intronic single-nucleotide polymorphism (rs4742610) in the PTPRD gene was associated with resistant hypertension in whites and Hispanics in the international verapamil SR trandolapril study (meta-analysis P = 3.2 × 10−5).
Conclusion
PTPRD was identified as a novel locus potentially associated with BP response to atenolol and resistant hypertension in multiple ethnic groups.
doi:10.1097/HJH.0000000000000714
PMCID: PMC4788379  PMID: 26425837
atenolol; blood pressure response; genome-wide association study; pharmacogenomic evaluation of antihypertensive responses; pharmacogenomics; PTPRD; resistant hypertension
6.  Long-term intake of animal flesh and risk of developing hypertension in three prospective cohort studies 
Journal of hypertension  2015;33(11):2231-2238.
Objective
Prospective data are scarce on the relation of red meat, seafood, and poultry consumption with hypertension risk. Although red and processed meats are generally considered to have adverse cardiovascular consequences, seafood is believed to be protective and poultry's effect is controversial.
Methods
We prospectively examined the independent association of long-term intake of animal flesh with incident hypertension in three longitudinal cohort studies of non-hypertensive individuals: Nurses' Health Study I (NHS I, n=62,273 women), Nurses' Health Study II (NHS II, n=88,831 women), and Health Professionals Follow-up Study (HPFS, n=37,414 men). We used multivariable Cox proportional hazards regression to study the associations of different types of animal flesh with the risk of developing hypertension while controlling for other hypertension risk factors. We then used fixed effects meta-analysis to derive pooled estimates of effect.
Results
Compared with participants whose consumption was <1 serving/month, the pooled hazard ratios (HR) among those whose intake was ≥1 serving/day were 1.30 (95% CI: 1.23-1.39) for total meat (a combination of processed and unprocessed red meat), 1.22 (1.12-1.34) for poultry, and 1.05 (0.98-1.13) for seafood. Seafood was associated with an increased risk of hypertension in HPFS and NHS II, but not NHS I. Consumption of any animal flesh ≥1 serving/day was associated with an increased hypertension risk (pooled HR=1.30 [1.16-1.47]).
Conclusions
Long-term intake of meat and poultry were associated with increased risk of hypertension. In contrast to our hypothesis, we found a weak but significant trend towards an increased risk of hypertension with increasing seafood consumption.
doi:10.1097/HJH.0000000000000722
PMCID: PMC4797063  PMID: 26237562
8.  Can arterial wave augmentation in young adults help account for variability of cardiovascular risk in different British ethnic groups? 
Journal of Hypertension  2016;34(11):2220-2226.
Objective:
Traditional cardiovascular risk factors do not fully account for ethnic differences in cardiovascular disease. We tested if arterial function indices, particularly augmentation index (AIx), and their determinants from childhood could underlie such ethnic variability among young British adults in the ‘DASH’ longitudinal study.
Methods:
DASH, at http://dash.sphsu.mrc.ac.uk/, includes representative samples of six main British ethnic groups. Pulse wave velocity (PWV) and AIx were recorded using the Arteriograph device at ages 21–23 years in a subsample (n = 666); psychosocial, anthropometric, and blood pressure (BP) measures were collected then and in two previous surveys at ages 11–13 years and 14–16 years. For n = 334, physical activity was measured over 5 days (ActivPal).
Results:
Unadjusted values and regression models for PWVs were similar or lower in ethnic minority than in White UK young adults, whereas AIx was higher – Caribbean (14.9, 95% confidence interval 12.3–17.0%), West African (15.3, 12.9–17.7%), Indian (15.1, 13.0–17.2%), and Pakistani/Bangladeshi (15.7, 13.7–17.7%), compared with White UK (11.9, 10.2–13.6%). In multivariate models, adjusted for sex, central SBP, height, and heart rate, Indian and Pakistani/Bangladeshi young adults had higher AIx (β = 3.35, 4.20, respectively, P < 0.01) than White UK with a similar trend for West Africans and Caribbeans but not statistically significant. Unlike PWV, physical activity, psychosocial or deprivation measures were not associated with AIx, with borderline associations from brachial BP but no other childhood variables.
Conclusion:
Early adult AIx, but not arterial stiffness, may be a useful tool for testing components of excess cardiovascular risk in some ethnic minority groups.
doi:10.1097/HJH.0000000000001066
PMCID: PMC5051531  PMID: 27490950
augmentation index; cardiovascular risk; ethnicity; vascular stiffness
9.  Paternal programming of offspring cardiometabolic diseases in later life 
Journal of Hypertension  2016;34(11):2111-2126.
Early – intrauterine – environmental factors are linked to the development of cardiovascular disease in later life. Traditionally, these factors are considered to be maternal factors such as maternal under and overnutrition, exposure to toxins, lack of micronutrients, and stress during pregnancy. However, in the recent years, it became obvious that also paternal environmental factors before conception and during sperm development determine the health of the offspring in later life. We will first describe clinical observational studies providing evidence for paternal programming of adulthood diseases in progeny. Next, we describe key animal studies proving this relationship, followed by a detailed analysis of our current understanding of the underlying molecular mechanisms of paternal programming. Alterations of noncoding sperm micro-RNAs, histone acetylation, and targeted as well as global DNA methylation seem to be in particular involved in paternal programming of offspring's diseases in later life.
doi:10.1097/HJH.0000000000001051
PMCID: PMC5051533  PMID: 27457668
cardiometabolic diseases; epigenetics; offspring; paternal programming; spermatogenesis; transgenerational effects
10.  Exaggerated Exercise Blood Pressure is Associated with Higher Left Ventricular Mass in Adolescence. The Avon Longitudinal Study of Parents and Children 
Journal of hypertension  2016;34(Suppl 1):e55.
Objective
Dynamic exercise results in an increase to systolic blood pressure (BP). Irrespective of resting BP, some individuals may experience an exaggerated rise in systolic BP with exercise, which in adulthood, is associated with greater risk of developing hypertension, cardiovascular morbidity and mortality. It is not known if exercise BP is associated with adverse cardiovascular risk during adolescence. We determined associations of exercise BP with left ventricular mass (LVM) in adolescents, with consideration of the possible confounding effect of body composition.
Design and method
We undertook a cross-sectional study of 3,949 adolescents (mean age 17.8 ± 0.4 years, 45% male) who were part of a UK population-based birth cohort study. A sub-maximal exercise step-test with automated BP measurement immediately post-exercise was completed and body composition (total fat and lean mass) assessed by dual-energy x-ray absorptiometry. A sub-sample (n = 1,241) underwent comprehensive echocardiographic assessment.
Results
Each 5 mmHg increase in post-exercise systolic BP was associated with 0.34 g/m2.7 (95% CI: 0.24, 0.45) greater LVM indexed to height2.7 with adjustment for age, sex and hypertension status (p < 0.001). Further adjustment for lean mass attenuated this association to 0.29 g/m2.7 (95% CI 0.19, 0.39; p < 0.001) for each 5 mmHg of post-exercise systolic BP, adjustment for fat mass attenuated it to 0.15 g/m2.7 (95% CI 0.05, 0.25; p = 0.003), and adjustment for both lean and fat mass attenuated it to 0.13 g/m2.7 (95% CI 0.03, 0.23; p = 0.012). Individuals with post-exercise systolic BP ≥150 mmHg (corresponding to post-exercise systolic BP >70th percentile) had a 7% greater LVM compared to those with post-exercise systolic BP < 150 mmHg (p < 0.001).
Conclusions
Exaggerated exercise systolic BP is associated with higher LVM, adjustment for body composition attenuates but does not abolish this association. These results may have important implications for cardiovascular risk in later life
doi:10.1097/01.hjh.0000499992.80444.b7
PMCID: PMC5051632  PMID: 27753917
12.  Taking the Tension Out of Hypertension: A Prospective Study of Psychological Well-Being and Hypertension 
Journal of hypertension  2014;32(6):1222-1228.
Background
Previous studies have shown that psychological well-being is associated with reduced risk of cardiovascular disease. However, whether well-being might be specifically associated with reduced risk of hypertension has not been rigorously investigated in prospective studies.
Objective
This study examined the prospective association between two measures of psychological well-being and incident hypertension.
Methods
Participants were 6,384 healthy British civil servants age 39 to 63 from the Whitehall II cohort. Psychological well-being (emotional vitality and optimism) and cardiovascular risk factors (demographic characteristics, health status, health behaviors, psychological ill-being) were assessed during the 1991-1994 baseline. Incident hypertension was defined by clinical measures of systolic or diastolic blood pressure >140/90 mmHg, self-reported physician-diagnosed hypertension, or treatment for hypertension. Follow-up assessments of hypertension took place approximately every three years through 2002-2004. Cox proportional hazards regression models estimated hazard ratios.
Results
There were 2,304 cases of incident hypertension during the follow-up period. High versus low emotional vitality was associated with a significantly reduced risk of hypertension in an age-adjusted model (hazard ratio = 0.89; 95% confidence interval 0.80-0.98). This association was maintained after controlling for demographic characteristics and health status, but was slightly attenuated after adjusting for health behaviors and ill-being. Optimism was not significantly associated with hypertension.
Conclusions
High emotional vitality was associated with reduced hypertension risk; favorable health behaviors explained only part of the relationship. Associations did not differ by age, were similar for men and women and were maintained after accounting for ill-being.
doi:10.1097/HJH.0000000000000175
PMCID: PMC5010231  PMID: 24786293
well-being; vitality; optimism; hypertension; blood pressure; longitudinal study; Whitehall II cohort; health behaviors; risk factors
13.  Spironolactone versus sympathetic renal denervation to treat true resistant hypertension: results from the DENERVHTA study – a randomized controlled trial 
Journal of Hypertension  2016;34(9):1863-1871.
Supplemental Digital Content is available in the text
Objective:
Both renal denervation (RDN) and spironolactone have been proposed for the treatment of resistant hypertension. However, they have not been compared in a randomized clinical trial. We aimed to compare the efficacy of spironolactone versus RDN in patients with resistant hypertension.
Methods:
A total of 24 patients with office SBP at least 150 mmHg and 24-h SBP at least 140 mmHg despite receiving at least three full-dose antihypertensive drugs, one a diuretic, but without aldosterone antagonists, were randomized to receive RDN or spironolactone (50 mg) as add-on therapy. Primary endpoint was change in 24-h SBP at 6 months. Comparisons between treatment groups were performed using generalized linear models adjusted by age, sex, and baseline values.
Results:
Spironolactone was more effective than RDN in reducing 24-h SBP and 24-h DBP: mean baseline-adjusted differences between the two groups were −17.9 mmHg (95%CI −30.9 to −4.9); P = 0.010 and −6.6 mmHg (95%CI −12.9 to −0.3); P = 0.041, for 24-h SBP and 24-h DBP, respectively. As regards changes in office blood pressure, mean baseline-adjusted differences between the two groups were −12.1 mmHg (95%CI −29.1 to 5.1); P = 0.158 and of −5.3 mmHg (95%CI −16.3 to 5.8); P = 0.332, for office SBP and office DBP, respectively. Otherwise, the decrease of estimated glomerular filtration rate was greater in the spironolactone group; mean baseline-adjusted difference between the two groups was −10.7 ml/min per 1.73 m2 (95%CI −20.1 to −1.4); P = 0.027.
Conclusion:
We conclude that spironolactone is more effective than RDN to reduce 24-h SBP and 24-h DBP in patients with resistant hypertension. Therefore, spironolactone should be the fourth antihypertensive drug to prescribe if deemed well tolerated’ in all patients with resistant hypertension before considering RDN.
doi:10.1097/HJH.0000000000001025
PMCID: PMC4972478  PMID: 27327441
ablation; hypertension; renal denervation; resistant hypertension; spironolactone
14.  The association between SBP and mortality risk differs with level of cognitive function in very old individuals 
Journal of Hypertension  2016;34(4):745-752.
Objective:
Cognitive impairment and dementia are highly prevalent in very old populations. Cardiovascular disease is a common cause of death in people with dementia.
This study investigated whether the association of blood pressure (BP) with mortality differed with respect to mini-mental state examination (MMSE) score in a representative sample of very old individuals.
Methods:
The sample consisted of 1115 participants aged 85, 90, and at least 95 years from the Umeå85+/GErontological Regional DAtabase cohort study. The main outcome was all-cause mortality within 2 years according to BP and MMSE score, using Cox proportional-hazard regression models adjusted for sociodemographic and clinical characteristics associated with death.
Results:
Mean age, MMSE score, and SBP and DBP were 89.4 ± 4.6 years, 21.1 ± 7.6, 146.1 ± 23.4 mmHg, and 74.1 ± 11.7 mmHg, respectively. Within 2 years, 293 (26%) participants died. BP was not associated independently with mortality risk, except among participants with MMSE scores of 0–10 among whom mortality risk was increased in association with SBP at least 165 mmHg and 125 mmHg or less, compared with 126–139 mmHg (adjusted hazard ratio 4.54, 95% confidence interval = 1.52–13.60 and hazard ratio 2.23, 95% confidence interval = 1.12–4.45, respectively). In age and sex-adjusted analyses, SBP 125 mmHg or less was associated with increased mortality risk in participants with MMSE scores at least 18.
Conclusion:
In people aged at least 85 years, the association of SBP with mortality appears to differ with respect to MMSE score. Very old individuals with very severe cognitive impairment and low or high BP may have increased mortality risk.
doi:10.1097/HJH.0000000000000831
PMCID: PMC4947532  PMID: 26938812
aged 80 and over; cognition disorders; dementia; hypertension; hypotension; mortality
15.  Effects of azilsartan medoxomil compared with olmesartan and valsartan on ambulatory and clinic blood pressure in patients with type 2 diabetes and prediabetes 
Journal of Hypertension  2016;34(4):788-797.
Background:
Angiotensin receptor blockers (ARBs) are preferred antihypertensive therapies in patients with type 2 diabetes mellitus (T2DM). Azilsartan medoxomil (AZL-M) is a potent ARB for the treatment of stages 1-2 hypertension. We compared the efficacy, safety, and metabolic effects of AZL-M to both valsartan (VAL) and olmesartan (OLM), separately in patients with impaired fasting glucose (prediabetes mellitus) and T2DM.
Methods:
A pooled analysis of 3821 patients from three separate randomized placebo-controlled trials comparing the effects of AZL-M (40 and 80 mg), OLM (40 mg), VAL (320 mg), and placebo on changes in ambulatory and clinic blood pressure (BP) among patients with hypertension and prediabetes mellitus or T2DM was performed. Two analysis pools were created to facilitate comparisons: Pool A included patients who received placebo, AZL-M or OLM and Pool B included those who received AZL-M or VAL. Within each pool, patients were stratified by glycemic subgroups (normoglycemic, prediabetes mellitus, or T2DM) based on hemoglobin A1c values. Changes from baseline in both 24-h and clinic SBP were the primary efficacy assessments.
Results:
Baseline 24-h mean SBPs were approximately 145 and 146 mmHg in the prediabetes mellitus and T2DM subgroups, respectively; corresponding clinic SBPs were approximately 158 and 159 mmHg. Baseline hemoglobin A1c values for each subgroup (both pools) were normoglycemic, 5.3%; prediabetes mellitus, 6.0%; and T2DM, 6.9%. Changes from baseline in 24-h or clinic SBP were significantly greater with AZL-M, 80 mg compared with either OLM 40 mg or VAL 320 mg in all subgroups in each pool. Safety and tolerability were similar among the active treatment and placebo subgroups.
Conclusion:
These analyses indicate that AZL-M, 80 mg/day lowers SBP by a greater magnitude than OLM or VAL at maximally approved doses in patients with prediabetes mellitus and T2DM. These findings have important clinical implications for this high-risk patient group.
doi:10.1097/HJH.0000000000000839
PMCID: PMC4947533  PMID: 26766564
ambulatory blood pressure; angiotensin receptor blockers; azilsartan medoxomil; prediabetes; type 2 diabetes
16.  Non-hemodynamic predictors of arterial stiffness after 17 years of follow-up: the Malmö Diet and Cancer study 
Journal of Hypertension  2015;33(5):957-965.
Background:
Arterial stiffness plays a fundamental role in the development of hypertension and is a risk factor for both cardiovascular disease and mortality. The stiffening that occurs with increasing age has, in numerous cross-sectional studies, been shown to be associated with several cardiovascular risk factors. This observational study aims to characterize the predictive and cross-sectional markers focusing on the non-hemodynamic component of arterial stiffness.
Method:
In all, 2679 men and women from Malmö, Sweden, were examined at baseline during 1991–1994, and again at follow-up during 2007–2012 (mean age 72 years, 38% men). Follow-up examination included measurement of arterial stiffness by carotid–femoral pulse wave velocity (c-fPWV), after a mean period of 17 years. The associations between c-fPWV and risk markers were calculated with multiple linear regression.
Results:
The results indicated that for both sexes, waist circumference (β = 0.17, P < 0.001), fasting glucose (β = 0.13, P < 0.001), Homeostatic Model Assessment – Insulin Resistance (β = 0.10, P < 0.001), triglycerides (β = 0.10, P < 0.001), and high-density lipoprotein cholesterol (β = −0.08, P < 0.001) were all predictors of cfPWV adjusted for mean arterial pressure and heart rate, as well as for classical cardiovascular risk factors and drug treatment. There were no associations between baseline or follow-up low-density lipoprotein cholesterol, smoking, or eGFR and c-fPWV.
Conclusion:
The non-hemodynamic cluster of risk markers and predictors of arterial stiffness in a middle-aged population includes abdominal obesity, hyperglycemia, and dyslipidemia, but not smoking and low-density lipoprotein cholesterol. This pattern existed in both sexes.
doi:10.1097/HJH.0000000000000520
PMCID: PMC4947539  PMID: 25634451
ageing; arterial stiffness; diabetes mellitus; epidemiology; follow-up; glucose; hypertension; pulse wave velocity
17.  The mechanisms underlying fructose-induced hypertension: a review 
Journal of Hypertension  2015;33(5):912-920.
We are currently in the midst of an epidemic of metabolic disorders, which may, in part, be explained by excess fructose intake. This theory is supported by epidemiological observations as well as experimental studies in animals and humans. Rising consumption of fructose has been matched with growing rates of hypertension, leading to concern from public health experts. At this stage, the mechanisms underlying fructose-induced hypertension have not been fully characterized and the bulk of our knowledge is derived from animal models. Animal studies have shown that high-fructose diets up-regulate sodium and chloride transporters, resulting in a state of salt overload that increases blood pressure. Excess fructose has also been found to activate vasoconstrictors, inactivate vasodilators, and over-stimulate the sympathetic nervous system. Further work is required to determine the relevance of these findings to humans and to establish the level at which dietary fructose increases the risk of developing hypertension
doi:10.1097/HJH.0000000000000551
PMCID: PMC4947541  PMID: 25715094
blood pressure; endothelium; fructose; hypertension; salt; sympathetic nervous system
18.  Digital interventions to promote self-management in adults with hypertension systematic review and meta-analysis 
Journal of Hypertension  2016;34(4):600-612.
Objective:
To synthesize the evidence for using interactive digital interventions (IDIs) to support patient self-management of hypertension, and to determine their impact on control and reduction of blood pressure.
Method:
Systematic review with meta-analysis was undertaken with a search performed in MEDLINE, EMBASE, CINAHL, PsycINFO, ERIC, Cochrane Library, DoPHER, TROPHI, Social Science Citation Index and Science Citation Index. The population was adults (>18 years) with hypertension, intervention was an IDI and the comparator was usual care. Primary outcomes were change in SBP and DBP. Only randomized controlled trials and studies published in journals and in English were eligible. Eligible IDIs included interventions accessed through a computer, smartphone or other hand-held device.
Results:
Four out of seven studies showed a significantly greater reduction for intervention compared to usual care for SBP, with no difference found for three. Overall, IDIs significantly reduced SBP, with the weighted mean difference being −3.74 mmHg [95% confidence interval (CI) −2.19 to −2.58] with no heterogeneity observed (I-squared = 0.0%, P = 0.990). For DBP, four out of six studies indicated a greater reduction for intervention compared to controls, with no difference found for two. For DBP, a significant reduction of −2.37 mmHg (95% CI −0.40 to −4.35) was found, but considerable heterogeneity was noted (I-squared = 80.1%, P = <0.001).
Conclusion:
IDIs lower both SBP and DBP compared to usual care. Results suggest these findings can be applied to a wide range of healthcare systems and populations. However, sustainability and long-term clinical effectiveness of these interventions remain uncertain.
doi:10.1097/HJH.0000000000000859
PMCID: PMC4947544  PMID: 26845284
blood pressure; digital intervention; hypertension
20.  Renal denervation in treatment-resistant essential hypertension. A randomized, SHAM-controlled, double-blinded 24-h blood pressure-based trial 
Journal of Hypertension  2016;34(8):1639-1647.
Background:
Renal denervation (RDN), treating resistant hypertension, has, in open trial design, been shown to lower blood pressure (BP) dramatically, but this was primarily with respect to office BP.
Method:
We conducted a SHAM-controlled, double-blind, randomized, single-center trial to establish efficacy data based on 24-h ambulatory BP measurements (ABPM). Inclusion criteria were daytime systolic ABPM at least 145 mmHg following 1 month of stable medication and 2 weeks of compliance registration. All RDN procedures were carried out by an experienced operator using the unipolar Medtronic Flex catheter (Medtronic, Santa Rosa, California, USA).
Results:
We randomized 69 patients with treatment-resistant hypertension to RDN (n = 36) or SHAM (n = 33). Groups were well balanced at baseline. Mean baseline daytime systolic ABPM was 159 ± 12 mmHg (RDN) and 159 ± 14 mmHg (SHAM). Groups had similar reductions in daytime systolic ABPM compared with baseline at 3 months [−6.2 ± 18.8 mmHg (RDN) vs. −6.0 ± 13.5 mmHg (SHAM)] and at 6 months [−6.1 ± 18.9 mmHg (RDN) vs. −4.3 ± 15.1 mmHg (SHAM)]. Mean usage of antihypertensive medication (daily defined doses) at 3 months was equal [6.8 ± 2.7 (RDN) vs. 7.0 ± 2.5 (SHAM)].
RDN performed at a single center and by a high-volume operator reduced ABPM to the same level as SHAM treatment and thus confirms the result of the HTN3 trial.
Conclusion:
Further, clinical use of RDN for treatment of resistant hypertension should await positive results from double-blinded, SHAM-controlled trials with multipolar ablation catheters or novel denervation techniques.
doi:10.1097/HJH.0000000000000977
PMCID: PMC4933576  PMID: 27228432
ambulatory blood pressure measurement; randomized controlled trial; renal denervation; SHAM procedure; treatment-resistant hypertension
21.  Management of hypertension and diabetes mellitus by cardiovascular and endocrine physicians: a China registry 
Journal of Hypertension  2016;34(8):1648-1653.
Objective:
We investigated hypertension and diabetes mellitus in two management settings, namely cardiology and endocrinology, and their associations with albuminuria while accounting for the management of these two diseases.
Methods:
Our multicentre registry included patients (≥20 years) seen for hypertension in cardiology or for diabetes mellitus in endocrinology. We administered a questionnaire and measured blood pressure, glycosylated haemoglobin A1c and albuminuria.
Results:
Presence of both hypertension and diabetes was observed in 32.9% of hypertensive patients in cardiology (n = 1291) and 58.9% of diabetic patients in endocrinology (n = 1168). When both diseases were present, the use of combination antihypertensive therapy [odds ratio (OR) 0.31, P < 0.0001] and inhibitors of the renin–angiotensin system (OR 0.66, P = 0.0009) was less frequent in endocrinology than cardiology, and the use of combination antidiabetic therapy (OR 0.16, P < 0.0001) was less frequent in cardiology than endocrinology. The control of hypertension and diabetes, however, was not different between the two management settings (P ≥ 0.21), regardless of the therapeutic target (SBP/DBP < 140/90 or 130/80 mmHg and glycosylated haemoglobin A1c <7.0 or 6.5%). The prevalence of albuminuria was higher (P ≤ 0.02) in the presence of both diseases (23.3%) than those with either hypertension (12.6%) or diabetes alone (15.9%).
Conclusion:
Hypertension and diabetes mellitus were often jointly present, especially in the setting of endocrinology. The management was insufficient on the use of combination antihypertensive therapy and inhibitors of the renin–angiotensin system in endocrinology and for combination antidiabetic therapy in cardiology, indicating a need for more intensive management and better control of both clinical conditions.
doi:10.1097/HJH.0000000000000994
PMCID: PMC4933577  PMID: 27270188
albuminuria; diabetes mellitus; hypertension; management; registry
22.  TET2 and CSMD1genes affect SBP response to hydrochlorothiazide in never-treated essential hypertensives 
Journal of hypertension  2015;33(6):1301-1309.
Background
Thiazide diuretics have been recommended as a first-line antihypertensive treatment, although the choice of ‘the right drug in the individual essential hypertensive patient’ remains still empirical. Essential hypertension is a complex, polygenic disease derived from the interaction of patient’s genetic background with the environment. Pharmacogenomics could be a useful tool to pinpoint gene variants involved in antihypertensive drug response, thus optimizing therapeutic advantages and minimizing side effects.
Methods and results
We looked for variants associated with blood pressure response to hydrochlorothiazide over an 8-week follow-up by means of a genome-wide association analysis in two Italian cohorts of never-treated essential hypertensive patients: 343 samples from Sardinia and 142 from Milan. TET2 and CSMD1 as plausible candidate genes to affect SBP response to hydrochlorothiazide were identified. The specificity of our findings for hydrochlorothiazide was confirmed in an independent cohort of essential hypertensive patients treated with losartan. Our best findings were also tested for replication in four independent hypertensive samples of European Ancestry, such as GENetics of drug RESponsiveness in essential hypertension, Genetic Epidemiology of Responses to Antihypertensives, NORdic DILtiazem intervention, Pharmacogenomics Evaluation of Antihypertensive Responses, and Campania Salute Network-StayOnDiur. We validated a polymorphism in CSMD1 and UGGT2.
Conclusion
This exploratory study reports two plausible loci associated with SBP response to hydrochlorothiazide: TET2, an aldosterone-responsive mediator of αENaC gene transcription; and CSMD1, previously described as associated with hypertension in a case–control study.
doi:10.1097/HJH.0000000000000541
PMCID: PMC4484731  PMID: 25695618
essential hypertension; genome-wide association study; genomics; pharmacogenomics; thiazides diuretics
23.  Association of Major Dietary Patterns and Blood Pressure Longitudinal Change in Bangladesh 
Journal of hypertension  2015;33(6):1193-1200.
Background
Observational studies and clinical trials have shown associations of diet and high blood pressure (BP). However, prospective studies on the association between dietary patterns and longitudinal BP change are lacking, especially in low-income populations.
Method
We evaluated the association of dietary patterns and food groups with longitudinal change of BP in 10,389 participants in the Health Effects of Arsenic Longitudinal Study (HEALS), with a median of 6.7 years of follow-up. Dietary information was obtained through a previously validated food-frequency questionnaire (FFQ). BP was measured at baseline and at each biennial follow-up using the same method.
Result
Each SD increase for the “gourd vegetable” dietary pattern score was related to a slower annual change of 0.08 mmHg, 0.04 mmHg, and 0.05 mmHg in systolic blood pressure (SBP), diastolic blood pressure (DBP) or pulse pressure (PP), respectively. Each SD increase in the “balanced” dietary pattern score was related to a decreasing annual change of 0.06 mmHg (p=0.012) and 0.08 mmHg in SBP and PP (p <0.001). On the other hand, one SD increase in “western” dietary pattern score was related to a greater annual increase of 0.07 mmHg (p=0.005) and 0.05 mmHg in SBP and PP (p=0.013). Higher intake of fruits and vegetables was associated with a slower rate of change in annual SBP and PP while higher meat intake was related to a more rapid increase in annual PP.
Conclusion
The findings suggest that dietary patterns play a significant role in the rate of BP change over time in a low-income population.
doi:10.1097/HJH.0000000000000534
PMCID: PMC4606930  PMID: 25693059
Dietary pattern; Blood pressure; Longitudinal analysis
24.  Mechanisms and Consequences of eNOS Dysfunction in Hypertension 
Journal of hypertension  2015;33(6):1128-1136.
Reduced nitric oxide (NO) bioavailability contributes to endothelial dysfunction and hypertension. The endothelial isoform of NO synthase (eNOS) is responsible for the production of NO within endothelium. Loss of eNOS cofactor tetrahydrobiopterin to initial increase in oxidative stress leads to uncoupling of eNOS, in which the enzyme produces superoxide anion rather than NO, further substantiating oxidative stress to induce vascular pathogenesis. The current review focuses on recent advances on the molecular mechanisms and consequences of eNOS dysfunction in hypertension, and potential novel therapeutic strategies restoring eNOS function to treat hypertension.
doi:10.1097/HJH.0000000000000587
PMCID: PMC4816601  PMID: 25882860
nitric oxide; endothelial nitric oxide synthase (eNOS); tetrahydrobiopterin; eNOS uncoupling; endothelial dysfunction; hypertension; oxidative stress; NADPH oxidase (NOX)
25.  Antihypertensive medications and sexual function in women: Baseline data from the Systolic Blood Pressure Intervention Trial (SPRINT) 
Journal of hypertension  2016;34(6):1224-1231.
Objectives
Hypertension is a risk factor for the development of cardiovascular and kidney disease, but treatment can substantially reduce risks. Many patients avoid antihypertensive medications due to fear of side effects. While associations between antihypertensives and sexual dysfunction in men have been documented, it remains unclear whether antihypertensives are associated with sexual dysfunction in women. We conducted a cross-sectional analysis of baseline data from women in the Systolic Blood Pressure Intervention Trial (SPRINT) to evaluate the relations among class of antihypertensive medication and the outcomes (a) sexual activity and (b) sexual function.
Methods
SPRINT enrolled individuals 50 and older with hypertension at high risk for cardiovascular disease. A subset of participants completed questionnaires regarding quality of life (QoL), including sexual function. Antihypertensive class was determined by medications taken at baseline.
Results
Of 690 women in the QoL subset of SPRINT, 183 (26.5%) were sexually active. There were no significant differences in sexual activity among women taking one or more antihypertensives and women not taking any. Women taking an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (ACEI/ARB) had higher odds of sexual activity [OR 1.66 (1.12-4.27), p=0.011]. Among sexually active women, the prevalence of sexual dysfunction was high (52.5%). No class of medication was associated with sexual dysfunction in the multivariable model.
Conclusions
ACEI/ARB use was associated with higher odds of sexual activity. While prevalence of sexual dysfunction was high, no single class of antihypertensive medication was associated with sexual dysfunction.
doi:10.1097/HJH.0000000000000911
PMCID: PMC4859426  PMID: 27032074
hypertension; antihypertensive agents; female sexual function; sexual activity

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