Status of Hypertension in Tehran: Potential impact of the ACC/AHA 2017 and JNC7 Guidelines, 2012–2015

This study aimed to determine the prevalence of hypertension, the recommended anti-hypertensive therapy and the percentage of hypertensive patients who had achieved the blood pressure (BP) target according to 2017 American College of Cardiology/American Heart Association (ACC/AHA) versus JNC7 and 8 guidelines, among Iranian population. Data of participants aged ≥20 years from the fifth phase (2012–2015) of the Tehran lipid and glucose study (N = 10,576) were analyzed, using survey analysis. The weighted prevalence of hypertension among those not on anti-hypertensive medications was 42.7 and 12.6%, applying the ACC/AHA and JNC7 guideline definitions, respectively; the corresponding values with including BP-lowering medication in definition of hypertension were 47.1% and 20.4%, respectively. However, 90% of these hypertensive people were found to have a 10-year cardiovascular disease risk of <10%. Applying the ACC/AHA guideline, anti-hypertensive medication was recommended for 21.9% of Tehranians, compared to 19.3 and 12.2% according to the JNC7 and 8 guidelines, respectively. Among Tehranians taking anti-hypertensive medication, 20% achieved the BP goal according to the ACC/AHA guideline, compared to the 42.1 and 53.6%, using JNC7 and 8 guidelines, respectively. Despite the tremendous increase in the prevalence of hypertension, most of the newly identified cases did not belong to the high-risk group.


Materials and Methods
Study population. The study sample was selected among participants of the Tehran Lipid and Glucose Study (TLGS), a population-based prospective study conducted on a representative sample of Tehranians (at baseline), to determine the risk factors for NCD and assess the prevention strategies for improving lifestyles. Data enrollment was done in two phases, i.e. the first (1999)(2000)(2001) 15 .
Our study sample was derived from 10,721 individuals aged ≥20 years, who had participated in the fifth phase of the TLGS. Furthermore, we excluded participants with missing data on SBP and DBP (n = 103) and the covariates included in 10-year predicted CVD risk factors according to the Pooled Cohort risk equations 16 , i.e. fasting plasma glucose (FPG), high density lipoprotein cholesterol (HDL-C), total cholesterol (TC) and smoking (n = 42). Therefore, data of 10,576 participants were eventually available for the current study. The medical ethics committee of the Research Institute for Endocrine Sciences (RIES) approved the study proposal and experimental protocols. Written informed consent was obtained from all participants. All methods of the current study were performed in accordance with the relevant guidelines and regulations.
Anthropometrics and laboratory measurements. Information on demographic data, personal and familial history of CVD, medical and medication history, and level of smoking habits were obtained by a trained interviewer using a standard questionnaire.
Based on the TLGS design 17 , using the Monica manual (part III, section I) 18 , two measurements of SBP and DBP were taken on the right arm after a 15-min rest in a sitting position. A Richter sphygmomanometer (Germany), the reliability and validity of which are confirmed and calibrated annually by the Institute of Standards & Industrial Research of Iran was used. The researcher was blinded to the samples, group (test or control). Furthermore, quality control was adopted to assure that data are collected uniformly over time according to the ARIC manuals 19 ; the mean of two measurements was considered as the subject's blood pressure.
A blood sample was taken after 12 to 14 hours overnight fasting between 7:00 and 9:00 AM from all study participants; FPG was measured using an enzymatic colorimetric method with glucose oxidase; inter-and intra-assay coefficients of variation (CV) at baseline and follow-up phases were both <2.3%. HDL-C was measured after precipitation of the apolipoprotein B containing lipoproteins with phosphotungistic acid. TC was assayed using the enzymatic colorimetric method with cholesterol esterase and cholesterol oxidase; both inter-and intra-assay coefficients of variation at baseline and follow-up phases were 1.9%. Serum creatinine (cr) level assessments were done using the kinetic colorimetric Jaffe.
All blood analyses were carried out in the TLGS research laboratory on the day of blood collection and analyses were performed using Pars Azmon kits (Pars Azmon Inc., Tehran, Iran) and a Selectra 2 auto-analyzer (Vital Scientific, Spankeren, Netherlands). Samples were only analyzed when internal quality control met the acceptable criteria.
Definition of terms. The definition of hypertension, criteria to recommend anti-hypertensive medication and treatment goal according to the 2017 ACC/AHA, 2003 JNC 7 and 2014 JNC8 are illustrated in Table 1. According to the 2017 ACC/AHA guideline, blood pressure among those not taking anti-hypertensive medication was categorized into five groups: Normal blood pressure (SBP < 120 and DBP <80 mmHg); elevated blood pressure (120-129 & <80 mm Hg); stage 1 hypertension (130-139/80-89 mm Hg), and stage 2 hypertension (≥140/≥90 mm Hg). Participants who were taking anti-hypertensive medication were categorized separately (Fig. 1). Smoking status was categorized into three categories, including current smokers, former smokers (those who used to smoke in the past) and never smokers. Estimated Glomerular Filtration Rate (eGFR; mL/min per 1.73 m 2 ) was estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) abbreviated prediction equation 20 . CKD was defined as eGFR <60 mL/min per 1.73 m 2 for >3 months 21 . www.nature.com/scientificreports www.nature.com/scientificreports/ Statistical analysis. A survey analysis was conducted to generalize TLGS results to the adult Tehranian population; data were weighted directly to the 2016 urban population of Tehran 22 , based on the 2016 national Iranian census, to match the age (10-year strata) and gender strata.
Using 2017 ACC/AHA and 2003 JNC7 guidelines, the demographic and clinical characteristics of the TLGS population across blood pressure stages were reported using mean (SE) values for continuous and frequencies (%) for categorical variables. The weighted prevalence and the frequency of hypertension and recommended anti-hypertensive medications for TLGS individuals according to 2017 ACC/AHA and the 2003 JNC7 guidelines and those only included in the 2017 ACC/AHA guideline were calculated for the overall population according to the age strata, gender, 10-year risk categories and those with prevalent CVD. Moreover, the frequency and the percentage of drug-treated hypertensive TLGS individuals who had reached the blood pressure target goal, according to 2017 ACC/AHA and 2003 JNC 7 guidelines and those only included in the 2003 JNC7 guideline www.nature.com/scientificreports www.nature.com/scientificreports/ were calculated for the overall population according to the age strata, gender and different medication categories. Furthermore, sensitivity analysis was done by recalculating the prevalence of hypertension and the prevalence of adults recommended anti-hypertensive medication, including those treated with anti-hypertensive medication as prevalent hypertensive cases. The same approach was also applied for 2014 JNC8 panel member report. Statistical analyses were done using Stata version 12.0 (Stata Corp LP, College Station, Texas).

Characteristics of TLGS data over hypertension categories.
Applying the 2017 ACC/AHA guideline, the prevalence of different categories of blood pressure among Tehranian adults for normal blood pressure, elevated blood pressure and stages 1 and 2 hypertension were 48.0, 5.0, 26.6 and 10.0%, respectively. Additionally, 10.4% of adults were taking antihypertensive medication. Tehranian participants with higher blood pressure were older, had higher levels of TC, FPG and mean 10-year predicted CVD risk scores and lower levels of HDL-C ( Table 2).
According to Sup Table 1, compared with the 2003 JNC7 guideline hypertension definition, Tehranian adults included only in the 2017 ACC/AHA guideline were younger, generally had more favorable CVD risk factors and ACC/AHA pooled risk scores, but showed higher rates of lipid lowering usage and had higher prevalence of CKD. Also, Tehranian adults, who were recommended anti-hypertensive medication, assessed only by the 2017 ACC/ AHA guideline, were older, had more favorable CVD risk factors, higher value of eGFR and lower level of ACC/ AHA pooled risk scores, compared with JNC7 guideline; however, they reported higher prevalence of CVD (76.3 vs. 4.8%, respectively).
Weighted characteristics of Tehranian adults taking anti-hypertensive medication with blood pressure, and those achieved the BP target goal are presented in Sup Table 2.
Comparison of the 2017 ACC/AHA guideline with JNC7 guidelines. The percentage (95% CI) of Tehranian adults meeting the definition of hypertension and recommended anti-hypertensive medication, among those without anti-hypertensive medication, according to the 2017 ACC/AHA and the 2003 JNC7 guidelines based on the TLGS data are shown in Table 3. Accordingly, the prevalence of hypertension was 42.7% and 12.6% using the 2017 ACC/AHA and the 2003 JNC7 guidelines definitions, respectively; higher prevalence of hypertension with the updated definition was observed, regardless of age groups, gender, presence of prevalent CVD and 10-year CVD risk categories. Accordingly, the greatest difference was seen in individuals aged 40-60 years, male gender and those who had a 10-year predicted risk of 5-10%. Using the 2017 ACC/AHA guideline, anti-hypertensive medication was recommended for 21.9% of Tehranian adults, compared to 19.3%, according to the 2003 JNC7 guideline; the higher rates were present regardless of age groups, gender, the presence of prevalent CVD and 10-year CVD risk categories. The greatest difference in the prevalence of adults recommended medication was observed in the 60-69 year age group and those who were categorized as having 10-20% risk of CVD.
After considering adults on anti-hypertensive medication as prevalent hypertensive cases, the updated prevalence of hypertension and the prevalence of adults who recommended anti-hypertensive medication by 2017 ACC/AHA and 2003 JNC7 guideline definitions are illustrated in Sup Table 3. Accordingly, the prevalence of hypertension was 47.1% and 20.4%, using the 2017 ACC/AHA and 2003 JNC7 guidelines definitions, respectively.
According to Fig. 2, of a total 8,257,493 Tehranians, aged ≥20 years 3,525,950 and 1,040,444 Tehranian adults met the definition of hypertension according to the 2017 ACC/AHA and the 2003 JNC7 guidelines, respectively. Overall, of the eligible Tehranian adults who belonged to only the newly diagnosed category (n = 2,485,506), 2,234,197 newly diagnosed participants had 10-year risk <10%, indicating that, about 90% of newly identified cases did not belong to the high-risk category.
As shown in Table 4, among Tehranian participants taking anti-hypertensive medication, 20% achieved the blood pressure target goal according to the 2017 ACC/AHA guideline, compared to the 42.1% using 2003 JNC7  Table 4).
As shown in Sup Tables 5 and 6, among Tehranian adults taking anti-hypertensive medication, 53.6% (513,734 individuals) achieved the blood pressure target goal according to the 2014 JNC8 panel member report, compared to the 20% (191,692 individuals) according to the 2017 ACC/AHA guideline.

Discussion
In the current study we investigated the impact of the 2017 ACC/AHA blood pressure guideline on the prevalence of hypertension, the prevalence of adults recommended antihypertensive medications and those who had achieved blood pressure target goals.
Our results show that the prevalence of hypertension among Tehranian participants not on antihypertensive medication was 42.7% according to the 2017 ACC/AHA blood pressure guideline (47.1% including those treated with anti-hypertensive medication as prevalent hypertensive subjects); this prevalence was almost three times higher than that estimated using 2003 JNC7 criteria, and was over two fold after inclusion of those treated with anti-hypertensive medication as prevalent hypertensive cases. Despite this noticeable increase in the prevalence  www.nature.com/scientificreports www.nature.com/scientificreports/ of hypertension, about 90% these newly identified cases belonged to the low-risk group (10-year risk <10%) and the percentage of adults recommended anti-hypertensive medication; besides non-pharmacological interventions increased only 2.6%, compared to those recommended by the 2003 JNC7 guideline. However, among Tehranian adults taking anti-hypertensive medication, only 20% reached the blood pressure target goals defined by the 2017 ACC/AHA guideline, compared with 42.1% and 53.6% based on the 2003 JNC7 and 2014 JNC8 guidelines, respectively.
The 2017 ACC/AHA guideline has modified the approach to hypertension worldwide in many ways. Data shows that the prevalence of hypertension increased from 31.9 to 45.6% in the USA using the 2017 ACC/AHA guideline, indicating that an additional 31 million individuals now need treatment; of these only 4.2 million are candidates for anti-hypertensive therapy and the rest can be managed by non-pharmacological interventions 12 . This large increase (13.6 vs. 31.5%) was also seen in Peru, a Latin American country 23 . There are three studies that compare the new guideline with previous ones in the East Asia [24][25][26] ; in China, the prevalence of hypertension based on 2017 ACC/AHA guideline was twice as high as that observed, based on the 2010 Chinese guideline (46.4 vs. 23.2%), which defines hypertension by the same thresholds as the 2003 JNC7 guideline 25 .
There are two important aspects that could justify the greater differences in the prevalence of hypertension using 2017 ACC/AHA guideline vs. the 2003 JNC7 guideline among Tehranian populations, compared to those reported in other studies; the first is that the increase in prevalence of hypertension based on 2017 ACC/AHA guideline compared to 2003 JNC7 guideline was more prominent among younger age groups ( Table 3). The prevalence of hypertension using 2017 ACC/AHA was 6 times higher than corresponding values using 2003 JNC7 criteria in younger age groups (i.e. 20-29 and 30-39 years), though these differences decreased at older ages; this was also clearly shown in studies conducted among populations from China, Peru and Bangladesh 23,25,27 ; for example among a population from Peru it was shown that the prevalence of hypertension based on the 2017 ACC/AHA guideline was almost 5 times higher than those reported in younger age groups by 2003 JNC7, a difference significantly attenuated in older aged participants 23 . These findings demonstrate that the impact of the 2017 ACC/ AHA guideline on the prevalence of hypertension is most noticeable in younger populations. In the current study, we enrolled participants, aged ≥20 years, 70% of which were under 50 years old (Table 3), whereas in the studies from Korea and Bangladesh, participants recruited were older 24,27 . Therefore, the marked difference between guidelines could be attributed to the younger population of our study, compared to other studies. The second www.nature.com/scientificreports www.nature.com/scientificreports/ point that should be considered is the high prevalence and incidence of pre-hypertension among Tehranian populations. Actually in the third national survey of risk factors of non-communicable disease (SuRFNCD) 2011, the prevalence of pre-hypertension was reported to be 39.8% (95% CI: 37.8-41.9) 28 . Moreover, we also reported a high incidence of pre-hypertension, i.e. 593/10000 person-years among an Iranian population 29 . Hence, labeling those with SBP 130-139 mmHg or DBP 80-89 mmHg as hypertensive, instead of pre-hypertensive individuals, using 2017 ACC/AHA guideline, can lead to a dramatic increase in the prevalence of hypertension.
Vaduganathan et al. investigated adults with established CVD or at high cardiovascular risk in the USA; based on the 2017 ACC/AHA guideline, 80% of the participants were classified as hypertensive patients at baseline 30 . In our study population, 70.2% of individuals with 10-year risk of CVD ≥20% and 55% of participants with prevalent CVD were classified as the hypertensive category. Many observational studies, as well as a meta-analysis indicated that an increase in blood pressure, even in pre-hypertensive individuals, according to 2003 JNC7 increased the risk of CVD, end-stage renal disease and cerebrovascular events [31][32][33][34][35] . Moreover, previously we also found that, in those with high normal blood pressure (SBP between 130 and 139 mmHg or DBP between 85 and 89 mmHg) the CVD risk increased to >60% among middle-aged Tehranian adults 35 . It is believed that these studies were fundamental for changes made in the 2017 ACC/AHA guideline. The systolic blood pressure intervention trial (SPRINT) evaluated the impact of the 2017 ACC/AHA vs. 2003 JNC7 guidelines on subsequent cardiovascular events; accordingly, in an >3.3-year median follow up, the 2017 ACC/AHA guideline identified a greater number of patients who experienced long-term cardiovascular events 30 .
Another difference of the 2017 ACC/AHA with 2003 JNC7 guidelines was the emphasis on cardiovascular risk. In the 2017 ACC/AHA guideline, the decision for initiating medication is made based on blood pressure in combination with cardiovascular risk and age. Individuals with high cardiovascular risk or age ≥65 years are recommended to initiate antihypertensive therapy at lower levels of blood pressure 9 . Although change in lifestyle is a key factor in the management of hypertension 36 , individuals with prehypertension may benefit from pharmacological interventions at some points, e.g. patients with high cardiovascular risk 37 . The prospective meta-analyses conducted by the Blood Pressure Lowering Treatment Trialists' indicates that incremental benefits from blood www.nature.com/scientificreports www.nature.com/scientificreports/ pressure lowering depend on baseline cardiovascular risk 38 . The Heart Outcomes Prevention Evaluation-3 (HOPE3) trial also showed that in participants with approximately 10% 10-year risk, no risk reduction was observed with 6 mmHg decrease in SBP 39 . Compared to the American population, our results showed a minimal increase in the prevalence of adults who are recommended anti-hypertensive medication using the 2017 ACC/ AHA guideline (2.6% vs. 1.9%); a great proportion of this increase (21%) was related to individuals with 10-year cardiovascular risk of between 10-20% and those with prevalent CVD (15.59%); corresponding values were 9.9 and 3.7% in the USA, respectively 12 . Hence considering the cardiovascular risk for management of hypertension, affects Iranian populations in a more obvious way, compared to American ones.
Recent trials have shown that hypertensive patients may benefit from more aggressive blood pressure reduction [40][41][42] . Lewington et al. demonstrated a 20 mmHg reduction in SBP was associated with a 40% and 50% decrease in CVD and stroke mortality, respectively 43 . Though the SPRINT trial showed that SBP reduction to <120 mmHg had significantly higher CVD protection, compared to SBP reduction to <140 mmHg, these benefits are obtained at the cost of serious adverse events including syncope, hypotension, acute kidney injuries, and electrolyte abnormalities 42 . A recent systematic review, focusing on clinical trials with a SBP target <130 mmHg, indicated that risk reductions were modestly attenuated compared to those with higher blood pressure target policies, although they were still significant for CVD and stroke 44 . Taking all the cost and benefits into account, the 2017 ACC/AHA guideline determined 130-and 80-mm Hg as blood pressure target goals, which are lower than those recommended by 2003 JNC7. Among Tehranian adults taking anti-hypertensive medication only 20% reached the blood pressure goals according to the 2017 AHA/ACC guideline; corresponding values among treated hypertensive patients in China and the USA were 14.9 and 46.6%, respectively 12,25 .
Prevalence of hypertension was reported to be 25% in Iranian adults, based on the 2003 JNC7 guideline, of whom, only 25% were taking prescribed medication and of those receiving pharmacological treatment, 24% were adequately controlled 13 . Another study using the 2003 JNC7 guideline, which was conducted in a rural area, reported that 41.8% of the Iranian population was hypertensive, 17.6% were treated and 32.1% of those treated had controlled hypertension 14 . Here we showed that the prevalence of hypertension in 2012-2015 in an urban    www.nature.com/scientificreports www.nature.com/scientificreports/ Tehranian population was 12.6%; 19.3% were recommended i.e. anti-hypertensive therapy and 42.1% of those taking medication were well controlled based on JNC7 criteria. Based on the above studies, it can be deduced that we already lacked proper management of hypertension. As mentioned, considering the new guideline the prevalence of hypertension increased to three-fold and the control rate decreased by 50% compared to the 2003 JNC7 guideline. However, most of the newly identified patients were not classified in the high-risk group and pharmacological treatment was not recommended for them, indicating that despite the marked increase in the prevalence of hypertension, only 11% required alterations in the treatment protocol. On the other hand, there is potential psychological harm from disease labeling for the rest 45,46 . Overall the impact of 2017 AHA/ACC guideline on the Tehranian population is often in the vague balance of benefits and harms.
This study is the sixth worldwide 12,[23][24][25]27 population-based study, to have examined the impact of implementation of the 2017 AHA/ACC guideline on the prevalence of hypertension, among individuals recommended medications and those who have achieved blood pressure target goals. Also, to the best of our knowledge, this study was the first study in the Middle East region, with a high burden of cardiovascular risk factors 7 that has compared the 2017 AHA/ACC guideline with those of 2003 JNC7 and 2014 JNC 8.
There are however some limitations in our study to note. First, we did not have data of the whole country and our results were limited to Tehran. Second, we used the data of the fifth phase of TLGS cohort, and their awareness and lifestyle may have been modified over these years (cohort effect); our results hence may have underestimated the true prevalence of hypertension and also have overestimated the control rate of hypertension.
The third limitation is that regarding the guidelines for detection of hypertension 47,48 , a raised blood pressure measurement must be confirmed at least at two separate visits to the health care provider's clinic or office; however this is not applicable in the population-based epidemiological studies 23,27 and this could overestimate the results due to white coat hypertension.
In conclusion, in this population-based study, the prevalence of hypertension was 42.7% according to the 2017 AHA/ACC blood pressure guideline, compared to 12.6% according to the 2003 JNC7 guideline. Despite the tremendous increase in the prevalence of hypertension in this relatively young population compared to other studies, most of these newly-labeled cases did not belong to the high-risk group and the percentage of adults recommended anti-hypertensive therapy increased about 3%, compared to those recommended by the 2003 JNC7 guideline. Hence, further investigation is needed regarding the possible incremental harm from disease labeling for this large population.

Data Availability
Data are available from the corresponding author on reasonable request.