research study on hypertension

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• Int J Hypertens
• v.2017; 2017

Prevalence and Associated Risk Factors of Hypertension: A Cross-Sectional Study in Urban Varanasi

Shikha singh.

1 Department of Community Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India

Ravi Shankar

Gyan prakash singh.

2 Division of Biostatistics, Department of Community Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India

Hypertension is a major public health problem and important area of research due to its high prevalence and being major risk factor for cardiovascular diseases and other complications. Objectives . (1) To assess the prevalence of hypertension and its associated factors and (2) to estimate awareness, treatment, and adequacy of control of hypertension among study subjects. Methods and Materials . A community based cross-sectional study with multistage sampling design was conducted among urban population of Varanasi. A modified WHO STEPS interview schedule on 640 study subjects aged 25–64 years was used. Results . The prevalence of hypertension was 32.9% (male: 40.9%, female: 26.0%). Mean systolic and diastolic BP were 124.25 ± 15.05 mmHg and 83.45 ± 9.49 mmHg, respectively. Higher odds of being hypertensive were found in male subjects, eldest age group, married subjects, subjects of upper socioeconomic status, illiterate subjects, and retired subjects. Tobacco and alcohol consumption, overweight, obesity, and abdominal obesity were also associated with hypertension. Out of the total hypertensive 211 subjects, only 81 (38.4%) were aware about their hypertension status; out of those, 57 (70.4%) were seeking treatment and 20 (35.08%) had their blood pressure adequately controlled. Conclusion . Around one-third of the subjects were hypertensive and half of the study subjects were prehypertensive in this area. The awareness, treatment, and control of high blood pressure were also very low.

1. Introduction

Hypertension is a major public health problem due to its high prevalence all around the globe [ 1 – 4 ]. Around 7.5 million deaths or 12.8% of the total of all annual deaths worldwide occur due to high blood pressure [ 5 ]. It is predicted to be increased to 1.56 billion adults with hypertension in 2025 [ 6 ].

Raised blood pressure is a major risk factor for chronic heart disease, stroke, and coronary heart disease. Elevated BP is positively correlated to the risk of stroke and coronary heart disease. Other than coronary heart disease and stroke, its complications include heart failure, peripheral vascular disease, renal impairment, retinal hemorrhage, and visual impairment [ 5 ].

Hypertension (or HTN) or high blood pressure is defined as abnormally high arterial blood pressure. According to the Joint National Committee 7 (JNC7), normal blood pressure is a systolic BP < 120 mmHg and diastolic BP < 80 mm Hg. Hypertension is defined as systolic BP level of ≥140 mmHg and/or diastolic BP level ≥ 90 mmHg. The grey area falling between 120–139 mmHg systolic BP and 80–89 mmHg diastolic BP is defined as “prehypertension” [ 7 , 8 ]. Although prehypertension is not a medical condition in itself, prehypertensive subjects are at more risk of developing HTN [ 1 ].

It is a silent killer as very rarely any symptom can be seen in its early stages until a severe medical crisis takes place like heart attack, stroke, or chronic kidney disease [ 8 – 10 ]. Since people are unaware of excessive blood pressure, it is only through measurements that detection can be done. Although majority of patients with hypertension remain asymptomatic, some people with HTN report headaches, lightheadedness, vertigo, altered vision, or fainting episode [ 11 ].

There are several factors predisposing to hypertension. These factors vary from country to country and even there is difference between urban and rural regions of the same place [ 12 ]. Realizing the effect of urbanization on our collective health, World Health Organization has chosen “Urbanization and Health” as the theme for World Health Day 2010 [ 13 ]. Urbanization is considered a determinant of health and one of the key drivers of noncommunicable diseases (NCDs), especially in low- and middle-income countries (LMICs) [ 14 ]. Urban people are more at risk of these diseases as compared to their rural counterparts. As per the findings of National Family Health Survey (NFHS-4), the prevalence of hypertension, obesity, and blood glucose in urban area of Uttar Pradesh was 10.5%, 23.9, and 9.9%, respectively. However, the prevalence of the same phenomenon was 8.3%, 10.8%, and 8.2%, respectively in rural area [ 15 ]. It is clear that all the parameters are having higher prevalence in urban area as compared to rural area. Rapid urbanization, increasing elderly population, mechanization, sedentary life, and dietary changes act together as a web of risk factors which entangles people in it and leads to several chronic diseases. In order to take effective prevention measures, identification of the risk factors is an essential prerequisite. This study intends to generate information on prevalence of hypertension and their associated risk factors in urban area of Varanasi. In addition, it will also look into the awareness and control of hypertension among the study subjects.

2. Materials and Methods

2.1. study area.

Varanasi is an Indian city on the bank of Ganges in Uttar Pradesh. It has total population of 3676841 as per Census 2011. As per Census 2011, out of total population, 52% people live in urban areas, while 48% live in the rural areas. There are 90 Census enumeration wards in Varanasi district. Out of these 90 wards, 5 wards were selected by using simple random sampling.

2.2. Study Design and Sample Size

A community based cross-sectional study was carried out among the people aged 25 to 64 years living in the selected study area. The sample size for the present study was calculated by taking most probable prevalence of hypertension as 50% and permissible error as 5% with 95% confidence interval. Fixing the permissible error as 50%, the minimum sample size was calculated as n = 384. Since sampling procedure was multistage, hence considering the design effect, the sample size was further increased by one and half times. Considering the nonresponse rate of 10% the final sample size in study was fixed as 640. In the present study, a prior written informed consent was also taken from the participants. Prior written informed consent was taken by the participants.

2.3. Sampling Methodology

A multistage sampling was used for this study. There were three stages and for each stage different sampling design was used.

At first, out of these 90 wards, 5 wards were selected by using simple random sampling. At second stage, from each selected ward the households were further selected by using systematic random sampling and probability proportional to size was done. At the third stage, one member of target age group was interviewed from selected household. If the selected family has more than one available eligible person then one was chosen randomly by using lottery method. In case of nonavailability of eligible person in a selected household, at the time of survey, the adjacent household was selected.

2.4. Selection of Study Subjects

2.4.1. inclusion criteria.

Individuals aged 25–64 years in the selected study area who gave consent for participation were considered.

2.4.2. Exclusion Criteria

Individuals who are unable to give response due to serious physical or mental illness and with whom anthropometry measurements cannot be performed were excluded from the study.

2.5. Tools of the Study

Interview schedule [modified and pretested WHO stepwise approach to chronic disease risk factor surveillance (STEPS)], Libra weighing machine, steel anthropometry rod, measuring tape, and Omron BP Machine were used.

2.6. Techniques of the Study

In all study participants, a structured and pretested interview schedule was administered to obtain data on sociodemographic parameters.

2.6.1. Blood Pressure Measurement

Blood pressure was measured two times on the right arm of the selected subject using automatic electronic device (OMRON HEM-7261). The average of two readings was used.

2.6.2. Anthropometric Measurements

All the anthropometric measurements were done by the following standardized technique. Weight was measured by Libra weighing machine having an accuracy of 0.1 kg and height was measured by using a steel anthropometry rod with accuracy of 0.1 cm using standard techniques. Body Mass Index was calculated using the following formula: BMI = weight (kg)/height (mt) 2 . Based on BMI obtained, the subjects were classified into different categories according to the WHO global classification [ 16 ]. Waist circumference (in cm) was measured using a nonstretchable measuring tape. Waist circumference was measured at the smallest horizontal girth between the costal margins and the iliac crest at the end of expiration. Hip circumference (in cm) was measured at the broadest part of the hips by using nonstretchable measuring tape. Waist-to-hip circumference (WHR) was calculated by dividing waist circumference by hip circumference [ 17 ].

2.7. Ethical Consideration

Ethical approval was obtained from the Institute Ethical Committee of the Institute of Medical Sciences, Banaras Hindu University Varanasi. Prior written consent was taken from the subjects who volunteered to participate in the study. Identified hypertensive subjects were referred to the nearby clinic for treatment.

2.8. Definitions Used

• (i) Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) classification was used for hypertension [ 8 ].
• (ii) Hypertension is defined as systolic BP level of ≥140 mmHg and/or diastolic BP level of ≥90 mmHg or being previously diagnosed as hypertensive by any health professional. The area falling between 120–139 mmHg systolic BP and 80–89 mmHg diastolic BP is defined as “prehypertension” [ 8 ].
• (iii) Isolated diastolic hypertension (IDH) having a systolic blood pressure ≤ 140 mmHg and diastolic blood pressure ≥ 90 mmHg and isolated systolic hypertension (ISH) having a systolic blood pressure ≥ 140 mmHg and diastolic blood pressure < 90 mmHg was used to diagnose IDH and ISH, respectively.
• (iv) Awareness was defined as history of hypertension based on diagnosis by a healthcare provider. Treatment was defined as taking any medication or other treatment for hypertension in the last two weeks prior to the survey and control was defined as blood pressure < 140 and <90 mmHg in subjects who were taking medications
• (v) WHO International BMI classification: BMI < 18.5 was classified as “underweight”; <16.00, “severe thinness”; 16.00–16.99, “moderate thinness”; 17.00–18.49, “mild thinness”; 18.50–24.99, “normal range”; BMI ≥ 25.00, “overweight” ; 25.0–29.99, “preobese” ; ≥30.00, “obese” ; 30.00–34.99, “obese class I” ; 35.00–39.99, “obese class II”; and >40.00, “obese class III.”

Revised modified BG Prasad socioeconomic classification scale, January 2014.

• (vii) Current daily smokers are defined as those who were currently smoking cigarettes, bidis, or hookah daily. Current daily smokeless tobacco users are defined as those who were currently using chewable tobacco products, gutka, naswar, khaini, or zarda paan daily. Current alcohol drinkers are defined as those who reported to consuming alcohol within the past one year [ 17 ].
• (viii) Physical activity was measured in three domains that is activity at work, to and from places, and recreational activities as well as time spent sitting. The interview schedule also covered type of activity (vigorous and moderate) at work and for recreational activities. Information was also collected on the number of days in a week spent on different activities and time spent in a day for each activity was also recorded [ 17 ]. Those who were not active in any domain were defined as “inactive,” those who were vigorously active in any category were defined as “vigorously active,” and the rest were “moderately active.”

2.9. Data Processing

The information obtained from the survey was entered into a database developed for the study, using SPSS 16.0 program. Descriptive statistics (mean and standard deviation) were calculated for continuous variables and frequencies and percentages were calculated to summarize qualitative data. Other statistical tests like chi-square test and ANOVA were applied. Logistic regression was applied to identify the risk factors for hypertension. A significance level of 0.05 was used.

A total of 640 study subjects were interviewed for the survey. Out of these, 301 (47%) were male subjects and 339 (53%) were female. The median age (±SD) of the study subjects was 39.0 (±11.9) years and for male and female it was 40.0 (±11.9) years and 38 (±11.8) years, respectively. Regarding religion and caste of the study subjects, around 96% subjects were Hindu and majority of the subjects were in general category, respectively. Majority of the study subjects were married and one-third of the subjects belonged to the upper socioeconomic class. Mean (±SD) BMI of the study subjects was 24.11 ± 3.94 kg/m 2 ; for men it was 23.78 ± 3.95 kg/m 2 and for women it was 24.41 ± 3.92 kg/m 2 . According to Body Mass Index (BMI), more than one-third of the study subjects were either overweight or obese. With regard to abdominal obesity as measured by waist circumference, 40% subjects were at risk ( Table 2 ).

Background characteristics of the study subjects ( N 640).

Table 3 depicts the mean values of systolic and diastolic BP according to age and gender. The mean systolic and diastolic BP of all the study subjects were 124.2 ± 15.0 mmHg and 83.4 ± 9.5 mmHg, respectively. In men, the highest mean systolic BP and mean diastolic BP were among the eldest age group and preceding eldest age group (45–54 years), respectively, while in female the highest mean value of systolic and diastolic BP both were among the 45–54-year age group. With regard to systolic BP, there was significant difference among all the age groups among both male and female study subjects and the same was with diastolic BP as well. The prevalence of isolated systolic BP was found to be 10.6% [95% CI: (8.27–13.37)] and isolated diastolic BP was 19.7% [95% CI: 16.6–23.18]. The proportion was higher in male (14.8%) as compared to female (6.8%). Among both groups (male and female), prevalence was higher among the eldest age group. The prevalence of isolated diastolic BP was higher among male subjects (28.1) against female subjects (12.2%). It was the highest among the second oldest age group among male and oldest age group in female subjects. With regard to systolic BP, age was associated with hypertension status among both genders, whereas diastolic BP was associated with age in male subjects only. There was no association between age and diastolic BP in female subjects.

Mean systolic and diastolic blood pressure (mm hg) and prevalence (%) of isolated systolic hypertensive and isolated diastolic hypertensive by age and gender.

# Excluding known hypertensive.

The overall prevalence of hypertension was 32.96% [95% CI: (29.4–36.7)]. The sex specific prevalence was 40.9% [95% CI: 35.5–46.5] for male and 26.0% [95% CI: 21.6–30.9] for female. Prehypertension was prevalent in 45.9% [95% CI: (40.3–51.5)] of men and 38.05% [95% CI: (33.0–43.2)] of women. In men, hypertension was significantly associated with age but in women, age does not have any effect on their hypertension status. History of hypertension or the prediagnosed cases of hypertension was more among female (6.7%) as compared to male (5.9%) subjects ( Table 4 ).

Prevalence of hypertension and prehypertension by gender and age groups among the study subjects ( N 640).

Table 5 shows the associated factors of prehypertension and hypertension. Gender, age, marital status, occupation, education status, tobacco use, and physical activity were significantly associated with the hypertension status of the study subjects ( p < 0.05). Both the rate of prehypertension and hypertension were higher among male. Hypertension was more prevalent in the 45–54 years, while prehypertension was more in the 35–44-year age group. Being married and government servant were found to be risk factors for both hypertension and prehypertension. Hypertension was found to be more among illiterate subjects, and with regard to prehypertension, primary educated subjects suffered more. Study subjects from lower and upper socioeconomic status were almost equal victims of hypertension. Tobacco use and alcohol use were found to be risk factors for being hypertensive in the study subjects. Although alcohol use was not significantly associated with hypertension status but rate of hypertension was higher among the alcohol users.

Prevalence of prehypertension and hypertension ∗ according to sociodemographic characteristics and behavioral risk factors.

∗ Excluding known hypertensive.

The binary logistic regression analysis showed that odds of being hypertensive were higher among the male subjects (OR: 1.97), eldest age group (OR: 6.49), married subjects (OR: 2.34), uneducated subjects (OR: 1.17), retired subjects (OR: 3.66), and those who were from upper socioeconomic status (1.31). With regard to anthropometric risk factors, being overweight (OR: 1.99), being obese (OR: 3.57), and having abdominal obesity (OR: 1.73) had higher odds of hypertension. Tobacco use (OR: 1.86), alcohol use (OR: 1.55), and nonvegetarian diet (OR: 1.10) also had higher odds of being hypertensive. Gender, age, marital status, occupation, BMI, abdominal obesity, and tobacco use were significantly associated with hypertension. Education, socioeconomic status, and alcohol use were not statistically associated with hypertension. Being female, younger in age, unmarried, highly educated, and staying away from any kind of addiction could serve as protective factors against hypertension ( Table 6 ).

Univariate analysis for the association of hypertension and sociodemographic characteristics, anthropometric measurements, and behavioral risk factors ( N 640).

Out of the total subjects with hypertension, around one-third of the subjects were aware of their condition. Out of those who were aware, 70% were seeking treatment. Only a third of the treated subjects with hypertension had their blood pressure adequately controlled ( Figure 1 ). Females were marginally more aware of their hypertensive status as compared to male counterparts (see Table 4 , history of hypertension). As age, education status, and socioeconomic status were advancing, the awareness of hypertensive status among study subjects was also increasing (not shown in the table).

Flow diagram showing awareness, treatment, and adequacy of control of hypertension among study subjects.

4. Discussion

India is a developing country and like other developing countries, it is going through a rapid demographic and epidemiological transition. In all such transitions, nutrition is the key ingredient and plays prime role. This cross-sectional community based study identified a high prevalence of prehypertension and hypertension in urban areas of Varanasi, which was 41.7%   and 32.96%, respectively. Only a quarter of subjects were in the normal category, which highlights the escalating burden of this silent killer.

The prevalence of hypertension in the present study (32.96%) was higher in comparison with the prevalence reported in other studies [ 4 , 6 , 10 , 19 – 22 ]. Few studies reported the results in line with the present study [ 23 , 24 ]. According to World Health Organization (2015), the overall prevalence of hypertension in India was 23.5% and gender specific prevalence was 24.2%  and 22.7% among the men and women, respectively [ 25 ].

The prevalence of prehypertension in the present study was 41.7% (male: 45.9% and female: 38.05%). The prevalence estimated in the present study was much higher than that estimated by Nellore (22.3%) [ 10 ] and Bihar (37.95%) [ 20 ]. The difference of prevalence observed between the present study and other studies with respect to hypertension and prehypertension could be due to social and cultural differences, dietary and lifestyle factors, and also the age span as well as the research methodology used.

Men exhibit higher prevalence of hypertension and prehypertension than their female counterparts (M: 40.9%  and F: 26.0%) and (M: 45.9%  and F: 38.05%), respectively. Similarly, various studies came out with the higher percentage of hypertension in men than women [ 20 , 22 , 23 , 26 – 29 ]. One of the possible explanations for this gender disparity in hypertension prevalence could be partially due to biological sex difference and partially due to behavioral risk factors like smoking, alcohol consumption, or physical activity. We speculate that absentia from alcohol and smoking might be few of those protective factors against hypertension in women. Other than that, women are more interested in health care services utilization and also more frequently report their poor health and therefore they are more likely to have better health [ 6 , 30 ].

Age was found to be an important risk factor for hypertension. As the age was advancing so did the prevalence of hypertension among both the sexes. Similar findings were reported by few other studies also where advancing age was positively related to hypertension [ 1 , 6 , 19 , 21 , 22 , 26 , 31 , 32 ]. With increasing age, the aorta and arteries walls will be stiffened and this contributes to the high prevalence of hypertension in older age groups [ 4 ].

In the present study, marital status, education, occupation, socioeconomic status, BMI, abdominal obesity, tobacco use, alcohol use, and physical activity were significantly associated with the hypertension.

Low literacy level and being too rich were associated with hypertension. The higher education level was negatively correlated to hypertension in the present study. These studies also supported this finding [ 6 , 12 , 33 ]. We speculate that it could be due to the reason that higher education imparts better knowledge and information about hypertension and subsequently those people with higher education had a healthier lifestyle.

Table 5 revealed that education was significantly associated with hypertension ( χ 2 = 17.049, df = 6 and p value = 0.009); however, when adjusted effect of education on hypertension was observed by logistic regression, then no statistical association was observed. Though some studies had shown a significant association of these two variables [ 6 , 12 ], in the study performed in the state of Kerala [ 33 ], insignificant association between education and hypertension was observed. We speculate that this insignificant association could be due to very few subjects in the illiterate and less educated category. There are so many studies which do not refute the finding of the present study that higher socioeconomic status is a risk for hypertension [ 3 , 22 , 24 , 32 , 34 – 36 ]. We assume that better socioeconomic status imparts people with more purchasing power on fast and convenience foods and less physical activity which are already proven to be contributing risk factors for overweight and obesity that subsequently linked to hypertension.

The different anthropometric measurements like BMI, waist circumference, and hip circumference were taken into account to measure overweight, obesity, and central or abdominal obesity. This study showed that overweight and obesity measured by both BMI and waist circumference were major modifiable risk factors to develop hypertension. Overweight subjects had twofold risk of being hypertensive and obese had more than threefold risk for the same in comparison to underweight subjects in this study. There was positive relation observed between increasing BMI and increasing rate of hypertension, which was consistent with other studies [ 1 – 4 , 6 , 12 , 20 , 21 , 23 , 32 , 36 – 39 ]. South Asians have tendency of developing centralized obesity without developing generalized obesity and because of this waist circumference and waist-hip ratio are better measures of body fat [ 40 ]. Abdominal obesity (OR: 1.73) also found to be positively linked to high blood pressure in the present study. Various epidemiological and pathophysiological mechanisms explained the link between obesity and hypertension. One of the probable reasons behind this positive relation between obesity and hypertension could be that increased weight increases cardiac output and increased peripheral resistance of arterioles. Other than that, urbanization is also a cause of changes in dietary habits and reduced physical activity which leads to obesity and subsequently results in hypertension [ 4 ].

Interestingly, we have found inverse association between physical activity and hypertension. Hypertension was more among physically active subjects as compared to inactive subjects (OR: 0.63) but no statistically significant difference was found. Similar result was reported by other study conducted in Turkey [ 1 ]. The exact reason behind this is unknown and yet to be explored. We speculate that they had started physical activity probably under medical advice after being diagnosed for hypertension or other risk factors like overweight or obesity.

As per WHO report, alcohol consumption was the third largest risk factor in the developed countries and tobacco use was being the second major cause of death worldwide [ 17 ]. This study indicated the positive association between alcohol and tobacco use and hypertension. Hypertension was more prevalent in tobacco users (OR: 1.86) and alcohol users (OR: 1.55) as compared to nonusers. This finding is supported by other studies also [ 19 , 23 , 32 , 36 ]. But there are several other studies with contradictory findings [ 1 , 21 , 41 ]. Although not statistically significant, odds of being hypertensive were more among nonvegetarian (OR: 1.10) subjects, while vegetarian diet was proved to be protective against hypertension in this study. Several other studies reported the same result [ 3 , 19 , 33 , 34 ]. A study conducted in Bihar [ 20 ] refutes this finding and reported that vegetarian diet was positively associated with hypertension.

A recent review study revealed that hypertension awareness rate has been doubled from less than 30% in 1980s to around 60% in present among urban populations and less than 10% in 1980s to 35–40% presently among rural population. However, the treatment and control status is still low at around 30% in urban and 20% in rural areas [ 42 ]. Rate of awareness, treatment, and control in the present study was observed as 38.4%, 70.4%, and 35.08%, respectively. Previous study conducted in rural Varanasi reported hypertension awareness, treatment, and control (26.5%, 55.6%, and 40%), respectively [ 7 ].

5. Conclusion & Recommendation

From the results of this study, it can be concluded that the prevalence of both prehypertension and hypertension is very high in urban Varanasi. This makes the people of this area vulnerable to several chronic diseases and other unbearable health consequences. Specifically men are at more risk of being hypertensive than female. Increasing age is proved to be an independent risk factor for hypertension. Programs are needed to improve the surveillance systems and implementation of community based screening programs for early detection of hypertension is also needed. As the awareness of the hypertension status among hypertensive cases was very poor, improving health literacy to increase the awareness of hypertension is also the need of the hour. Interventions like weight management, increased physical activity, increased fruits and vegetables consumption, and reduction in tobacco and alcohol use are required and recommended.

Acknowledgments

The authors would like to thank all the participants for participating in the study.

Additional Points

Limitations of the Study . This study suffers from few of the following limitations. (i) One of the main limitations of this study was the cross-sectional design of the study which restricts examining causal associations. (ii) The study was only conducted in urban areas. (iii) Stress is a major risk factor for hypertension. It could also be considered in the present study for better results.

Conflicts of Interest

There were no conflicts of interest regarding the publication of this article.

• Open access
• Published: 01 May 2022

Interventions in hypertension: systematic review and meta-analysis of natural and quasi-experiments

• Tong Xia   ORCID: orcid.org/0000-0001-7136-8361 1 ,
• Fan Zhao   ORCID: orcid.org/0000-0002-1261-5841 1 &
• Roch A. Nianogo   ORCID: orcid.org/0000-0001-5932-6169 1 , 2  

Clinical Hypertension volume  28 , Article number:  13 ( 2022 ) Cite this article

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Hypertension is an urgent public health problem. Consistent summary from natural and quasi-experiments employed to evaluate interventions that aim at preventing or controlling hypertension is lacking in the current literature. This study aims to summarize the evidence from natural and quasi-experiments that evaluated interventions used to prevent or control hypertension.

We searched PubMed, Embase and Web of Science for natural and quasi-experiments evaluating interventions used to prevent hypertension, improve blood pressure control or reduce blood pressure levels from January 2008 to November 2018. Descriptions of studies and interventions were systematically summarized, and a meta-analysis was conducted.

Thirty studies were identified, and all used quasi-experimental designs including a difference-in-difference, a pre-post with a control group or a propensity score matching design. Education and counseling on lifestyle modifications such as promoting physical activity (PA), promoting a healthy diet and smoking cessation consultations could help prevent hypertension in healthy people. The use of computerized clinical practice guidelines by general practitioners, education and management of hypertension, the screening for cardiovascular disease (CVD) goals and referral could help improve hypertension control in patients with hypertension. The educating and counseling on PA and diet, the monitoring of patients’ metabolic factors and chronic diseases, the combination of education on lifestyles with management of hypertension, the screening for economic risk factors, medical needs, and CVD risk factors and referral all could help reduce blood pressure. In the meta-analysis, the largest reduction in blood pressure was seen for interventions which combined education, counseling and management strategies: weighted mean difference in systolic blood pressure was − 5.34 mmHg (95% confidence interval [CI], − 7.35 to − 3.33) and in diastolic blood pressure was − 3.23 mmHg (95% CI, − 5.51 to − 0.96).

Conclusions

Interventions that used education and counseling strategies; those that used management strategies; those that used combined education, counseling and management strategies and those that used screening and referral strategies were beneficial in preventing, controlling hypertension and reducing blood pressure levels. The combination of education, counseling and management strategies appeared to be the most beneficial intervention to reduce blood pressure levels.

Cardiovascular diseases (CVD) represent the leading cause of death, accounting for one in three deaths in the United States (US) and worldwide [ 1 , 2 , 3 ]. One of their most potent risk factors, hypertension (also known as high blood pressure), is a common risk factor for CVD [ 3 , 4 ]. Approximately 40% of adults aged 25 and over had elevated blood pressure in 2008 [ 3 ]. What is more, hypertension is responsible for at least 45% of deaths due to heart diseases and 51% of deaths due to stroke worldwide [ 3 , 4 ]. In the US alone, the direct medical and indirect expenses from CVDs were estimated at approximately $329 billion in 2013 to 2014 [ 5 ]. Effective large-scale interventions to prevent or treat hypertension are therefore urgently needed to reverse this trend. Yet, as new and promising interventions are surfacing every day, the need for rigorous evaluation of these interventions to inform evidence-based policies and clinical practice is ever growing.

To this effect, several randomized clinical trials (RCT) have been conducted to evaluate interventions used to prevent hypertension or improve its control [ 6 , 7 , 8 ]. However, although RCTs represent the gold standard for evaluating the efficacy (i.e., impact under ideal conditions) of most health interventions because of their high internal validity [ 9 , 10 ], they are not always feasible, appropriate or ethical for the evaluation of certain types of interventions. Furthermore, results from RCTs are not always generalizable to populations or settings of interest due to the highly selected sample and because the intervention is generally conducted under more stringent conditions ( low external validity ) [ 11 ]. To evaluate the effectiveness of an intervention (i.e., impact under real conditions) and to increase the uptake and implementation of evidence-based health interventions in the communities of interests, other types of experimental designs have been proposed. One such example is natural and quasi-experiments. The terms “natural experiments” and “quasi-experiments” are sometimes used interchangeably. In this study, and as described by others [ 12 ], we will distinguish these two concepts. Natural and quasi-experiments are similar in that, in both cases, there is no randomization of treatments or exposures (i.e., no random assignment). They differ, however, in that, natural experiments are those that involve naturally occurring or unplanned events (e.g., a national policy, new law), while quasi-experiments involve intentional or planned interventions implemented (typically for the purpose of research/evaluation) to change a specific outcome of interest (e.g., a community intervention program). Furthermore, in natural experiments, the investigator does not have control over the treatment assignment whereas in quasi-experiments, the investigator has control over the treatment assignment [ 12 ]. These experiments include difference-in-difference (DID) designs, synthetic controls and regression discontinuity designs to name a few [ 13 , 14 , 15 ].

As utilization of natural and quasi-experiments is increasing in public health and in the biomedical field [ 13 , 14 , 15 ], more natural and quasi-experiments are being conducted to evaluate interventions targeted to prevent or control hypertension [ 16 , 17 , 18 , 19 ]. This could be due to recent development or the reframing of classical approaches for determining causality in natural and quasi- experiments [ 13 , 14 , 15 , 20 ]. However, unlike RCTs of interventions aiming to prevent hypertension or improve its control [ 6 , 7 , 8 ], consistent summary and synthesis of evidence from natural and quasi- experiments is lacking in the current literature. The primary aim of the current systematic review is to summarize the evidence from natural and quasi-experiments that have evaluated interventions used to prevent, control hypertension or reduce blood pressure levels. A secondary aim of this study is to conduct a meta-analysis to summarize intervention effectiveness.

Data sources and strategy

We searched PubMed, Embase and Web of Science from January 2008 to November 2018. This time frame was selected to encompass studies that would have likely benefited from recent development and improvement in natural and quasi- experiments [ 13 , 20 ]. Briefly, the search strategy consisted in intersecting keywords related to the study methods (e.g., natural experiments, quasi-experiments, DID, synthetic control, interrupted time series, etc.) with the environment or settings (e.g., community, nation, organization, etc.) and the outcome (e.g., hypertension, elevated blood pressure, etc.). The full search strategy is described in Table S 1 . This systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement [ 21 ] (Fig. 1 ).

Study search and selection flow

Study selection

Two trained members (TX, FZ) screened abstracts and full-text articles. Disagreements were decided by a third member (RN). We included studies that used natural and quasi-experiments to evaluate interventions aimed at preventing hypertension, controlling hypertension or reducing blood pressure levels. The outcome measures were prevalence of hypertension and changes in mean blood pressure. Studies were excluded if they were not in English, were not a natural experiment or a quasi-experimental design, did not include a control group (as it has higher risk to internal validity due to the absence of comparison to adjust for time trends and confounding) [ 22 ], did not include blood pressure or hypertension as their outcome or included participants that were 13 years old or younger. In addition, we excluded studies that were not original research articles (e.g., study protocol, books, commentary, dissertations, conference proceedings, comments, systematic reviews, modeling and simulation studies), or had no full text available.

Data extraction and quality assessment

The following information was extracted: study design, sample size, study duration, data source, geographic location, participants’ socio-demographic characteristics, intervention types, intervention levels (e.g., individuals, community, school, clinic and national levels as suggested by the socio-ecological model [ 23 ]), behavior targeted and outcome measures (prevalence of hypertension or mean blood pressure change) (Table 1 , Table S 2 ).

The interventions were classified by strategies into four types:

Education and counseling: This subcategory includes strategies that aim at educating and providing knowledge and counseling to participants on lifestyle modifications (e.g., increasing physical activity (PA), eating better, avoiding or stopping smoking, etc.).

Management: This subcategory includes strategies that aim at monitoring patients’ metabolic factors and chronic diseases (e.g., blood pressure, cholesterol level, etc.) as well as patients’ adherence to medication. These strategies are generally done or facilitated by physicians, general practitioners (e.g., by assessing computerized clinical guidelines in the electronic health record management system), nurses, other staffs, or patients themselves.

Education, counseling and management: This subcategory combines education and counseling strategies with management strategies as described above.

Screening and referral for management: This subcategory includes strategies that aim at screening for (i.e., checking for the presence of) economic risk factors, medical needs, and CVD risk factors, followed by the referral of participants who screened positive to professionals who specialize in the management of those needs.

We also classified the interventions by settings into (1) community level; (2) health center level (i.e., primary care center or general practices), (3) organization level and (4) nationwide. In addition, we have classified the intervention by duration of the study into short-term (i.e., participants were followed for less than 12 months) and long-term (i.e., participants were followed for longer than or equal to 12 months).

We implemented the Cochrane Risk of Bias Tool for risk of bias and used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to assess the quality of the evidence for mean blood pressure change outcome [ 50 ], since the meta-analysis focused on this outcome. The risk of bias for studies included in this review could be found in Table S 3 and the quality of studies has also been summarized in Table S 4 .

Meta-analysis

To summarize the effectiveness of interventions on mean blood pressure changes, we also conducted a meta-analysis. Due to the high heterogeneity in the studies and interventions, we undertook a random-effects model and only summarized the effectiveness of intervention strategies by subgroup defined by intervention types, settings and duration. We estimated the weighted mean difference (WMD) of blood pressure and 95% confidence intervals (CIs). The studies included in the meta-analysis were only those whose outcomes were mean differences (MDs) in blood pressure ( n = 27) [ 16 , 19 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ] as these studies provided the data needed for performing the meta-analysis. Three studies [ 38 , 39 , 43 ] were excluded as they did not provide enough information to compute the standard errors (SEs). To estimate the average effect of the intervention when not directly provided, we subtracted the before-and-after change in the intervention group from that in the control group or subtracted the intervention-to-control difference at follow-up to that at baseline (pre-post design with a control group). Methods to calculate intervention impact and SEs were outlined in the appendix (Figs. S 1 , S 2 , Table S 5 ).

We presented the meta-analysis results using forest plots (Table 2 , Fig. 2 , Figs. S 3 , S 4 ). We assessed the heterogeneity by using the I 2 (Table 2 , Fig. 2 , Figs. S 3 , S 4 ). We did not perform meta-regression as it is not recommended when the number of studies is small (< 10 studies per covariate) [ 51 ]. We assessed publication bias by using funnel plots of SEs (Figs. S 5 , S 6 , S 7 ). To test the robustness of our results, we performed sensitivity analyses by removing one study at a time from the pool of studies to assess its impact on the findings (Tables S 6  , S 7 , S 8 , Figs. S 8 , S 9 , S 10 ). Data were analyzed with Stata 15.1 (StataCorp LLC, College Station, TX, USA).

Forest plot stratified by intervention types for blood pressure. A Forest plot stratified by intervention types for systolic blood pressure (SBP). B Forest plot stratified by intervention types for diastolic blood pressure (DBP)

Overall, 788 titles of potentially relevant studies were identified and screened. In total, 545 were excluded and 243 full papers were retrieved, then 30 studies were included in the final sample ( Fig. 1 ) .

Study characteristics

Of the 30 studies included in this review [ 16 , 17 , 18 , 19 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ], three studies reported changes in hypertension prevalence, among which one study reported preventing hypertension in the general population [ 24 ] and two studies reported blood pressure control in patients with hypertension [ 17 , 18 ]; 25 studies reported mean blood pressure changes [ 16 , 19 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ]; two studies reported both outcome measures (changes in hypertension prevalence and mean blood pressure changes) [ 25 , 26 ]. Thirteen studies used education and counseling intervention strategies [ 24 , 25 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ]; four studies used management intervention strategies [ 18 , 19 , 38 , 39 ]; seven studies combined education, counseling and management intervention strategies [ 26 , 40 , 41 , 42 , 43 , 44 , 45 ]; and six studies used screening and referral for management intervention strategies [ 16 , 17 , 46 , 47 , 48 , 49 ]. Fourteen studies followed participants for less than 12 months (i.e., short-term interventions) [ 17 , 26 , 27 , 29 , 30 , 32 , 33 , 34 , 36 , 40 , 41 , 42 , 43 , 45 ]. Twelve studies were conducted in the US [ 16 , 17 , 19 , 24 , 27 , 28 , 32 , 33 , 39 , 41 , 43 , 46 ] and most studies included both genders [ 16 , 17 , 18 , 19 , 24 , 25 , 26 , 28 , 29 , 30 , 31 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ] and all racial/ethnic groups [ 16 , 17 , 18 , 19 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ]. We found no natural experiments according to the definition used in this study (Table 1 , Table S 2 ).

Quality ratings

According to the Cochrane Risk of Bias Tool, most studies included in this review were found to have a high risk of bias ( Table S 3 ). This was so because the Cochrane Risk of Bias Tool was mostly designed for RCTs. Studies included in this review only used quasi-experiment designs and as such did not use randomization, allocation concealment, blinding of participants and personnel, and blinding of outcome assessment. Using the GRADE approach, the quality of evidence was deemed of low quality for the mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) change outcome (Table S 4 ).

Studies that reported prevalence of hypertension in the general population or changes in the prevalence of controlled blood pressure in hypertension patients after intervention

Outcome of interest: prevention of hypertension in healthy people, education and counseling intervention strategies.

Two studies evaluated the education and counseling intervention strategies, and both found that those strategies could help prevent hypertension in healthy people [ 24 , 25 ]. One study in the US found that nutritional education and giving access to fruits and vegetables through community gardens helped reduce hypertension prevalence (61.0% vs. 45.0%; P < 0.01), whereas the prevalence of hypertension in the control group did not change (46.7% vs. 49.8%; P = 0.39) [ 24 ]. The other study in Africa showed that an education strategy which promoted PA and healthy diet and combined with free smoking cessation consultations could help reduce the prevalence of hypertension (22.8% vs. 16.2%; P = 0.01), compared to that in control group (14.0% vs. 15.1%; P = 0.52) [ 25 ].

Outcome of interest: improvement of hypertension control in patients with hypertension

Management intervention strategies.

A study in the US showed that patients whose general practitioners accessed the computerized clinical practice guideline at least twice a day improved their hypertension control compared to the patients whose general practitioners never accessed the computerized clinical practice guideline ( P < 0.001) [ 18 ].

Education, counseling and management intervention strategies

A study in the US found that patients who received education about hypertension and did home blood pressure monitoring had a better control of their hypertension compared to the control group ( P = 0.03) [ 26 ].

Screening and referral for management intervention strategies

A study in the US showed that for White patients, interventions which involved a coordinator who identified and reached out to patients not meeting CVD goals and linked them to management programs could improve the odds of blood pressure control (odds ratio, 1.13; 95% CI, 1.05 to 1.22) compared to no intervention [ 17 ].

Studies that reported mean blood pressure changes after intervention

Outcome of interest: reduction in mean blood pressure.

Seven [ 25 , 27 , 28 , 29 , 30 , 34 , 35 ] of twelve [ 25 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ] (58.3%) studies showed that the education and counseling intervention strategies could help reduce mean blood pressure compared to the control group. Education and counseling interventions targeting lifestyle modifications (e.g., diet and PA) have been found effective in reducing blood pressure in the workplace. A study in US female nursing assistants found that combining education and continuing motivation (e.g., counseling on questions of interventions and receiving feedback) on diet and PA led to more reduction in DBP compared to the control group who only received the education (MD, − 6.70 mmHg; 95% CI, − 13.35 to − 0.05) [ 27 ]. Two other studies also found that multi-component lifestyle interventions in the workplace including sharing health information by messages, putting up posters, using pedometers, and giving education on PA could help healthy employees or employees with hypertension lower blood pressure [ 28 , 29 ]. Besides the workplace, interventions implemented in a community setting also appeared to work in reducing blood pressure. A study that included participants age 55 years or more in Asia found that people who attended 60-min Tai Chi three times per week for 12 weeks had a larger reduction in SBP (MD, − 14.30 mmHg; 95% CI, − 19.20 to − 9.40) and in DBP (MD, − 7.02 mmHg; 95% CI, − 10.62 to − 3.42) compared to people maintaining usual daily activities [ 30 ]. Another study among patients with hypertension in Asia found that education about the nutritional behavior and guidelines from dietary approaches to stop hypertension (DASH) approach could help reduce blood pressure more in the intervention group compared to the control group who only received the instruction booklets used in intervention group (SBP: MD, − 13.50 mmHg; 95% CI, − 16.15 to − 10.85; DBP: MD, − 6.60 mmHg; 95% CI, − 8.17 to − 5.03) [ 34 ]. One study in Africa also showed that education on promoting PA and healthy diet, combined with free smoking cessation consultations could help reduce SBP in the intervention group [ 25 ].

Two [ 19 , 39 ] of three [ 19 , 38 , 39 ] (66.7%) studies showed that the management intervention strategies could help reduce mean blood pressure compared to the control group. A study in the US showed that supporting diabetes patients’ self-management of hypertension by team-based chronic models (e.g., proactive patient outreach, depression screening, and health coaching) could decrease more DBP over a 6-month period compared to the usual care (MD, − 1.13 mmHg; 95% CI, − 2.23 to − 0.04) [ 19 ]. A study among hypertension patients in Asia showed that improving the social health insurance system by increasing outpatient expenditure reimbursement ratio could help reduce more SBP (MD, − 2.9 mmHg; P = 0.01) compared to outpatient expense not covered [ 38 ]. The other study among diabetes patients in the US also showed that team-based treatment with trained staff on medical management and self-management helped lower SBP (MD, − 0.88 mmHg; P = 0.01), but it did not compare the MD between treatment and control group [ 39 ].

Six [ 26 , 40 , 42 , 43 , 44 , 45 ] of seven [ 26 , 40 , 41 , 42 , 43 , 44 , 45 ] (85.7%) studies showed that the combination of education, counseling and management intervention strategies led to more blood pressure reduction compared to the control group. One study among hypertension patients in Europe found that management of stress by biofeedback-assisted relaxation and lifestyle counseling on diet and PA reduced more SBP (MD, − 2.62 mmHg; 95% CI, − 3.96 to − 1.29) and DBP (MD, − 1.00 mmHg; 95% CI, − 1.90 to − 0.93) compared to the control group [ 40 ]. One study among hypertension patients in the US also found that education about hypertension and home blood pressure monitoring could help reduce more SBP (MD, − 4.70 mmHg; 95% CI, − 7.14 to − 2.26) and DBP (MD, − 2.20 mmHg; 95% CI, − 3.80 to − 0.60) compared to controls [ 26 ]. A study among 65-year-and-older hypertension patients in Asia found that the intervention group who received education on hypertension management, community-based eHealth monitoring, and monthly telephone counseling had more reduction in SBP (MD, − 10.80 mmHg; 95% CI, − 14.99 to − 6.61) compared to the control group who only received a poster about hypertension management [ 42 ]. A study among hypertension patients in the US also showed that interventions on lifestyle modifications, and nutritional, pharmacological therapies as well as medication adherence lowered SBP and DBP compared to the control group [ 43 ]. A study among hypertension patients in Asia found that integration of preventive-curative services delivery and cooperation among village-town-county physicians for education on lifestyle modifications, taking blood pressure drugs regularly and monitoring the blood pressure could help reduce blood pressure more in the intervention group [ 44 ]. The other study in Asia also found that integrated program with health education on home blood pressure monitoring and hypertension measurement skills could help reduce blood pressure more in the intervention group [ 45 ].

Four [ 16 , 46 , 47 , 48 ] of five [ 16 , 46 , 47 , 48 , 49 ] (80.0%) studies showed that the screening and referral for management intervention strategies could help reduce more blood pressure compared to the control group. Screening for medical or economic needs followed by offering treatment and resources has been found helpful. One study in the US found that screening for unmet needs in primary care and offering those who screened positive some resources could reduce SBP (MD, − 2.6 mmHg; 95% CI, − 3.5 to − 1.7]) and DBP (MD, − 1.4 mmHg; 95% CI, − 1.9 to − 0.9) in patients [ 16 ]. The other study among patients with serious mental illness in the US also found that using registry for general medical needs and outcomes, screening and referral for general medical illness prevention and treatment could help reduce more DBP compared to controls (MD, − 3.00 mmHg; 95% CI, − 4.96 to − 1.04) [ 46 ]. Assessing and screening CVD risk followed by a management program has also been found beneficial to reduce blood pressure. A study in Europe showed that participating in CVD risk assessment and management program, including screening and tailored strategies for lifestyle advice on CVD risk factors could reduce more SBP (MD, − 2.51 mmHg; 95% CI, − 2.77 to − 2.25) and DBP (MD, − 1.46 mmHg; 95% CI, − 1.62 to − 1.29) compared to controls [ 47 ]. A study among hypertension patients in Asia also found that a standardized CVD-risk assessment, a hypertension complication screening and adherence to medications could help reduce more blood pressure compared to the usual care [ 48 ].

Meta-analysis of the effectiveness of interventions on mean blood pressure change

Intervention type sub-group analysis.

The largest blood pressure reduction (SBP: WMD, − 5.34 mmHg; 95% CI, − 7.35 to − 3.33; DBP: WMD, − 3.23 mmHg; 95% CI, − 5.51 to − 0.96) was seen for interventions that combined education, counseling and management intervention strategies (Table 2 , Fig. 2 ).

Intervention setting sub-group analysis

Participants who experienced interventions implemented in community settings (WMD, − 3.77 mmHg; 95% CI, − 6.17 to − 1.37) and in health center settings (WMD, − 3.77 mmHg; 95% CI, − 5.78 to − 1.76) had large SBP reduction. Participants experienced interventions implemented in organization settings had large DBP reduction (WMD, − 3.92 mmHg; 95% CI, − 5.80 to − 2.04) (Table 2 , Fig. S 3 ).

Intervention duration sub-group analysis

Participants who were followed for less than 12 months (i.e., short-term interventions) had a large reduction in blood pressure (SBP: WMD, − 6.25 mmHg; 95% CI, − 9.28 to − 3.21; DBP: WMD, − 3.54 mmHg; 95% CI, − 5.21 to − 1.87) and participants who were followed for longer than or equal to 12 months (i.e., long-term interventions) had a moderate reduction in blood pressure (SBP: WMD, − 1.89 mmHg; 95% CI, − 2.80 to − 0.97; DBP: WMD, − 1.33 mmHg; 95% CI, − 2.11 to − 0.55) (Table 2 , Fig. S 4 ).

We summarized the evidence from quasi-experiments that have evaluated interventions used to (1) prevent hypertension in the general population, (2) improve hypertension control in patients with hypertension or (3) reduce blood pressure levels in both the general population and patients.

In this systematic review, we found that the intervention strategies such as (1) education and counseling, (2) management, (3) education, counseling and management and (4) screening and referral for management were beneficial in preventing, controlling hypertension or reducing blood pressure levels. In particular, we found that education and counseling on lifestyle modifications (i.e., promoting PA, healthy diet, smoking cessation consultations) could help prevent hypertension in healthy people. The use of computerized clinical practice guidelines by general practitioners, education and management of hypertension, screening for CVD goals and referral to management could help improve hypertension control in patients with hypertension. The education and counseling on lifestyle modifications, the monitoring of patients’ metabolic factors and chronic diseases (e.g., blood pressure, cholesterol level, etc.) as well as patients’ adherence to medication, the combined education and management of hypertension, the screening for economic risk factors, medical needs, and CVD risk factors, followed by the referral to management all could help reduce blood pressure levels. Our study is one of the few systematic reviews that have summarized the evidence from quasi-experiments on hypertension prevention and control. A previous systematic review [ 52 ] which summarized evidence from cluster-randomized trials and quasi-experimental studies had been conducted and found that education, counseling and management strategies were also beneficial in controlling hypertension and reducing blood pressure. It showed that educating healthcare providers and patients, facilitating relay of clinical data to providers, promoting patients’ accesses to resources were associated with improved hypertension control and decreased blood pressure [ 52 ]. Another systematic review which summarized evidence from RCTs found that several interventions including blood pressure self-monitoring, educational strategies, improving the delivery of care, and appointment reminder systems could help control hypertension and reduce blood pressure [ 6 ]. Another study also found that community-based health workers interventions including health education and counseling, navigating the health care system, managing care, as well as giving social services and support had a significant effect on improving hypertension control and decreasing blood pressure [ 53 ]. A review from observational studies and RCT evidence from the US Preventive Services Task Force found that office measurement of blood pressure could effectively screen adults for hypertension [ 7 ].

Our review did not find natural experiments studies according to the definition used in this study. Quasi-experimental designs included DID, propensity score matching and pre-post designs with a control group (PPCG). While PPCG designs generally involve two groups (intervention and control) and two different time points (before and after the intervention), DID designs generally involve two or more intervention and control groups and multiple time points [ 13 ]. In this review, we did not include pre-post without a control group design because of its higher risk to internal validity due to the absence of comparison to adjust for time trends and confounding [ 22 ]. The findings in this review, highlight that, quasi-experiments are increasingly used to evaluate the effectiveness of health interventions for hypertension management when RCTs are not feasible or appropriate. For instance, several studies included in our systematic review often indicated that RCTs would have been difficult to be implemented given that the intervention was conducted in a particular setting such as a pragmatic clinical setting [ 16 , 43 , 45 , 48 ], a community setting [ 24 , 35 , 36 , 42 ], or a real-world organizational setting [ 33 ] because of ethical concerns and human resources issues. Another reason why quasi-experiments were chosen had to do with the need for translation and generalizability of the evidence in a specific community setting [ 32 ]. In fact, RCTs are not always generalizable to the communities or settings of interests [ 11 ]. The growing interest in and hence the increase in the use of natural and quasi-experiments in public health may be due to the recognition and realization of its usefulness in evaluating health interventions [ 14 , 54 ].

Given that there was high heterogeneity in the studies included in this systematic review, we have performed a random effects model and have only presented the subgroup analysis by intervention types, settings and duration of the study. Overall, our study suggested that interventions that combined education, counseling and management strategies appeared to show a relatively large beneficial effect for reducing blood pressure. However, our finding should be interpreted with caution due to the high-risk of bias and lower quality of evidence given the quasi-experimental nature of the designs (as opposed to evidence from randomized experiments). Nevertheless, the findings here can give us some insights on the benefit of interventions such as education, counseling and management, especially given that our findings are in line with previous studies [ 6 , 8 , 52 , 55 ]. Given that RCTs are not always feasible or appropriate, scientists should develop more rigorous methods to increase the internal validity of non-randomized studies. Compared to previous studies, one systematic review with meta-analysis including cluster-randomized trials and quasi-experiment studies showed that multi-component interventions which incorporated education of health care providers and patients, facilitating relay of clinical data to providers, and promoting patients’ accesses to resources could reduce more blood pressure compared to controls [ 52 ]. A recent systematic review with meta-analysis of RCTs also reported that interventions which included blood pressure self-monitoring, appointment reminder systems, educational strategies, and improving the delivery of care showed beneficial effects on lowering blood pressure [ 6 ]. Another systematic review and meta-analysis of RCTs also showed that self-measured blood pressure monitoring lowered SBP by 3.9 mmHg and DBP by 2.4 mmHg at 6 months compared to the usual care group [ 8 ]. One systematic review and meta-analysis of RCTs found that diet improvement, aerobic exercise, alcohol and sodium restriction, and fish oil supplements reduced blood pressure as well [ 55 ].

Limitations

This review has some limitations. First, the definition of natural and quasi-experiments is not consistent across fields. Second, the main limitation in most if not all the quasi-experimental study designs noted in this review was the potential for unobserved and uncontrolled confounding, which is a threat to internal validity and could lead to biased findings. Third, our findings may not be generalizable to all countries and settings as we only included studies published in the English language in this review. Fourth, as is the case in most other reviews, we could have missed relevant studies despite our best attempt to conduct a thorough search of the literature. Fifth, we found that most studies included in this study had a high risk of bias. It might be because we used the Cochrane Risk of Bias Tool to assess bias which was designed for examining RCTs. Studies in this review only used quasi-experiment designs and did not have randomization, allocation concealment, blinding of participants and personnel, and blinding of outcome assessment. Sixth, studies generally reported the measure of intervention impact differently across studies, making it difficult to combine the findings. In addition, studies were highly heterogeneous in terms of the types of individuals included in the study (e.g., healthy individuals and patients). We conducted the subgroup meta-analysis to reduce the heterogeneity, but the high heterogeneity still existed. Therefore, the results from meta-analysis need to be interpreted with caution. The individual impact reported for each individual study and the results from systematic review should be given more consideration.

In this systematic review, interventions that used education and counseling strategies; those that used management strategies; those that combined education, counseling and management strategies and those that used screening and referral for management strategies were beneficial in preventing, controlling hypertension and reducing blood pressure levels. The combination of education, counseling and management strategies appeared to be the most beneficial intervention to reduce blood pressure levels. The findings in this review, highlight that, a number of interventions that aim at preventing, controlling hypertension or reducing blood pressure levels are being evaluated through the use of quasi-experimental studies. Given that RCTs are not always feasible or appropriate, scientists should develop more rigorous methods to increase the internal validity of such quasi-experimental studies.

Availability of data and materials

The data supporting the conclusions of this article is included within the article and the additional file.

Abbreviations

Confidence interval

Cardiovascular disease

Dietary approaches to stop hypertension

Diastolic blood pressure

Difference-in-difference

Grading of Recommendations, Assessment, Development, and Evaluation

Mean difference

Physical activity

Pre-post designs with a control group

Randomized clinical trial

Systolic blood pressure

Standard error

United States

Weighted mean difference

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TX participated in the study conception, design and analysis and wrote the initial first draft of the article. FZ participated in the study conception, design and reviewed the first draft of the article. RN conceived and supervised the design and analysis, finalized the first draft and critically reviewed and revised the manuscript. All authors provided critical input and insights into the development and writing of the article and approved the final manuscript as submitted.

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Supplementary Information

Additional file 1: table s1..

Search words. Table S2. Summary of the characteristics of the studies included in this review ( n = 30). Table S3. Risk of Bias Tool Assessments Across Studies (n = 30). Table S4. GRADE Evidence Profiles Across Studies in Meta-analysis ( n = 24). Table S5. Estimates and parameters in studies that reported on the mean difference in blood pressure ( n = 27). Table S6. Sensitivity analysis for systolic blood pressure (SBP) and diastolic blood pressure (DBP) in meta-analysis stratified by intervention type. Table S7. Sensitivity analysis for systolic blood pressure (SBP) and diastolic blood pressure (DBP) in meta-analysis stratified by intervention setting. Table S8. Sensitivity analysis for systolic blood pressure (SBP) and diastolic blood pressure (DBP) in meta-analysis stratified by intervention duration. Fig. S1. Methods to calculate mean differences (MD). Fig. S2. Methods to calculate standard errors (SE). Fig. S3. Forest plot stratified by intervention settings for blood pressure. (A) Forest plot stratified by intervention settings for systolic blood pressure (SBP). (B) Forest plot stratified by intervention settings for diastolic blood pressure (DBP). Fig. S4. Forest plot stratified by intervention duration for blood pressure. ( A) Forest plot stratified by intervention duration for systolic blood pressure (SBP). ( B) Forest plot stratified by intervention duration for diastolic blood pressure (DBP). Fig. S5. Funnel plot of systolic blood pressure (SBP), diastolic blood pressure (DBP) stratified by intervention types. Fig. S6. Funnel plot of systolic blood pressure (SBP), diastolic blood pressure (DBP) stratified by intervention settings. Fig. S7. Funnel plot of systolic blood pressure (SBP), diastolic blood pressure (DBP) stratified by intervention duration. Fig. S8. Sensitivity analysis of systolic blood pressure (SBP), diastolic blood pressure (DBP) stratified by intervention types. Fig. S9. Sensitivity analysis of systolic blood pressure (SBP), diastolic blood pressure (DBP) stratified by intervention settings. Fig. S10. Sensitivity analysis of systolic blood pressure (SBP), diastolic blood pressure (DBP) stratified by intervention duration

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Xia, T., Zhao, F. & Nianogo, R.A. Interventions in hypertension: systematic review and meta-analysis of natural and quasi-experiments. Clin Hypertens 28 , 13 (2022). https://doi.org/10.1186/s40885-022-00198-2

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Clinical Hypertension

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Clinical Trials

High blood pressure (hypertension).

Displaying 31 studies

The purpose of this study is to evaluate the feasibility and effectiveness of adopting the use of a Hypertension management interactive care plan (ICP) using a remote BP monitoring device in primary care practice (device connected BP ICP).

The purpose of this study is to learn about whether a community health clinic program on heart disease risk factors delivered through a digital app on smartphones and tablet devices will promote healthy habits and improve blood pressure among African-Americans.

The primary goal of this study is to evaluate the overall user experience of the Pregnancy Coach and ensure that it is well tolerated and used properly before moving to a larger randomized efficacy trial.

The purpose of this study is to determine how hypertension impacts blood pressure responses during exercise. 

This is a Phase Ib, open-label, randomized, multicenter, two-arm study designed to assess the safety, efficacy, and pharmacokinetics of cobimetinib administered in combination with niraparib, with or without atezolizumab, to patients with advanced platinum-sensitive ovarian cancer.

Hypertension is a major risk factor for cardiovascular and renal disease, and a leading cause of premature mortality worldwide. Early hypertension studies showed that treating elevated blood pressure (BP) reduces patients' risk of cardiovascular disease and all-cause mortality. In subsequent research, patients achieved greater improvement in cardiovascular outcomes when their treatment was aimed at a moderate systolic BP target (<150mmHg) than at higher targets. Although observational data suggest that even lower BP targets may be beneficial, this has not been seen in randomized trials; instead, "intense" treatment of hypertension (i.e., to a target systolic BP <120mmHg) was found to have ...

The purpose of this study is to determine if ultrasound waves (SW) treatment changes single kidney blood flow, restores kidney function, increases the number of circulating endothelial progenitor cell (EPC), or lowers high blood pressure.

The purpose of this study is to evaluate the cardiovascular properties of MANP in African Americans (AA) with hypertension.

The purpose of this study is to assess if it is possible to use a carotid MRI/MRA to see if cholesterol lowering medication is causing a reduction in the amount of plaque in the arteries.

The aim of this study is two fold: First the investigators want to determine the safe and most effective dose of subcutaneous (SQ) BNP in subjects with resistant hypertension. Second, the investigators want to demonstrate efficacy of chronically (one week) administered SQ BNP in resistant hypertension in reducing blood pressure.

Evidence suggests that roughly 30% of the US adult population sleeps less than 7 hours per night, and those who do show 20-52% increased risk to develop cardiovascular diseases, particularly hypertension. 

The purpose of this study is to look at the cardiovascular and metabolic effects of prolonged sleep in prehypertensive and stage 1 hypertensive people who report habitual short sleep.

SYMPHONY is prospective, multi-center, open-label, single-arm, Phase 3b psychometric validation study of the PAH-SYMPACT, a new quality of life questionnaire for patients with pulmonary arterial hypertension. Patients will be in the study for 5 1/2 months, 4 months of which they will receive macitentan, 10 mg, once daily.

The primary objectives are to demonstrate the final content validity of the PAH SYMPACT instrument, to demonstrate the psychometric characteristics of reliability and construct validity of the PAH-SYMPACT instrument, and to demonstrate the ability of the PAH SYMPACT instrument to detect change. The secondary objective is to assess the safety of macitentan in ...

Blood pressure rises in postmenopausal (PM) women and may be caused by widespread microvascular vasodilator dysfunction in conjunction with increased efferent sympathetic vasoconstrictor nerve activity. The goal of this study is to measure the effects of regular physical activity on vasodilator effects of acute administration of estrogen in postmenopausal women.

The primary purpose of this study is to determine the effect of latanoprostene bunod (LBN) ophthalmic solution 0.024% (a single dose and 7 days of once daily [QD] dosing) on 2 aspects of aqueous humor (AqH) dynamics (episcleral venous pressure [EVP] and outflow facility) in participants with ocular hypertension (OHT).

The purpose of this study is to determine how menopause influences blood pressure responses during exercise in women.

24-week study to evaluate the efficacy and safety of macitentan for the treatment of portopulmonary hypertension.

Hypertension is the major risk factor for cardiovascular and cerebrovascular diseases worldwide. The escalating prevalence of inadequate sleep now parallels that of hypertension. Observational and experimental evidence favoring a causal relation between insufficient sleep and hypertension are particularly compelling - sleeping 6 hours or less per night is associated with a 20-32% higher probability of incident hypertension. Since sleep curtailment is largely voluntary, sleep deficiency may be corrected and the detrimental health consequences potentially reversed. In this study the investigators aim to investigate the effects of 8 weeks of sleep enhancement/extension vs health education in prehypertensive and stage 1 hypertensive ...

The purpose of the study is to show the blood pressure lowering effect of aprocitentan, a new drug, when added to other anti-hypertensive drugs of patients with difficult to control (resistant) high blood pressure (hypertension), and to show that blood pressure reduction is kept for long period of time.

The purpose of this study is to evaluate the safety, tolerability and effect of 1 or 2 mg baxdrostat versus placebo, administered once daily (QD) orally, on the reduction of systolic blood pressure in approximately 720 participants aged ≥ 18 years with hypertension, despite a stable regimen of 2 antihypertensive agents at baseline, one of which is a diuretic (uncontrolled hypertension); or ≥ 3 antihypertensive agents at baseline, one of which is a diuretic (treatment-resistant hypertension).

This study is being done to see how a subcutaneous (SQ or subcu) injection of a new natriuretic peptide, or hormone, called MANP affects your blood pressure, the glucose and lipids levels and other peptide (hormone) levels in your blood.

The aims of this study are to determine the types and severity of previously undiagnosed sleep deficiencies in otherwise healthy Somali Americans, apply a research framework to define psychosocial, behavioral, environmental, and biological mechanisms mediating sleep deficiencies in Somali Americans, and examine the relationship between sleep deficiencies and increased blood pressure in Somali Americans.

The investigators believe epilepsy alters the way the body controls blood pressure, heart rate and breathing, and these changes increase the risk of sudden unexpected death in patients with epilepsy (SUDEP). SUDEP-7 is a risk scoring tool which may correlate with these changes to the heart and blood vessels. This research study measures those differences which may help identify new markers to help predict those patients at greatest risk in the future.

We propose a pilot study to assess safety and benefit of renal artery ablation at the time of planned atrial fibrillation ablation.

A surveillance of respiratory tract related adverse events in patients treated with Tyvaso® (treprostinil) Inhalation Solution versus other FDA approved therapies.

The purpose of this research study is to better understand why patients with a disease that causes problems with the autonomic nervous system often have high blood pressure when they lie down. We hope that if we learn more about the cause for this problem, we will be able to treat the problem better in the future.

The objectives of this study are to demonstrate that patients with CNS hypersomnias exhibit cardiovascular and cognitive disturbances, and to demonstrate that CNS medications medications impact these cardiovascular and cognitive disturbances.

Evidence suggests a relationship between sleep deprivation and cardiovascular disease. The investigators wish to determine whether 9 nights of modest sleep restriction results in activation of cardiovascular disease mechanisms, thus potentially increasing the risk of cardiovascular disease. The investigators hypothesize that sleep restriction will result in elevated blood pressure, inflammation, and neurocognitive deficits.

The purpose of this study is to learn how uterine fibroids may be connected to heart disease and high blood pressure. It is not known what causes fibroids, but they frequently occur in women who also have high blood pressure, heart disease, and stroke. The investigators of this study want to learn if certain changes in the blood vessels or nerve activity can put women at risk for these diseases and for fibroids.

Hypothesis: We hypothesize that patients from the Family Medicine Department at Mayo Clinic Florida who participate in RPM will have significantly reduced emergency room visits, hospitalizations, and hospital contacts.  

Aims, purpose, or objectives: In this study, we will compare the RPM group to a control group that does not receive RPM. The primary objective is to determine if there are significant group differences in emergency room visits, hospitalizations, outpatient primary care visits, outpatient specialty care visits, and hospital contacts (inbound patient portal messages and phone calls). The secondary objective is to determine if there are ...

The purpose of this study is to determine whether short-term treatment with Fisetin reduces the rate of death and long term complications related to COVID-19.

The purpose of this study is to evaluate the effietiveness of remdesivir (RDV) in reducing the rate of of all-cause medically attended visits (MAVs; medical visits attended in person by the participant and a health care professional) or death in non-hospitalized participants with early stage coronavirus disease 2019 (COVID-19) and to evaluate the safety of RDV administered in an outpatient setting.

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High Blood Pressure: Prevention, Treatment and Research

Reviewed By:

Roger Scott Blumenthal, M.D. 

Michael Joseph Blaha, M.D. M.P.H.

We all have “blood pressure.” This simply refers to the way blood pushes against the walls of your arteries as your heart pumps. However, one in three American adults have a potentially dangerous condition known as high blood pressure, also called hypertension. For those with high blood pressure, blood moves more forcefully through the arteries than it should.

It’s normal for blood pressure to increase when you exercise or are under stress. But when the pressure is too high even when you’re at rest, and stays too high for too long, it can stretch and damage your arteries. The resulting health problems from high blood pressure can include heart disease, heart failure, stroke, kidney damage, vision loss, and memory loss and cognitive decline.

Following a healthy lifestyle is considered the best way to maintain blood pressure within the recommended range. How to do it:

Keep your weight healthy. The higher your body mass index (BMI), the greater your odds of developing high blood pressure. Learn your BMI from your doctor and aim for the normal range of weight for your height.

Track your blood pressure. “Take your blood pressure at home often and bring a blood pressure log of your readings to the doctor,” suggests Blaha. It’s especially important to have it checked often if you’re over age 40, overweight, sedentary, or have a family history of heart disease or high blood pressure.

Eat heart-healthy foods. That means a diet high in whole grains, fruits and vegetables, and lean protein, and low in sodium and alcohol. Get practical ideas to eat for heart health in Eat Smart .

Get, or stay, fit. Being active helps keep weight in check and reduces your odds of many different heart problems.

Don’t smoke, or, if you do now, quit. Smoking damages blood vessels.

Learn healthy ways to manage stress. Many people find yoga , meditation , music and tai chi helpful.

A blood pressure reading has two numbers: systolic (“sis-TOL-ick,” the first or top number in a reading) and diastolic (“dye-a-STOL-ick,” the second or bottom number in a reading). Systolic pressure is the force of the blood against the artery walls when the heart contracts to pump blood. Systolic pressure is always the higher number. Diastolic pressure is the pressure against the arteries between heartbeats, as the heart relaxes. The unit of measurement is in millimeters of mercury (mm Hg).

Optimal blood pressure is 120/80 mm Hg (referred to as “120 over 80”) or below. High blood pressure is defined for adults as systolic pressure above 140 or diastolic pressure above 90. Generally, a diagnosis of high blood pressure results when you have high readings on three different occasions during a single week. Some people’s blood pressure is changeable, and others have what’s called “white coat hypertension”—higher readings as a result of feeling stressed in a doctor’s office, says Blaha. You may be asked to wear a portable blood pressure monitor to get an accurate reading.

Move more. A good guideline: Aim for 30 minutes a day of aerobic exercise (fast walking, running, swimming) on most days of the week. If you’re new to exercise, get your doctor’s OK before you start a workout program.

Quit smoking. Talk to your doctor about support programs that can help.

Take medications as prescribed. Because drugs for high blood pressure work in different ways, you may be prescribed more than one.

Living With...

Controlling your blood pressure is a long-term effort. Once diagnosed, most people need lifetime treatment. The payoff, though, is improved overall health and a reduced risk of serious heart problems, such as stroke and heart attack. In addition to following healthy lifestyle habits:

Let your doctor know immediately if you notice any side effects from blood pressure medications. Take medications as directed and never discontinue use without consulting your doctor.

Know the warning signs of too-high blood pressure. In most cases the condition is symptomless, but in extreme cases of dangerously high blood pressure, a person may develop ringing in the ears, dizziness, headaches, nosebleeds, tingling or numbness in the hands and feet, drowsiness or confusion.

Learn how to take your blood pressure at home. It’s easy to learn, devices are readily available at pharmacies and elsewhere, and your doctor can show you how, says Blaha.

Johns Hopkins researchers and clinicians continue to explore ways to prevent and manage high blood pressure and its effects. Among their noteworthy research:

Antihypertensive drugs may help preserve cognitive function in people with high blood pressure. Johns Hopkins researchers led a study showing that hypertension in midlife raises the odds of memory problems in old age. When treated early, though, this risk may drop.

Higher weight and weight gain raises the risk of high blood pressure. This is especially true from young adulthood through midlife. A Johns Hopkins study helped to solidify the link between high body mass index and high blood pressure.

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Next Generation Research Uses Real-World Data to Identify Most Effective Hypertension Drugs for Patients

Listen to "next generation research uses real-world data to identify most effective hypertension drugs for patients".

More than 100 million U.S. adults have been diagnosed with hypertension , one of the leading risk factors for cardiovascular disease. While more than 70% of people with hypertension cannot achieve adequate blood pressure control with just one drug, current guidelines only make recommendations for first-line therapy.

“The question is: when the first drug is not enough, what is the optimal second drug to add?” said Yuan Lu, ScD , assistant professor of medicine (cardiology) and assistant professor of biomedical informatics and data science and of epidemiology (chronic disease). “There are more than 50 drugs across five major classes available for treating hypertension. Conducting clinical trials to compare every possible drug and combination thereof is impractical; it would be incredibly time-consuming and costly. Consequently, this creates a significant gap in evidence.”

Lu recently received a Research Project Grant (R01) from the National Institutes of Health (NIH) for the project, “Real-World Evidence to Inform Decisions for Hypertension Treatment Escalation,” to help address this question.

Lu and her team will analyze real-world data that is routinely collected by clinicians in health care settings to compare the effectiveness of second antihypertensive agents on major cardiovascular events as well as their comparative risk on potential drug-related adverse events. This study will also look at the effectiveness and safety of each second hypertensive agent when used in different patient subgroups defined by age, sex, race, ethnicity, and comorbidities, which Lu hopes will help address disparities for patients with hypertension. This is the first research study of its kind that uses real-world data assets and reproducible methods to comprehensively evaluate the safety and effectiveness of second anti-hypertensive drugs added after monotherapy.

“Clinicians often face this important patient scenario and lack comprehensive, high-quality evidence on how best to guide the implementation of the available drug options for patients into real-world practice,” said Eric Velazquez, MD , Robert W. Berliner Professor of Medicine and chief of Yale Cardiovascular Medicine. “Hypertension impacts nearly every family in the world. It has been a substantial frustration for me that randomized clinical trials such as ACCOMPLISH , which we completed over 15 years ago, have not been adequately integrated into everyday care. Yuan’s work is pivotal to ensure our research meets its potential to improve the lives of millions of people living with hypertension.”

The study will analyze data from more than 100 million patients in the United States in five electronic health record (EHR) databases. Lu and her team are collaborating with the Observational Health Data Science and Informatics (OHDSI) , a multi-stakeholder, international organization that aims to use systematic approaches to improve observational study. OHDSI created the OMOP Common Data Model , which is an open community data standard that allows institutions to efficiently share data for analysis.

“By mapping EHR data into a common data model, we can now combine the power of computing, data science, and clinical knowledge to generate new evidence to address these important clinical questions,” said Lu. “We hope our research will inform the prioritization of future clinical trials, assisting investigators in selecting the most promising drug combinations for testing.”

Lu joined Yale in 2015 after receiving her ScD in Global Health and Population at the Harvard School of Public Health. “I was intrigued by this area of study because instead of a doctor, who can only treat 20 or 30 patients a day, I would have the opportunity to impact health at the population level,” she said.

She hopes that this research will inform the development of clinical guidelines. Even though clinical trials provide the highest quality of evidence, real-world data from observational studies can provide important evidence to complement clinical trials and support guideline development, especially when clinical trials are too expensive or unethical to conduct.

“Physicians can’t just wait for clinical trials to end before they help their patients. They need to keep treating people using the best available information and practices,” said Lu.

Eventually, Lu and her team plan to develop a clinical decision support tool that would incorporate the knowledge gained from this project. The tool would help doctors quickly and easily see recommendations about the types of combination therapies that may work best for their individual patients. “It’s often said that it takes about 17 years to translate about 14% of research findings to be implemented into routine clinical practice. It’s a long time. I want to try to reduce the time it takes to get research into clinical practice and increase the percentage of knowledge translation," she said.

The research team is beginning to refine their protocol for the study, which they aim to publish online via GitHub so that anyone interested in this work can read the proposal and provide feedback to help make improvements. Lu sees tremendous potential for this type of study in other areas of medicine, including diabetes, obesity, and other common health conditions. She and other team members are already beginning work on other projects using real-world data.

For example, Lu, along with other researchers from Yale and colleagues at Sentara Health, recently published a paper in the Journal of the American Heart Association (JAHA) , which used real-world EHR data to identify the prevalence, control rates, and diagnostic codes used in a large patient population. The study found that prevalence is increasing, a quarter of patients’ hypertension was not controlled, and there were marked disparities between non-Hispanic Black patients and other racial and ethnic groups. Lu and the study authors say other regional health systems could emulate this study to better understand their hypertension prevalence and control rates and to inform strategies to improve hypertension care. Other study authors include: Yuntian Liu, MPH , Shu-Xia Li, PhD , Mitsuaki Sawano, MD , Patrick Young, PhD , Wade Schulz, MD , and Harlan Krumholz, MD, SM , from Yale, and John E. Brush, Jr., MD, Jordan R. Asher, MD, MS, Mark Anderson, AS, and John S. Burrows, MBA.

“I feel so fortunate that I decided to come to Yale. As an investigator, it can sometimes seem like the only deliverable is a paper. But at Yale, I’m able to work closely with clinicians and see how this knowledge can inform their clinical practice or help them do their job better,” Lu said. “I’m excited to come to work every day.”

• National Institutes of Health (NIH)
• Internal Medicine
• Cardiovascular Medicine

Featured in this article

• Yuan Lu, ScD Assistant Professor of Medicine (Cardiology) and of Biomedical Informatics and Data Science and of Epidemiology (Chronic Diseases)
• Yuntian Liu Statistician I
• Shu-Xia Li, PhD Staff Affiliate - YNHH; Associate Director, Data Management & Analytics, Center for Outcomes Research & Evaluation (CORE)
• Mitsuaki Sawano, MD, PhD Associate Research Scientist
• Wade Schulz, MD, PhD Assistant Professor; Director of Informatics, Laboratory Medicine; Director, CORE Center for Computational Health, Center for Outcomes Research & Evaluation (CORE)
• Patrick Young, PhD Associate Research Scientist
• Harlan Krumholz, MD, SM Harold H. Hines, Jr. Professor of Medicine (Cardiology) and Professor in the Institute for Social and Policy Studies, of Investigative Medicine and of Public Health (Health Policy); Founder, Center for Outcomes Research and Evaluation (CORE)
• Eric Velazquez, MD Robert W. Berliner Professor of Medicine (Cardiology); Chief, Cardiovascular Medicine; Chief, Cardiovascular Medicine, Yale New Haven Hospital; Physician-in-Chief, Heart and Vascular Center, Yale New Haven Health System; Deputy Director, Clinical Trials Innovation, Yale Center for Clinical Investigation (YCCI); Co-Chair, Clinical and Translational Research Oversight Committee; President’s contingency planning committee, Clinical Practice/Clinical Research Subcommittee

Related Links

• Digital Health Tools Help Manage Hypertension for Populations Experiencing Health Disparities
• Enhancing Treatment for Persistent Hypertension: Unleashing the Power of Actionable Taxonomy from EHR Data for Precision Medicine
• The Unmet Potential of Clinical Decision Support Tools in Cardiology

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Study shows AI health coach lowers blood pressure and boosts engagement in patients with hypertension

by JMIR Publications

A new study in JMIR Cardio shows that a fully digital, artificial intelligence (AI)–driven lifestyle coaching program can effectively reduce blood pressure (BP) in adults with hypertension. This AI-based program leverages data from wearable activity trackers and BP monitors as well as a mobile app questionnaire to tailor lifestyle guidance.

The research team, led by Jared Leitner of the University of California, San Diego, used this innovative intervention to help manage hypertension and enhance patient engagement, offering a promising alternative to traditional coaching models.

The researchers employed a single-arm nonrandomized trial to evaluate the effects of the program's personalized lifestyle guidance, which was delivered to 141 participants through SMS text messages and a mobile app.

Over 24 weeks, participants with stage 2 hypertension showed significant reductions in both systolic and diastolic BP. At 12 weeks, systolic BP decreased by an average of 9.6 mm Hg and diastolic BP by 5.7 mm Hg. These reductions were even more pronounced at 24 weeks, with systolic BP dropping by 14.2 mm Hg and diastolic BP by 8.1 mm Hg.

This precision coaching program led to an increase in participants achieving BP control and a decrease in participants with stage 2 hypertension. The study also highlighted high participant engagement and minimal need for manual clinician outreach. This indicates that the AI-driven approach not only enhances BP control but also substantially reduces the workload for health care providers .

"By pinpointing the top lifestyle contributors to patients' hypertension and providing precise guidance, the AI-powered lifestyle coaching was able to maintain high patient engagement , leading to improved patient outcomes. This study demonstrates how an AI-based, autonomous approach to hypertension-related lifestyle coaching can increase scalability and accessibility to effective blood pressure management," remarked Dr. Leitner.

This research underscores the potential for digital health innovations to transform hypertension management, providing scalable, cost-effective, and personalized care options for patients.

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• Open access
• Published: 24 May 2024

Identification of differentially expressed ER stress-related genes and their association with pulmonary arterial hypertension

• Qi Yang 1 , 2   na1 ,
• Banghui Lai 1 , 2   na1 ,
• Hao Xie 1 , 2 ,
• Mingbin Deng 1 , 2 ,
• Yan Yang 2 ,
• Juyi Wan 1 , 2 ,
• Bin Liao 1 , 2 &
• Feng Liu 1 , 2  

Respiratory Research volume  25 , Article number:  220 ( 2024 ) Cite this article

166 Accesses

Metrics details

Pulmonary arterial hypertension (PAH) is a complex and progressive illness that has a multifaceted origin, significant fatality rates, and profound effects on health. The pathogenesis of PAH is poorly defined due to the insufficient understanding of the combined impact of endoplasmic reticulum (ER) stress and immune infiltration, both of which play vital roles in PAH development. This study aims to identify potential ER stress-related biomarkers in PAH and investigate their involvement in immune infiltration.

The GEO database was used to download gene expression profiles. Genes associated with ER stress were obtained from the MSigDB database. Weighted gene co-expression network analysis (WGCNA), GO, KEGG, and protein-protein interaction (PPI) were utilized to conduct screening of hub genes and explore potential molecular mechanisms. Furthermore, the investigation also delved into the presence of immune cells in PAH tissues and the correlation between hub genes and the immune system. Finally, we validated the diagnostic value and expression levels of the hub genes in PAH using subject-workup characterization curves and real-time quantitative PCR.

In the PAH and control groups, a total of 31 genes related to ER stress were found to be differentially expressed. The enrichment analysis revealed that these genes were primarily enriched in reacting to stress in the endoplasmic reticulum, dealing with unfolded proteins, transporting proteins, and processing proteins within the endoplasmic reticulum. EIF2S1, NPLOC4, SEC61B, SYVN1, and DERL1 were identified as the top 5 hub genes in the PPI network. Immune infiltration analysis revealed that these hub genes were closely related to immune cells. The receiver operating characteristic (ROC) curves revealed that the hub genes exhibited excellent diagnostic efficacy for PAH. The levels of SEC61B, NPLOC4, and EIF2S1 expression were in agreement with the findings of bioinformatics analysis in the PAH group.

Conclusions

Potential biomarkers that could be utilized are SEC61B, NPLOC4, and EIF2S1, as identified in this study. The infiltration of immune cells was crucial to the development and advancement of PAH. This study provided new potential therapeutic targets for PAH.

Introduction

PAH, also known as pulmonary arterial hypertension, is a complex and life-threatening condition that involves various factors leading to increased pressure in the arteries of the lungs, ultimately affecting the right ventricle [ 1 ]. The development of PAH involves a combination of genetic predispositions and environmental influences. Central to the pathogenesis of PAH is the interaction between endoplasmic reticulum (ER) stress and systemic inflammation. ER stress, often triggered by protein misfolding and accumulation within the ER, activates the unfolded protein response (UPR). This response, while initially protective, can become maladaptive, releasing inflammatory cytokines that contribute to vascular injury and exacerbating ER stress by overwhelming the ER’s folding capacity, thus perpetuating a cycle of damage. This feedback loop is crucial in driving the pathophysiological changes observed in PAH, including the development of neointimal lesions and plexiform lesions, hallmark features of advanced PAH [ 2 , 3 , 4 ]. Numerous proposed potential mechanisms involve the malfunction of endothelial cells in the pulmonary blood vessels, genetic mutations, inflammation, immune reactions, remodeling of blood vessels, blood clot formation, abnormalities in ion channels, and additional factors [ 3 , 4 , 5 , 6 , 7 ]. Basic therapy and targeted drug therapy are the main approaches used to treat pulmonary arterial hypertension (PAH) at present. Although these treatments can effectively relieve patients’ clinical symptoms, they do not have the ability to halt the progression of the disease or substantially decrease mortality rates [ 8 , 9 ]. Further research on mechanisms and biomarkers is needed to enable early diagnosis and more effective treatments.

The response to endoplasmic reticulum (ER) stress is characterized by the initiation of signaling pathways, including the unfolded protein response (UPR), the ER overload response, and the caspase-12 mediated apoptosis pathway in response to disrupted protein folding, accumulation of misfolded proteins, calcium ion imbalance, and calcium levels within the ER. This response can result in cytoprotective outcomes, cellular damage, or apoptosis [ 10 , 11 ]. According to recent research, ER stress is also extensively implicated in cancer, cardiovascular disorders, diabetes, and various other ailments [ 12 , 13 , 14 ]. ER stress is a prevalent factor in PAH, and there is evidence indicating its involvement in the proliferation of smooth muscle cells in the pulmonary artery (PASMCs) and the enhancement of the inflammatory response. The abnormal growth and resistance to cell death of PASMCs play a crucial role in the pathological changes to blood vessels seen in PAH [ 15 ]. Therapeutically, targeting ER stress represents an innovative approach for the clinical treatment of PAH. Research shows that 4-phenylbutyrate and similar chemical chaperones can alleviate ER stress and potentially treat PAH in animal models. This is achieved by inhibiting the proliferation of PASMC, promoting apoptosis, and decreasing the expression of factors related to ER stress [ 16 ]. However, clinical testing remains absent. However, these preliminary results suggest that decreasing ER stress may offer a hopeful approach for treating PAH.

High levels of various cytokines, chemokines, and autoantibodies have been confirmed in animal models of PAH and in PAH patients. Significantly, the degree of perivascular inflammation in the lungs in PAH is associated with pulmonary hemodynamics, remodeling of blood vessels, and clinical results [ 17 ]. A recent study using impartial computational flow cytometry analysis of the lungs in individuals with idiopathic PAH and healthy donors revealed that macrophage recruitment can be enhanced [ 18 ]. Increased levels of C-reactive protein enhance the proliferation of smooth muscle cells in the pulmonary arteries, trigger the secretion of endothelin, decrease the production of nitric oxide, and worsen vascular remodeling. Moreover, C-reactive protein further stimulates inflammatory responses, resulting in the secretion of additional inflammatory agents and worsening the state of individuals with PAH [ 19 ]. Although the role of ER stress and immune responses in the development of PAH is well-known, there is still a lack of research on their synergistic impact, which requires further investigation.

For this investigation, we utilized bioinformatics methods to examine chip data sourced from the GEO database. Our aim was to pinpoint hub genes that are differentially expressed and associated with ER stress in PAH. Additionally, we explored the functions of endoplasmic reticulum stress and the infiltration of the immune system in PAH. The results of our study indicate possible indicators and treatment targets for PAH.

Materials and methods

Data acquisition.

The dataset GSE113439 based on the GPL6244 platform was downloaded from the National Center for Biotechnology Information database ( https://www.ncbi.nlm.nih.gov/ ) for further analysis. The dataset included lung tissue transcriptome data from 15 PAH patients and 11 normal control groups.

Detection of genes with differential expression

The Limma software package (version 3.58.1) was employed for identifying differentially expressed genes (DEGs) between the PAH group and the control group. DEGs with an absolute log fold change greater than 0.585 and a p -value less than 0.05 were deemed statistically significant. “ggplot2” and “pheatmap” packages were used to plot volcanoes and heat maps of DEGs.

Weighted gene co-expression network analysis (WGCNA)

The gene co-expression networks were constructed using the R package ‘WGCNA’ by utilizing the merged database. Initially, the software R was employed to calculate a gentle threshold power β, which was then applied to elevate the co-expression similarity for determining the degree of neighborliness. Next, the mean linked hierarchical clustering technique was employed to group genes exhibiting comparable patterns into indistinguishable modules. For the merging of modules, we employed a threshold of 0.25, ensuring that each module comprised a minimum of 30 genes. Modules associated with clinical shape were identified by utilizing correlations between branches of the clustering tree and various color phenotypes. The clinical traits of the modules were calculated using gene significance (GS) and module membership (MM). In conclusion, an examination was conducted on core modules that exhibited a strong correlation with clinical characteristics.

Identification of ER stress-related DEGs (ER- DEGs)

The genes associated with ER stress (GOBP response to endoplasmic reticulum stress and GOBP regulation of endoplasmic reticulum stress) were acquired from the Molecular Signature Database v7.0 (MSigDB). The VennDiagram software package was used to obtain ER-DEGs linked to PAH by intersecting all DEGs, genes related to ER, and core module genes. The clusterProfiler (version 4.10.0) was utilized to conduct GO and KEGG pathway enrichment analyses, with entries having a P -value less than 0.05 deemed as statistically significant.

Identification and correlation analysis of hub genes

The overlapping genes were uploaded to the STRING database to conduct PPI analysis, where the minimum interaction score was set to 0.4. The visualization was performed using Cytoscape 3.9.1, and the identification of hub genes was carried out by applying the MCC algorithm through the CytoHubba plug-in. Next, the software package ggplot2 was utilized to create box plots illustrating the gene expression profiles of central genes. For further analysis, we utilized the pROC software package to conduct ROC curve analysis on hub genes, with an AUC > 0.8 being deemed as the optimal diagnostic value. The circle software was utilized to examine the association between hub genes and optimal diagnostic value.

Analysis of immune infiltration

The presence and growth of immune cells play a crucial role in the onset and progression of PAH. Consequently, we investigated if these central genes were associated with the infiltration of diverse immune cells. We evaluated the correlation of 28 immune cell infiltrates in the GSE113439 sample by employing single-sample (ss) GSEA (version 1.42.1).

Animal model

The Ethics Committee for Animal Experiments of Southwest Medical University granted approval for this study. A total of sixteen male SD rats, aged 4 weeks and obtained from Luzhou Yinhui Biotechnology Co., Ltd., were randomly assigned to two groups: a model group (referred to as the PAH group, consisting of 8 rats) and a control group (referred to as the CON group, also consisting of 8 rats). The PAH group established a rat PAH model through complete removal of the left lung, while the CON group remained unoperated. For a duration of 4 weeks, the experimental animals were housed in identical conditions within an SPF-grade environment at the Animal Center of Southwest Medical University. Following a period of 4 weeks, the rats were administered anesthesia and a catheter was inserted through the right internal jugular vein to access the right ventricle. The BL-420 S Biofunctional Experiment System (Chengdu, China, Taimeng) was utilized to measure the right ventricular systolic pressure (RVSP). Subsequently, the rats used in the experiment were put to death, and their lung and heart tissues were gathered. The heart was partitioned into the right ventricle (RV), left ventricle (LV), and interventricular septum (S). Subsequently, the index for right ventricular hypertrophy (RVHI) was computed using the formula RVHI = weight RV /weight LV+S . H.E. staining was performed on formaldehyde-fixed, paraffin-embedded partial lung tissues obtained from experimental rats. Frozen lung tissues were used for subsequent qRT-PCR analysis using real-time quantitative polymerase chain reaction.

To further examine the expression of central genes in lung tissues of rats with PAH, qRT-PCR was employed. TRIZOL was utilized to extract total RNA from lung tissues, which was then reverse transcribed into cDNA using a reverse transcription kit from Roche. The completion of qRT-PCR involved the utilization of SYBR green from Roche. The supplementary material S1 displays the primers utilized for amplification. The expression of the target gene was demonstrated as 2-ΔΔCt relative to the GAPDH gene. The experimental results were presented as the average plus or minus the standard deviation, and a p -value less than 0.05 was deemed to be statistically significant.

Statistical analysis

Statistical analyses were conducted using R software (version 4.3.1) and GraphPad Prism 10.0.0. qRT-PCR assays were performed with three replicates. The data was analyzed and converted into bar graphs using GraphPad Prism. The analysis of differences between two independent groups was conducted using the Student’s t-test. Statistical tests were conducted on both sides, and a p  value < 0.05, after correction, was deemed to be statistically significant.

Identification of differential expressed and modular genes

The overall process of the study is showed in Fig.  1 . In the GSE113439 dataset, a total of 1733 differentially expressed genes (DEGs) were found between the PAH and control groups. Among these DEGs, 1127 genes were up-regulated while 606 genes were down-regulated, as shown in Fig.  2 A and B). In the WGCNA analysis, the dendrogram encompassed the gene sets of all samples(Fig.  3 A and D). The threshold for softness was established at 14 (R2 = 0.86), and the scale-free network was constructed (Fig.  3 B and C), which identified nine modules (Fig.  4 A). The blue and cyan modules were chosen for further investigation based on a correlation coefficient that exceeded 0.8 (Fig.  4 B and C). Specifically, MM represents the inclusion of a gene within a module, quantified as the closeness of the gene to the module eigengene, which is the principal component of the module’s expression matrix. GS measures the correlation between gene expression and the clinical traits associated with PAH, providing a numerical indication of each gene’s relevance to the traits being studied.

Schematic representation of the pathophysiological mechanisms involved in pulmonary arterial hypertension (PAH). This diagram illustrates the key processes contributing to the development and progression of PAH, including endothelial dysfunction, smooth muscle cell proliferation, and inflammatory responses. The figure highlights the interaction between endoplasmic reticulum (ER) stress and systemic inflammation, detailing how ER stress activates the unfolded protein response (UPR), which can exacerbate vascular injury and contribute to neointimal formation and plexiform lesions. Each pathway and its role in PAH pathogenesis are clearly labeled to facilitate understanding of the complex disease mechanisms

Differential genes expression in pulmonary arterial hypertension (PAH). A : Volcano plot illustrating differentially expressed genes (DEGs) between PAH and control groups. Upregulated genes are indicated by red dots, downregulated genes by blue dots, and genes with no significant expression change are represented by black dots. The x-axis displays the log2 fold change, while the y-axis represents the negative log10 of the adjusted p -value, underscoring both the magnitude and significance of expression changes. B : Heatmap showing the expression patterns of top DEGs across samples. Hierarchical clustering groups genes with similar expression profiles (y-axis) and segregates control (CON) from PAH samples (x-axis). The color gradient, from blue to red, indicates expression levels from downregulated to upregulated, with the color intensity reflecting the z-score normalized expression values

Weighted Gene Co-Expression Network Analysis (WGCNA) for the identification of gene modules associated with pulmonary arterial hypertension (PAH). A : Dendrogram produced by hierarchical clustering of samples based on gene expression profiles, showing the grouping of PAH (blue) and control (light purple) samples. B : Analysis of network topology for various soft-thresholding powers. The red line indicates the selected power (β) at which the scale-free fit index curve flattens out, suggesting a suitable model fit. C : Plot of mean connectivity as a function of the soft-thresholding power, with the red line marking the chosen power based on when the scale independence meets the criteria for a scale-free network. D : Dendrogram of all genes clustered based on a dissimilarity measure (1-TOM), with the resultant module colors displayed below. Each color represents a module of highly interconnected genes, with the dynamic tree cut illustrating the modules’ divisions

Module-trait relationships and identification of genes associated with pulmonary arterial hypertension (PAH). A : Heatmap depicting the correlation between gene modules and clinical traits (PAH and control). Each row corresponds to a gene module color-coded as per the legend, and each column represents a clinical trait. The color within the heatmap reflects the correlation coefficient, with the scale shown on the right, and the numbers in each cell represent the p -values, indicating the significance of the correlation. B : Scatterplot demonstrating the correlation between Module Membership (MM) in the blue module and Gene Significance (GS) for PAH. A high degree of correlation indicates that genes most central to the module are also highly significant for the trait. C : Scatterplot showing the correlation between MM in the cyan module and GS for PAH, with a similarly strong correlation suggesting that this module is significantly related to the disease. D : Venn diagram illustrating the overlap between differentially expressed genes (DEGs), genes identified through Weighted Gene Co-expression Network Analysis (WGCNA), and genes related to ER stress. The numbers in the intersections represent genes common to the groups, indicating potential key candidates involved in PAH pathogenesis

Screening and functional enrichment analysis of candidate genes

Figure  4 D showed the identification of 31 candidate hub genes related to PAH and ER stress by intersecting 1733 DEGs, 4602 modular genes, and 258 ER stress-associated genes. Using GO and KEGG pathway analysis, the hub genes of the candidate were enriched in 30 GO terms (Fig.  5 A), such as protein processing in the endoplasmic reticulum, the unfolded protein response, and ER-associated degradation pathways were identified. These pathways are critical for maintaining cellular homeostasis and play a pivotal role in the pathogenesis of PAH by influencing endothelial function, smooth muscle cell proliferation, and inflammatory responses. Key genes within these clusters, such as SEC61B, EIF2S1, and DERL1, are involved in the translocation of newly synthesized proteins into the ER and the degradation of misfolded proteins. The dysfunction of these processes can lead to ER stress, a condition that contributes to vascular remodeling and pulmonary hypertension. For example, EIF2S1 is integral to the initiation of translation in response to ER stress and can influence cellular survival pathways, potentially impacting vascular stability and resistance to apoptosis in PAH. By connecting these functions to ER stress, we underscore potential therapeutic targets. Modulating the activity of pathways such as the unfolded protein response could offer new avenues for treatment aimed at alleviating ER stress and its downstream effects on pulmonary arterial pressure and vascular remodeling. Enrichment of candidate genes in four KEGG pathways was observed, including protein processing in the endoplasmic reticulum, amyotrophic lateral sclerosis, pathways of neurodegeneration in multiple diseases, and ubiquitin mediated proteolysis (Fig.  5 B).

Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of genes associated with pulmonary arterial hypertension (PAH). A : Bar chart of the GO term enrichment analysis results categorized into biological processes (BP), cellular components (CC), and molecular functions (MF). The length of each bar represents the gene count associated with each term, with color intensity indicating the q-value, a measure of significance after correcting for multiple testing. B : KEGG pathway enrichment analysis bar chart showing the pathways most significantly associated with the hub genes. The number of genes is denoted by the bar’s length, while the color gradient represents the -log10( p -value), highlighting the statistical significance of the enrichment

Identification of hub genes

To identify the hub genes, a PPI network was constructed through the STRING online website (Fig.  6 A), and 5 hub genes were obtained using the MCC algorithm in Cytoscape (Fig.  6 B). In the GSE113439 dataset, there was differential expression observed in all 5 hub genes between the PAH and control groups. Controls exhibited higher expression levels of SYVN1 and DERL1 (Fig.  7 ). Based on ROC curve analysis, we identified five genes (EIF2S1, NPLOC4, SEC61B, SYVN1, and DERL1) that showed differential expression between PAH and control samples (Fig.  8 A), for further analysis. Figure  8 B indicated that SEC61B and DERL1 displayed the most robust positive correlation, whereas EIF2S1 and SYVN1 displayed the most robust negative correlation.

Protein-Protein Interaction (PPI) networks of hub genes related to pulmonary arterial hypertension (PAH). A : A detailed PPI network visualization highlighting the interactions among proteins encoded by the hub genes. Each node represents a protein, and the connecting lines represent the interactions with line colors indicating the types of evidence supporting the interaction. B : A simplified PPI network focusing on the five hub genes identified in the study. Nodes are color-coded based on their gene expression level with larger, darker nodes such as DERL1 and SYVN1 indicating a higher degree of differential expression. The thickness of the lines between the nodes reflects the strength of the data support for the interaction

Expression levels of hub genes in control (CON) and pulmonary arterial hypertension (PAH) groups. A-E : Boxplots compare the expression levels of five key hub genes (A: DERL1, B: SYVN1, C: SEC61B, D: NPLOC4, E: EIF2S1) between control (CON) and PAH patient samples. Each panel represents one gene, In each plot, the y-axis indicates the expression level of the gene, and the x-axis categorizes the samples into control and PAH groups. The boxes encompass the interquartile range (IQR) of the data, with the median represented by the line within the box. Outliers are shown as individual points. The asterisks above the boxes denote the level of statistical significance, with ‘***’ indicating p  < 0.001, illustrating a significant difference in expression between the groups. F-J : Boxplots compare the expression levels of five key hub genes (A: DERL1, B: SYVN1, C: SEC61B, D: NPLOC4, E: EIF2S1) between control (CON) and PAH patient samples from public data

Evaluation of hub gene discriminative ability and correlation analysis in pulmonary arterial hypertension (PAH). A : Receiver Operating Characteristic (ROC) curves for each hub gene, assessing their performance in distinguishing between PAH and control groups. The Area Under the Curve (AUC) values are provided for each gene, indicating the accuracy of the gene as a potential biomarker for PAH. B : Correlation matrix showing the pairwise relationships between the hub genes. The size and color of the circles represent the strength and direction of the correlation, respectively, with red indicating a positive correlation, blue indicating a negative correlation, and color intensity reflecting the magnitude of the correlation coefficient

These genes form part of larger gene sets significantly associated with ER stress pathways that are pivotal in PAH development. For example, EIF2S1 and SEC61B are known to be involved in crucial processes such as the translocation of newly synthesized proteins into the ER and the degradation of misfolded proteins—key aspects of the unfolded protein response (UPR). Malfunctions in these processes can lead to exacerbated ER stress, contributing to the pathophysiological landscape of PAH by influencing endothelial dysfunction, smooth muscle cell proliferation, and inflammatory responses.

Investigation of immune infiltration and its association with hub genes

In order to examine the impact of hub gene expression on immune infiltration in PAH, we evaluated the relationship between the expression of central genes and the levels of infiltration by particular types of immune cells. The expression of DERL1 showed a strong correlation with eight different types of immune cells. In particular, the expression of DERL1 showed a positive correlation with memory B lymphocytes, CD56 bright NK cells, effector memory CD4 T lymphocytes, neutrophils, activated B lymphocytes, and plasmacytoid dendritic cells. In contrast, the expression of DERL1 showed a negative correlation with effector memory CD8 T cells and macrophages, as shown in Fig.  9 A. Figure  9 B showed a positive correlation between SYVN1 expression and monocytes, and a negative correlation with activated CD4 T cells. The expression of NPLOC4 showed a positive association solely with gamma delta T cells and did not demonstrate any significant correlation with other immune cell infiltrates. The expression of SEC61B showed a positive correlation with neutrophils and mast cells, but a negative correlation with regulatory T cells and monocytes. EIF2S1 expression showed no association with immune cell infiltration (see Supplementary Figure S2 ). These observations demonstrate multiple distinct immune microenvironments within tissue samples from PAH patients when compared to controls.

Correlations of immune cell infiltration scores with expression levels of hub genes. ( A ) DERL1; ( B ) SYVN1. The size of each dot is proportional to the absolute value of the correlation coefficient, while the color indicates the p -value, ranging from green (most significant) to red (least significant)

Rat PAH model

To confirm the successful establishment of the PAH model, we observed the rats in the PAH group for a duration of 4 weeks following a complete removal of the left lung. Throughout this time frame, it was noted that the rats in the PAH group exhibited a considerably reduced body weight compared to the control group (Fig.  10 A). In the PAH group, right ventricular systolic pressure (RVSP) was markedly higher after 4 weeks than in the control group (Fig.  10 C, D and E). The hemodynamic results were further confirmed by HE staining, which revealed notable vascular remodeling and thickening of the pulmonary artery wall in the PAH group in comparison to the control group (Fig.  9 B). Moreover, the PAH group exhibited a significant increase in the right ventricular hypertrophy index (RVHI) compared to the control group ( p  < 0.05, Fig.  10 F). The data collectively showed successful development of pulmonary hypertension and remodeling of the pulmonary blood vessels through complete removal of the left lung.

Longitudinal analysis of PAH progression and physiological assessment in a rat model. A : Body weight trajectory of control (CON) and PAH rats over a 5-week period post-operation, illustrating the weight gain or loss trends in both groups. B : Representative histological sections stained with hematoxylin and eosin (H&E) showing lung tissue from CON and PAH groups. The images provide a comparative view of the pulmonary architecture and potential pathological changes due to PAH. C : Electrocardiogram (ECG) trace from a control rat showing normal cardiac electrical activity. D : ECG trace from a PAH rat depicting alterations in cardiac electrical activity indicative of PAH-related heart stress or damage. E : Bar graph comparing the right ventricular systolic pressure (RVSP) between CON and PAH rats, a measure of the severity of pulmonary hypertension. F : Bar graph showing the right ventricular hypertrophy index (RVHI), a marker of heart muscle adaptation or strain in response to increased pulmonary arterial pressure, contrasting CON and PAH rats. **** in panels E and F indicates a statistically significant difference with a p -value < 0.0001 between the control and PAH groups

Validation of hub genes

After the onset of PAH, the expression levels of 5 hub genes were analyzed in lung tissues using qRT-PCR and experimentally validated. The expression pattern of SEC61B, NPLOC4, and EIF2S1 in PAH lung samples, as depicted in Fig.  11 , aligned with the findings of bioinformatics analysis. However, DERL1 and SYVN1 exhibited contrasting trends in their expression ( p  < 0.05).

Expression levels of hub genes in control and pulmonary arterial hypertension (PAH) groups. Each panel ( A-E ) represents a scatter plot comparing the relative mRNA expression levels of a specific hub gene between control (CON) and PAH samples. The horizontal lines indicate the mean ± standard deviation of expression. A : Relative expression of NPLOC4. B : Relative expression of SYVN1. C : Relative expression of DERL1. D : Relative expression of SEC61B. E : Relative expression of EIF2S1. Statistical significance is denoted by asterisks: * p  < 0.05, ** p  < 0.01, *** p  < 0.001, **** p  < 0.0001

PAH is a serious disease affecting the pulmonary blood vessels, which has a major impact on the health and quality of life of patients. So far, the pathogenic mechanisms underlying PAH are still not fully elucidated and effective treatments remain lacking [ 20 , 21 ]. Further investigation into the pathogenic basis of PAH and potential therapeutic targets is critically needed. Prior research has suggested that the occurrence of endoplasmic reticulum (ER) stress [ 22 ] and activation of immune cells, including macrophage polarization, infiltration of B-cells, and alterations in T cell subsets, play a role in the advancement of PAH [ 23 ]. Nevertheless, the precise impact of the combined regulation of ER stress and immune cell infiltration on the development and progression of PAH remains inadequately characterized. To uncover the pathogenesis and progression of PAH, this research employed bioinformatics analysis and experimental validation, examining the impact of ER stress and immune infiltration in combination.

To analyze ER stress, the study made use of MSigDB databases to identify genes associated with ER and utilized the WGCNA module to filter out 31 differentially expressed genes (DEGs) for further investigation. The analysis of functional enrichment showed that these differentially expressed genes (DEGs) in the ER were engaged in diverse biological processes associated with the ER, including reacting to ER stress, reacting to misfolded proteins, and binding to proteins at ubiquitin-like protein junctions. The pathway enrichment analysis indicated potential involvement of these genes in the development and advancement of PAH through pathways related to amyotrophic lateral sclerosis, neurodegeneration, protein processing in the endoplasmic reticulum, and protein hydrolysis mediated by ubiquitin. The genes comprised SEC61B, a fundamental element of the ER membrane protein translocation complex; NPLOC4, engaged in protein coding; EIF2S1, an initiator factor accountable for catalyzing protein synthesis; and DERL1 and SYVN1, coding genes implicated in ER-associated degradation. By utilizing the expression levels of these 5 hub genes, a diagnostic model was successfully able to differentiate patients from the controls with great accuracy and precision.

In earlier research, it was found that Let-7b-5p plays a role in the regulation of SERP1 and its associated protein SEC61B during the ER stress response, which affects the inflammation and apoptosis of lung cells in cases of acute pulmonary embolism [ 24 ]. Furthermore, the removal of SEC61B caused ER stress in both mammalian cells and Caenorhabditis elegans [ 25 ]. Moreover, it has been suggested that muscle atrophy could be alleviated by targeting the p97-NPLOC4 complex [ 26 ]. The identification of EIF2S1/eIF2α phosphorylation as a crucial mechanism helps regulate pathways for unfolded proteins and uphold intracellular homeostasis [ 27 ]. MDA-T68 cells showed significant upregulation of DERL1 in both thyroid cancer tissues and cell lines. Additionally, the overexpression of miR-575 resulted in the inhibition of DERL1 in these cells [ 28 ]. Hrd1, also referred to as Synviolin (SYVN1), was identified as one of the RING E3 ligases [ 29 ]. SYVN1 may control cell death caused by ER stress by facilitating the ubiquitination and breakdown of IRE1 [ 29 ]. To summarize, the involvement of these 5 hub genes in ER stress response suggests their potential contribution to various diseases. In order to experimentally validate these findings, we established a PAH rat model. The RT-qPCR findings demonstrated that the expression profile of SEC61B, NPLOC4, and EIF2S1 genes in the central genes aligned with the outcomes of bioinformatics analysis, justifying the need for additional exploration.

Immune infiltration is common in PAH and exacerbates the disease’s progression [ 18 , 30 , 31 ]. Increasing evidence indicates that signaling molecules associated with ER stress, such as ATF6, Eif2α, and CHOP, as well as inflammatory factors like IL-6, CCL-2, and MCP-1, are elevated in the pulmonary arteries of rats with PAH induced by wild larkin. Moreover, the application of clindamycin, an inducer of ER stress, leads to increased expression of inflammatory cytokines such as IL-6, IL-1β, and IL-2 in PASMCs. In contrast, the administration of Salubrinal, an inhibitor of ER stress, reduces the secretion of inflammatory molecules in PASMCs [ 32 ].

Furthermore, PAH is characterized by the chronic overexpression of Endothelin-1 (ET-1), a powerful peptide that constricts blood vessels, in both human and animal PAH models. When rat primary PASMCs are exposed to ET-1, it triggers the activation of unfolded protein response signaling pathway components like ATF6, Sxbp1, and eIF2α. This activation leads to the rapid buildup of ATF6 in the nucleus, which in turn stimulates the generation of pro-inflammatory factors in PASMCs, including interleukins and hyaluronic acid [ 33 ]. Additionally, our research revealed a notable correlation between hub genes associated with ER stress and the infiltration of immune cells in PAH. It is worth mentioning that the majority of the central genes showed a correlation with the infiltration of T cells and macrophages (refer to Supplementary Material S2 ). Consequently, our findings enhance the comprehension of the interplay between ER stress and immune cells in the context of PAH.

Through bioinformatics analysis, we investigated the correlation between endoplasmic reticulum stress and the infiltration of immune cells in individuals diagnosed with PAH. By conducting experiments, we confirmed that three key genes (SEC61B, NPLOC4, and EIF2S1) have the potential to be molecular targets, providing valuable understanding of the mechanisms involved in PAH. However, there are constraints to our study. Initially, the main dataset was obtained from the GEO repository and we included only a restricted group of patients, emphasizing the necessity for validation in more extensive populations. Secondly, we confirmed the gene expression in rat models, but our study lacked corroborative clinical evidence. Furthermore, despite conducting comprehensive bioinformatics analysis, the study did not include experimental verification of how ER stress-related genes affect the immune microenvironment and the progression of PAH. Therefore, further exploration is needed to determine the specific functions of ER stress and immune infiltration in PAH, both in vivo and in vitro. This will be the primary focus of our future research efforts.

Data availability

No datasets were generated or analysed during the current study.

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Acknowledgements

Not applicable.

This work was supported by Sichuan Science and Technology Program (2022YFS0610, 2022YFS0607, 2021YJ0207), the National Natural Science Foundation of China (82070277, 82170325), and Luzhou Science and Technology Program (2020LZXNYDJ07).

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Qi Yang and Banghui Lai contributed equally to this work.

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Department of Cardiovascular Surgery, The Affiliated Hospital, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Key Laboratory of Cardiovascular Remodeling and Dysfunction, Southwest Medical University, Luzhou, Sichuan, 646000, P.R. China

Qi Yang, Banghui Lai, Hao Xie, Mingbin Deng, Juyi Wan, Bin Liao & Feng Liu

Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, 646000, P.R. China

Qi Yang, Banghui Lai, Hao Xie, Mingbin Deng, Jun Li, Yan Yang, Juyi Wan, Bin Liao & Feng Liu

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Q.Y. and BH.L. wrote the main manuscript. Q.Y. and BH.L. prepared Figs.  1 , 2 , 3 , 4 and 5 . and 10 - 11 . H.X. and MB.D. prepared Figs.  6 and 7 . J.L. Y.Y. and JY.W. prepared Figs.  8 and 9 . B.L. and F.L. designed the study and revised the manuscript. All authors reviewed the manuscript.

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Supplementary Material 1: Supplementary Table S1. Primers sequence of hub ER-DEGs

12931_2024_2849_moesm2_esm.pdf.

Supplementary Material 2: Correlations of immune cell infiltration scores with expression levels of hub genes. EIF2S1; ERN2; HM13; NPLOC4; PRKN; SEC61B; STUB1; USP19; The size of each dot is proportional to the absolute value of the correlation coefficient, while the color indicates the p -value, ranging from green (most significant) to red (least significant)

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Yang, Q., Lai, B., Xie, H. et al. Identification of differentially expressed ER stress-related genes and their association with pulmonary arterial hypertension. Respir Res 25 , 220 (2024). https://doi.org/10.1186/s12931-024-02849-4

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Ai health coach lowers blood pressure and boosts engagement in patients with hypertension.

TORONTO , May 30, 2024 /PRNewswire/ -- A new study in JMIR Cardio , published by JMIR Publications , shows that a fully digital, artificial intelligence (AI)-driven lifestyle coaching program can effectively reduce blood pressure (BP) in adults with hypertension. This AI-based program leverages data from wearable activity trackers and BP monitors as well as a mobile app questionnaire to tailor lifestyle guidance. The research team, led by Jared Leitner of the University of California, San Diego , used this innovative intervention to help manage hypertension and enhance patient engagement, offering a promising alternative to traditional coaching models.

The researchers employed a single-arm nonrandomized trial to evaluate the effects of the program's personalized lifestyle guidance, which was delivered to 141 participants through SMS text messages and a mobile app. Over 24 weeks, participants with stage 2 hypertension showed significant reductions in both systolic and diastolic BP. At 12 weeks, systolic BP decreased by an average of 9.6 mm Hg and diastolic BP by 5.7 mm Hg. These reductions were even more pronounced at 24 weeks, with systolic BP dropping by 14.2 mm Hg and diastolic BP by 8.1 mm Hg.

This precision coaching program led to an increase in participants achieving BP control and a decrease in participants with stage 2 hypertension. The study also highlighted high participant engagement and minimal need for manual clinician outreach. This indicates that the AI-driven approach not only enhances BP control but also substantially reduces the workload for health care providers.

"By pinpointing the top lifestyle contributors to patients' hypertension and providing precise guidance, the AI-powered lifestyle coaching was able to maintain high patient engagement leading to improved patient outcomes. This study demonstrates how an AI-based, autonomous approach to hypertension-related lifestyle coaching can increase scalability and accessibility to effective blood pressure management," remarked Dr. Leitner.

This research underscores the potential for digital health innovations to transform hypertension management, providing scalable, cost-effective, and personalized care options for patients.

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Leitner J, Chiang PH, Agnihotri P, Dey S.

The Effect of an AI-Based, Autonomous, Digital Health Intervention Using Precise Lifestyle Guidance on Blood Pressure in Adults With Hypertension: Single-Arm Nonrandomized Trial.

JMIR Cardio 2024;8:e51916

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Comment on: Risk of heart failure in ambulatory resistant hypertension: a meta-analysis of observational studies

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Patients with resistant hypertension (ARH) are on the rise worldwide, and its association with heart failure (HF) has been a focus of attention in cardiovascular medicine. A recent meta-analysis published in Hypertension Research provides valuable data and insights showing that patients with ARH have a significantly higher risk of heart failure (1.7 to 2.3 times) compared to patients with well-controlled hypertension, uncontrolled resistant hypertension, and apparent non-resistant hypertension [ 1 ]. This finding not only deepens our understanding of the role of different phenotypes of hypertension in the pathogenesis of cardiovascular disease, but also emphasizes the importance of assessing and managing the risk of heart failure in patients with ARH in clinical practice. Moreover, considering that ARH is associated with higher 24-hour systolic and diastolic blood pressure levels, this further confirms the important role of continuous blood pressure monitoring in predicting cardiovascular risk.

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Coccina F, Salles GF, Banegas JR, Hermida RC, Bastos JM, Cardoso CRL et al. Risk of heart failure in ambulatory resistant hypertension: a meta-analysis of observational studies. Hypertens Res. 2024. https://doi.org/10.1038/s41440-024-01632-8 .

Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25:603–5. https://doi.org/10.1007/s10654-010-9491-z .

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